**Is the Phenylalanine-Restricted Diet a Risk Factor for Overweight or Obesity in Patients with Phenylketonuria (PKU)? A Systematic Review and Meta-Analysis**

**Catarina Rodrigues 1,2, Alex Pinto 3, Ana Faria 1,2,4, Diana Teixeira 1,2,4, Annemiek M. J. van Wegberg 5, Kirsten Ahring 6, François Feillet 7, Conceição Calhau 1,4, Anita MacDonald 3, André Moreira-Rosário 1,4,\*,† and Júlio César Rocha 1,4,8,\*,†**


**Abstract:** Although there is a general assumption that a phenylalanine (Phe)-restricted diet promotes overweight in patients with phenylketonuria (PKU), it is unclear if this presumption is supported by scientific evidence. This systematic review aimed to determine if patients with PKU are at a higher risk of overweight compared to healthy individuals. A literature search was carried out on PubMed, Cochrane Library, and Embase databases. Risk of bias of individual studies was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and the quality of the evidence for each outcome was assessed using the NutriGrade scoring system. From 829 articles identified, 15 were included in the systematic review and 12 in the meta-analysis. Body mass index (BMI) was similar between patients with PKU and healthy controls, providing no evidence to support the idea that a Phe-restricted diet is a risk factor for the development of overweight. However, a subgroup of patients with classical PKU had a significantly higher BMI than healthy controls. Given the increasing prevalence of overweight in the general population, patients with PKU require lifelong follow-up, receiving personalised nutritional counselling, with methodical nutritional status monitoring from a multidisciplinary team in inherited metabolic disorders.

**Keywords:** body mass index; obesity; overweight; phenylalanine restriction; phenylalanine-restricted diet; phenylketonuria

#### **1. Introduction**

In phenylketonuria (PKU), the prevalence and patient susceptibility to overweight and obesity has been widely discussed. Several retrospective studies have reported a higher body mass index (BMI) and a higher prevalence of overweight in patients with

**Citation:** Rodrigues, C.; Pinto, A.; Faria, A.; Teixeira, D.; van Wegberg, A.M.J.; Ahring, K.; Feillet, F.; Calhau, C.; MacDonald, A.; Moreira-Rosário, A.; et al. Is the Phenylalanine-Restricted Diet a Risk Factor for Overweight or Obesity in Patients with Phenylketonuria (PKU)? A Systematic Review and Meta-Analysis. *Nutrients* **2021**, *13*, 3443. https://doi.org/10.3390/ nu13103443

Academic Editor: Arrigo Cicero

Received: 27 July 2021 Accepted: 22 September 2021 Published: 28 September 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

PKU compared to the normal population [1–4], especially in females [1,5–9]. Generally, the prevalence of overweight worldwide has almost tripled since 1975 [10]. This multifactorial comorbidity is mainly associated with poor dietary habits and lack of physical activity, but other factors, such as social economic status and family history, may also influence outcome [11].

The World Health Organisation (WHO) defines overweight and obesity as abnormal or excessive fat accumulation. This has numerous negative health consequences including cardiovascular diseases, non-insulin-dependent diabetes mellitus, musculoskeletal disorders, pulmonary diseases, and cancer [12–14].

PKU is a rare autosomal recessive inborn error of phenylalanine (Phe) metabolism, and if untreated, can cause severe and irreversible neurological damage [15]. The main treatment is a Phe-restricted diet, composed of three parts: (1) strict control of natural protein intake according to individual Phe tolerance, (2) administration of a synthetic protein derived from Phe-free amino acids (L-AAs) or low-Phe glycomacropeptide supplemented with amino acids (GMP-AA), and (3) and low-Phe foods including the use of special low-protein foods (SLPFs). The primary aim is to prevent neurological sequelae by maintaining blood Phe levels within a therapeutic target range [14], whilst maintaining nutritional requirements to achieve normal growth and body composition.

Adequate dietary energy is essential to maintain blood Phe stability, particularly in patients with classical PKU, by promoting anabolism and counteracting catabolism, which increases blood Phe levels [15]. Energy is obtained from fruits and some vegetables, sugars, fats, and oils, as well as SLPFs such as bread, pasta, rice, cereals, and milk replacements, aiming to replace regular foods. Pena et al. [16] analysed the food labels of several SLPFs and found that, when compared to their regular foods, 75% had a higher energy content, 58% a higher fat content, and 92% a higher carbohydrate (CHO) content. Moreover, the quality of fat and fibre differs from regular foods [17]. Their consumption without moderation may lead to excessive energy intake, with a low supply of micronutrients, although these are usually supplied by protein substitutes (PS) [18,19]. Overall, a Phe-restricted diet is characterised by higher CHO intake compared with the general population [19,20].

Due to concerns over increasing obesity in PKU, industry has reformulated many of their PS, adding less CHO to their products [21]. Furthermore, a higher prevalence of overweight in patients with PKU is used to support the need for alternative treatments, even though a systematic analysis of published data is not available to verify this claim. In addition, some studies have found no differences in BMI and prevalence of overweight and obesity between patients with PKU and healthy individuals [22–26].

This lack of consensus highlights the need to assess the quality of evidence that reports the prevalence of overweight and obesity in PKU. This systematic review aims to (1) determine if patients with PKU are at a higher risk of overweight compared to healthy individuals, and to (2) understand the association between early exposure to Phe restriction and overweight in patients with PKU.

#### **2. Materials and Methods**

#### *2.1. Protocol and Registration*

This systematic review with meta-analysis was developed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [27] and the Cochrane Handbook for Systematic Reviews of Interventions [28] guidelines. The protocol was registered (CRD42020214436) in the International Prospective Register of Systematic Reviews (PROSPERO).

#### *2.2. Selection Criteria*

Inclusion and exclusion criteria were defined according to the PECO (Population, Exposure, Comparator, Outcome) strategy. Inclusion criteria: (1) patients with PKU (Population) on a Phe-restricted diet (Exposure) and followed up at a PKU centre; (2) studies included healthy controls (Comparator); (3) reported anthropometric measures or prevalence

of overweight (Outcome); (4) published as a full paper; and (5) included only randomised controlled trials (RCTs), non-randomised controlled trials (non-RCTs), or observational (case–control, cohort, and cross-sectional) studies.

Non-human studies, review articles, systematic reviews, meta-analysis, letters, conference abstracts, case reports, case series, position papers, and authors' replies were excluded. Only studies published in English were included.

#### *2.3. Search Strategy*

A literature search was carried out on PubMed, The Cochrane Library, and Embase databases on the 16 January 2020. Both medical subject headings (MeSH or Emtree) and text words related to overweight, obesity, and PKU were used. The PubMed search strategy was converted to search in other databases as described in detail in the Supplementary Materials, Section A.

#### *2.4. Study Selection*

All articles identified in the search were included in the screening process and duplicates excluded. Two independent reviewers (A.M. and J.C.R.) screened the titles and abstracts of the articles for relevance, and full-text articles were reviewed when title and abstract did not provide enough information. Once potentially relevant studies were identified, full-text articles were then assessed for eligibility according to previously established criteria. The reference lists of the included articles were screened to ensure that no relevant studies were missed.

#### *2.5. Data Extraction*

Data items were extracted by two authors (C.R. and A.P.) using a standard data extraction form. For each study, first author, year of publication, country of origin, study design, sample characteristics, methods, and outcomes were extracted. In cases where information was missing or incomplete, the correspondence authors were contacted requesting further information.

#### *2.6. Assessment of Risk of Bias in Individual Studies*

Risk of bias of individual studies was assessed by two independent reviewers (C.R. and A.P.) using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies [29]. The following domains were assessed: (1) research question; (2) study population; (3) eligibility criteria; (4) justification of the sample size; (5) exposure measures and assessment; (6) time frame between exposure and outcome assessment; (7) outcome measures; (8) blinding of outcome assessors; (9) follow-up rate; and (10) adjustment of confounders. Reviewers were blinded to each other's assessment, and disagreements were solved by reaching consensus.

#### *2.7. Quantitative Synthesis*

Standardised mean difference (SMD) was used as an effect measure for the continuous variable 'BMI'. Odds ratio (OR) was used as an effect measure for the dichotomous variable 'prevalence of overweight'. The SMD and OR were converted to a common metric and then combined across studies. A sensitivity analysis was performed to compare the metaanalysis results with and without the converted study [30]. Effect measures were reported along with the 95% confidence interval (CI).

The Cochran's Q (significance level of 0.1) and I2 tests were used to assess heterogeneity. According to the Cochrane guidelines [28], the I2 values were interpreted as follows: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% represent considerable heterogeneity.

Mean BMI from Evans et al. [31] was calculated with values from the last evaluation (longest time-point of exposure). In the studies from Evans et al. [25] and Huemer et al. [26], only the mean BMI from the first evaluation (baseline) could be included. In the study from Schulpis et al. [32], consisting of patients both adhering to their diet and on a 'relaxed diet', only the BMI of the patients adhering to the diet was included in the meta-analysis.

Pooled estimates were computed and weighted using generic inverse-variance and random-effect modelling. A *p*-value < 0.05 was considered as statistically significant. Statistical analysis was performed using Review Manager (RevMan), version 5.4, The Cochrane Collaboration, 2020.

#### *2.8. Grading the Evidence*

Funnel plots were used to assess evidence of publication bias. Quality assessment of the evidence for each outcome was performed by two independent authors (C.R. and A.P.) using the NutriGrade scoring system [33]. The meta-analysis was scored with a maximum of 10 points, according to (1) risk of bias, (2) precision, (3) heterogeneity, (4) directness, (5) publication bias, (6) funding bias, (7) effect-size, and (8) dose–response. On the basis of the final score, we classified the quality of the evidence as high, moderate, low, or very low.

#### **3. Results**

#### *3.1. Study Selection*

A total of 829 articles were identified through database search (Figure 1). Titles and abstracts of 551 articles were screened for relevance, after removing duplicates. Once potentially relevant studies were identified, a total of 56 full-text articles were assessed for eligibility. Studies not fulfilling these criteria were excluded from the analysis (*n* = 41) (Supplementary Materials, Section B). Two studies by Rocha et al. [22,34] included two overlapping patient cohorts. To avoid duplicate publication bias, we included the study with more complete information [34]. From the included studies, only 12 provided data on BMI or the prevalence of overweight, qualifying them for quantitative analysis [7,18,25,26,30–32,34–38].

#### *3.2. Study Characteristics*

A summary of the main characteristics of included studies is given in Table 1. All studies were observational: 11 cross-sectional studies [7,18,30,32,34–40], 2 cross-sectional with nested longitudinal cohort studies [26,41], and 2 prospective studies [25,31]. Nine studies were conducted in Europe [7,26,30–32,34–37], three in Australia [25,39,41], two in Brazil [38,40], and one in the USA [18]. Studies were published between 1995 and 2020. In prospective studies, duration of follow-up ranged from 1 to 2 years. The total sample size of the 15 studies was 640 patients with PKU, and 503 were included in the meta-analysis (12 studies). All studies included patients with PKU from both genders (301 females and 299 males). Fisberg et al. [40] did not specify children's gender. The age range of the participants ranged from 2 months to 52 years. Most studies included children and adolescents, four included children, adolescents, and adults [30,34,37,38], and Azabdaftari et al. [36] included adults only.

The methods used to assess dietary intake varied between the included studies and are given in Table 2. No valid and reliable methods to assess exposure were used in five studies [7,35,37–39].

Patients with PKU were compared to 593 healthy controls, 455 of which were included in the meta-analysis. Healthy controls were from both genders, and the age range varied from 1 month to 50 years. The majority were matched for age and gender, and some studies included family relatives, friends, or healthy individuals with similar characteristics in the PKU group.

**Figure 1.** PRISMA study flow diagram describing the process of study selection. Abbreviation: PECO: Population, Exposure, Comparator, Outcome.

Most studies examined the association between a Phe-restricted diet and BMI [7,18,25,26,31,32,34–38]. Six studies examined the association between a Phe-restricted diet and overweight prevalence [18,30,31,34,37,38]. Eleven studies examined the association of different or additional parameters, such as weight-for-height and weight z-scores and body fat percentage [7,18,25,26,31,34,35,38–41].

From 15 studies included in the qualitative synthesis, 12 did not find significant differences in BMI and overweight prevalence between patients with PKU on a Pherestricted diet, compared with healthy controls [7,18,25,26,31,32,34,37–41] (Table 1). Only 3 of 15 studies found a significantly higher BMI or higher prevalence of overweight in patients with PKU than controls [30,35,36].


systematic review.

> **Table 1.**

Characteristics

 of the studies included in the


 =


Abbreviations:

phenylketonuria;

for

Observational

 Cohort and

Cross-Sectional

 Studies; 2 at baseline; 3 two patients refused physical examination.

 SD: standard deviation; UK: United Kingdom; USA: United States of America; y years. 1 Assessed using the National Institutes of Health (NIH) Quality Assessment Tool

 BH4: sapropterin; BMI: body mass index; F: female; HPA:

hyperphenylalaninaemia;

 M: male; NA: not available; NBS: newborn screening; Phe:

phenylalanine;

 PKU:



PKU; NA: not available; PE: protein equivalent; PS: protein substitute; RDA:

PKU phenotype, five studies included only patients with classical PKU

recommended

[7,18,26,32,41],

 seven mixed phenotypes [30,31,34–38],

 and three did not specify [25,39,40].

 dietary allowances; y: years. 1 Total protein (g/kg/day); 2 at 24 months of age. Examining

#### *3.3. NutriGrade Assessment*

On the basis of the NutriGrade assessment (Supplementary Materials, Section C— Table S5), we found that the quality of the evidence for the meta-analysis using BMI was low, with meta-evidence limited and uncertain. The quality of the evidence for the metaanalysis using body fat percentage was very low, with meta-evidence very limited and uncertain.

#### *3.4. Risk of Bias Assessment*

Using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, we found that 4 studies were assessed as fair with moderate risk of bias [26,30,31,34], and 11 as poor with high risk of bias [7,18,25,32,35–41]. Figure 2 presents the percentages of compliance for each tool item across all included studies. The risk of bias summary with review authors' judgments about each item for all included studies can be found in the Supplementary Materials, Section C—Figure S1.

**Figure 2.** Risk of bias: judgements about each risk of bias item presented as percentages across all included studies.

Visual inspection of the funnel plot did not indicate substantial asymmetry (Supplementary Materials, Section C—Figure S7).

#### *3.5. Synthesis of Results*

3.5.1. Patients with PKU vs. Healthy Controls

In the 12 studies included in the meta-analysis, there were no differences for BMI of patients with PKU compared with healthy controls (SMD = 0.12 [−0.04, 0.28], *p* = 0.14; I <sup>2</sup> = 27%, *p* = 0.18; Figure 3).


**Figure 3.** Forest plot comparing the BMI between patients with PKU and healthy controls. Abbreviations: BMI: body mass index; CI: confidence interval; df: degrees of freedom; IV: inverse variance; PKU: phenylketonuria; SE: standard error; Std: standardised. Moderate risk of bias: Couce 2018, Evans 2019, Huemer 2007, and Rocha 2012. High risk of bias: Albersen 2010, Azabdaftari 2019, Doulgeraki 2014, Evans 2017, Hermida-Ameijeiras 2017, Mazzola 2016, Sailer 2020, and Schulpis 2000. Time of diagnosis: Couce 2018 included 70 early and 13 late diagnosed patients, Hermida-Ameijeiras 2017 included both early and late diagnosed patients, Mazzola 2016 included 11 early and 16 late diagnosed patients, and Schulpis 2000 did not provide information on the time of diagnosis. Metabolic control: Azabdaftari 2019 included only one patient with good metabolic control (Phe blood levels < 600 μmol/L). BH4 treatment: Couce 2018 included 10 (12%) patients taking BH4, Evans 2017 included 5 (14%), Hermida-Ameijeiras 2017 included 7 (17%), and Sailer 2020 included 4 (13%).

#### 3.5.2. Moderate vs. Poor Risk of Bias Studies

A subgroup analysis was conducted according to the risk of bias for each study (Supplementary Materials, Section C—Figure S2). Studies assessed as fair with moderate risk of bias [26,30,31,34] found no difference in BMI between patients and healthy controls (SMD = −0.02 [−0.30, 0.27], *<sup>p</sup>* = 0.91; I<sup>2</sup> = 43%, *<sup>p</sup>* = 0.16). Studies assessed as poor with high risk of bias [7,18,25,32,35–38] found a significantly higher BMI in patients with PKU compared to healthy controls (SMD = 0.20 [0.03, 0.37], *p* = 0.02; I2 = 1%, *p* = 0.42).

#### 3.5.3. Time of Diagnosis

Three studies included late diagnosed patients in their samples [30,37,38], and Schulpis et al. [32] did not provide information on diagnostic age. Thus, a subgroup analysis was conducted according to diagnostic age (Supplementary Materials, Section C—Figure S3). The subgroup of studies including only early diagnosed patients found no differences in BMI between patients and healthy controls (SMD = 0.11 [−0.10, 0.31], *p* = 0.32; I <sup>2</sup> = 35%, *p* = 0.15). Moreover, the subgroup of studies including both early and late diagnosed patients found no differences between patients with PKU and healthy controls (SMD = 0.18 [−0.17, 0.52], *p* = 0.31; I<sup>2</sup> = 43%, *p* = 0.18). There were no statistical differences between the two subgroups (*p* = 0.73).

#### 3.5.4. Age

The studies included in the meta-analysis covered a wide patient age. We performed a subgroup analysis (Supplementary Materials, Section C—Figure S4) comparing studies including children and adolescents only [7,18,25,26,31,32,35], adults only [36], and all age groups (children, adolescents, and adults) [30,34,37,38]. We found no differences between the three subgroups (*p* = 0.15), and a higher heterogeneity in the subgroup of studies that included all age groups (I2 = 61%). The subgroup that included adults only had one study [36] that identified adult patients with PKU, having a significantly higher BMI when compared to healthy adults.

#### 3.5.5. Sapropterin (BH4) Treatment

Four studies included patients prescribed BH4 in their patient cohort [18,25,30,37]. To understand if there was any difference between studies that included patients taking BH4 (mixed sample) and studies that included only patients on a Phe-restricted diet, we performed a subgroup analysis (Supplementary Materials, Section C—Figure S5).

Studies that included some patients with PKU treated with diet and BH4 [18,25,30,37] found a significantly higher BMI in the overall group than in healthy controls (SMD = 0.30 [0.07, 0.52], *p* = 0.01; I2 = 0%, *p* = 0.97). Studies that included only patients on a Phe-restricted diet [7,26,31,32,34–36,38] found no differences between the PKU group and healthy controls (SMD = 0.04 [−0.17, 0.24], *<sup>p</sup>* = 0.74; I2 = 35%, *<sup>p</sup>* = 0.15).

#### 3.5.6. Phenotype

Four studies in the meta-analysis included only patients with classical PKU [7,18,26,32]. The remaining studies included patients with different phenotypes and reported their BMI together; therefore, it was not possible to analyse any association between different phenotypes and BMI from these studies [30,31,34–38]. To understand if there were any differences between studies including only patients with classical PKU and studies that included patients with different phenotypes, we performed a subgroup analysis (Supplementary Materials, Section C—Figure S6). In both subgroups, there were no differences between patients with PKU and controls.

#### 3.5.7. Patients with Classical PKU vs. Healthy Controls

Several authors of the included studies provided individual participant data, including disease severity [7,18,31,34–36]. On the basis of this additional data, we conducted a meta-analysis comparing patients with classical PKU only with healthy controls (Figure 4) [7,18,26,32]. In the remaining studies, we calculated the mean BMI of patients with classical PKU [30,31,34–36] and excluded data from patients with other phenotypes. Individual participant data was unavailable from two studies (Hermida-Ameijeiras et al. [37] and Mazzola et al. [38]), and Evans et al. [25] did not include information on the patient phenotype. Therefore, these three studies were excluded from this meta-analysis.


**Figure 4.** Forest plot comparing the BMI between patients with classical PKU and healthy controls. Abbreviations: BMI: body mass index; CI: confidence interval; df: degrees of freedom; IV: inverse variance; PKU: phenylketonuria; SE: standard error; Std: standardised. Moderate risk of bias: Couce 2018, Evans 2019, Huemer 2007, and Rocha 2012. High risk of bias: Albersen 2010, Azabdaftari 2019, Doulgeraki 2014, Sailer 2020, and Schulpis 2000. Time of diagnosis: Couce 2018 included 70 early- and 13 late-diagnosed patients, and Schulpis 2000 did not provide information on the time of diagnosis. Metabolic control: Azabdaftari 2019 included only one patient with good metabolic control (Phe blood levels < 600 μmol/L). BH4 treatment: Couce 2018 included 1 (3%) patient taking BH4, and Sailer 2020 included 4 (13%) patients.

We found that patients with classical PKU had a significantly higher BMI than healthy controls (SMD = 0.24 [0.04, 0.45], *p* = 0.02; I2 = 31%, *p* = 0.17).

To reject the hypothesis that this result was due to the removal of the three studies, whose individual participant data is unknown, we performed the first meta-analysis (Figure 3) without them. Removing these three studies did not affect the overall result, compared with the 12 included studies (SMD = 0.12 [−0.07, 0.31], *<sup>p</sup>* = 0.22; I2 = 34%, *p* = 0.15).

#### 3.5.8. Sex

Only six studies provided adequate information to establish a comparison on sex, which limits the subsequent interpretation of its effect on overweight. However, when comparing females with PKU and healthy females, all studies found a trend towards a higher BMI in females with PKU (Supplementary Materials, Section C—Table S4).

