*Case Report* **Characterization of Speech and Language Phenotype in GLUT1DS**

**Martina Paola Zanaboni 1,†, Ludovica Pasca 1,2,\* ,†, Barbara Valeria Villa <sup>1</sup> , Antonella Faggio <sup>1</sup> , Serena Grumi <sup>1</sup> , Livio Provenzi <sup>1</sup> , Costanza Varesio 1,2,† and Valentina De Giorgis 1,†**


**Abstract:** Background: To analyze the oral motor, speech and language phenotype in a sample of pediatric patients with GLUT 1 transporter deficiency syndrome (GLUT1DS). Methods: eight Italianspeaking children with GLUT1DS (aged 4.6–15.4 years) in stable treatment with ketogenic diet from a variable time underwent a specific and standardized speech and language assessment battery. Results: All patients showed deficits with different degrees of impairment in multiple speech and language areas. In particular, orofacial praxis, parallel and total movements were the most impaired in the oromotor domain; in the speech domain patients obtained a poor performance in the diadochokinesis rate and in the repetition of words that resulted as severely deficient in seven out of eight patients; in the language domain the most affected abilities were semantic/phonological fluency and receptive grammar. Conclusions: GLUT1DS is associated to different levels of speech and language impairment, which should guide diagnostic and therapeutic intervention. Larger population data are needed to identify more precisely a speech and language profile in GLUT1DS patients.

**Keywords:** GLUT 1 transporter deficiency syndrome (GLUT1DS); language; speech; oral motor; dysarthria

### **1. Introduction**

GLUT 1 transporter deficiency syndrome (GLUT1DS) is a rare, treatable, metabolic encephalopathy due to mutations in SLC2A1 gene [1], which causes a non-functional glucose uptake by GLUT1 transporter, primarily expressed in endothelial cells forming the blood-brain barrier and in astrocytes [2]. Ketogenic dietary therapies (KDTs) are recognized as the gold standard treatment for GLUT1DS since they provide alternative fuel, namely ketone bodies, for brain energy metabolism [2]. Symptoms develop in age-specific pattern [2] and the classical disease phenotype includes a wide range of movement disorders, drugresistant epilepsy, neurodevelopmental impairment, and acquired microcephaly. Moreover, ataxia, dystonia, dysarthria, persistent tremor, spasticity are typical findings at neurological examination. Milder and atypical phenotypic variants are continuously reported and GLUT1DS phenotypic spectrum is progressively expanding. KDTs introduction, especially when occurring early in life, could lead to improvement of certain symptoms, as often occurs with epileptic manifestations, intellectual and social adaptive skills [3], whereas its beneficial effects on movement disorders are less evident [2].

Intellectual disability (ID) is a usual finding in GLUT1DS patients, ranging from severe to mild; only a minority of affected patients shows normal intelligence quotient (IQ) [4]. Genotype-phenotype correlation has not been clearly defined so far. Some reports described a milder phenotype or later disease onset in patients with missense mutations or

**Citation:** Zanaboni, M.P.; Pasca, L.; Villa, B.V.; Faggio, A.; Grumi, S.; Provenzi, L.; Varesio, C.; De Giorgis, V. Characterization of Speech and Language Phenotype in GLUT1DS. *Children* **2021**, *8*, 344. https:// doi.org/10.3390/children8050344

Academic Editor: Eva Aguilar Mediavilla

Received: 25 March 2021 Accepted: 23 April 2021 Published: 27 April 2021

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higher cerebrospinal fluid (CSF)/blood glucose ratio [5]. The existence of a proportional relationship between ID and disease severity is debated: there have been reports both supporting and disproving this relation [6–8]. De Giorgis et al. defined a typical cognitive phenotype of GLUT1DS [4], evaluating the neuropsychological profile of 25 patients before and after KDTs introduction. The typical phenotype observed was characterized by a performance IQ more affected than verbal IQ (VIQ), together with greater difficulties in visuospatial and visuomotor skills. In the same study, a significant direct correlation between IQ (total IQ (TIQ) and VIQ) and CSF/blood glucose ratio values was observed.

Speech and language functions in patients with GLUT1DS are the least documented in literature and, to the best of our knowledge, they have only been assessed in the context of broad neuropsychological batteries [5,6,9,10] and have not been deeply characterized yet. To date, the presence of different degrees of speech and language impairments, with varying degrees of motor incoordination, have been described as common features in children and adults with GLUT1DS [2]. In particular, Hully and colleagues [6] reported language delay with dysarthric speech in almost 80% of GLUT1DS patients. In the study by Ramm-Pettersen et al. [10], an improvement of those aspects was recorded after KDTs introduction: the caregivers of six patients reported progress concerning general alertness, expressive language, articulation, and physical endurance in the wake of the dietary treatment. The sooner the KDTs is introduced, the greater is its potential of changing the disease course [2].

The phenotypic variability and the different response to KDTs therapy according to introduction timing should be read considering that glucose utilization in the brain increases threefold from infancy to 3 years of age [11] and thus, for patients with GLUT1DS, that period represents a critical frame if left untreated. Moreover, the neuroconstructivism approach underlies the bidirectional interactions between human biology and social environment, the development itself might be seen as playing a crucial role in shaping phenotypical outcomes [12].

