4.2. Impact of Blood Phe Fluctuations
Few studies have assessed the impact of blood Phe variability on neurocognitive function. In 1998, Arnold et al. described associations of blood Phe variability with executive functions but not with cognition or motor skills [
9]. Hood et al. (2014) reported that blood Phe variability predicted cognitive outcomes more strongly than the mean Phe level or the index of dietary control [
13]. They also cited a study by Vilaseca et al. (2010), a paper that focused on the impact of dietary control on general intelligence without discussion of particular neurocognitive tests and domains [
20]. Similar to Hood et al., Romani and colleagues (2017) listed a number of correlations between Phe fluctuations and various cognitive measures [
16]. In contrast, Viau et al. (2011) found no relationship between Phe fluctuations and cognitive performance [
11]. An earlier study by Anastasoaie et al. (2008) suggested a potential relationship between variability in Phe and IQ, reporting a trend without statistical significance; neurocognitive function was not investigated in that study [
10].
In our study, blood Phe fluctuations had no impact on FSIQ development in patients treated with a classic diet. However, in patients treated with Sapropterin dihydrochloride (Kuvan™), mean FSIQ improved with increasing blood Phe level fluctuations. This observation seems to be in contrast to previous studies, which claimed that high blood Phe level fluctuations are detrimental to cognitive performance in patients with PKU. However, in our study, even increased Phe fluctuations were still within or close to the target range.
According to our results, blood Phe level fluctuations are not threatening for some patients with PKU. These patients had moderate PKU, were treated with Sapropterin dihydrochloride (Kuvan™), and showed a comparatively lower blood Phe tolerance before treatment. Their increasing blood Phe level fluctuations are correlated to a gain in FSIQ that can be traced back primarily to a speed gain in information processing. Interestingly, this was seen in patients whose processing speed before treatment was poor.
The considerable increase in mean FSIQ in patients treated with Sapropterin dihydrochloride (Kuvan™) following increasing blood Phe level fluctuations is difficult to discuss. Sapropterin dihydrochloride (Kuvan™) enhances Phe tolerance in patients with PKU. Patients, thus, may relax their Phe-restricted diet and are ‘allowed’ to exist on a normal or close to normal diet. A Phe-restricted diet with amino acid supplementation is a true blessing for patients with PKU. However, a normal diet may still be in favor if normal cognitive development is considered. Thus, Sapropterin dihydrochloride (Kuvan™) may not have a direct impact on cognitive development in treated patients. It seems, however, to positively influence cognitive development in patients by allowing them to enjoy a normal or close-to-normal dietary life.
In patients treated with Sapropterin dihydrochloride (Kuvan™), considerable gain in IQ was particularly found in those patients who had a lower blood Phe tolerance (before and during therapy) and comparatively higher blood Phe levels (during therapy). These patients may have relaxed their Phe-restricted diet more than those patients with comparatively lower blood Phe levels. They, thus, may have an even higher benefit from diet change.
If so, what is the role blood Phe fluctuations play in FSIQ alterations? First of all, blood Phe fluctuations may not be as detrimental to cognitive development as has been stated before. Then again, changes in blood Phe fluctuations seem to be a result of blood Phe level changes in patients treated with Sapropterin dihydrochloride (Kuvan™). Increasing blood Phe fluctuations, thus, may indicate a successful treatment that not only allows for the diet to be relaxed but also leads to remediation of FSIQ in patients.
4.3. Limitations
The limitations of this study should be acknowledged. Follow-up compliance was poor in patients treated with a classic diet. With regard to age and sex, the patients who dropped out did not differ from those who remained in this study. The single-sided dropout may be due to a different compliance of patients who presumably feel successfully treated (with Sapropterin dihydrochloride) compared to patients who may just feel controlled (metabolic control via classic diet) and missing a continuous personal benefit from study adherence.
On the other hand, the patients who dropped out had higher blood Phe levels than patients who remained in this study. Presumably, patients who dropped out had lower overall compliance, which affected not only their adherence to diet but also their adherence to this study.
At the time of recruitment, patients’ age varied from five to 18 years. Similar to what Trefz et al. (2011) discuss regarding the assessment of treatment success, our sample heterogeneity may limit conclusions about the impact of Phe fluctuations on clinical outcomes in various age groups [
15]. Each age group may require a different set of neurocognitive tests, but the definition of age groups often depends on practical issues of sample selection and less on neuropsychologically justified age discrimination [
21,
22]. As van Spronsen et al. (2011) point out, monitoring neurocognitive functioning in PKU patients requires the same conceptually informed instruments for different age groups [
23].
The intergroup comparisons of patients treated with Sapropterin dihydrochloride (Kuvan™) and patients treated with classic diet might have suffered from a selection bias as patients treated with Sapropterin dihydrochloride (Kuvan™) tend to have milder phenotypes given their residual enzyme function. However, this bias does not affect the conclusions regarding the relationship between overall cognitive performance and blood Phe level fluctuations.