#### 3.5.9. Metabolic Control

We tried to explore the association between metabolic control and BMI. However, only five studies provided information on metabolic control, and the comparison between patients with poor metabolic control and healthy controls (Supplementary Materials, Section C—Table S4) had substantial heterogeneity (I<sup>2</sup> = 58%, *p* = 0.05); thus, we were unable to present accurate data on metabolic control.

#### 3.5.10. Body Fat Percentage

The methods used to assess body fat percentage across studies were different. This led to a heterogeneous overall result, rendering it unfeasible to present and compare body fat results (Supplementary Materials, Section C—Table S4).

#### **4. Discussion**

#### *4.1. Summary of Evidence*

To the best of our knowledge, this is the first systematic review with meta-analysis evaluating the association between a Phe-restricted diet and overweight and obesity in patients with PKU. We pooled data from 12 observational studies for the meta-analysis and found no differences between patients with PKU and healthy controls for BMI. The pooled data included diverse patient phenotypes with variable Phe-restriction, with dissimilar contributions from the PS and SLPFs to total protein and energy intake [16,42,43]. Our metaanalysis suggests that dietary Phe-restriction alone is not a risk factor for the development of overweight and obesity.

However, patients with classical PKU had a significantly higher BMI than healthy controls. This observation resulted from nine studies, including only patients with classical PKU and studies whose authors provided additional individual participant data, although these results should be considered with caution. One plausible explanation is that more calories may be given to patients with classical PKU in order to prevent catabolism that causes higher blood Phe levels. This may lead to the development of overweight.

Among the studies included in qualitative synthesis, 4 studies had a moderate risk of bias and 11 had a high risk of bias using the NIH Quality Assessment Tool. The subgroup of studies with moderate risk of bias did not find a higher BMI in patients with PKU. In contrast, studies assessed as poor due to their methodological flaws found a significantly higher BMI in patients with PKU compared to healthy controls. Therefore, this work highlights the fragility of the evidence supporting the idea that a Phe-restricted diet promotes overweight and indicates the need for controlled studies with improved methodology and comprehensive data collection.

Three of the seven most common flaws observed in the studies were limited description of the study population using demographics (who), location (where), and time period (when) (question 2 of the NIH tool) [7,18,25,26,31,32,35,36,38–41]; absence of sample size justification (question 5 of the NIH tool) [18,25,26,30,32,35,37,38,40,41]; and outcome

assessors being aware of participants' exposure status (question 12 of the NIH tool) in all included studies. These flaws were not considered fatal, and studies that failed these criteria could still be classified as fair with moderate risk of bias.

Eleven studies were cross-sectional [7,18,30,32,34–40], and the exposure was not assessed prior to outcome measurement (question 6 of the NIH tool). For this reason, it is not possible to establish a relation of causality between the exposure to a Phe-restricted diet and overweight.

For the different levels of exposure assessment (question 8 of the NIH tool), from the 10 studies that included patients with different phenotypes, the use of BH4 with a relaxed Phe-restriction or patients who were late diagnosed with PKU, only five studies considered these factors [25,30,32,34,35]. These different levels of exposure to the Phe-restricted diet renders it difficult to analyse the association between the Phe-restricted diet and overweight. For example, we identified three studies that included patients with HPA [30,34,35] and, in two of three of these studies, patients were on an unrestricted diet [30,35]. The fact that most studies included patients with different phenotypes does not allow for conclusions about the association between phenotype and overweight, as verified in the subgroup analysis by phenotypes (Supplementary Materials, Section C—Figure S6).

In addition, between 20 and 50% of patients with PKU are responsive to the synthetic form of the cofactor (BH4), meaning that a less restricted diet is followed. Evidence suggests that 51% of patients on BH4 therapy completely stop PS intake [44]. In our meta-analysis, the studies that included patients taking both BH4 combined with patients on a traditional Phe-restricted diet only found a significantly higher BMI in the overall group of patients with PKU compared to healthy controls. Although this is an interesting finding, it is unknown as to how many of these patients were overweight before BH4 commencement. A study conducted in Spain, including patients from 13 hospitals, found that patients taking BH4 had significantly higher BMI z-scores than patients on a Phe-restricted diet only, with follow up consistently over 2 years [45]. These results highlight the need for a continuous nutritional monitoring and specialised nutritional care, even in patients under pharmacological treatment. This observation warrants further study.

Of the 12 studies included in the meta-analysis, 4 did not assess patients' dietary intake [7,35,37,38]. In the remaining eight studies, the methods used to assess intake were different, and only four studies [18,31,32,34] provided detailed information on the amount of protein, CHO, fat, and energy patients consumed. This information is central to accurately address our review question and is considered an important omission in studies. Different reimbursement policies in different countries determine access to PS and SLPFs, which ultimately will alter the intake of macronutrients supplied by a Phe-restricted diet [46,47].

We also tried to determine if there was an association between patients' BMI and metabolic control (which may reflect patients' exposure to the Phe-restricted diet). However, most of the studies did not report patients' BMI, nor its comparison with metabolic control. In the literature, some studies have found a positive correlation between mean Phe levels and BMI [3,36,48], and between mean Phe levels and the prevalence of overweight [1,9,34], indicating that good metabolic control is associated with a lower risk of overweight. Conversely, two studies from Spain found a higher prevalence of overweight and BMI in patients with good metabolic control compared to poorly controlled patients [30,49].

Most of the included studies did not adjust for key prognostic variables, such as physical activity, family history, socioeconomic status, parents' weight, and epigenetics, among other determinant factors that may be associated with overweight.

Finally, none of the included studies considered the regular follow-up of patients by a nutritionist. Nutritionists play a crucial role in monitoring the patient's weight while ensuring they meet their complex dietary needs [50]. Consequently, we were not only analysing the influence of the Phe-restricted diet alone on overweight, but also on the quality of the follow-up that the patients receive.

#### *4.2. Strengths and Limitations of This Study*

Several limitations in this systematic review should be acknowledged. First, our systematic review included observational studies only. Observational evidence usually provides lower strength evidence than RCTs, due to confounding variables. Nevertheless, RCTs addressing our question have not been conducted, which is unsurprising, given that PKU is a rare disease and the exposure to an unrestricted Phe-diet is clinical and ethically unacceptable. In addition, there was large heterogeneity in the design of observational studies and in the reporting of results.

The diversity of the study populations also contributes to the heterogeneity of the results. For instance, some studies included patients with different disease severities, with variable degrees of Phe-restriction, being diagnosed early and later on, patients on BH4 treatment, and patients with poor metabolic control. Additionally, patients had a wide age range.

The Phe-restricted diet was not always well defined: not all studies reported patients' dietary intake, and some studies did not assess it.

In relation to the comparator, we did not define any inclusion criteria for healthy controls. Most of them were matched for age and gender only, and the number of controls included in our work was less than the number of patients with PKU.

Regarding the outcome, one study [30] only presented the prevalence of overweight, which led us to convert the respective OR to a SMD to include it in the meta-analysis. Although BMI is an important predictor of adiposity and is a tool widely used in clinical practice [23], it may not always identify individuals with increased fat mass percentage [51], which underlines the weakness of the BMI as an indicator of adiposity. Measuring body composition appears to be a better approach to identify individuals with increased fat mass percentage, specifically those at a higher risk of metabolic complications, which is crucial to help prevent the development of comorbidities [51]. Increased abdominal obesity is associated with dyslipidaemia, hypertension, insulin resistance, and inflammation.

Finally, most of the included studies had a high risk of bias according to the NIH tool. On the basis of the NutriGrade assessment, we found that the quality of the meta-analysis comparing all patients with PKU to controls was 'low', and the quality of the meta-analysis comparing patients with classical PKU to controls was 'very low'.

In order to strengthen the conclusions of our systematic review with meta-analysis, we used the best methodology, namely, (1) following the PRISMA guidelines and registering on the PROSPERO database—studies that do appear to be of higher quality [27,52]; (2) clear definition of the aim of our work; (3) clear definition of the inclusion and exclusion criteria, according to the PECO strategy; (4) using several databases for the search and searching reference lists of the retrieved studies; (5) describing the study selection process using a flow diagram; (6) providing the list of the excluded studies and the reasons; (7) providing of the characteristics of individual studies; (8) contacting the correspondence authors to request further information; (9) performing meta-analysis and subgroup analysis; and (10) having two independent authors performing study selection, data extraction, and assessment of the risk of bias and the quality of the evidence.

As the study of risk factors is based on comparisons between exposed and unexposed individuals [53], only studies with a control group were included in our systematic review, which is another strength of this meta-analysis. Indeed, several studies that propose that the Phe-restricted diet promotes overweight did not include a control group.

Finally, our systematic review provides a clear overview of the available evidence on the topic overweight and PKU and will be useful in guideline development. It also identifies the main flaws and pitfalls that should be avoided when designing novel studies to address this question in the future.

#### **5. Conclusions**

We found no differences between patients with PKU and healthy controls in BMI. Thus, there is no evidence to support the concept of Phe-restricted diet as a risk factor

for the development of overweight. However, a subgroup of patients with classical PKU had a significantly higher BMI than healthy controls. In addition, studies assessed as poor with high risk of bias and studies that included both diet-treated and BH4-treated patients found a significantly higher BMI in patients with PKU compared to healthy controls.

Given the increasing prevalence of overweight in the general population, patients with PKU should remain in long-term follow-up, receiving personalised nutritional advice with systematic nutritional status monitoring by a multidisciplinary team in inherited metabolic disorders. This is essential to prevent overweight, obesity, and its related comorbidities.

Future studies with improved methodology are needed to properly address this question and to help in guiding the clinical practice of health professionals.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/nu13103443/s1, Figure S1: Risk of bias summary: Review authors' judgements about each risk of bias item for each included study. Figure S2: Forest plot comparing the BMI between patients with PKU and healthy controls among studies with moderate and high risk of bias. Figure S3: Forest plot comparing the BMI between patients with PKU and healthy controls among studies including only early diagnosed patients and studies including both early and late diagnosed patients. Figure S4: Forest plot comparing the BMI between patients with PKU and healthy controls among studies including only children and adolescents; studies including only adults; and studies including children, adolescents, and adults. Figure S5: Forest plot comparing the BMI between patients with PKU and healthy controls among studies including both patients taking BH4 and patients not taking BH4, as well as studies including only patients not taking BH4. Figure S6: Forest plot comparing the BMI between patients with PKU and healthy controls among studies including patients with mixed phenotypes and studies including only patients with classical PKU. Figure S7: Publication bias plot. The SMD of BMI is plotted on the *x*-axis and the SE of the SMD is plotted on the *y*-axis. Table S1: Syntax of Mesh/Emtree terms per database. Table S2: Syntax of title, abstract, and author keyword per database. Table S3: Studies excluded from the systematic review with reasons. Table S4: Summary of between-group meta-analysis results. Table S5: NutriGrade assessment of the quality of the evidence.

**Author Contributions:** A.M.-R. and J.C.R. conceived and designed the protocol for this systematic review and supervised the study. A.M.-R. designed the methodology and the statistical analysis. A.M.J.v.W. defined the search strategy. A.M. and J.C.R. searched the literature and performed the study selection. C.R. and A.P. extracted the data and applied the risk of bias and NutriGrade assessments tools. C.R. performed the statistical analysis and drafted the manuscript. A.P., A.F., D.T., A.M.J.v.W., K.A., F.F., C.C., A.M., A.M.-R. and J.C.R. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** CINTESIS—UIDB/4255/2020 a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência, through national funds is acknowledged. Support from Human Nutrition and Metabolism Master Program from NOVA Medical School, Universidade Nova de Lisboa is ackowledged.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Acknowledgments:** We would like to thank the following authors of the studies included in our systematic review for providing their data: Aline Azabdaftari from the Department of Pediatrics, Division of Gastroenterology, Nephrology and Metabolic Diseases, Charité—Universitätsmedizin Berlin, Berlin, Germany; Artemis Doulgeraki from the Department of Bone and Mineral Metabolism, Institute of Child Health, Athens, Greece; Gepke Visser from the Department of Metabolic and Endocrine Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands; Maureen Evans from the Department of Metabolic Medicine, The Royal Children's Hospital, Melbourne, Australia, and the Department of Nutrition and Food Services, Royal Children's Hospital, Melbourne, Australia; Melanie Gillingham from the Departments Molecular and Medical Genetics, Graduate Programs in Human Nutrition at Oregon Health and Science University, Oregon, USA; and Sharon Evans from the Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom.

**Conflicts of Interest:** A.P. has received an educational grant from Cambrooke Therapeutics and grants from Vitaflo, Nutricia, Merck Serono, Biomarin, and Mevalia to attend scientific meetings. A.M.J.W. received a research grant from Nutricia, honoraria from Biomarin as a speaker, and travel support from Nutricia and Vitaflo. K.A. is a member of the European Nutrition Expert Panel (Biomarin). F.F. has been a board member and received payments for, e.g., lectures/honoraria, and support for travel, accommodations, and/or meeting expenses from BioMarin, Genzyme, Merck-Serono, Nutricia, and Vitaflo. A.M. received research funding and honoraria from Nutricia, Vitaflo International, and Merck Serono. She is a member of the European Nutrition Expert Panel (Biomarin), member of Sapropterin Advisory Board (Biomarin), member of the Advisory Board entitled ELE-MENT (Danone-Nutricia), and member of an Advisory Board for Arla and Applied Pharma Research. J.C.R. is a member of the European Nutritionist Expert Panel (Biomarin), the Advisory Board for Applied Pharma Research and Nutricia, and has received honoraria as a speaker from APR, Merck Serono, Biomarin, Nutricia, Vitaflo, Cambrooke, PIAM, and Lifediet.

#### **References**


## *Article* **Provision and Supervision of Food and Protein Substitute in School for Children with PKU: Parent Experiences**

**Hannah Jones 1, Alex Pinto 2, Sharon Evans 2, Suzanne Ford 3,4, Mike O'Driscoll 5, Sharon Buckley 6, Catherine Ashmore 2, Anne Daly <sup>2</sup> and Anita MacDonald 2,\***


**Abstract:** Children spend a substantial part of their childhood in school, so provision of dietary care and inclusion of children with phenylketonuria (PKU) in this setting is essential. There are no reports describing the dietary support children with PKU receive whilst at school. The aim of this cross-sectional study was to explore the experiences of the dietary management of children with PKU in schools across the UK. Data was collected using an online survey completed by parents/caregivers of children with PKU. Of 159 questionnaire responses, 92% (*n* = 146) of children attended state school, 6% (*n* = 10) private school and 2% (*n* = 3) other. Fourteen per cent (*n* = 21/154) were at nursery/preschool, 51% (*n* = 79/154) primary and 35% (*n* = 54/154) secondary school. Sixty-one per cent (*n* = 97/159) said their child did not have school meals, with some catering services refusing to provide suitable food and some parents distrusting the school meals service. Sixty-one per cent of children had an individual health care plan (IHCP) (*n* = 95/155). Children were commonly unsupervised at lunchtime (40%, *n* = 63/159), with snacks (46%, *n* = 71/155) and protein substitute (30%, *n* = 47/157), with significantly less supervision in secondary than primary school (*p* < 0.001). An IHCP was significantly associated with improved supervision of food and protein substitute administration (*p* < 0.01), and better communication between parents/caregivers and the school team (*p* < 0.05). Children commonly accessed non-permitted foods in school. Therefore, parents/caregivers described important issues concerning the school provision of low phenylalanine food and protein substitute. Every child should have an IHCP which details their dietary needs and how these will be met safely and discreetly. It is imperative that children with PKU are supported in school.

**Keywords:** PKU; food; protein substitute; school; IHCP; parent/caregiver experiences

#### **1. Introduction**

In the UK, it is estimated there are approximately 800 children with phenylketonuria (PKU) aged 5 to 16 years [1]; they are expected to attain normal educational achievement and attend mainstream school. Children with classical PKU are treated with a phenylalanine restricted diet only; if they have mild PKU they may be treated with an adjunct therapy, sapropterin. Children with classical PKU usually tolerate < 80% of usual natural protein intake and treatment includes: avoidance of high protein foods, strict measurement and limited intake of moderate protein containing foods, inclusion of special low protein

**Citation:** Jones, H.; Pinto, A.; Evans, S.; Ford, S.; O'Driscoll, M.; Buckley, S.; Ashmore, C.; Daly, A.; MacDonald, A. Provision and Supervision of Food and Protein Substitute in School for Children with PKU: Parent Experiences. *Nutrients* **2021**, *13*, 3863. https://doi.org/10.3390/nu13113863

Academic Editor: Shanon L. Casperson

Received: 8 September 2021 Accepted: 28 October 2021 Published: 28 October 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

foods (SLPF's) and supplementation with a low phenylalanine protein substitute [2]. Most children will be expected to eat at least one meal and take one dose of protein substitute at school. It is essential that there is safe provision and supervision of dietary treatment with appropriate adjustments that integrates the medical needs of a child with PKU into school life.

Section 100 of the UK Children and Families Act 2014, updated in 2015, states that schools in the UK have a duty to support pupils with medical conditions [3,4]. This act mandates that children with PKU are properly supported, enabling them to have a full and active role in school, remain healthy and achieve their academic potential. It states that school leaders should consult health and social care professionals, pupils, and parents so that the needs of children with medical conditions are accurately understood and effectively met. Schools have a duty to ensure that all relevant staff are trained to provide the support that pupils' need, and that policies, plans, procedures, and systems are implemented. Although not mandatory, each school should have policies to ensure all relevant staff are aware of the child's condition; that there are cover arrangements in case of staff absences or staff turnover, and that risk assessments are conducted for school visits, holidays, and other activities outside the normal timetable. Failure to make reasonable adjustment for a child with a disability is considered discrimination under the UK Equality Act 2010 [5].

Ideally each child with PKU should have an individual health care plan (IHCP) although these are not obligatory by law [4]. These should be developed in partnership between the school, parents, pupils, and relevant healthcare professionals who can advise on individual medical care needs. An IHCP should ensure that schools know how to support children with PKU effectively by providing clarity about what needs to be done, when and by whom. They should be reviewed at least annually or earlier if health care needs change. School governing bodies should ensure that their schools have policies and appoint staff who are responsible for managing IHCP's.

In addition, in UK state-funded schools, every child in reception, year 1 and 2 (children aged 4–7 years) are entitled to a free school lunch [6]. They should have access to a healthy, balanced diet and it is recommended that they have at least one hot meal provided every day. Food and drinks provided by school must comply with certain nutritional standards [7] and reasonable adjustment should be made for children on special diets. The Education Act 1996 requires maintained schools and academies to provide free school meals to disadvantaged pupils aged between 5 to 16 years, with 20.8% of children in England (2020/2021) being entitled to this service [8].

Dietary treatment is expected to have both a physiological and psychological impact on the lives of young people with PKU in school. Whilst consumption of non-permitted foods and poor adherence to protein substitute will lead to elevated blood phenylalanine and neurological dysfunction, teacher/peer insensitivity and exclusion may have an enduring impact on a child's mental health, and attitude and acceptance of PKU. There are no studies examining care provision in school and the opinions and experiences of parents of school children with PKU are unknown. The aim of this study was to explore the views and experiences of parents/caregivers of children with PKU in school and nursery. Additionally, the care of children with and without an IHCP was also studied.

#### **2. Materials and Methods**

#### *2.1. Study Design*

This was a cross-sectional study using an online survey that collected both qualitative and quantitative data from UK parents of children aged 3 to 16 y with PKU attending school or nursery. Non-UK respondents were excluded.

The questionnaire was built in the Online Surveys platform (https://www.onlinesurv eys.ac.uk, accessed on 28 October 2021) to gather quantitative data. This was placed on the UK National Society for Phenylketonuria (NSPKU) website, with additional promotion on the NSPKU Twitter, Instagram and Facebook. The survey was open for five months, from 20 March until 20 August 2020.

#### *2.2. Questionnaire*

The non-validated questionnaire contained 22 questions: *n* = 17 multiple choice (with *n* = 14 inviting additional comments), *n* = 3 multiple responses, *n* = 1 Likert scale and *n* = 1 open ended questions (Supplementary Material).

The questionnaire was developed collaboratively by dietitians with expert practical and scientific knowledge of PKU (AP, SE, AM), a colleague from the NSPKU (SF), a researcher (MO) and a student dietitian from Birmingham City University (HJ). It was reviewed amongst colleagues and lay people to ensure its readability and then amended according to feedback.

#### *2.3. Data Collected*

The questionnaire was divided into four sections. Information collected included: the age of the child, type of school, school year group, the availability of an IHCP, administration of protein substitute in school, provision and acceptance of lunches provided by school catering services, information about the suitability of school lunches, school staff training and supervision of food and protein substitute. All data that was collected was based on the parents own perception or knowledge about the quality of the care and support provided by the nursery or school.

#### *2.4. Statistics*

Quantitative data analysis (inferential and descriptive statistics) was carried out with the Statistical Package for the Social Sciences (SPSS) version 25 (SPSS Inc., Chicago, IL, USA). Multiple response questions were analysed with descriptive statistics only. Statistical significance was set at *p* < 0.05.

Qualitative data analyses of 14 open-ended responses were carried out in NVIVO v 12 PRO. The whole survey dataset was imported into NVIVO, so that coding of openended responses could be broken down by attributes of survey questions. All open-ended question responses were analysed thematically.

#### *2.5. Ethics*

Ethical approval was obtained from the Birmingham City University ethics committee prior to commencement of the study (Jones/5042/R(A)/2020/Mar/HELS FAEC - Provision of school food for children with PKU: A parent's perspective. Approved 19/3/2020). At the beginning of the online questionnaire, respondents gave consent, and it was emphasized that questionnaire completion was voluntary. Potential respondents were advised that data from the survey may be published in an anonymized form. If names of schools or hospitals were mentioned in verbatim abstracts these were removed from results presented in this manuscript.