We believe that recognition of a typical speech and language profile might be crucial for disease assessment and targeted rehabilitation.

For this purpose, the present study aimed to characterize in detail language development and to analyze the oral-motor, speech and language phenotype in a pediatric population of patients with GLUT1DS, through the use of standardized tests.

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

### *2.1. Participants*

This was a mono-center study. Among 25 patients with established clinical and genetic diagnosis of GLUT1DS of all ages treated with KDTs and regularly followed at our clinic [4], we included eight monolingual Italian-speaking patients (four females and four males), aged 4.6–15.4 years (median age 10; standard deviation (SD) 3.79; range 4.6–15.4 years).

For each patient, information such as sociodemographic and clinical variables were collected (child's pre-peri and post-natal clinically events, developmental history, presence of otitis' history or auditory impairment, previous diagnosis other than GLUT1DS, time of GLUT1DS diagnosis, CSF/blood glucose ratio, SLC2A1 mutation, family history of GLUT1DS, family history of epilepsy, epilepsy history, presence of movement disorder, KDTs and rehabilitation initiation timing) (see Table 1).



Abbreviations: M, mean; SD, standard deviation; n, number; na, not available; KDTs, Ketogenic dietary therapies; Un, unremarkable.

In detail, five patients have a missense mutation, two patients have a deletion of SLC2A1 gene and one patient a truncating mutation. Pregnancy was uncomplicated in all but one patients. No patient suffered from recurrent otitis media during the first years of life, nor auditory deficits. Based on parental reports, the following information was obtained: babbling onset was mainly delayed (age 13.29 months; SD 5.61; range 9–24) and so was the age of first-word onset (age 18.25 months; SD 7.2; range 12–30) and age of combinatory speech (age 34.5 months; SD 16.27; range 24–60). Three patients showed unintelligible speech during the preschool years. Psychomotor development was delayed in two patients. Before the genetic and clinical diagnosis of GLUT1DS, three patients were diagnosed with a speech disorder and two patients with 'dysarthria and ataxia' of unknown origin at first disease manifestations. Age at GLUT1DS diagnosis ranged from 24 to 122 months (mean 72.87 months; SD 26.70). Two patients had a family member affected by GLUT1DS and four patients had a family history of epilepsy. Epilepsy onset in the described sample occurred from 12 to 84 months (mean 36.28 months; SD 24.71). The median age at KDTs initiation was 76.75 months (SD 29.85; range 24–121 months). All patients had movement disorders: seven with mild severity and one with moderate severity. Rehabilitation was provided in all cases but one: six patients underwent speech and language therapy, four patients psychomotor therapy, and one patient underwent cognitive rehabilitation. Rehabilitation started at a median age of 49.71 months (SD 30.53, range 24–108) and the therapy duration reported lasted from 1.5 years to eight years (median 4.78 years, SD 2.57).

All patients were on stable KDTs therapy from more than six months at the evaluation time.

### *2.2. Materials and Procedures*

All patients underwent a cognitive and speech and language evaluation. Speech and language assessment investigated three domains: oromotor, speech, and language abilities (see Table 2 for a detailed list of standardized tests performed).


**Table 2.** Description of the tests included in the administered battery.


**Table 2.** *Cont.*

Test administration was carried out individually by a professional neuropsychologist and a speech and language therapist. Both speech and language and cognitive assessments were performed by administering a comprehensive battery of tests depending on patient's age. Language development patterns were reviewed by an expert neuropsychologist and a speech and language therapist through a standardized questionnaire and by collecting detailed medical and developmental milestones history.

This study was approved by our Ethical Committee (P-20190033749), IRCCS Mondino Foundation, Pavia. Written informed consent was obtained from caregivers.

### *2.3. Statistical Analysis*

We firstly performed a set of descriptive analyses. Then, a set of Spearman's rank correlation (rho) coefficients were calculated between the age onset of babbling, age at first word, age at combinatory speech, and the neuropsychological tasks' results.

### **3. Results**

### *3.1. Tests Evaluation*

### 3.1.1. Oromotor Skills

Oromotor skills were evaluated with nonverbal tasks, and demonstrated impaired functioning on at least one subtest. The worst performances were obtained in orofacial praxis verbal requests, parallel movements, and total score. In particular, in orofacial praxis verbal request (mean z-score −2.72, SD 3.1; range −9.66 0.75) 4/8 subjects showed a severely impaired performance and 3/8 had a poor performance; in 'parallel movements' 5/8 subjects scored a severely impaired performance (mean z-score −3.08, SD 3.42; range −6.09–1.10) and in 'total score verbal request condition' (mean z-score −2.63, SD 2.29; range −6.83 0.43) 4/8 patients had a severely impaired result and 2/8 patients a mildly impaired score. See Table 3.



Comprehension Index; PRI = Perceptual Reasoning Index; WMI = Working memory index; PSI = Processing speed index.
