Genotype / phenotype relationship in phenylketonuria: phenylalanine tolerance of patients with A300S and E390G mutations

Aim: The aim of the present study was to evaluate phenilalanine (Phe) tolerance of the cases with p.A300S and p.E390G mutations who present clinical manifestations between mild hyperphenylalaninemia (PAH) which does not require any treatment and mild phenylketonuria (PKU), and to reveal the association between the phenotype and genotype through the cases evaluated for definite nutritional therapy indication and lifetime Phe tolerance. Material and Method: This cross-sectional study included the cases with p.A300S (n=47) or p.E390G (n=38) (59 and 47 alleles) mutations in the phenylalanine hydroxylase gene, regardless of the age. Demographic, initial diagnosis, clinical phenotype and genotype, BH4 responsiveness, nutritional therapy and Phe tolerance were evaluated. Current body weight and height, Phe-restricted Tyrosine (Tyr) rich nutritional therapy, and three-day (two weekdays, one weekend day) food records (FRs) were evaluated. FRs data were analyzed by BeBIS 7.2 program and determined natural protein consumed (gr/day) and Phe-free medical L-amino acid formula protein (gr/day), carbohydrate (gr/day), fat (gr/day), energy (kcal/day) and Phe (mg/day). Phe tolerances (mg/day and mg/kg/day) were calculated in patients with quantitative Phe levels within adequate limits according to the age on nutritional therapy during PKU follow-up. All data were evaluated with SPSS 22 program. Results: It was observed that clinical phenotype of the first diagnosis may change during follow-up. The change was 25.5% (n=12) in cases with p.A300S mutation and 47.4% (n=18) in cases with p.E390G mutation. Phe tolerance (mg/day) of cases with both p.E390G and p.A300S mutations increased linearly with age. Conclusion: Our study reveals that, in determining the true clinical phenotype of HPA cases, the initial diagnosis is more meaningful to assess individual Phe tolerance in follow-up than in quantitative Phe level. Furthermore, it is essential to determine the tolerance of life-long Phe tolerance and shows the importance of the individual nutritional treatment plan.