#### **3. Results**

There were 159 responses. The number of respondents who answered each question was variable (as not all questions were applicable to each respondent). All respondents were parents/caregivers of children with PKU. A description of the school type, school age group and provision of IHCP for children is given in Table 1.


**Table 1.** School type, age group and provision of IHCP.


When considering the provision of written IHCP's, there was no difference between state or private school or between school year groups (Pearson Chi-Square test, *p* > 0.5).

#### *3.1. Uptake of School Meals*

Uptake of school lunches and entitlement to free school meals is given in Table 2. Most parents/caregivers (61%, *n* = 96/157) said their children were not eating meals provided by the school catering service.


**Table 2.** Uptake of school lunches and entitlement to free school lunches.

Sixty-two per cent (*n* = 73/117) of parents/caregivers said that they would like their child to have school lunches more often. Only 52% (*n* = 29/56) utilized their free school

lunch entitlement. Of those with free school meal entitlement, 41% were eating school lunches 4–5 times a week compared to 16% of those without the entitlement (Pearson Chi-Square test *p* = 0.05). Of the children eating school lunches, 76% (*n* = 48/63) of parents were satisfied with the school lunch service.

Respondents were asked in two open-ended questions, about barriers to accessing school meals more frequently. The main themes which emerged were: school refusing to cater for children with PKU, limited food choice offered by school, child or parent preferring packed lunch, parents did not trust school to prepare appropriate food for their child with PKU, parents were more in control of what their child eats with packed lunches, and children refuse school meals because they openly advertise that they are different. Some parents described how the school or school catering were unwilling or reluctant to cater for children with PKU, particularly in secondary school. They described the inflexibility of catering services, how some parents had to supplement the school lunch with food prepared at home, and exclusion from special occasion meals such as Christmas dinner.

Parents/caregivers verbatim quotes:


#### *3.2. Food Included in School Lunch Service*

The type of school meal plans and variety of low protein foods given are outlined in Table 3.


**Table 3.** Meal provision within school and type of special low protein foods used.

'free from': food without one or more specific ingredients, designed for people with food allergies or other intolerances/diseases). \* 40% (*n* = 8/20) of children that had food chosen from standard school menu were taking sapropterin and were permitted a higher protein intake.

Parents usually supplied the SLPF's such as pasta and bread which they obtained on prescription; the school usually provided low protein/vegan cheese and 'fishless' fingers purchased from wholesalers. Some parents said the school 'do not provide anything.' Children with an IHCP (68%, *n* = 25/37) were much more likely than those without IHCP (50%, *n* = 7/14) to have alternative meals prepared but the difference was not statistically significant (Pearson Chi Square test *p* > 0.05). Children in private school were more likely to have a separate meal prepared (100%, *n* = 5/5) compared with 58% (*n* = 26/45) of state

Low protein 'meat'/'fish' substitutes (40%, *n* = 25/63)

'Fishless' fingers (17%, *n* = 11/63)

schools, but the difference did not reach statistical difference due to the small numbers of children in private school. There were no clear differences related to the school year of the child.

Fifty-nine percent (*n* = 37/63) said catering staff measured or weighed protein exchange foods (e.g., mashed potato or peas) and 2% (*n* = 1/63) were unaware if foods were measured. Some parents commented that it was unnecessary for the school to weigh protein exchanges because they either provided the food pre-measured, the main meal did not contain protein exchanges, or they did not ask the school catering to weigh exchange foods.

Weighing and measuring of food protein exchanges was most common (80%, *n* = 12/15) in nursery/reception school compared to other school age groups (57%, *n* = 24/42) [Pearson Chi-Square test, *p* = 0.014]. Parents/caregivers were asked to score satisfaction with the school meal service on a scale of 1 (extremely dissatisfied) to 5 (extremely satisfied). They gave a higher satisfaction score (median 5) when the school measured/weighed protein exchanges compared with scoring for schools who did not weigh/measure protein exchanges (median 4) (Mann–Whitney U test, *p* = 0.003)

There were some parent comments about the quality, variety and presentation of food provided by the school catering service.

Parents/caregivers verbatim quotes:


#### *3.3. Training and Knowledge about PKU and Diet*

Parents/caregivers said that only 47% (*n* = 74/159) of their child's class teachers and 54% (*n* = 33/61) of catering staff (for those receiving school meals) had received PKU training from a health professional. Of the teachers and catering team who had received training, 82% (*n* = 58/71) of teachers and 85% (*n* = 35/41) of the catering team received training in the previous 2 years. The training was mainly delivered by the child's dietitian.

#### *3.4. Supervision of Food in School*

Children were commonly unsupervised at lunchtime (43%, *n* = 66/154) or snack time (48%, *n* = 74/155). Lack of meal supervision was significantly more common in secondary schools (61%, *n* = 33/54) than in primary schools (27%, *n* = 21/79) (Pearson Chi-Squared test *p* < 0.001).

Those without an IHCP (40%, *n* = 59/148) were more commonly unsupervised at school at meal and snack time (60%, *n* = 32/53) compared to those who had a plan (28%, *n* = 27/95) (Pearson Chi-Square test *p* < 0.01). Of the children supervised at lunchtime, school lunchtime supervisors most commonly did this task (27%, *n* = 24/88), whereas snacks were mainly supervised by teaching assistants (30%, *n* = 24/81).

#### *3.5. Feedback about Food Eaten in School*

Only 36% (*n* = 57/157) of parents/caregivers said they received feedback about what their children eat in school. Feedback was more common for children with an IHCP in a state school compared with children without one (Pearson Chi-square test *p* < 0.05); and more common for children in nursery/reception and primary school (year 1 to 3) (64%, *n* = 27/42) than in secondary school (15% *n* = 8/53) (Pearson Chi-square test *p* < 0.001). It was marginally more common in private school (40%, *n* = 4/10) compared to state school (35%, 51/144) [Pearson Chi-square test *p* > 0.05].

When feedback was received, 56% (*n* = 32/57) of parents/caregivers received a written record of food eaten, 25% (*n* = 14/57) verbal feedback and 11% (*n* = 6/57) photographs of food eaten via online systems. Nine per cent (*n* = 5/57) received feedback in 'other' forms such as: lunch wrappers and uneaten food being left in the bag (as evidence of what

has been eaten), the online system for monitoring school meal purchases, messages in a schoolbook/homework book, and an email or telephone call from the school.

#### *3.6. Incidents of Eating Foods at School That Were Not Permitted*

Parents reported 53 incidents of incorrect foods being given accidentally/purposely to children in school in the previous 6 months. Forty per cent (*n* = 21/53) of parents/caregivers said that it had happened once; 19% (*n* = 10/53) said 2 to 3 times, 8% (*n* = 4/53) said 4 to 5 times and 34% (*n* = 18/53) said that it had happened more than five times. Respondents were asked to describe incidents of their child eating non permitted food at school, and these responses (*n* = 39) were thematically analysed. The main themes describing incidents were associated with staff errors (*n* = 4), other children sharing inappropriate foods (*n* = 11), child choosing inappropriate foods (*n* = 5) and trying to fit in with others (*n* = 4). Two parents mentioned that they felt it was much harder for the school to supervise the child's eating once they were in secondary school.

Parents/caregivers verbatim quotes:


Secondary school children were much more likely to have eaten foods which were not permitted as part of a low phenylalanine diet (45% (*n* = 10/22) of secondary school children (year 10 to 11) compared with 26% (*n* = 9/35) of primary school children (Year 1 to 3) but the differences were not statistically significant (Pearson Chi-square test *p* > 0.05).

Two-thirds (66%, *n* = 35/53) of parents/caregivers said that they did not feel adequately informed about food incidents. Parents/caregivers were much more likely to say that they felt adequately informed of the incident if children were in nursery/reception (60%, *n* = 3/5) and primary school (years 4-6) (58%, *n* = 7/12) [Pearson Chi-square test *p* > 0.05]. Respondents were asked (open-ended question) to comment about the communication they received from the school staff about food incidents. The main common themes from the 25 responses were: informed by child (*n* = 7), staff were slow or late in informing us (*n* = 4), should be greater staff understanding or awareness (*n* = 4), and staff don't care (*n* = 3).

Parents/caregivers verbatim quotes:


#### *3.7. School Strategies to Prevent Children Being Given the Incorrect Foods at School*

The parents of nursery/reception and primary school (years 1–3) children were much more likely to state that there were strategies in place to prevent incorrect food being eaten at school compared with older children with PKU (Pearson Chi-Square test *p* < 0.001). Thirty-eight (*n* = 60/158) of respondents said there were no procedures in place to prevent such incidents reoccurring. However, parents gave many examples of strategies used by the school staff to try and ensure children were given the correct food Table 4.

**Table 4.** All strategies suggested by parents/caregivers to prevent incorrect foods being eaten by children with PKU in school.

#### **Supervision at mealtime**


#### **Communication/education with school staff**


#### **Communication with previous school/nursery**

• School visited the nursery and saw the systems that they had in place there and all the measures that they took which I think helped them visualise them in real terms.

#### *3.8. Exclusion: Feeling and Looking Different in School*

Thematic analysis of general comments received about provision of food in school showed that parents/caregivers were concerned that their child was either excluded from activities/school events because of PKU or that they looked different from others in school. Parents/caregivers verbatim quotes:


#### *3.9. Support with Special Diet by the School*

Many parents/caregivers (*n* = 29) positively described the support they received from the school. However, some outlined the amount of work and liaison they have to do with the school team to receive a better service for their children.

Parents/caregivers verbatim quotes:

• "*I have been extremely lucky with the support we have for my son at school. They will do everything they can to ensure my son is as included as we would like him to be. They have* *gained a lot of knowledge and continue to check in and ask questions or change their 'usual' foods where needed.*"

• "*When my daughter has been on residential holidays with the school the staff have been excellent arranging catering with staff wherever they have stayed (France and UK).*"

#### *3.10. Negative Comments about School Care for PKU Children*

Thematic analysis indicated a further 34 negative experiences with school and management of PKU by respondents.

Parents/caregivers verbatim quotes:


#### *3.11. Secondary School Provision*

Parents/caregivers gave 10 comments about the issues for children in secondary school. They described the fear children experience and how they do not want to look different from their peers and the difficulties they experience.

Parents/caregivers verbatim quotes:


#### *3.12. Administration of Protein Substitute in School*

Protein substitute administration was more commonly unsupervised in children in secondary (77%, *n* = 34/44) than primary school (17%, *n* = 11/66) (Pearson Chi-Square Test *p* = 0.001). Those who did not have an IHCP (57%, *n* = 25/44) were less likely to be supervised compared to those who did have a plan (24%, *n* = 18/75) (Pearson Chi-Square test *p* = 0.001). Any supervision was mostly provided by teaching assistants.

Some parents commented that the school had helped with the transition of protein substitute from a paste to a liquid, others described the measures that the school staff took to ensure that a child took the protein substitute. Some described how they chose not to give protein substitute at school because it was unsupervised and consequently not taken. Others explained there that there was less supervision in secondary school, with one respondent describing a medical room being locked so their child could not gain access to their supply of protein substitute.

Parents/caregivers verbatim quotes:


#### **4. Discussion**

This is the first study to explore the views and experiences of parents and caregivers of children with PKU in school and nursery. Additionally, the care of children with and without an IHCP were studied. The responses to this questionnaire represent approximately 20% of school-aged children with PKU in the UK [9]. The experiences of parents/caregivers in relation to schools were highly variable ranging from excellent support, to care that was unsafe, potentially adversely impacting metabolic control of children with PKU. Findings from this questionnaire suggest that pre-admission school planning, health professional training of school team members, and a carefully written IHCP that is reviewed at least annually are all essential components of successful PKU management within schools.

Although every child has the right to a varied and nutritious menu in school, uptake of school meals by parents/caregivers of children with PKU was considerably lower than the general population. Only 39% of children with PKU compared with 58% to 79% of UK school aged children received school meals [10]; and 50% of parents did not utilize their child's entitlement to free school lunches. Some parents/caregivers preferred to give their children packed lunches because of safety concerns, so they could maintain control over their child's food. Others reported that this allowed their child to retain some anonymity about the condition because a low phenylalanine packed lunch looked like a regular packed lunch. Consequently, this situation further penalizes families with PKU by increasing their workload and expenditure on food when they are already managing a stringent and costly dietary treatment.

Parents reported numerous barriers to school meals provided by school catering services including poor food quality, inadequate variety, requirement for extra parental organization and liaison, and operational systems in meal delivery (children having to ask for their special meal, wearing lanyards, child photographs) that brought unwelcome attention to the child. When external catering services provided school lunches, greater difficulty with food provision was reported. They appeared 'rigid' in their approach using allergy concerns with risks of cross-contamination as reasons for not providing school meals, and refusal to use SLPF's supplied via parents for children with PKU, despite being unprepared to purchase SLPF's themselves due to the extra cost and their own operating procedures. This refusal and failure to provide appropriate low phenylalanine school meals is discriminatory [4]. To help children with PKU who are entitled to free school lunches but unable to utilize them, the government should consider issuing money vouchers to assist with extra food costs.

Around 60% of children with PKU had a written IHCP but it is unknown how this compares with use of IHCPs in other chronic health conditions. There is some data that predates the 2014 education act to suggest that only 50% of children with conditions such as diabetes, epilepsy and asthma had an IHCP [11]. Although IHCP's are not mandatory, they helped improve care provision for children with PKU at school. Children with PKU with an IHCP were more likely to have protein substitute administration supervised, have alternative suitable low phenylalanine meals prepared, receive supervision at snack and school lunch time and receive feedback from the school staff. It was also evident that some parents worked very hard with schools, particularly at school entry to establish good care for their children. Some described setbacks, but clear management strategies with regular review of the IHCP plan helped.

IHCP's should include information about PKU and treatment, including protein substitute (dose, time, administration, storage), snack and meal choices, protein exchanges, and the level of support needed (some secondary school children may be able to take responsibility for their own health needs). It is mandatory that schools ensure that written records are kept of all protein substitute that is administered. If a child is self-managing their protein substitute and low phenylalanine diet within secondary school, this should be clearly stated, with appropriate arrangements for monitoring, documenting who will provide any additional support, and their training needs. There should be a clear pathway with named personnel about how and from whom they can obtain help if issues arise at school. All arrangements should generate confidence for parents and pupils. The Department of Health has also produced IHCP templates which healthcare professionals and schools may find useful [3]. PKU specific templates are also available online from the UK National Society of Phenylketonuria [12].

Inadequate staff training and lack of supervision with food was commonly described by parents/caregivers and carried a considerable safety risk for children with PKU. There were several descriptions of children eating or being offered the wrong foods either accidentally or purposely due to inadequate supervision. Better training is needed to enable staff to fully support children at school and this should include all school staff who provide care for children with PKU. Teaching assistants often have an important role in supervising protein substitutes and snacks but are commonly omitted from professional training sessions. Lunch time supervisors are also overlooked for training, but they are central to ensuring that children receive the correct food at mealtimes. Although the parents of a child will often be key in providing relevant information to school staff, training should be provided by a health professional. In addition, availability of online training resources developed by health professionals will help improve the school team's basic knowledge of PKU. In conditions such as diabetes, it is reported that attitudes of teachers and their lack of understanding impact on their ability to manage the condition [13].

Parents/caregivers described some of the school strategies used that led to better management of PKU. Some schools had helped with the transition from a spoonable/paste to a liquid protein substitute. At lunch time, if children were allowed to have a friend queue and visit food counters with them it was considered more discreet and enabled children to feel less special and more supported. Teachers or teaching assistants sitting in the dining room or at the table with the children helped check the correct foods were consumed. Photographing meals pre and post consumption helped parents understand what foods had been offered and eaten by children. Cashless payment systems in secondary schools enabled parents to go online to see what foods their children had purchased. Procedures to cover any transitional arrangements between primary and secondary schools (or nursery and primary school), were also highlighted as important.

Parents/caregivers commonly described their concerns about social exclusion. Children may be unintentionally excluded because of inadequate inclusive opportunities with suitable food provision. Social exclusion frequently causes psychological harm and can have negative outcomes on emotional and mental health, lowering self-esteem, increasing feelings of anxiety, depression and aggression and may even have a detrimental impact on academic performance [14]. Generally, older children with chronic health conditions are almost three times as likely as healthy peers to suffer social exclusion in school [15], as they are seen as different from their peers [14]. This has previously been reported in PKU [16].

The transition into secondary school is naturally associated with greater independence amongst adolescents. Parents reported difficulties with managing a low phenylalanine diet once their child entered secondary school and it was commonly associated with deteriorating blood phenylalanine control [17,18]. Children were self-conscious about their condition and were fearful about mistreatment by peers if their disability became known; dietary management was effectively sacrificed to avoid bullying and harassment by other pupils in school. They commonly avoided any special food that appeared different from regular foods and refused protein substitute administration at school. There was also limited staff training in secondary school, so less teacher empathy and support for the child with PKU. Commonly the position of secondary schools is that children with disability should develop independency with their care needs, but there is a high measure of responsibility on a child as they enter their journey through secondary school. It is important that schools, parents, and school governors work together to help ensure that the secondary school culture is supportive and inclusive and that it encourages acceptance of children with a range of differences. A lack of sensitivity toward people with disabilities is a problem that requires attitude change and training. The impact of children attending secondary school and its association with declining blood phenylalanine control warrants further investigation.

#### *Limitations*

There are several limitations to this study. This questionnaire was not validated. Data was not collected about individual protein tolerance or about all food provided by school within the day such as breakfast clubs, after school clubs, tuck shops and celebrations in order to ensure that the questionnaire was not too burdensome to complete. The questionnaires were completed at the start of the Covid 19 pandemic, but respondents were asked to document their usual experience at school. Each questionnaire collected information about one child with PKU in a family; it did not refer/collect information about other children in the family with or without PKU. Data was collected based on parents/caregivers' perception of the service or school incidents, so some answers maybe subjective. The respondents were not randomly selected, and participation was voluntary. Additionally, individuals without internet access may have been unable to participate. The survey was promoted on the NSPKU Twitter and Facebook page, meaning participants were more likely to be NSPKU members who may be more proactive and informed about PKU. Therefore, the survey population may not be representative of the entire PKU population although it is estimated that this questionnaire covers around 20% of the children in school with PKU in the UK.

#### **5. Conclusions**

There was disparity in the support given to children with PKU across the UK. They received school meals less commonly than their peers, even when they were entitled to 'free school meals.' Some catering services discriminated against children with PKU by refusing to provide suitable food; some parents distrusted the school meals service. Children were commonly unsupervised with food, leading to the consumption of inappropriate foods. Improved supervision and communication were associated with a written IHCP. We recommend that every child with PKU should have an IHCP, with mandatory training of all staff involved in their care. It is imperative that every child with PKU is supported in school, and their individual dietary and health needs are met safely and discreetly.

**Supplementary Materials:** The following is available online at https://www.mdpi.com/article/10. 3390/nu13113863/s1, Full questionnaire.

**Author Contributions:** Conceptualization, A.M., A.P. and H.J.; methodology, A.M., A.P., S.E., S.F., M.O. and H.J.; formal analysis, M.O.; writing—original draft preparation, A.M.; writing—review and editing, H.J., A.P., S.E., S.F., M.O., S.B., C.A., A.D. and A.M.; supervision, A.M. and A.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Birmingham City University ethics committee prior to commencement of the study (Jones/5042/R(A)/2020/Mar/HELS FAEC—Provision of school food for children with PKU: A parent's perspective. Approved 19/3/2020).

**Informed Consent Statement:**Informed consent was given by all subjects when filling in the questionnaire.

**Data Availability Statement:** The data will be made available from the authors upon reasonable request.

**Acknowledgments:** We would like to acknowledge and thank all the patients and families that have taken their time to fill in this survey.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

1. Newborn Blood Spot Screening Programme in the UK. Data collection and performance analysis report 2016 to 2017. Public Health England leads the NHS Screening Programmes. Available online: https://assets.publishing.service.gov.uk/government/ uploads/system/uploads/attachment\_data/file/709367/Newborn\_blood\_spot\_screening\_data\_collection\_and\_performanc e\_analysis\_report\_2016\_to\_2017.pdf (accessed on 10 August 2021).


## *Article* **Special Low Protein Foods Prescribed in England for PKU Patients: An Analysis of Prescribing Patterns and Cost**

**Georgina Wood 1,\*, Alex Pinto 2, Sharon Evans 2, Anne Daly 2, Sandra Adams 3, Susie Costelloe 4, Joanna Gribben 5, Charlotte Ellerton 6, Anita Emm 7, Sarah Firman 5, Suzanne Ford 8, Moira French 9, Lisa Gaff 10, Emily Giuliano 11, Melanie Hill 12, Inderdip Hunjan 13, Camille Newby 14, Allison Mackenzie 15, Rachel Pereira 16, Celine Prescott 10, Louise Robertson 17, Heidi Seabert 18, Rachel Skeath 19, Simon Tapley 20, Allyson Terry 21, Alison Tooke 22, Karen van Wyk 23, Fiona J. White 23, Lucy White 24, Alison Woodall 25, Júlio César Rocha 26,27,28 and Anita MacDonald <sup>2</sup>**


**Citation:** Wood, G.; Pinto, A.; Evans, S.; Daly, A.; Adams, S.; Costelloe, S.; Gribben, J.; Ellerton, C.; Emm, A.; Firman, S.; et al. Special Low Protein Foods Prescribed in England for PKU Patients: An Analysis of Prescribing Patterns and Cost. *Nutrients* **2021**, *13*, 3977. https://doi.org/10.3390/ nu13113977

Academic Editor: Adamasco Cupisti

Received: 11 October 2021 Accepted: 3 November 2021 Published: 8 November 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal


**Abstract:** Patients with phenylketonuria (PKU) are reliant on special low protein foods (SLPFs) as part of their dietary treatment. In England, several issues regarding the accessibility of SLPFs through the national prescribing system have been highlighted. Therefore, prescribing patterns and expenditure on all SLPFs available on prescription in England (*n* = 142) were examined. Their costs in comparison to regular protein-containing (*n* = 182) and *'free-from'* products (*n* = 135) were also analysed. Similar foods were grouped into subgroups (*n* = 40). The number of units and costs of SLPFs prescribed in total and per subgroup from January to December 2020 were calculated using National Health Service (NHS) Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool) for England. Monthly patient SLPF units prescribed were calculated using patient numbers with PKU and non-PKU inherited metabolic disorders (IMD) consuming SLPFs. This was compared to the National Society for PKU (NSPKU) prescribing guidance. Ninety-eight percent of SLPF subgroups (*n =* 39/40) were more expensive than regular and *'free-from'* food subgroups. However, costs to prescribe SLPFs are significantly less than theoretical calculations. From January to December 2020, 208,932 units of SLPFs were prescribed (excluding milk replacers), costing the NHS £2,151,973 (including milk replacers). This equates to £962 per patient annually, and prescribed amounts are well below the upper limits suggested by the NSPKU, indicating under prescribing of SLPFs. It is recommended that a simpler and improved system should be implemented. Ideally, specialist metabolic dietitians should have responsibility for prescribing SLPFs. This would ensure that patients with PKU have the necessary access to their essential dietary treatment, which, in turn, should help promote dietary adherence and improve metabolic control.

**Keywords:** special low protein foods; phenylketonuria; England; prescribing patterns; costs

#### **1. Introduction**

Phenylketonuria (PKU), an inborn error of amino acid metabolism, is caused by phenylalanine hydroxylase deficiency, an enzyme that converts phenylalanine to tyrosine [1]. This leads to neurotoxicity, causing severe intellectual disability if untreated [2]. It is managed by a life-long phenylalanine-restricted diet supplemented with a phenylalanine free/low phenylalanine protein substitute, although adjunct pharmacological therapies may also be prescribed to some patients [2,3]. In particular, patients with classical PKU require severe restrictions of natural protein, commonly tolerating ≤25% of a normal protein intake [1,2]. Regular protein containing foods e.g., bread, flour and pasta, are replaced with special low protein foods (SLPFs) that contain minimal protein [2,3]. These deliver a substantial source of energy, providing up to 50% of daily energy intake [4–6], fibre [7], they offer essential bulk, add variety and so help to sustain dietary adherence and ultimately aid metabolic control [8–10].

The cost of SLPFs to patients in England is reimbursed by the National Health Service (NHS), as these foods are considered borderline substances and are available on NHS prescription [11–13]. Borderline substances are nutritional or dermatological products specifically formulated to manage a medical condition [12]. There are around 150 SLPFs available on borderline substance prescription in England [13]. Each SLPF is approved by the United Kingdom (UK) Advisory Committee on Borderline Substances (ACBS) [12–14], which considers the clinical need of a product, its efficacy and the total price to the NHS [15]. Manufacturers/suppliers of SLPFs provide the ACBS with a statement outlining the proposed NHS list price and any distribution costs charged to dispensers [15]. For SLPFs that are broadly similar to existing products, the ACBS recommends a maximum benchmark cost to the NHS for that category [15]. When a company chooses to increase their NHS

list price and maintain 'ACBS status', price increases are benchmarked against a standard inflation comparator [15].

General Practitioners (GPs) issue prescriptions for SLPFs monthly on request, which are then dispensed through local pharmacists or specialist home delivery companies linked to the suppliers of SLPFs [16]. The NHS then pays pharmacists or dispensing doctors a fee for each item they dispense [17,18]. The National Society for PKU (NSPKU) has produced a guide outlining the maximum monthly number of units of SLPFs (e.g., 1 unit = 1 pack of pasta up to 500 g—see Appendix A for full list of definitions for each product) which can be prescribed [19,20]. This guide considers patient age and circumstances to support GPs in prescribing these products and to ensure that expenditure on SLPFs is controlled. This guide has been widely adopted by GPs. In England, NHS prescriptions are free of charge for patients in the following categories: under 16 years of age; aged 16–18 years if in full time education; over 60 years of age; pregnant; receive income support or in other specific circumstances [21]. All other patients must pay a set fee per item, or they can purchase a three-monthly or annual prescription prepayment certificate which covers all of their NHS prescriptions [21].

However, there are many challenges in accessing SLPFs with the current prescribing system [16,22]. Some patients with PKU report that they have had their prescription requests refused; some describe how their GPs advise that they should purchase these foods rather than obtain them on prescription [16]. Others report that their GPs refuse to prescribe the appropriate range of products, as they consider some foods luxury items (e.g., cake mix or cereal bars) or the quantity of SLPFs is reduced due to their costs [16]. In a study by MacDonald et al., 2019, 43% (*n =* 25/58) of caregivers and parents said they needed more SLPFs for their children than they had been prescribed [22]. These challenges will impact on nutritional intake, directly affecting nutritional status and ultimately metabolic control.

Although studies have considered the cost of SLPFs, the majority were conducted outside the UK, where different reimbursement systems exist [23–26]. One study compared the theoretical costs in 10 international centres, where costs of SLPFs in the UK appeared to be higher than in many other countries [11]. Two nonpeer reviewed articles also discussed the theoretical cost of SLPFs in the UK and suggested that some SLPFs are expensive, but emphasised they are essential in the management of PKU [27,28]. Several papers have discussed costs when looking at the challenges of living with PKU in the UK, but this has not been the single focus of their work [3,16,22,29,30]. No study has compared the costs of SLPFs with regular foods or foods used in other therapeutic diets. Furthermore, no study has considered the prescribing pattern of SLPFs for low protein diets in England, or the UK as a whole.

This study therefore aimed to:


#### **2. Materials and Methods**

#### *2.1. Cost of SLPFs in England in Comparison to Regular Foods and 'Free-From' Foods*

Data was collected from August to October 2020 on the price of all individual SLPFs available on ACBS prescription in England using British National Formulary (BNF) resources (Website, mobile phone app and book) and from the following suppliers or manufacturers websites if prices were stated:


When individual prices of items were unavailable or unclear, companies were contacted directly via email. The cost per kg of each SLPF was calculated. SLPFs were divided

into 40 subgroups of equivalent food product types, e.g., low protein burgers, sausages, cookies/biscuits, cake mixes. The mean and range costs across subgroups of similar products were calculated.

The mean and range cost per kg were collected and calculated for at least two regular protein-containing comparable foods and at least two '*free-from*' comparable foods, from major supermarkets in England with data available online (ASDA, Morrisons, Sainsburys, Tesco, Waitrose, Ocado and Marks & Spencer). A '*free-from*' food was defined as a food made without one or more specific ingredients, designed for people with food allergies or other intolerances/diseases e.g., coeliac disease. If data was unavailable from a supermarket's website, it was obtained from alternative online shops or directly from the manufacturer. Where prices differed between supermarkets for the same regular protein-containing food or '*free-from*' food, the mean value was recorded. Percentage differences between SLPFs and regular/*'free-from'* food subgroups for all mean costs were determined. Variations within ± 10% were considered comparable.

#### *2.2. NHS Prescribing Patterns for SLPFs and Expenditure in England*

One of the authors (A.P.) was given approval to access and extract prescribing data about SLPFs from the NHS Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool 2) for the costs and quantity of SLPFs prescribed in total and for each subgroup in England. This tool provided access to prescription data from the NHSBSA from January to December 2020. An ePACT2 bespoke training session was arranged with NHSBSA to ensure that all data was obtained and interpreted correctly. NSPKU prescribing guidance describing the definition of one unit for each SLPF was used to calculate the number of units of SLPFs prescribed in total and for each subgroup (Appendix A) [19,20].

In order to estimate the number of patients with PKU cared for by NHS centres in England, all NHS centres known to treat and monitor PKU patients were contacted in order to determine the number of patients with PKU (paediatric and adult), the number on dietary treatment (defined as those receiving prescribed protein substitutes and therefore potentially SLPFs), the number of shared care patients and the number of non-PKU inherited metabolic disorders (IMD) patients accessing SLPFs. Information was supplied by dietitians working in *n =* 26 NHS England hospitals/centres who care for patients with PKU. These data were used to calculate how many units of SLPFs were being prescribed per patient per month and the cost to the NHS per patient per month in England. This was then compared to NSPKU prescribing guidance.

#### **3. Results**

#### *3.1. SLPFs, Regular Foods and Free-From Foods Costing Comparison*

One hundred and forty-six SLPFs were identified as being available on ACBS prescription in England, with these products grouped and further subcategorised for comparison with at least two regular food products per subgroup. Regular and '*free-from*' comparators for four SLPFs (Calogen neutral, Calogen banana, Calogen strawberry and Duocal—Nutricia) were unavailable. Thus, 142 SLPFs were available for comparison with 182 regular products and 135 '*free-from*' products. Table 1 displays all SLPF, regular product and '*free-from*' food subgroups (*n* = 40), the mean cost per kg of products within each subgroup and % differences between costs.

Sixty-eight of 142 SLPFs (48%) were unavailable on BNF resources at the time of data collection (August to October 2020), and therefore, their costs had to be obtained directly from the manufacturer or supplier's website or through email contact with the manufacturer/supplier.

When analysed by subgroup, all SLPFs were more expensive than regular foods and '*free-from*' foods, except for regular eggs and *'free-from'* flavour puddings, where their cost per kg was comparable to low protein equivalents.


**Table 1.** Cost of low protein, regular and *'free-from'* food products for each subgroup and the % differences between costs.


**Table 1.** *Cont.*

Abbreviations: *n* = number of products; SLPFs = special low protein foods. Values displayed as mean (range).

Low protein crispbread crackers, Xpots (low protein equivalent of a pot noodle) and milk replacements (liquid) had the highest percentage cost difference, being 1117% to 1143% more expensive than the regular food comparator. When compared to *'free-from'* foods, low protein flour, bread mix and egg whites had the highest percentage differences (575% to 825%) in costs. In contrast, low protein milk powder, fish substitute and jelly were only 27% to 61% more expensive than their *'free-from'* food comparators. Basic SLPFs, including bread, pasta, rice, noodles and milk replacers (liquid), were 76% to 451% more expensive than '*free-from*' equivalent foods.

#### *3.2. NHS Prescribing and Costing Data in England for SLPFs*

Table 2 displays the prescribing and costing data for SLPFs from January–December 2020.

**Table 2.** Number of units, actual cost of prescribing SLPFs, and percentage of total units and total actual costs of all SLPFs by subgroup from January to December 2020 by the NHS for England.


Abbreviations: *n* = number of products; SLPFs = special low protein foods \* Actual Costs on ePACT2 is calculated as the Net Ingredient Cost of the item(s) supplied, less the National Average Discount Percentage (NADP) plus Payment for Consumables, Out of Pocket Expenses and Payment for Containers. \*\* Data from June 2020–December 2020 only.

> In total, 208,932 units of SLPFs (monthly mean of 17,451 units) were prescribed from January to December 2020. This equated to a total actual cost of £2,151,973 (monthly mean cost of £179,566). The most frequently prescribed subgroups were bread, pasta/rice and flour, in total equating to 54.6% of all SLPFs prescribed. Milk replacers accounted for

the highest percentage (30.5%) of the total actual cost of these products. There is not a definition for a unit of milk replacer, as the amount prescribed should be determined on an individual patient basis (Appendix A) [19,20]. Flour, pasta/rice and bread each accounted for just over 10% of total actual cost of SLPFs from January to December 2020 (11.1%, 13.7% and 10.8%, respectively).

Other expenses included payment for containers, consumables and out of pocket expenses, contributing 4.4% (£94,669) of the annual SLPFs costs to the NHS in England. Out of pocket expenses reimbursed to the pharmacy may include: postage and packaging costs; handling costs; and the cost of phone calls to manufacturers or suppliers to order products [32]. Payment at a rate of 10p for every prescription item is paid for containers where the quantity of a prescription item is ordered outside of the pack size or a multiple of the pack size (except for those granted 'special container status' where it is not practical to split a pack) [33]. An additional payment of 1.24p is made for all prescriptions including SLPFs in case additional consumables may need to be dispensed by the pharmacist (e.g., oral syringes, measuring spoons), although SLPFs usually do not need additional consumables. [33]. Also, a dispensing fee of £1.29 is allocated for each item prescribed [18].

#### *3.3. NHS Patient Prescribing and Costing Data for SLPFs in England Compared to NSPKU Guidelines*

Patients with PKU are the major consumers of SLPFs. It is estimated that there were 2359 patients with PKU in hospital follow-up in England (1436 adult patients, 923 paediatric patients), with *n* = 1814 (77%) on dietary treatment (Table 3). There were a further 422 patients using SLPFs with other inherited metabolic disorders of protein metabolism in England, suggesting that approximately 2236 patients in total were accessing SLPFs. On average, 93 units were prescribed per patient per year, which equates to approximately 8 units per month per patient. This is significantly less than the recommended maximum number of units per patient that could be prescribed each month as outlined by the NSPKU (Table 4). Actual cost data suggest that it costs a monthly mean of £80 per patient.

For the 877 paediatric patients with PKU on full or partial diet, it was estimated that 20% were aged 4 months–3 years (*n* = 175), 20% 4–6 years (*n* = 175), 20% 7–10 years (*n* = 175) and 40% 11–18 years (*n* = 352). Therefore, if all of these children, combined with adults with PKU on a full or partial diet (*n* = 937) were receiving the maximum number of low protein items on prescription each month, as per NSPKU guidance (Table 4), this would equate to 77,575 units each month. This is much higher than the average monthly prescribed units of 17,451 (excluding milk replacers) for the calendar year of 2020.

**Table 3.** Number of patients in England with PKU and/or using SLPFs under the care of an NHS hospital/centre.



**Table 3.** *Cont.*

Abbreviations: SLPFs = special low protein foods; PKU = phenylketonuria; Phe = phenylalanine. ( ) shared care with another unit so numbers not included in totals. \*\*\* This includes patients with mild PKU/hyperphenylalaninaemia who maintain phenylalanine levels within target therapeutic range without dietary treatment.

**Table 4.** NSPKU guideline for recommended amounts of special low protein products per month [19] compared with monthly average per patient estimated in the current study which does not include milk replacers.


Abbreviations: SLPFs = special low protein foods; PKU = phenylketonuria; NSPKU = The National Society for Phenylketonuria.

#### **4. Discussion**

This is the first study to examine the cost of all SLPFs available on prescription in England compared to regular and *'free-from'* foods available in supermarkets. It is also the first study to examine the number and type of low protein items prescribed and expenditure on individual SLPFs and total SLPFs prescribed by the NHS in England over 1 year. There is a lower than expected volume of SLPFs prescribed in England, meaning that the costs to prescribe these products are significantly less than theoretically calculated [11,28], with a total of 17,451 units per month, costing £179,566. This equates to an estimated annual cost to the NHS per person with PKU in England of £962 with just 8 units (excluding low protein milk) prescribed per person per month, indicating that patients are receiving significantly less than the upper NSPKU prescribing guidance [16,19,20].

Over half (54.6%) of the units of SLPFs prescribed from January to December 2020 were basic foods such as bread, flour/mixes and pasta/rice. This accounted for just over one-third (35.6%) of the total annual costs. Just under a third (30.5%) of the costs were attributed to prescribing special low protein milks (liquid). It is likely that it is primarily children accessing SLPFs, as recent research suggested that it is mainly children aged <10 years with PKU who use prescribed special low protein milks [6]. There was previous concern that there may be over prescription of sweet SLPFs [8]. In Scotland, a 2014 survey found that special low protein pasta/rice/couscous, biscuits and flour were most commonly ordered by children, whereas adults with PKU mainly ordered pasta/rice/couscous, flour and bread [8]. In contrast, the amount of special low protein snacks and desserts (*n* = 14/40 subgroups including low protein chocolate, cookies, biscuits, cakes, and crisps) prescribed in England was minimal, with each subgroup only accounting for 0.1–5.9% of all SLPFs prescribed and contributing just 0.1–3.0% of the total NHS expenditure on SLPFs from January to December 2020. This is consistent with research reporting that special low protein cakes, biscuits and chocolate provide minimal contributions to daily energy intake in children with PKU [6]. It is clear that the expenditure on prescribing SLPFs is limited, particularly for sweet foods.

Overall, very little is known about SLPFs usage by adults with PKU in England. Our study suggests that 35% of adults with PKU were not following a phenylalanine restricted diet (Table 3). Although some adult patients may use SLPFs, others may not attempt to access them due to the complexity of the access system or the costs of the prescription fee for every food item ordered, unless the individual is entitled to free prescriptions. In one UK survey, 15% of patients with PKU stated that recurrent access problems with SLPFs was frustrating, and even led them to abandon their dietary treatment [16]. GP administration staff have been described as unhelpful, judgemental or obstructive when ordering SLPFs [8,16]; home delivery services are complex and sometimes unreliable, and SLPFs may arrive out of date or damaged, or of poor quality [16]. Some children with PKU were not on dietary treatment or not accessing SLPFs; this was associated with mild PKU, a higher natural protein tolerance, using sapropterin as an adjunct therapy, young infants not yet on solids or a dislike of SLPFs.

It is understandable that SLPFs cost more than regular and *'free-from'* foods. The demand for SLPFs is small in a limited global market. Few companies manufacture or distribute SLPFs in the UK [13]. Production runs are small scale with high staffing ratios, leading to increased costs. Some of the raw ingredients and packaging materials are purchased in low volumes, increasing productions costs. Packaging may be subject to frequent label changes due to alterations in legislation. Manufacturing wastage may be high if final products do not meet the necessary standards. Manufacturers also need to make some profit to allow them to invest in research and development to improve and expand their SLPF range.

The availability, accessibility and cost of SLPFs vary between countries [5,7,8,11,13,23–25,34]. Comparisons are challenging due to differences in currency, age of patients, degree of dietary adherence and study methodology. China reported a mean cost of \$573 (American dollars or approximately £415) a year per patient for SLPFs [25], whereas the United States

of America found a mean cost of \$1615 (approximately £1171) for children aged 0–17 years for SLPFs and just \$967 (approximately £701) for adults [23]. The Netherlands reported a mean annual cost of €680 (approximately £576) on SLPFs, whereas the Czech Republic found this value to be significantly higher at €1560 (approximately £1321) [24,26].

The overall use of SLPFs is affected by the national access system and any consequential economic burden [11,23–26]. Some countries do not reimburse SLPFs costs; but may be funded by insurance coverage [11,24]. When national reimbursement schemes do not exist, families have to self-finance the purchase of SLPFs [11,23,25,26]. This is a huge financial burden for patients, which influences their ability to adhere to dietary treatment [11,23,25,26].

For patients with PKU to have better access to SLPFs through the NHS, several recommendations should be implemented. Consistent with previous suggestions by MacDonald et al. and Ford et al. [16,22], specialist metabolic dietitians should play a key role in prescribing SLPFs, as they control dietary management and oversee any dietary changes according to the individual patient's metabolic control, nutritional needs, growth and overall nutritional status. This would be more efficient, minimise administration time and professional and patient confusion and enable patients with PKU to have minimal contact with healthcare professionals/prescribers who know very little about their condition and how it is managed. Instead, their SLPF prescriptions would be managed by those who are most equipped to support them in meeting their dietary needs and maintaining good metabolic control.

This study has some limitations. When obtaining the cost of each SLPF in August– October 2020, 68 products were not visible on any BNF resource, and therefore, prices were obtained directly from the manufacturer or supplier of SLPFs. The selection of protein-containing foods and *'free-from'* foods as comparators, and how the products were grouped, was subjective. Certain powdered/dried SLPF products e.g., burger mix, had to be compared to a prepared regular protein-containing or '*free-from*' product e.g., cooked burger; therefore, the cost of the SLPF in its prepared form per kg was estimated. This study only examined products accessible on prescription in England compared with proteincontaining products and *'free-from'* foods available from supermarket websites in England. Also, NHS prescribing and costing data were only available for England and not the whole of the UK, and were only collected from January to December 2020. From March 2020 onwards, England experienced multiple 'lockdowns' due to the coronavirus pandemic, and it is possible that this may have affected food behaviours and, consequently, the number and/or types of SLPFs that patients were requesting on prescription. However, there was no evidence from clinical practice that use or supplies of SLPFs were affected in England.

When calculating the number of units of SLPF and the costs per person with PKU in England, the numbers of patients on dietary treatment were estimated. However, dietetic colleagues throughout England provided representative and recent data from their clinics. It is difficult to state exactly how many patients were requesting SLPFs, as we did not examine individual prescribing data for each patient. On ePACT2, there were nine occasions in 2020 where a SLPF appeared on a prescription, but the quantity prescribed was unclear. Consequently, these data were removed from our spreadsheet. It is possible that there may be under-reporting of SLPFs by the NHSBSA ePACT2. The NHSBSA ePACT2 trainers/help team stated that there was a small possibility that data can be incorrectly processed, but that data is scanned from each prescription form directly, so the NHSBSA ePACT2 should accurately reflect all the prescriptions issued in England.

#### **5. Conclusions**

The annual cost to the NHS in England to prescribe SLPFs is £962 per patient with PKU and non-PKU IMD conditions. Surveys have repeatedly shown that patients or caregivers have access difficulties with current systems. If patients with PKU are expected to adhere to their dietary treatment for life, they must be able to easily access all SLPFs on prescription in a timely manner via the NHS. Given how little is currently being spent on prescribing

SLPFs in England in comparison to the upper NSPKU guidance, cost should not be given as a reason to restrict a patient's access to their essential dietary treatment. A review of how SLPFs are prescribed, supplied and controlled is warranted to improve the system, which, in turn, could lead to increased dietary adherence and improved patient outcomes.

**Author Contributions:** Conceptualization, A.M. (Anita MacDonald) and A.P.; methodology, G.W., A.M. (Anita MacDonald) and A.P.; formal analysis, G.W. and S.E.; investigation, all authors except J.C.R. and A.D.; data curation, G.W., A.P. and S.E.; writing—original draft preparation, G.W.; writing—review and editing, all authors; visualization, G.W., A.P., S.E. and A.M. (Anita MacDonald); supervision, A.M (Anita MacDonald). All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** NHSBSA prescribing data on special low protein foods in England was obtained from ePACT2.

**Acknowledgments:** Thank you to the manufacturers and suppliers of special low protein foods for providing data on their products. Thank you to the NHSBSA for giving A.P. permission to access prescribing data on special low protein foods and providing support and guidance with running our reports on ePACT2.

**Conflicts of Interest:** A.M. (Anita MacDonald) is a member of, the advisory board ELEMENT Danone-Nutricia, the advisory board for Arla and Applied Pharma Research, and received research funding and honoraria from Nutricia, Vitaflo International, Biomarin, MetaHealth, Metax and Merck Serono. S.E. receives research funding from Nutricia, and has received financial support and honoraria from Nutricia and Vitaflo to attend/speak at study days and conferences. A.P. received an educational grant from Cambrooke Therapeutics and grants from Vitaflo International, Nutricia, Merck Serono, Biomarin and Mevalia to attend scientific meetings. A.D. received research funding from Vitaflo International, financial support from Nutricia, Mevalia and Vitaflo International to attend study days and conferences. J.C.R. is a member of the European Nutritionist Expert Panel (Biomarin), the Advisory Board for Applied Pharma Research and Nutricia, and has received honoraria as a speaker from APR, Merck Serono, Biomarin, Nutricia, Vitaflo, Cambrooke, PIAM, and Lifediet. S.F. (Suzanne Ford) is a member of the advisory board for Nutricia, and MetaHealth and has received financial support and honoraria from Cambrooke and Vitaflo. R.S. has received sponsorship to attend conferences and study days, payment to present at conferences from Nutricia Metabolics, Vitaflo Internation and Mevalia. C.E. has received honoraria and educational grants to attend events from Vitaflo, Nutricia, Meta Healthcare and SOBI and is a member of the Advisory Commitee on Borderline Substances. S.F. (Sarah Firman) has received funding to attend conferences and study days from Nutricia, Vitaflo International and Dr. Schär UK Ltd., and consulting fees from Vitaflo International and Meta Healthcare Ltd. C.N. has received financial support and honoraria from Nutricia and Vitaflo to attend/speak at study days and conferences. L.R. is a member of the Nutricia adult advisory board and received honorarium from Nutricia and Vitaflo in the past. F.J.W. receives honoraria, educational and travel grants from Nutricia and Vitaflo. M.H. is a member of advisory board Nutricia Danone and Applied Pharma and has received financial support and honoraria from Nutricia, Vitaflo, Cambrooke, Mevalia, Promin for attendance at conferences/meetings and speakers fee. A.T. (Allyson Terry) has received payment from Vitaflo International for speaking at a patient event. K.vW. receives honoraria and educational grants from Nutricia, Vitaflo and Meta Healthcare. S.T. is expected to receive honoraria from Vitaflo International for providing feedback and reviewing guidelines for PKU Sphere. G.W., M.F., L.G., C.P., S.A., A.M. (Allison Mackenzie), A.T. (Alison Tooke), A.W., E.G., L.W., I.H., H.S., J.G., A.E., S.C., R.P. have no conflicts of interest to declare.

#### **Appendix A**

**Table A1.** Definition of 1 unit for each SLPF (table adapted slightly from NSPKU special low protein foods on prescription document) [20].



**Table A1.** *Cont.*


PK Foods Low Protein Orange Jelly Mix 4 × 80 g 1


**Table A1.** *Cont.*

Abbreviations: SLPFs = special low protein foods; NSPKU = The National Society for Phenylketonuria.

#### **References**


## *Article* **Dietetic Management of Adults with Phenylketonuria (PKU) in the UK: A Care Consensus Document**

**Louise Robertson 1,\*, Sarah Adam 2, Charlotte Ellerton 3, Suzanne Ford 4,5, Melanie Hill 6, Gemma Randles 7, Alison Woodall 8, Carla Young <sup>2</sup> and Anita MacDonald <sup>9</sup>**


**Abstract:** There is an increasing number of adults and elderly patients with phenylketonuria (PKU) who are either early, late treated, or untreated. The principal treatment is a phenylalanine-restricted diet. There is no established UK training for dietitians who work with adults within the specialty of Inherited Metabolic Disorders (IMDs), including PKU. To address this, a group of experienced dietitians specializing in IMDs created a standard operating procedure (SOP) on the dietetic management of adults with PKU to promote equity of care in IMD dietetic services and to support service provision across the UK. The group met virtually over a period of 12 months until they reached 100% consensus on the SOP content. Areas of limited evidence included optimal blood phenylalanine reporting times to patients, protein requirements in older adults, management of weight and obesity, and management of disordered eating and eating disorders. The SOP does not include guidance on maternal PKU management. The SOP can be used as a tool for training dietitians new to the specialty and to raise the standard of education and care for patients with PKU in the UK.

**Keywords:** phenylketonuria; adult phenylketonuria; standard operating procedure; inherited metabolic disorders; dietary management; phenylalanine; protein substitute

#### **1. Introduction**

Phenylketonuria (PKU) is an autosomal recessive disorder of protein metabolism that is caused by a deficiency of phenylalanine hydroxylase, the enzyme which metabolizes the amino acid phenylalanine to tyrosine. The incidence in the UK is 1 in 10,000 [1], with regional variations. Individuals are recommended to follow a lifelong phenylalaninerestricted diet, supplemented with a low-phenylalanine protein substitute [2,3] to protect the brain from the toxic effect of elevated phenylalanine. In the UK, PKU is detected through neonatal screening, which began in 1969.

Neonatal screening and subsequent early diagnosis and initiation of treatment have changed the outcome of PKU [4], enabling the affected individuals to reach their full cognitive and intellectual potential. The healthcare and social-care savings are highly

**Citation:** Robertson, L.; Adam, S.; Ellerton, C.; Ford, S.; Hill, M.; Randles, G.; Woodall, A.; Young, C.; MacDonald, A. Dietetic Management of Adults with Phenylketonuria (PKU) in the UK: A Care Consensus Document. *Nutrients* **2022**, *14*, 576. https://doi.org/10.3390/ nu14030576

Academic Editor: J. Mark Brown

Received: 22 December 2021 Accepted: 21 January 2022 Published: 28 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

significant, as individuals do not need institutional care. Those with late-treated PKU are more likely to require special community care packages [5]. The burden of dietary treatment to individuals and carers cannot be underestimated [6–9].

A range of cognitive sequelae are seen in some patients with PKU [10–12]; however, the impact of current phenylalanine levels compared to historical childhood control is still uncertain [3]. There are variations in reported psychosocial outcomes for adults with PKU and indications that partial adherence to treatment negatively impacts on quality of life [8,10].

Dietitians play an important role in helping patients access and achieve effective treatment for PKU. There are several established metabolic centers across the UK that are dedicated to supporting adults living with an inherited metabolic disorder (IMD), including PKU. The needs of adults living with PKU are considerably different from those of pediatric patients, and these change over time as individuals become older. Research has indicated that transition of patients with PKU to adult services is successful with maintenance of metabolic control and high levels of patient engagement [13,14]. Adult clinics also support up to 23% of patients who are not following dietary treatment [15], usually because they maintain phenylalanine levels within target range without treatment (hyperphenylalaninemia) or the dietary treatment was discontinued in childhood by medical teams prior to life-long treatment recommendations. There are adult patients who recognize the benefits of maintaining lower phenylalanine levels but find it too challenging and impractical to sustain dietary treatment. Maintaining contact with this group of patients is important to monitor clinical outcome; to ensure good overall nutritional status; and to keep them informed of any treatment recommendation changes, new research, and developments. A number of adults with PKU choose (and are supported) to restart dietary treatment after a period of discontinuation in adolescence and/or adulthood [16]. Adults with PKU are a highly heterogeneous patient group in terms of treatment history, which includes late diagnosed and late treated, untreated, early treated who have stopped treatment at different stages in childhood, and early and continuously treated patients. This variability in treatment exposure may be reflected in a spectrum of different cognitive, co-morbidities, and life outcomes in adults with PKU attending metabolic clinics.

Dietitians working in the field of adult IMD have scarce access to formal specialty training. Few rotational or dietetic training posts exist within the UK, and therefore identifying the need for and creating a Standard Operating Procedure (SOP) forms part of the standardization of training and dietetic care for adults with PKU. Within the British Inherited Metabolic Disease Group-dietitians' group, there is a subgroup for adult dietitians. The adult dietitians group meets to specifically discuss dietetic management, develop resources, and arrange adult-focused education and training events to support learning and development within the specialty.

The publication of the first European PKU guidelines in 2017 set out clear standards for care, including for adults with PKU [2,3]. The guidelines explicitly state the need for adult metabolic services that are staffed by healthcare professionals with training in this specialty.

Standard Operating Procedures set out clear guidance about what needs to be achieved to support best practice, ensure transparency, and reduce ambiguity [17]. The aim of this dietetic SOP is to outline the role of the dietetic team in treating adults with PKU. The dietitian is an autonomous practitioner, and this SOP does not replace the dietitian's decision-making about the care of each individual patient, using evidence and his or her clinical judgment [18]. Dietitians have unique skills to counsel regarding dietary care. This document defines the standards of care that should be offered to all adults with PKU attending specialist care in the UK to ensure equity. This was guided by the first publication of the European PKU guidelines [2,3].

#### **2. Materials and Methods**

Eight experienced Dietitians specializing in the care of adults with IMDs in the UK met regularly over 12 months (September 2020–September 2021) to discuss the best practice in PKU care in the UK and to create the SOP. The SOP was based on the European PKU guidelines [3] and clinical expertise. Meetings were held virtually for one hour every 1–2 months, with a total of nine over one year. After each meeting, the draft SOP was emailed to all group members who reviewed and commented on this before the next meeting. All ideas and opinions were discussed at the following meting and adjustments made to SOP after 100% verbal consensus at each stage.

This SOP was based on existing SOPs at individual centers which were reviewed and further developed, and then a 100% consensus gained within the group in the meetings. The core group consisted of experienced IMD dietitians working in England and Scotland, and comments were sought from dietitians working in Wales and Northern Ireland to ensure that the whole of the UK was represented.

Once written, the SOP was reviewed by seven adults with PKU via an anonymous online survey, the British Inherited Metabolic Diseases (BIMDG) dietitians' group, the BIMDG committee, and the National Society for PKU (NSPKU). Feedback was provided and the SOP adapted as required.

The following areas were discussed: (1) glossary, (2) scope, (3) clinical SOP introduction, (4) aims and objectives of the SOP, (5) duties of the adult IMD dietitian, (6) SOP delivery and implementation, and (7) monitoring and assurance. In Appendix A, the section on SOP delivery and implementation examines dietetic assessment and interventions for adults with PKU. These sections include additional adult-specific areas, such as weight management and obesity, eating disorders or disordered eating, and patients who have discontinued dietary treatment.

A separate SOP for maternal PKU will be developed in the future.

#### **3. Results**

The full SOP is given in Appendix A.

This SOP addresses the standards of dietetic care and intervention for adults with PKU. The aspects of care described in the SOP include the following:

	- Protein substitutes.
	- Avoidance of foods high in phenylalanine.
	- Prescribed special low-protein foods, e.g., low-protein bread or pasta.
	- Importance of including naturally low-protein foods, such as fruits and vegetables.
	- Specific considerations for females.
	- Adults not on treatment.
	- Those returning to diet.
	- Late treated PKU starting back on diet.
	- Weight management/obesity.
	- Eating disorders.
	- Blood phenylalanine monitoring.
	- Nutritional blood biochemistry/nutritional status.

Variance from the European guidelines [3] occurred where differences in practice across the centers was evident or barriers existed to implementation of the guidelines. Areas requiring further consideration and research included the timescale of informing patients of their phenylalanine blood results, protein requirements, and the inclusion of the assessment and management of disordered eating and eating disorders.

It was agreed that dietitians should report blood phenylalanine results within three days of receipt from the hospital laboratory. All members of the group shared their experience of managing patients with PKU who described disordered eating behaviors. The SOP therefore includes guidance on the identification of disordered eating and eating disorders, provision of support, and signposting to other services if an overt eating disorder was suspected.

It is recommended that the SOP is reviewed every 3 years or is updated within 6 months if any new evidence or guidance is published that necessitates a change in practice. The authors also recommend that all services should perform an annual audit by using a representative sample of patients, using this SOP as a benchmark.

#### **4. Discussion**

This PKU Adult dietetic SOP is a practical interpretation of the European PKU guidelines [3]. It helps the adult IMD dietitian to translate and further develop the guidance into care in the UK. This document is the first consensus SOP for the dietetic management of an IMD in adults in the UK. Its purpose is to promote care equity for patients with PKU, followed up in IMD dietetic services across the UK and to support service provision. It can be used as a tool for training dietitians new to the specialty.

Patient-centered care is important to build positive dietitian–patient relationships. These relationships enable problem-solving, engagement in care, and earning of patient trust [19]. Working in collaboration with patients and carefully considering their beliefs and values will help guide shared decision-making between the dietitian and the patient [18]. The World Health Organization defines patient-centered care as care that which "meets people's expectations and respects their wishes" [20]. The dietitian can use the SOP as a treatment guide whilst maintaining patient-centered care at the forefront of management.

To provide holistic nutritional care, the SOP examines aspects of care specific to adults with PKU, including protein intake, weight management and obesity, eating disorders or disordered eating, non-dietary treatment, and patients lost to the service and co-morbidities.

#### Calculation of protein requirements

The calculation of protein requirements for adults with PKU was considered (Table 1). There are two components: (1) calculation of total protein requirements and (2) calculation of the dose of protein substitute required (which usually provides 52–80% of the total protein intake for a person with PKU treated with a phenylalanine restriction only [21]). The level and type of physical activity undertaken by individuals when calculating their protein requirements should also be considered.

The European PKU guidelines propose "*providing an additional 20% of L-amino acids to compensate for the 'digestible indispensable amino acid score' and also a further 20% of L-amino acids to optimize their impact on blood Phenylalanine control*" [3]. The incremental factors serve to compensate for the reduced uptake and utilization of amino acids from protein substitutes and offer metabolic benefits from the large neutral amino acid (LNAA) content. The above refers to protein substitutes derived from L-amino acids, and there may be differences in protein utilization with casein-glycomacropeptide (C-GMP) protein substitutes [22].

Minimum protein requirements are commonly derived from "safe levels" of protein intake [23] that are age-specific until the age of 19 years and then remain constant over the adult lifespan. In a recent review paper, Firman et al. [24] suggests that this may not be suitable for older adults with PKU with higher demands for protein associated with ageing. More research is needed to understand optimal protein needs for adults at different life stages and to investigate the body composition of older adults with PKU.

Given the awareness of overweight and obesity amongst adults with PKU [25], it is recommended that protein requirements be based on ideal body weight [3,26]. It is also important to consider patient tolerance of higher doses of protein substitute and the energy balance implications of additional calories supplied at higher prescribed doses of protein substitute.


**Table 1.** Outlining different ways of calculating protein requirements in adults.

Weight management and Obesity

In 1982, White et al. [29] observed an increased likelihood of an increased body mass index (BMI) in children with PKU. Since then, several studies have found the female PKU population (both adults and children) to have increased levels of overweight and obesity in comparison to the general population [25,30,31]. In a recent systematic review, Rodrigues et al. [32] conducted a meta-analysis and found that the BMI of patients with PKU was similar to their healthy controls; however, a subgroup of patients with classical PKU had a significantly higher BMI. The meta-analysis dataset included both adults and children; the age range was between 0.2 and 52 years. The authors also noted a trend towards a higher BMI in females with PKU in all studies with male and female datasets.

Interestingly, it has been noted that LDL cholesterol and other biomarkers of increased cardiovascular risk that may be increased in obesity are not elevated in patients with PKU. In fact, studies have shown biomarkers of cardiovascular risk, including LDL cholesterol, were reduced in healthy participants with PKU [33,34]. It is not currently known if the decreased levels of cardiovascular biomarkers in PKU confers a protective effect against cardiovascular events in the PKU population.

The likelihood of a patient with PKU being overweight or obese does not correlate with choice of protein substitute [35] and may be associated with treatment adherence. Cammatta et al. [31] observed no correlation between treatment adherence and prevalence of obesity in Brazilian patients with PKU. However, in UK patients over 16 years old, high phenylalanine levels were found to correlate with obesity [36]. Cammatta et al. [31] also observed that 94% of patients with PKU were sedentary.

It is important that the need for weight-management advice, including advice around exercise and activity, is considered within the dietetic-assessment process for all patients with PKU. Further work is needed to monitor the incidence of overweight and obesity and identify the underlying causes in all patients with PKU. Referral to specialist weightmanagement services (with appropriate support from the IMD dietitian) may be indicated. Bariatric surgery is also possible for adults with PKU who meet the referral criteria; however, careful consideration is needed for both pre- and post-operative management to ensure that a phenylalanine-restricted diet can be maintained.

#### Disordered eating and eating disorders

Disordered eating and eating disorders occur in adults with PKU. Disordered eating is described as eating behaviors that are lower in severity and intensity than that of an eating disorder. However, both can have an impact of everyday life of the adult with PKU.

The occurrence of eating disorders is recognized in the European Guidelines for PKU [3], but due to the paucity of the literature, they could only recommend that this area required further study. The prevalence of eating disorders self-reported in the PKU patient population is significantly higher than in the general population [37]. Patients with disordered eating are also at a greater risk of developing eating disorders and should have early referral to specialists in psychology and dietetics [20].

Studies also suggest that patients with poor metabolic control are more likely to exhibit symptoms of disordered eating and may be more at risk of developing eating disorders [21,38]. In adolescents and adults with PKU, the occurrence of eating disorders has not been systematically reviewed and is under-reported, so it may not be detected and treated [3].

Disordered eating patterns may be common in patients with PKU without their having an overt eating disorder; regular health-professional support, especially from a psychologist, may provide some measure of protection [3]. Contact with the patient's general physician and signposting to local support agencies may be warranted as appropriate.

Diagnosing an eating disorder in a patient with PKU is challenging. Existing validated tools for eating disorders may not be appropriate for in individuals with PKU, as they often answer questions differently, due to their prescribed dietary treatment. This can produce false positive or low sensitivity at identifying an eating disorder [38]. Another challenge is the treatment of PKU versus the treatment of the eating disorder. The treatment of PKU involves a low-protein diet which restricts foods high in protein. This is at odds with the treatment of eating disorders such as anorexia nervosa, where the aim of treatment is to remove the self-imposed restriction of food. Regarding referral and treatment of an overt eating disorder, appropriate national guidelines [39,40] and/or local policies should be followed.

It is important that IMD dietitians support individuals with PKU diagnosed with an eating disorder and work in close liaison with dietitians specializing in eating disorders and the wider MDT in a shared care approach. The eating-disorders team is unlikely to have any experience in managing PKU.

#### Reporting Blood Phenylalanine Concentrations

The NHS England Specialist Services Quality Dashboard for IMD Services [41] directs laboratories to report results within three days of receipt. The European guidelines [3] advise that the ideal standard for time between blood sampling and receiving results should be no more than five days. Barriers to reporting results within five days of the sample being taken include delays in postal service and samples not being posted/given to the laboratory immediately after the procedure is completed. The Australasian PKU Guidelines do not suggest any specific timeframe but advise that dietitians should report results to patients as soon as possible once received from the laboratory [42]. It is important that blood phenylalanine results are reported promptly so that patients can recall how they managed their PKU in the immediate period prior to the blood test, and timely changes can be advised to maintain metabolic control. The European PKU guidelines also recommend that adults should have their phenylalanine concentrations measured monthly [3]. The current group acknowledged that dietitians can only be responsible for the time between results being reported by laboratories to the patient receiving their results. Therefore, for the purposes of this SOP, a realistic standard for patients receiving their results from the dietitian was agreed at three days from receipt of blood results from the laboratory. The best practice is to report the phenylalanine result as soon as possible, but the group acknowledges that this is not always practical, due to inadequate staffing levels. Three days was agreed on an arbitrary basis and is a pragmatic goal for the timeframe of blood phenylalanine reporting.

#### Non-Dietary Treatments for PKU

Currently there is only one non-dietary adjunct treatment, sapropterin, that has recently been funded by NHS England only for treating adults with PKU. Dietitians will adjust natural protein and protein substitute intake, as well as (potentially) sapropterin dose, for patients who are responsive to this therapy. In Northern Ireland and Wales, sapropterin is routinely available for people with PKU up to the age of 22, and it is hoped that access will be extended to adults. Scottish healthcare has not yet commissioned sapropterin for routine use as a treatment for PKU. Sapropterin management protocols are currently being agreed.

#### Maintaining Patient Engagement and Avoidance of Patients Being "Lost to Follow Up"

Adult patients vary greatly in their neurocognitive abilities, from having profound learning disabilities and high levels of dependence on nursing care for engagement with treatment (associated with late treated PKU) to complete independence with the dietary regimen. Adults with PKU can present with levels of functioning in between these points, with subtler executive function deficits.

Patients' variable neurocognitive abilities or executive function deficits that are associated with their heterogeneous treatment experiences and disorder severity need consideration when organizing adult clinics. Impairment of working memory, planning, cognitive flexibility, and sustained attention [8,10] is likely to impact on consistent clinic attendance.

The European Guidelines recommendation is that all adults with PKU should be under systematic follow-up at specialist metabolic clinics and organization of clinics should support adults' continued engagement [3]. Mechanisms such as reminders to attend just prior to appointments, additional telephone or text messages prompting attendance, and removal of barriers to re-access clinics after missing appointments support better outcomes than systems which discharge patients after a one- or two-time non-attendance. Transition of patients from pediatric to adult clinics is a point in care when patients might be "lost to follow up" for a variety of reasons. Robust transition arrangements will reduce this [21]. Finally, remote clinic appointments using video or telephone calls may support patient attendance if (independent) travel is a barrier to attending adult clinics.

#### Shared Care

Services caring for people with long-term conditions need to consider the holistic needs of patients with co-morbidities, particularly if this affects dietary management. Comorbidities may include diabetes mellitus, cancer, inflammatory bowel disorders, irritable bowel syndrome, and dysphagia (late treated) [43]. Collaboration with other medical teams is necessary to advocate for and support PKU treatment alongside concurrent treatments and management of co-morbidities. Additionally, awareness of the impact of PKU management on concurrent conditions or illnesses is essential to adequately support adults with PKU. Although PKU is not a decompensating metabolic disorder, during any hospital admission, provision of a phenylalanine restricted diet supplemented with a low-phenylalanine protein substitute should be organized and supplied. If there is a requirement for enteral feeding, a modular feed using the protein substitute, a natural protein source, fat and carbohydrate modules, and electrolytes can be designed. IMD dietitians should work collaboratively with services supporting hospital admissions and consider any comorbidities to ensure that the requirements of PKU are considered alongside their treatment.

#### Monitoring and assurance of the SOP

It is important that the SOP is reviewed regularly (every 3 years) to ensure that it remains up to date and informed by clinical practice. If any new evidence or guidance is published which necessitates a change in practice, the SOP will be revised within 6 months of publication. Adult IMD dietitians can use this SOP as a benchmark to audit their service. By providing agreed and defined national guidance for dietetic treatment of PKU in the UK, this SOP will allow all Adult Inherited Metabolic Disorders (AIMD) services to audit provision of care against an agreed national standard. This will also promote consistency of care between services. The SOP will be disseminated via the BIMDG dietitians' group. This provides an exciting opportunity for services to collaborate on a national audit or future research, with the SOP defining agreed outcomes of dietetic care.

#### Limitations

The SOP is based on the consensus opinion drawn from the experience of the authors and their interpretation of a scarce evidence base. As the authors are UK-based dietitians working within the UK National Health Services, there is a primary focus on UK services. Official methodology was not used to reach consensus, but 100% consensus was reached in all aspects of the SOP.

There are minimal outcome data on early and continuous treated adults and late treated adults with PKU. The provision of dietary care within adult IMD services (in the UK) is variable due to lack of funding and limited dietetic staffing, which may prevent the recommendations in the SOP from being incorporated into practice.

This SOP document is for the dietetic care only; it does not include the role of the rest of the IMD team in management of the adult with PKU. As more non-dietary treatments become available and adults are at increased risk of other co-morbidities, e.g., diabetes and metabolic syndrome, then future work on the SOP should include the role of the whole team.

#### **5. Conclusions**

This is the first dietetic SOP for adults with PKU in the UK. The SOP outlines the role of the dietetic team in treating adults with PKU. The SOP and this supporting publication aim to strengthen service provision and achieve equity in the dietetic management of patients in the UK with PKU. The SOP is a consensus based on experience in an area where there is a limited or minimal evidence base to support dietetic management at the present time.

As further non-dietary treatments are expected to become available in the UK, the SOP will be updated to reflect this. Future work is needed, especially in key areas where current evidence is scarce. These include determining protein requirements across the adult lifespan, developing strategies to effectively prevent and manage obesity, and improving the understanding of etiology and optimal treatment approaches with regard to eating disorders. Research focused on adults with PKU remains a high priority to ensure optimal care throughout the lifespan.

**Author Contributions:** Conceptualization, L.R., S.A., C.E., S.F., M.H., G.R., A.W. and C.Y.; funding acquisition, L.R. and S.F.; project administration, L.R.; supervision, A.M.; writing—original draft, L.R., S.A., C.E., S.F., M.H., G.R., A.W. and C.Y.; writing—review and editing, L.R., S.A., C.E., S.F., M.H., G.R., A.W., C.Y. and A.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding. The publication cost was funded by the National Society for Phenylketonuria (NSPKU) and University Hospitals Birmingham Charity.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The development of the PKU SOP was guided by the SOP standards from the Nutrition and Dietetic Department at Guy's and St Thomas' Hospital. We thank all who reviewed the SOP, including Sarah Bailey, Clinical Lead Dietitian, The All Wales Inherited Metabolic Disease Service; Nicola McStravick, Advanced Practitioner Dietitian in IMD, The Royal Hospitals Belfast, Belfast Health and Social Care Trust; Sarah Firman, Specialist Dietitian Guy's & St Thomas' NHS Foundation Trust; British Inherited Metabolic Disorders (BIMDG) dietitians' group, BIMDG committee, National Society for Phenylketonuria (NSPKU) committee; Adults with PKU. The National Society for Phenylketonuria (NSPKU) and University Hospitals Birmingham Charity for funding publication costs.

**Conflicts of Interest:** L.R. is a member of the Nutricia Danone advisory board and received honorarium from Nutricia and Vitaflo. S.A. is a member of the Nutricia Danone Advisory Board and for Meta Healthcare, has received honoraria/speaker's fees from Nutricia and Vitaflo and financial support for attendance at meetings from Nutricia, Vitaflo and Cambrooke. C.E. has received honoraria and educational grants to attend events from Vitaflo, Nutricia, Meta Healthcare and SOBI and is a member of the Advisory Committee on Borderline Substances. S.F. is a member of the advisory board for Nutricia Danone and Meta Healthcare and has received financial support and honoraria from Cambrooke and Vitaflo. M.H. is a member of advisory board Nutricia Danone and Applied Pharma and has received financial support and honoraria from Nutricia, Vitaflo, Cambrooke, Mevalia, and Promin for attendance at conferences/meetings and speaker's fees. A.W. has received speakers fee from Nutricia and honoraria from Travere. C.Y. has received educational grants and financial support for attendance at conferences/meetings from Nutricia.

#### **Appendix A**

SOP for the Dietetic Management of Adults with Phenylketonuria (PKU) in the UK Written by Louise Robertson, Sarah Adam, Charlotte Ellerton, Suzanne Ford, Melanie

Hill, Gemma Randles, Alison Woodall, and Carla Young on December 2021. **Contents**

	- 6.1 Key stakeholders;
	- 6.2 Dietetic assessment and interventions for adults with PKU;
		- 6.2.1 Dietetic Assessment
		- 6.2.2 Interventions
		- 6.2.3 Follow up
		- 6.2.4 Potential outcome measures
		- 6.2.5 Resources

#### **1. Glossary**


#### **2. Scope**


#### **3. Introduction to the clinical SOP**

	- -Standardize the dietetic care of all adult patients with PKU across the UK.
	- - Provide a framework to support the dietitian's decision-making around treatment of patients with PKU.
	- - Assist development and supervision of AIMD dietitians in the UK and ensure that all AIMD dietitians are providing equal standards of care to patients with PKU.

#### **4. Aim and Objectives of this SOP**


#### **5. Duties of the AIMD dietitian**


#### **6. SOP Delivery and Implementation 6.1 Key stakeholders in the SOP**


#### **6.2 Dietetic Assessment and Interventions for Adults with PKU**

Please also refer to Appendix B Pathway for Dietetic Management of Adults with Phenylketonuria (PKU) in the UK.

#### **Aims of dietetic care**


#### **6.2.1 Dietetic Assessment**

#### **For patient on a phenylalanine restricted diet**

	- Total protein intake (including food sources) and distribution over the day; prescribed and actual intake.
	- Quantity and timing of protein substitute, prescribed and actual intake.
	- How much low-protein food is being used and confidence with incorporating low-protein foods in the diet.
	- Menu planning and cooking skills.
	- Home delivery/local dispensing of protein substitutes and low-protein foods.
	- Discussion regarding patient's regulation of protein intake, e.g., if he or she is using phenylalanine exchange system/counting grams of protein.
	- Meal timings.
	- Additional vitamin and mineral, omega 3 supplementation, and history of nutritional deficiencies.
	- Overall dietary adequacy, including assessment of total energy intake.

#### **For patients not on treatment**

• Check identification of the patient and seek consent for assessment.

	- Diet history, including the following:
		- Total protein intake and distribution.
		- Meal timings
		- Any extra nutritional supplementation of vitamins and minerals, trace elements, and omega 3.
		- Overall dietary adequacy.
		- Protein aversion.
	- Patient- and non-patient-related factors affecting treatment management and any specific concerns the patient has relating to his or her PKU.

### **6.2.2 Interventions**

### **Protein substitutes**


#### **Patient switching protein substitute or starting new protein substitute**


#### **Avoidance of food high in phenylalanine**

	- Avoiding high-phenylalanine foods.
	- Suitable natural low-phenylalanine foods.
	- Measuring and counting phenylalanine exchanges.
	- Avoidance of aspartame and discuss suitable phenylalanine-free sweeteners.
	- Appropriate alcohol consumption.
	- Provide sufficient resources to prepare low-phenylalanine meals.
	- Ensure patient understands how to read food labels.

#### **Prescribed low-protein foods**


#### **Females**


#### **Adults not on treatment**


#### **Patients returning to a low-phenylalanine diet**


#### **Late Treated PKU patients starting back on diet**

Determine:


Identify:


#### **Weight Management/Obesity**


#### **Eating Disorders**


#### **Phenylalanine monitoring**


#### **Nutritional biochemical blood tests**

• Discuss with medical consultant if these are required and refer to the European PKU guidelines [3].

#### **Advances in research/developments**

• To inform and discuss any new research, treatments, or guidelines as appropriate.

#### **6.2.3 Follow-up**


#### **Follow-up contact in between clinic appointments**


#### **Guiding patient to access support from other agencies or other Healthcare Professionals (HCP)**


#### **Discharge/transfer arrangements if appropriate**


#### **6.2.4 Potential outcome measures**


#### **6.2.5 Resources**


#### **7. Monitoring and Assurance**

SOP group: The SOP working group will review this document every three years to ensure it remains up to date and informed by clinical guidance and evidence. The SOP was written in December 2021, and the review date will be in December 2024. If any new evidence or guidance is published which requires a change in practice, it will be updated within 6 months of publication. The working group will meet to update this.

Service level: AIMD dietetic services should use this SOP as a benchmark to audit provision of services to patients, to highlight gaps in services, and to identify changes in service provision required to conform to the latest guidelines and requirements and the in development of business cases.

It is recommended that each AIMD dietetic service complete an annual audit on a representative sample of patients on key outcomes outlined in this document (such as frequency of consultations and time take to report blood phenylalanine results) and act on the findings of the audit appropriately.

A suggestion for an audit tool which could be used on a representative sample of the patient group is outlined in Appendix C.

#### **Appendix B**

**Figure A1.** Pathway for Dietetic Management of Adults with Phenylketonuria (PKU) in the UK.

#### **Appendix C**

**Table A1.** Suggested Audit tool for the SOP.


#### **References**


## *Article* **Hungry for Change: The Experiences of People with PKU, and Their Caregivers, When Eating Out**

**Grace Poole 1, Alex Pinto 2, Sharon Evans 2, Suzanne Ford 3,4, Mike O'Driscoll 5, Sharon Buckley 6, Catherine Ashmore 2, Anne Daly <sup>2</sup> and Anita MacDonald 2,\***


**Abstract:** For patients with phenylketonuria (PKU), stringent dietary management is demanding and eating out may pose many challenges. Often, there is little awareness about special dietary requirements within the hospitality sector. This study's aim was to investigate the experiences and behaviours of people with PKU and their caregivers when dining out. We also sought to identify common problems in order to improve their experiences when eating outside the home. Individuals with PKU or their caregivers residing in the UK were invited to complete a cross-sectional online survey that collected both qualitative and quantitative data about their experiences when eating out. Data were available from 254 questionnaire respondents (136 caregivers or patients with PKU < 18 years and 118 patients with PKU ≥ 18 years (*n* = 100) or their caregivers (*n* = 18)). Fifty-eight per cent dined out once per month or less (*n* = 147/254) and the biggest barrier to more frequent dining was 'limited choice of suitable low-protein foods' (90%, *n* = 184/204), followed by 'no information about the protein content of foods' (67%, *n* = 137/204). Sixty-nine per cent (*n* = 176/254) rated their dining experience as less than satisfactory. Respondents ranked restaurant employees' knowledge of the PKU diet as very poor with an overall median rating of 1.6 (on a scale of 1 for extremely poor to 10 for extremely good). Forty-four per cent (*n* = 110/252) of respondents said that restaurants had refused to prepare alternative suitable foods; 44% (*n* = 110/252) were not allowed to eat their own prepared food in a restaurant, and 46% (*n* = 115/252) reported that restaurants had refused to cook special low-protein foods. Forty per cent (*n* = 101/254) of respondents felt anxious before entering restaurants. People with PKU commonly experienced discrimination in restaurants, with hospitality staff failing to support their dietary needs, frequently using allergy laws and concerns about cross-contamination as a reason not to provide suitable food options. It is important that restaurant staff receive training regarding low-protein diets, offer more low-protein options, provide protein analysis information on all menu items, and be more flexible in their approach to cooking low-protein foods supplied by the person with PKU. This may help people with PKU enjoy safe meals when dining out and socialising with others.

**Keywords:** phenylketonuria; eating out; low protein food; restaurants

**Citation:** Poole, G.; Pinto, A.; Evans, S.; Ford, S.; O'Driscoll, M.; Buckley, S.; Ashmore, C.; Daly, A.; MacDonald, A. Hungry for Change: The Experiences of People with PKU, and Their Caregivers, When Eating Out. *Nutrients* **2022**, *14*, 626. https:// doi.org/10.3390/nu14030626

Academic Editor: Jose Lara

Received: 18 December 2021 Accepted: 27 January 2022 Published: 31 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Eating out, defined as eating foods that are prepared by others and consumed out of the home in food establishments such as restaurants, cafes, canteens, and fast-food outlets, is a growing trend. It is a well-established core social activity among people in the UK [1,2]. Eating similar foods is a cue for social connection, providing an avenue for people to communicate and relate to each other and many people prefer to gather to share a meal rather than eat alone [3,4]. People with phenylketonuria (PKU), an inherited metabolic disorder, characterised by the inability to hydrolyse the amino acid phenylalanine, are treated with a low-phenylalanine and aspartame-free diet. Whilst this dietary treatment is critical to avoid neurological damage, it is complex, with the natural protein intake of patients with classical PKU being decreased to as low as 20% of regular intake when prescribed dietary treatment only. Eating outside the home may be uncomfortable for people with PKU as they must constantly navigate social situations in which they are unable to eat what others eat, with most of the regular meal items being excluded.

There is an expectation in society that people can eat out at any time, any place, anywhere. Food and drinks are at the heart of consumer culture, increasing the pressure and desire on people with PKU to eat outside the home. According to the Kantar Worldpanel survey, in 2018, 98% of people in the UK reported eating or drinking 'out', with overall UK expenditure on food and drink reaching £49 billion a year [5]. Also in 2018, in an English survey of 2241 people aged 16 years and over, 68% had eaten in a restaurant in the last month, while 41% had eaten in a pub, bar or nightclub. Restaurants, takeaway food and cafes or coffee shops were the most popular options for eating out in the UK [6]. The Office for National Statistics (ONS) (2019) estimated that a UK household spent on average £38.80/week on food prepared out of the home, including £18.60 on restaurants and cafés. In a Food Standards Survey (2018), 85% of respondents ate out for dinner, 70% for lunch and 38% for breakfast; this was more common among young people (aged 16–34 years) and men tended to eat out more than women for breakfast, lunch and dinner.

Eating out in restaurants presents many challenges for individuals with PKU. Menu choices in restaurants usually do not state what ingredients are added to dishes or give their protein content, leaving a person with PKU the difficult choice of non-participation or choosing inappropriate foods, intensifying dietary adherence issues that may lead to poor metabolic control. They may lack self-confidence skills to seek the necessary help to secure appropriate food choices. Although there is legislation (The Food Information Regulations 2014 ("FIR") [7] and The Food Information (Amendment) (England) Regulations 2019) [8] requiring all operators to disclose food allergens, there is no mandatory catering training for special dietary provision. Evidence suggests that there are significant knowledge gaps regarding special diets among the employees of the UK hospitality industry [9–11]. The workforce in restaurants often consists of young employees, some of whom are undertaking their first job, and there may be high employee turnover with low engagement. When training is initiated, it is usually for new employees and there may be infrequent training updates [10].

Therefore, it is important to explore factors that contribute towards experiences of people with PKU when eating out. This will help to characterise the main issues encountered, any social impacts and the effect on their ability to follow their dietary treatment. Thus, this study was designed to investigate the experiences of patients with PKU, and their caregivers, in eating establishments. The aim was to identify common problems of eating out in order to improve their dining experiences in the future.

#### **2. Materials and Methods**

#### *2.1. Methods*

This was a cross-sectional study using an online survey that collected both qualitative and quantitative data from adults with PKU and caregivers of children and adults. Respondents were excluded if they did not reside in the UK.

The questionnaire was built in the Online Surveys platform (https://www.onlinesurveys. ac.uk, accessed on the 2 November 2020) to gather quantitative data. This was placed on the UK National Society for Phenylketonuria (NSPKU) website, with additional promotion on the NSPKU Twitter, Instagram and Facebook pages. The questionnaire was open for 7 months, from April until October 2020.

#### *2.2. Questionnaire*

The non-validated questionnaire contained 20 questions (Table S1). Eight questions were multiple choice, *n* = 8 multiple responses, *n* = 2 Likert scale and *n* = 2 open ended questions. Thirteen questions invited additional comments.

The questionnaire was developed by dietitians with expert practical and scientific knowledge of PKU (AP, SE, CA, AD, AM), a colleague from the NSPKU (SF), a researcher (MO) and a student dietitian from Birmingham City University (GP). It was reviewed by colleagues and lay people to ensure its readability and then amended according to feedback.

#### *2.3. Data Collected*

The questionnaire was divided into three sections, collecting information on patient age, frequency of eating out, factors that prevented the individual from eating out, impact of low protein diet, factors that affected the choice of restaurant, and influences that affected meal choice in restaurants. Information on the perception of knowledge about a low-protein diet by restaurant staff, descriptions, and characteristics of good restaurants for patients with PKU, and opinion of restaurant chains was also requested. All data collected were based on the patients/caregiver's experiences when eating out.

#### *2.4. Statistics*

Quantitative data analysis (inferential and descriptive statistics) was carried out with the Statistical Package for the Social Sciences (SPSS) version 25 (SPSS Inc., Chicago, IL, USA). For multiple response questions, only descriptive statistics were used (inferential statistics are not normally used with such questions). For testing differences between two categorical variables, chi square was used. Statistical significance was set at *p* < 0.05.

Qualitative data analyses of open-ended responses were carried out in NVIVO version 12 PRO (QSR International Pty Ltd.). The whole survey dataset was imported into NVIVO so that the coding of open-ended responses could be broken down by survey questions. All open-ended questions responses were analysed thematically.

#### *2.5. Ethics*

Ethical approval was obtained from the Birmingham City University ethics committee prior to commencement of the study (Poole/6128/R(A)/2020/Mar/HELS FAEC: What knowledge and attitudes do restaurateurs have about provision of the phenylketonuria (PKU) diet?/What are the experiences of people with PKU, and their caregivers, when eating out in restaurants or cafes?). At the beginning of the online questionnaire, respondents gave consent, and it was emphasised that the questionnaire completion was voluntary. Potential respondents were advised that data from the survey may be published in an anonymized form. If names or hospitals were mentioned in verbatim abstracts these were removed from results presented in this manuscript.

#### **3. Results**

Data were available from 254 participants (whole or partial completions of the questionnaire). The number of respondents for each question varied, as not all respondents answered all questions. Fifty-four per cent (*n* = 136/254) of responses were related to people with PKU under 18 years of age. Forty-six per cent (*n* = 118/254) of responses were from people aged ≥18 years of age 100 adults with PKU and 18 caregivers of adults with PKU aged ≥18 years.

#### *3.1. Frequency of Dining Out*

Most respondents of the questionnaire dined out only once per month or less (*n* = 147/254; 58%). Eighteen per cent (*n* = 46/254) reported doing so 'once per week', 18% (*n* = 45/254) said they did so 'once per fortnight', and 6% (*n* = 15/254) did so '2–3 times per week.' Furthermore, most participants (*n* = 204; 80%) expressed the desire to dine out more often; and reported factors which prevent this (Table 1). The biggest barrier overall was 'limited choice of suitable low protein foods' (90%, *n* = 184/204) followed by 'no information about the protein content of foods' (67%, *n* = 137/204). More adults with PKU (*n* = 27, 30%) said they 'Have no choice but to eat foods that are not permitted in the PKU diet' compared to the responses of children's caregivers (*n* = 12, 10%). More caregivers of children compared with adults with PKU described issues such as 'restaurants refusing to prepare low protein foods they provided' e.g., pasta (41%, *n* = 47 children vs. 33%, *n* = 29 adults); 'feeling hungry after eating out due to limited food choice' (34%, *n* = 39 children vs. 24%, *n* = 21 adults); and 'no information about the protein content of foods (72%, *n* = 83 children vs. 60%, *n* = 53).

**Table 1.** Factors that prevent people with phenylketonuria (PKU) from eating out (*n* = 204) \*.


\* Multiple response question.

Twenty-two responses answered "other". Several responses indicated that the cost of dining out was higher or of poor value for people with PKU e.g., 'often it ends up costing quite a lot of money for what is actually eaten'. They said there was more wasted food, or they provided low-protein ingredients for the restaurant to cook without a price reduction or they had to pay more than they received if sharing the bill with people who do not have PKU. Other issues identified by respondents included: 'if no information is provided about the food's protein content, I tend to go over my daily allowance and suffer migraines and I do not feel 100% the next day;' and 'I will not ask for low-protein food to be cooked, as too many people are within earshot. Usually, staff taking orders are very young'.

#### *3.2. Choice of Restaurant*

Eighty-nine per cent (*n* = 227/254) said the choice of restaurant was influenced by the need to follow a low-protein diet for the person with PKU. Factors that influenced the choice of restaurant are given in Table 2. Parents of children < 18 years of age were more likely to choose a restaurant if 'catering staff were happy to cook with low-protein foods', (46%, *n* = 63 vs. 34%, *n* = 40 of those aged ≥18 years). Parents of children < 18 years of age were less likely than adults with PKU to say 'Like to socialise with friends/family regardless of food choice' (*n* = 30, 22% vs. adults *n* = 50, 42%), and 'good choice of low protein foods on the menu' (parents of children aged <18 years: *n* = 93, 68% vs. adults: *n* = 93, 79%).

**Table 2.** Factors that influence the choice of restaurant/café when the person with PKU is eating out (*n* = 254) \*.


\* Multiple response question.

Respondents added 17 verbatim comments describing factors that influenced their restaurant choice. These included: 'My daughter goes to places she's tried before just so she has the information she needs about protein content in food'; 'she will always Google the menu to see if there is anything on the menu, if nothing available she will make an excuse to her friends to decline going'. Other comments included: 'there are limited places to go and even then, the same food is eaten every time'; and 'the majority of restaurants will not cook food I supply for my 5-year-old daughter so we can't go very far'.

#### *3.3. Practices When Eating Out*

Seventy-four per cent (*n* = 188/254) of respondents said that they ordered from the menu and chose something that may be suitable for PKU. Respondents for children under 18 years of age were more likely than adults with PKU to bring in some low protein food from home and ask the restaurant/cafe to cook it or to prepare an alternative meal (Table 3). Differences by age were statistically significant (*p* < 0.001). There were 20 other comments about food choices when eating out which included: 'we usually feed our child with PKU before going out and then choose either chips or olives in the restaurant'; 'I call ahead to

discuss suitable food choices'; and 'I do a combination of ordering low-protein options, taking low-protein bread with me, sometimes pasta too'.


**Table 3.** What people with PKU normally do when eating out divided by age of respondents (*n* = 254).

#### *3.4. Views on Restaurant Brands*

Respondents rated a series of popular chain restaurants regarding the suitability of meal choices and the customer services they received to help them with their dietary needs. The scale ran from 'very poor' to 'very good.' The results are summarised in Table 4. Only one restaurant scored more than 50% of ratings as good or very good (Hungry Horse, 53%, *n* = 82/154). Many high street chain restaurants had less than 25% of users saying they were good or very good at helping provide suitable food or supporting patients with PKU.

**Table 4.** Percentage of UK restaurant chains scored by adult patients or parents/caregivers of children with PKU scoring "good or very good" for their provision of low protein foods.


#### *3.5. Overall Satisfaction When Eating Out*

The overall dining experience was unsatisfactory for most respondents. The median overall satisfaction rating was 4 (*n* = 254) (on a scale of 1 for extremely poor to 10 for extremely good). Sixty-nine per cent (*n* = 176/254) of respondents rated overall satisfaction as 5 or less.

#### *3.6. Rating of Restaurant/Café Employee Staff Knowledge about Phenylketonuria (PKU)*

Knowledge of PKU and dietary management was rated as very poor by respondents with an overall median rating of 1.6 from 254 responses (on a scale of 1 for extremely poor to 10 for extremely good). There were 100 free text comments to this question from which the themes given in Table 5 were derived.

**Table 5.** Open-ended responses to the questionnaire rating restaurant/café employee staff knowledge about PKU.


Verbatim comments are presented in italic.

#### *3.7. Helpfulness of Restaurants/Cafes in Finding a Solution to Cater for PKU*

Sixty-three per cent (*n* = 159/254) of respondents said that they had at least one positive experience when dining out, particularly at local/ independent restaurants and non-chain restaurants ('after repeated visits, they went out of their way to cater for PKU') and it was considered particularly helpful when restaurants provided a full list of ingredients with their protein content. However, only one third of respondents (33%, *n* = 83/254) considered that restaurants/cafes were always or often helpful, 39% (*n* = 100/254) felt that they were 'sometimes' helpful, and 21% (*n* = 54/254) thought that they were rarely or never helpful.

Forty-four per cent (*n* = 110/252) of respondents said that they had experienced restaurants refusing to prepare alternative foods; 44% (*n* = 110/252) said that they had not been allowed to eat their own prepared food in a restaurant; and 46% (*n* = 115/252) said that a restaurant had refused to cook low-protein pasta, burger mix or pizzas. The lack of low-protein food choices and inflexibility was considered unhelpful.

#### *3.8. Changes That Would Encourage People with PKU to Dine Out*

Seventy-nine per cent (*n* = 200/254) of respondents said changes would help improve their experience dining outside the home but 21% (*n* = 54/254) said changes would not help. There were 200 free text responses. The main themes are shown below and illustrated through a selection of verbatim quotes in Table 6.

**Table 6.** Open ended responses to the questionnaire describing the changes that would help people with PKU dine out.




Verbatim comments are presented in italic.

*3.9. Emotions around Dining Out*

Respondents' feelings and emotions before dining out are presented in Table 7.

**Table 7.** Emotions of adults with PKU/caregivers of children before dining out (n = 254) from multiple response question.


When leaving a restaurant/café, only 35% (*n* = 88/254) of respondents said they were satisfied, with only 31% (*n* = 79/252) saying they were happy. Twenty-eight per cent (*n* = 71/254) left disappointed, 26% (*n* = 66/254) frustrated and 22% (*n* = 57/254) were still hungry. Adults with PKU (*n* = 43/118, 36%) were more than twice as likely to feel frustrated post-meal than caregivers of children under the age of 18 years (*n* = 23/136, 17%).

#### **4. Discussion**

This research is the first to purposefully investigate the eating out experiences, behaviours and concerns of people with PKU or their caregivers. Although eating out is a routine activity enjoyed by the general population, people with PKU chose not to do this regularly. While it is expected that people dining outside the home should derive social and psychological enjoyment [12], with satisfaction of appetite, and respite from low-protein meal preparation, our results suggest that people with PKU or their caregivers were unable to enjoy stress-free and spontaneous meals. In fact, 40% said eating out was associated with anxiety, only 9% derived any pleasure from it, with over one quarter of survey participants leaving restaurants feeling frustrated, disappointed, and still hungry.

Individuals with PKU or their caregivers were eager to find restaurants that were willing to accommodate their dietary needs. Personalisation of menu choices with unlimited access to vegetables was considered almost mandatory for people with PKU. They commonly favoured familiar, non-chain/independent eating out venues that they had visited previously, with a proven track-record of preparing appropriate low-protein foods. Most preferred restaurants who cooked with fresh ingredients onsite rather than those who used pre-assembled meals that could not be modified. Some used eating establishments that had 'build-your-own options' (e.g., brands such as Subway or salad bars) allowing for more customization. Many found food-chain restaurants inflexible scoring disappointingly when rated by people with PKU or their caregivers. Restaurants often used pre-prepared foods, with some vegetable options being coated in wheat flour. Although vegan meal choices are now common in restaurants, they are usually high in protein.

Overall, incompatibility of menu choice with low-protein diets, inadequate food choice, uncertainty about the protein content of meals, and limited suitable drink options were all concerns of people with PKU or their caregivers. Consumers with PKU need transparency around meal ingredients, protein content and food portion size. Some restaurants only sell aspartame-containing soft drinks to avoid extra costs associated with sugar taxes. There was frustration that some restaurants would not agree to cook or even allow people with PKU to eat their own special low-protein foods e.g., low-protein bread, pasta and pizza bases prescribed by their general practitioner on their premises, even though the restaurant staff were unable to supply these foods themselves. Although some restaurants could offer gluten-free equivalents, these foods were often too high in protein for most people with PKU.

Written information about the protein content of food provided on a website that could be studied in advance of a restaurant booking was considered helpful as it enabled the person with PKU or parents/caregivers to assess the suitability of food choices without the need for conversations with restaurant staff. Although most restaurants post their menus online, not all give their nutritional content and food portion sizes may differ if unweighted. Some fast-food chains post online the protein content of meals, but this information may be difficult to locate and given in small print tables. It was requested that restaurant food nutritional analysis and portion sizes should also be available by mobile app, with written reviews about special diet provision. There are currently no mandatory labelling requirements for any unpackaged products sold by catering businesses to state the protein content or list all the ingredients (except allergens, some additives and aspartame) [13]. The UK Government plans to introduce a new menu-labelling requirements law, which will enforce major foodservice operators to include a calorie count on the food items of both their digital and physical menus by April 2022, but it does not specify other nutrients or require provision of a full list of ingredients [14].

The results of this survey indicated that some people with PKU were reluctant to eat outside the home and experienced a spike in anxiety when visiting a restaurant because they anticipate it will not be a pleasurable experience. In another study on PKU, families reported avoiding eating out in restaurants, to prevent children from feeling excluded [15]. In our study, there was commonly social embarrassment, discomfort, and much sensitivity in the behaviours associated with social eating. The respondents experienced food worries about how others perceive them based on what they eat. To avoid causing others (e.g., staff or social companions) inconvenience, some respondents deliberately downplayed or did not mention their low-protein dietary requirements in conversations and opted for food options that were lower in protein and safe such as a baked potato, potato chips or a side salad. If they asked for alternative food choices, they felt that they were making unreasonable and excessive demands on staff. Some even felt they were being difficult when asking restaurant staff about the ingredients added to foods and the protein content of dishes. Others feared that the food venue would refuse to serve them after they had explained their dietary needs. Generally, people with PKU did not like drawing extra attention to their dietary needs within restaurants and any public discussions about their condition were commonly unwelcome.

The quality of the relationship or interaction that people with PKU or their parents/caregivers experience with food venues is important. They should be able to comfortably communicate with restaurant staff regarding their dietary needs. However, many perceive themselves as being made to feel as though they were a 'fussy customer' or a 'nuisance' so it constrained any conversation about food risks associated with incorrect food choices being served. Restaurant staff rarely proactively ask customers about special dietary needs, therefore leaving consumers to initiate any communication with staff regarding their requirements [16,17]. If the restaurant team genuinely listened to the dietary issues through taking the time to speak to the person and paying attention to what they said, the customer would be more forthcoming to discuss their dietary needs. This could lead to a willingness to modify food choices on a 'plate' in order to accommodate consumers' needs and discretion whilst still holding conversations regarding dietary requirements. These actions are signs of extra care and respect. Commonly the waiter/waitress fail to understand the requests for low-protein food as there is no/low awareness of PKU, and people with PKU say 'it is sometimes like talking to a brick wall'. The lack of knowledge leads to a customer perception of poor-quality provision. People with PKU might be more candid with staff whom they consider caring and trustworthy. The readiness of food establishments to adapt the dishes whilst respecting consumers' food preferences and desire to try out different foods was also highly valued by patients with foods allergies [18,19].

A large proportion of the hospitality industry possess no or a very limited knowledge of special diets and may be unable to respond adequately to low-protein requests and this was clear from the results of the survey. However, ignorance of special diets by those people involved in delivering special dietary menus is not a defense for failing to meet the customer's needs and expectations. Any current mandatory training predominantly focuses on food safety and technical preparation skills only, with an absence of education on special dietary requirements [20]. There should be mandatory special diet training for all employees who work in catering establishments. Special diet training has been shown to be effective. A short training programme on allergies was found to increase the knowledge and awareness of employees from all restaurants in one UK town as well as encouraging more information to be available for customers [21]. Furthermore, a survey that included 861 restaurant staff and members of the general public, found high levels of awareness of allergies and coeliac disease among trained chefs, in comparison to the general public and untrained staff, demonstrating the effectiveness of training [22].

#### *Limitations*

Recruitment of participants for this online survey was via the NSPKU website and promoted on PKU social media sites, so respondents were limited to any individuals who had access to the internet using the appropriate technology. It is likely that respondents were people who accessed social media sites frequently, were not randomly selected, and the extent to which the sample matched the demographic characteristics of the general PKU population is unknown. However, the sample size was large, so this factor is likely to have had minimal impact on the overall results. In addition, caregivers acted as proxy respondents on behalf of children and described what they perceived to be their child's feelings when eating out, so their answers may have been inaccurate. We did not distinguish between male and female respondents. Also, the number of respondents to scaled questions varied which may added errors to the results. Additionally, the questionnaire was nonvalidated, and the respondent's level of understanding was unknown. Protein tolerance was not reported, and this may have influenced the respondents dining experiences.

Furthermore, research to compare dining out experiences of patients with PKU and those with other conditions requiring dietary management may be useful to give additional insight into this practical issue.

#### **5. Conclusions**

In summary, there is a considerable lack of awareness and inability to successfully meet the needs of people with PKU on low-protein diets in restaurants and catering establishments in the UK. Reputation, revenue and customer relationships may be jeopardized if hospitality businesses do not meet the dietary needs of their customers. There is a need to better understand the knowledge and practices of restaurant and food-service establishment personnel toward the management of special diets in order to improve consumer experiences when eating out. Changes to staff training, flexibility to adapt menus, provision of more low-protein options, and a change in the law to enforce better availability of nutritional information in restaurants should be implemented. It is necessary to improve the experience of people with PKU and end the barriers they continually face in trying to enjoy a basic human social activity (dining out together) that most people can take for granted.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/nu14030626/s1, Table S1: Full Questionnaire.

**Author Contributions:** Conceptualization, A.M., A.P. and G.P.; methodology, A.M., A.P., S.E., S.F., M.O., S.B. and G.P.; formal analysis, M.O.; writing original draft preparation, A.M.; writing, review and editing, G.P., A.P., S.E., S.F., M.O., S.B., C.A., A.D., S.B. and A.M.; supervision, A.M. and A.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Birmingham City University ethics committee prior to commencement of the study (Poole/6128/R(A)/2020/Mar/HELS FAEC: What knowledge and attitudes do restaurateurs have about provision of the phenylketonuria (PKU) diet?; and What are the experiences of people with PKU, and their caregivers, when eating out in restaurants or cafes?).

**Informed Consent Statement:** Informed consent was given by all subjects when filling inthe questionnaire.

**Data Availability Statement:** The data will be made available from the authors upon reasonable request.

**Acknowledgments:** We would like to acknowledge and thank all the patients and families that have taken their time to fill in this survey.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


### *Review* **Glycomacropeptide in PKU—Does It Live Up to Its Potential?**

**Anne Daly \*, Alex Pinto, Sharon Evans and Anita MacDonald**

Birmingham Women's and Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham B4 6NH, UK; alex.pinto@nhs.net (A.P.); evanss21@me.com (S.E.); anita.macdonald@nhs.net (A.M.) **\*** Correspondence: a.daly3@nhs.net

**Abstract:** The use of casein glycomacropeptide (CGMP) as a protein substitute in phenylketonuria (PKU) has grown in popularity. CGMP is derived from κ casein and is a sialic-rich glycophosphopeptide, formed by the action of chymosin during the production of cheese. It comprises 20–25% of total protein in whey products and has key biomodulatory properties. In PKU, the amino acid sequence of CGMP has been adapted by adding the amino acids histidine, leucine, methionine, tyrosine and tryptophan naturally low in CGMP. The use of CGMP compared to mono amino acids (L-AAs) as a protein substitute in the treatment of PKU promises several potential clinical benefits, although any advantage is supported only by evidence from non-PKU conditions or PKU animal models. This review examines if there is sufficient evidence to support the bioactive properties of CGMP leading to physiological benefits when compared to L-AAs in PKU, with a focus on blood phenylalanine control and stability, body composition, growth, bone density, breath odour and palatability.

**Keywords:** glycomacropeptide; PKU; protein substitute; amino acids

#### **1. Introduction**

It is estimated there are 0.45 million people worldwide with the inherited metabolic disorder phenylketonuria (PKU) [1], which causes irreversible neurological damage if untreated. Although pharmaceutical therapies are being actively developed, a phenylalanine restricted diet remains the only effective treatment. In classical PKU, protein substitutes (low phenylalanine protein replacements) provide up to 80% of dietary protein requirements and are essential to ensure metabolic stability and growth. Protein substitutes are derived from either phenylalanine free amino acids (L-AAs) or a combination of low phenylalanine peptides with added amino acids (casein glycomacropeptide: CGMP). They are usually supplemented with vitamins, minerals and trace elements, and may contain essential and/or long chain fatty acids and prebiotics. In 1953, the first protein substitute was made using a low phenylalanine hydrolysed casein [2,3]; subsequently, the number and type of manufactured preparations have exponentially increased [4]. In 2008, CGMP, a by-product of whey from the manufacture of cheese, was introduced as an alternative protein substitute to L-AAs, but it is still unclear if this protein source has any advantage over conventional L-AAs in the dietary management of PKU. Overall, their composition, bioavailability and long term impact on metabolic efficacy has received limited systematic investigation in PKU.

This review examines the evidence of using the bioactive protein substitute CGMP compared to L-AAs in the treatment of PKU, focusing on benefits to blood phenylalanine stability, body composition, bone mass, density and geometry and the influence of protein substitutes on breath malodour and palatability.

#### **2. Protein Substitutes Pharmacological Benefits**

Protein substitutes meet the protein requirement for cellular function and growth and have several pharmacological and physiological functions (Table 1). They improve phenylalanine tolerance and optimise metabolic control by suppressing blood phenylalanine

**Citation:** Daly, A.; Pinto, A.; Evans, S.; MacDonald, A. Glycomacropeptide in PKU—Does It Live Up to Its Potential?. *Nutrients* **2022**, *14*, 807. https://doi.org/ 10.3390/nu14040807

Academic Editors: Shanon L. Casperson and Adamasco Cupisti

Received: 31 December 2021 Accepted: 7 February 2022 Published: 14 February 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

concentrations. This is particularly important during illness and trauma, where protein substitutes have a protective role by counteracting protein catabolism [5–8]. Irrespective of their nitrogen source, each protein substitute has a different amino acid profile consisting of essential and non-essential amino acids, and around 40% large neutral amino acids (LNAAs). They provide the principal source of tyrosine, although there is no consensus on the optimal amount required [9]. Similarly, there is no agreement on the quantity and ratio of branched chain amino acids, and there is also limited data about the absorption and retention of amino acids [10–13].

**Table 1.** Functional properties of protein substitutes in PKU.


#### **3. The Role of Functional Amino Acids in Protein Substitutes**

Amino acids in protein substitutes have several nutritional, biochemical and physiological roles linked to growth, health and disease prevention [22,25]. Functional amino acids (essential or non-essential) regulate key metabolic pathways. They provide nitrogen, hydrocarbon skeletons and sulphur [26]; both nitrogen and sulphur are unable to be synthesised de novo. Some roles of functional amino acids include regulation of body composition and bone health, others include modulating bacterial flora, glucose homeostasis and inflammatory responses. Amino acids are also involved in cell signalling (including mammalian target of rapamycin complex 1 (mTORC1), and the interaction and generation of small peptides, glucagon-like peptide 1 (GLP-1), peptide-YY (PYY), serotonin and insulin. Insulin plays a key regulatory role in amino acid metabolism, and amino acids alter insulin action by regulating glucose and protein metabolism [27,28]. The composition of a protein substitute affects the rate at which amino acids are delivered into the systemic system, changing their cellular uptake and biological utilisation. Different rates of absorption have been reported when amino acids are ingested as free amino acids, peptides or bound to proteins [13,26,29]. Free amino acids appear in the peripheral plasma more quickly than

those from an intact protein source [10]. Any protein substitute that can maximise amino acid absorption will increase anabolism and subsequently alter phenylalanine metabolism.

#### **4. What Is a Casein Glycomacropeptide (CGMP)?**

In 1954 while working on a variant of *lactobacillus bifidus*, György et al. [30] found evidence of protein bound sialic acid (N acetylneuraminic acid) in cow's milk. In 1965, Delfour et al. [31] established that this milk bound sialic acid protein was called κ casein and reported that CGMP was formed by separation of κ casein by the action of chymosin during cheese production. CGMP is found in the soluble whey elute [32] and constitutes 20–25% of total proteins in whey products manufactured from cheese whey. It is a 64 amino acid phosphoglycoprotein [33]. Five oligosaccharides (glycans) have been identified as part of the glycomacropeptide structure [32].

In its pure form, the glycophosphopeptide has an unusual amino acid sequence containing no aromatic amino acids (tryptophan, tyrosine, phenylalanine) or the sulphur amino acid cysteine [34]. Of the five glycan structures common to bovine CGMP, the one of most interest is the nine-carbon sugar molecule, sialic acid, which forms 7–9% of CGMP. This is a component of human milk oligosaccharides and neural tissues and is an integral part of brain gangliosides and glycoproteins. The glycan chains are attached via two types of glycosylation: *N*-linked when the glycan chain is attached to the amide side chain of the asparagine residue, and *O*-linked when the glycan is attached to the oxygen of a serine or threonine residue [35,36]. Around 60% of CGMP is glycosylated [37] with exclusively *O*-linking glycans. There is evidence to suggest glycosylation is a controlled hierarchical process that influences the associated biological activities of CGMP [38,39]. These bioactive properties provide a functional ingredient for the food and pharmaceutical industry.

#### **5. Potential Clinical Properties of CGMP**

Carbohydrates, whether free or bound to proteins or lipids, are essential communication molecules in inter and intracellular processes. The biological properties associated with CGMP include immunomodulatory, antimicrobial and prebiotic [32,35,40]. CGMP interacts with cholera toxins through the glycan chains [41,42], and bind to *E. coli* and *Salmonella enteritidis* [43]. It also has an important role in anticariogenesis; CGMP inhibits adherence of oral bacteria, preventing tooth decay [44,45]. In animal experiments, a CGMP enriched infant formula increased learning ability, which was linked to an increase in sialioprotein in the frontal brain cortex [46]. These findings need further investigation.

#### **6. Potential Commercial Use of CGMP**

CGMP is an acidic peptide, highly soluble and heat stable [35]. It also has a wide pH range and solubility, and has emulsifying, gel and foaming properties, making it desirable in the food and nutritional products industry as it alters the structural matrix of foods and improves the texture and mouth feel.

#### **7. Adaptation of CGMP for Use as a Low Phenylalanine Protein Substitute in PKU**

Isolating CGMP from cheese whey is difficult and expensive, with residual phenylalanine remaining in the final product [32]. CGMP has inadequate amounts of five indispensable amino acids: histidine, leucine, methionine, tryptophan, and tyrosine, but supplementation with these amino acids enables it to be used as an alternative to L-AAs [47].

The first case study using CGMP [47] was reported in a 29-year-old male with PKU. Over 15 weeks, CGMP and L-AA protein substitutes were compared. CGMP was supplemented with histidine, leucine and tryptophan providing 130% and tyrosine at 150% of the USA 2002 recommendation [48]. Added vitamins, minerals and trace elements were supplemented when taking CGMP. An additional 500 mg of tyrosine was taken orally twice daily, providing the same tyrosine intake as that from L-AAs. Significant increases in plasma glutamine, isoleucine, proline and threonine, with an overall increase in the LNAAs and a 16% increase in the BCAAs were noted. CGMP is naturally higher in threonine and isoleucine, explaining the observed increases. In a subsequent study in 2009, van Calcar et al. [49] compared the effects of L-AAs and CGMP in 11 subjects with PKU over 8 days. The CGMP product was supplemented with histidine, leucine, methionine and tryptophan, but the additional supplement of 1000 mg/day of tyrosine was omitted. This led to a mean fasting tyrosine concentration below the normal reference range in the CGMP group, with an expected increase in isoleucine and threonine consistent with the higher concentration in CGMP. After an overnight fast, plasma blood concentration of arginine, a conditionally essential amino acid, was significantly lower. The limiting amino acids added to the CGMP, histidine, leucine methionine and tryptophan, remained within the normal biochemical reference ranges, but tyrosine and arginine concentrations required further supplementation. Methionine supplementation was stopped as there was an adequate amount in the CGMP to meet the new lower requirements as suggested by Humayun et al. [50].

#### **8. The Impact of CGMP on Blood Phenylalanine Control in PKU**

Ten published studies have investigated the effect of CGMP compared to L-AAs on blood phenylalanine control. The majority (*n* = 7/10, 70%) have suggested no significant alteration in blood phenylalanine concentrations despite residual phenylalanine being present in CGMP [49,51–54]. Nine of ten studies reported higher blood phenylalanine concentrations when using CGMP, but only three studies demonstrated a statistically significant increase. All three studies were in children from one centre, but this included two long term longitudinal studies over 6 and 12 months [55,56], and one randomised controlled study over 6 weeks [57]. Four other studies collected data mainly in adults for a minimal period of 8 to 21 days, with suboptimal blood phenylalanine concentration at study baseline; some subjects were taking adjunctive sapropterin treatment that improved phenylalanine tolerance. Two studies were retrospective reviews in 11 teenagers and adults, with follow up at 20 and 29 months [58,59]. One study [54] examined CGMP as a food (GMP soft cheese) supplement in children; it was consumed 3 times daily over 9 weeks. No information was provided on its residual phenylalanine content or amino acid profile. The supplement was provided in combination with L-AAs and provided 50% of the total protein substitute intake.

It is difficult to interpret the effectiveness of results from short-term studies. One of the earliest studies [49] suggested that the residual phenylalanine in the CGMP was too high at 0.4 g/100 g of product. This was only given to three subjects, all with high phenylalanine tolerance. In the remaining nine subjects, the CGMP composition was refined, with a phenylalanine content of 0.2 g/100 g of product. A statistically significant increase in blood phenylalanine was only evident in the longitudinal studies in children, with blood phenylalanine being maintained within a narrow therapeutic target range of 120 to 360 μmol/L. This suggests caution is necessary when using CGMP that contains residual phenylalanine, particularly in children with classical PKU. Table 2 lists the PKU studies using CGMP and their outcomes. The impact of residual phenylalanine may be less important in patients using adjunct drug management that improves phenylalanine tolerance or in teenagers and adults who maintain blood phenylalanine levels under a higher upper therapeutic target. Further studies are needed in adults and in pregnancy when CGMP is the only protein substitute source.



Legend: PKU phenylketonuria; L-AA, amino acid protein substitute; CGMP, caseinglycomacropeptide; PS, protein substitute; ns, not significant; HPA, hyperphenylalaninemia; F, female; M, male; y, years; m, months; vs, versus.

#### **9. Kinetic Properties of Protein Substitutes**

There is evidence from animal studies that protein substitutes engineered to slowly release amino acids have improved physiological functions, but proving this remains a challenge in PKU [61]. The speed of absorption of dietary amino acids by the gut varies according to the type of ingested dietary protein. Whey protein is established as a 'fast' protein and casein as a 'slow' protein, the latter provides greater nitrogen retention and whole-body protein anabolism [62,63]. L-AAs are incapable of replicating the physiological actions of whole protein being directly absorbed from the small intestine [22]. Amino acids from L-AAs are rapidly absorbed, peak but then fall rapidly compared to amino acids slowly released from whole protein, and this influences their utilization [12,64,65]. Herrmann et al. [66] demonstrated that ingestion of large doses of L-AAs increased amino

acid oxidation and nitrogen excretion, decreasing their availability for cellular functioning. For effective protein synthesis, all essential amino acids must be available to the tissues in appropriate amounts simultaneously [29]. There is circumstantial evidence to suggest that CGMP lowers the rate of amino acid absorption and improves nitrogen retention. Van Calcar et al. studied 11 subjects with PKU over 4 days and reported lower blood phenylalanine after an overnight fast using CGMP compared to L-AAs, implying a slower release of amino acids in CGMP. Two-hour post prandial blood urea nitrogen concentrations were lower, and insulin concentrations were marginally but significantly higher in the CGMP group, suggesting lower nitrogen excretion and improved amino acid utilisation. Any protein substitute that will imitate the physiological absorption of whole protein will theoretically improve growth, body composition and bone density, and may possibly influence inflammatory responses and appetite.

There are no kinetic studies reviewing the action of L-AAs versus CGMP on blood urea nitrogen, insulin or amino acid absorption. Until studies are reported, it cannot be concluded that CGMP improves amino acid utilisation. However, CGMP does influence phenylalanine and tyrosine variability over a 24-h period. In a randomised controlled crossover study [57], children with PKU were randomised to three groups taking CGMP or L-AAs as a protein substitute: group R1 (no dietary adjustment with CGMP), group R2 (dietary adjustment with phenylalanine from CGMP deducted from the dietary phenylalanine allowance) and group R3 (no dietary adjustment with L-AAs). Each arm of the study was for 14 days, and on the last 2 days, subjects had 4-hourly day and night blood spots measuring blood phenylalanine and tyrosine. All median phenylalanine concentrations were within recommended target ranges, there was a significant difference in median phenylalanine at each time point between R1 and R2 (*p* = 0.0027) and R1 and R3 (*p* < 0.0001), but no differences between R2 and R3. Tyrosine was significantly higher in the CGMP groups. This work shows two main findings: the residual phenylalanine given in R1 increased blood phenylalanine concentrations (in this group, 18% had phenylalanine concentrations greater than the target reference range compared to none in the R3 group), and secondly, CGMP appears to give less blood phenylalanine variability when compared to L-AAs. Any mechanism that permits a constant delivery of amino acids would allow a steady state of protein synthesis, improving body protein balance and skeletal muscle protein synthesis.

In a preliminary investigation [67] to review if CGMP compared to L-AAs altered pre and post prandial amino acid profiles in children with PKU, quantitative amino acids were measured after an overnight fast and 2 h post prandially after consuming breakfast and 20 g protein equivalent from the allocated protein substitute. CGMP was provided as CGMP1, in which the amino acid profile met WHO recommendations, or CGMP2, which had higher concentrations of histidine, tyrosine, tryptophan and valine. Forty-three children, median age 9 years (range 5–16 years) were studied; 11 took CGMP1, 18 CGMP2 and 14 L-AAs. The results showed, regardless of the protein substitute source, there was a significant increase in post prandial amino acids. In CGMP2, post prandial histidine (*p* < 0.001), leucine (*p* < 0.001) and tyrosine (*p* < 0.001) were higher than in CGMP1 (reflecting the additional amounts in this formulation), and leucine (*p* < 0.001), threonine (*p* < 0.001) and tyrosine (*p* = 0.003) were higher in CGMP2 than in L-AAs, reflecting the amino acid composition of the three different protein substitute formulations. There is a suggestion that CGMP does alter amino acid absorption, leading to a greater stability of phenylalanine over 24 h, but controlled kinetic studies are necessary.

#### **10. The Impact of CGMP on Growth and Body Composition in Children with PKU**

In PKU, the impact of using a phenylalanine-restricted diet on physical growth was first reported in the late 1970s, and despite improvements in dietary treatment, contradictory findings on growth outcome are reported [68–71]. Early studies [72] demonstrated that children had improved growth if they were prescribed a protein equivalent from protein substitute that exceeded the WHO/FAO/UNU 1973 [73] safe levels of protein

intake. Smith et al. [74] showed that even if amino acids are efficiently absorbed from the intestinal tract, there is a higher loss of nitrogen as urea when compared to natural protein. McBurnie et al. and Holm et al. [75,76] assessed height, weight and head circumference in two prospective collaborative studies, evaluating 133 and 124 children with PKU over 8 and 4 years, respectively. In both studies, weight and height increased similarly to that of control groups.

In contrast, three European studies [77–79] found children with PKU had reduced height growth when compared to control subjects. Protein substitute intake was not always reported, but typical total protein intake only provided safe recommended intakes [73]. It is possible that phenylalanine deficiency may have occurred but was not described. Dhondt et al. [77] reported normal height and weight were achieved after dietary relaxation at 8 years of age. Schaefer et al. [78] reported negative weight and height in the first 2 years with catch up by 3 years of age. A recent systematic and meta-analysis examining growth in subjects with PKU [70] reported normal growth at birth and during infancy, but children were significantly shorter and had lower weight for age compared with reference populations during the first four years of life. Linear growth was reduced until the end of adolescence. These findings were not identified in patients with mild hyperphenylalaninemia on no dietary restrictions.

Overall, optimal growth was noted in studies where total protein intake (a combined protein intake from natural protein and protein substitute) was higher [80–83]. Nitrogen balance is regulated by urea production [63,84], which is produced linearly in response to plasma amino acid concentrations. Ney et al. and Calcar et al. [49,85] suggested that CGMP may induce a slower and more sustained release of amino acids, leading to decreased urea and greater availability of amino acids for protein synthesis, possibly leading to improved growth.

In PKU, it is important to monitor lean and fat mass, but there are no long-term prospective studies or systematic/meta-analyses describing body composition in PKU. Of eleven studies reported in children (Table 3), any comparison is challenging due to an absence of national reference standards, different body composition techniques, variable pubertal status and different PKU phenotypes. Of six controlled studies, compared with healthy controls, four showed no statistically significant differences in body composition. One study demonstrated a correlation with increased blood phenylalanine concentrations and higher fat mass in male subjects with PKU only [86]. Albersen et al. [87] showed body fat was significantly higher in subjects with PKU, and higher in females >11 years. Longterm associated comorbidities such as type II diabetes and cardiometabolic diseases may be linked to altered body composition, with evidence suggesting an association between abdominal obesity, increased insulin resistance and cardiovascular disease. Therefore, the composition of a protein substitute needs careful formulation as this may alter body composition and possibly long-term health outcomes [88–90].

**Table 3.** Studies measuring body composition in children with PKU.





Legend: Sapropterin, drug treatment for PKU; BMI, body mass index; PKU, Phenylketonuria; L-AA, amino acid protein substitute; CGMP, caseinglycomacropeptide protein substitute; PS, protein substitute; ns, not significant; F, female; M, male; HPA, hyperphenylalaninemia; y, years

To date, only two studies have examined the role of CGMP compared to L-AAs on body composition and growth in PKU: one three-year prospective study [99] in children, and a retrospective review in adults by Pena et al. in 2021. In the three-year study, *n* = 19 children (median age 11 years; range 5–15 years) took L-AAs only, *n* = 16 (median age 7.3 years; range 5–15 years) took a combination of CGMP and L-AAs (CGMP50), and *n* = 13 (median age 9.2 years; range 5–16 years) took CGMP only (CGMP100). A dualenergy X-ray absorptiometry (DXA) scan at enrolment and 36 months measured lean body mass (LBM), % body fat (%BF) and fat mass (FM). Height was measured at enrolment, 12, 24 and 36 months. No correlation or statistically significant differences (after adjusting for age, gender, puberty and phenylalanine blood concentrations) were found between the three groups. The change in height z-scores (L-AAs 0, CGMP50 +0.4 and CGMP100 +0.7) showed a trend that children in the CGMP100 group were taller, had improved LBM with decreased FM and %BF, although this did not reach statistical significance. We can only speculate about this suggested trend shown in the CGMP100 group. One possibility is that the branched-chain amino acids leucine and isoleucine (the latter is naturally higher in CGMP) modulate protein turnover, as both are potent modulators of insulin and glucose metabolism [100]. If insulin sensitivity is enhanced, it is possible that growth could be improved. Further long term studies are needed to confirm these findings.

#### **11. Impact of CGMP Compared to L-AAs on Bone Mass, Density and Geometry in Children with PKU**

Bone mass is maintained by a complex and dynamic process involving resorption of bone by the osteoclast and formation of bone by the osteoblast. In children, this is a dynamic continuous process of modelling and remodelling [101]. Peak bone mass, which programmes the future risk of osteoporosis, is established in childhood and adolescence [102,103]. Factors that influence bone mass include genetics, lean mass, adiposity, adipocytokines, physical activity and nutrition. The relationship between fat and bone is contentious. Evidence [103] suggests that in early childhood, obesity confers a structural advantage, but with age this relationship is reversed, and excessive fat is detrimental. Clark et al. [104] in 3082 healthy children, reported a positive relationship between adiposity and bone mass accrual. Others have reported conflicting findings [105,106]. Lean body mass is the strongest significant predictor of bone mineral content [107,108] and relates to bone mass and skeletal development in children.

Dietary protein promotes peripubertal bone growth and slows bone loss [109]. Protein is necessary for optimal bone metabolism during growth, positively influencing bone mass, density and strength [109–111]. In children and adults with PKU, bone density is inconsistently reported [112–118]. Four systematic and three meta-analysis studies report mixed results. Enns et al. reported nine suboptimal bone health outcomes. The scope of this review was on general health problems in PKU, and therefore it failed to interpret the results on bone health in depth. Hansen et al. described a lower spine bone mineral density, but this review had methodological errors and assessment bias. Demirdas et al. [119] reported bone mineral density (BMD) was within the normal range; although it was lower than normal, it was not clinically significant. There was no correlation with phenylalanine concentrations, vitamin D, parathyroid hormone and individual nutrients. De Castro et al. [120] supported the findings from Demirdas et al., showing BMD was lower than that of the reference groups but within the normal range. They also demonstrated an imbalance between bone formation and resorption, favouring bone removal.

Solverson et al. [121] studied the effect of three different diets on bone strength in mice with or without PKU. They were given a low-protein diet with (a) CGMP, (b) L-AAs or (c) a normal (casein) diet. The PKU mice fed either CGMP or L-AAs had a lower BMD compared with non-PKU mice. In PKU mice fed the L-AAs, the femur length independent of gender was significantly shorter compared to that of the PKU mice given CGMP or a normal diet. Skeletal fragility (brittle and weak femora) was a consistent finding in the PKU mice regardless of gender or diet. The reduction of BMD and bone mineral content (BMC) of the femora measured by DXA was more pronounced in the mice receiving L-AAs compared to those receiving CGMP. This group concluded that the type of protein influenced bone outcome in mice, with CGMP giving better results compared to L-AAs. However, careful consideration is needed to determine the impact of CGMP or L-AAs on bone growth. In humans, bone growth is a slow, multifaceted process affected by hormonal patterns, gender, obesity, dietary intake and physical activity.

Only one three-year longitudinal study [122] in children with PKU has compared the impact of CGMP and L-AAs on bone mass, density and geometry (comparing the same group of children who participated in the body composition study previously described). Measurements were taken by DXA and peripheral quantitative computer tomography (pQCT), in addition to blood biochemistry and bone turnover markers. No statistical significance was evident between the three study groups (L-AAs, CGMP50 or CGMP100). In all three groups, there was a strong positive correlation between bone resorption and formation markers: type 1 collagen cross-linked C telopeptide (β CTX) and procollagen type 1 terminal propeptide (P1NP), and there was evidence of an increased PINP in the CGMP100 group independent of age compared to the L-AA group (*p* = 0.04). The synergy between bone formation and resorption shows active bone turnover and reflects appropriate bone growth since these markers are derived from physiological processes. Bone density was clinically normal, although the median z-scores were below the population mean and

agreed with the findings of systematic reviews by Demirdis et al. and de Castro et al. Bone remodelling processes appeared active in children with PKU taking either L-AAs or CGMP, but it was unknown why the median z-scores were below the population norm.

#### **12. Does Glycomacropeptide Improve Palatability of Protein Substitutes?**

A potential advantage of using a peptide-based protein substitute is the altered taste profile. L-AAs are generally bitter tasting, and both children and adults dislike the aftertaste they leave post consumption [123]. In a blind sensory study, Lim et al. 2007 evaluated the acceptability of CGMP compared to L-AAs and found CGMP was rated favourable for odour and taste. This improved taste profile has been observed by other researchers [49,51,52,54,55,59,124]. Pena et al. [53] highlighted the lack of uniformity in the methods used to evaluate palatability, with some studies evaluating food and others liquid based CGMP protein substitutes. The improved taste profile may improve concordance with a lifelong rigorous diet.

#### **13. Impact of CGMP on Breath Malodour in Children with PKU**

In clinical practice, caregivers of children with PKU report their children have breath malodour, particularly after protein substitute consumption. This may increase non adherence by lowering self-esteem and affect interpersonal communication, leading to social isolation. No study has quantitatively measured breath odour in children with PKU. In a randomised, crossover study using gas chromatography ion mobility spectrometry (GS-IMS), exhaled volatile organic compounds were measured in children taking CGMP or L-AAs over the course of 10 h [123]

Forty children (20 PKU; 20 healthy non-PKU controls) were recruited; the children with PKU took either L-AAs or CGMP exclusively for one week in a randomised order. On the seventh day, seven exhaled breath samples were collected over a 10-h period. Subjects than transferred to the alternative protein substitute for a week, and the breath sampling process was repeated. In the PKU group, the aim was to collect breath samples 30 min after consuming their protein substitute; this happened in all but three cases, when breath samples were collected 5 min after protein substitute consumption. In all three groups (L-AAs, CGMP and controls), fasting breath samples contained similar numbers of volatile organic compounds (VOCs) (10–12). Similarly, post prandial samples showed no significant differences in the number of exhaled VOCs (12–18) between L-AAs/CGMP and controls, or between L-AAs and CGMP. A different breath signature occurred in the three subjects who had breath measurements 5 min post completing their protein substitute. In this subset, a higher number of VOCs (25–30) were detected; however, these were no longer detectable at 30 min post consumption. This study demonstrated that protein substitutes have a transient effect on exhaled breath, and after 30 min post consumption, VOCs in children with PKU were no different to those of controls. Timing food and drink with protein substitute consumption may potentially reduce or eliminate the immediate unpleasant protein substitute breath odour.

#### **14. Summary**

In PKU, evidence suggests that the use of a bioactive CGMP protein substitute does not show any overwhelming benefit compared to L-AAs on post prandial amino acid absorption, body composition, bone mineral density or breath odour. It is clear that CGMP increases blood phenylalanine concentrations, particularly in children with a low phenylalanine tolerance. However, there is a trend that children taking CGMP as their sole source of protein substitute are taller, with improved lean body mass and decreased fat mass. Overall, the residual phenylalanine content in CGMP appears to be a limitation, particularly for those with minimal or no phenylalanine hydroxylase activity. The full clinical potential of CGMP in PKU has not yet been determined, and its role in gut microbiota and potential brain development awaits further investigation.

**Author Contributions:** Conceptualization, A.D. and A.M.; investigation, A.D.; supervision, A.M. writing—original draft, A.D.; writing—review and editing, A.D., A.P., S.E. and A.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** No funding has been provided.

**Data Availability Statement:** Data available at the request of the corresponding author.

**Conflicts of Interest:** A.D., research funding from Vitaflo International, financial support from Nutricia, Mevalia and Vitaflo International to attend study days and conferences. S.E., research funding from Nutricia, financial support from Nutricia and Vitaflo International to attend study days and conferences. A.P. has received an educational grant from Cambrooke Therapeutics and grants from Vitaflo International, Nutricia, Merck Serono, Biomarin and Mevalia to attend scientific meetings. A.M. received research funding and honoraria from Nutricia, Vitaflo International and Merck Serono, and is a member of the European Nutrition Expert Panel (Merck Serono International), the Sapropterin Advisory Board (Merck Seronointernational) and the Advisory Board Element (Danone-Nutricia).

#### **References**

