Hyperphenylalaninemias genotyping: Results of over 60 years of history in Lombardy, Italy

Abstract

Background: Hyperphenylalaninemias (HPA) are due to several gene mutations, of which the PAH gene is the most frequently involved. Prevalence and incidence of disease vary between populations, with genotype/phenotype correlations not always capable to correctly predict disease severity. The aim of this study was to give an overview of PAH mutations among one of the largest cohort of patients among Europe, born in Lombardy (Italy) starting from late 1970 s and including over a 60 years of activity; furthermore, to evaluate and discuss identified genotype/phenotype correlations and related reliability.

Patients/methods: Eight hundred and twenty-six HPA patients in current follow-up at the San Paolo Hospital in Milan (Italy) were retrospectively reviewed, including molecular results and allelic phenotype and genotype values (attributed on the basis of the APV/GPV system) to verify genotype-phenotype correlations.

Results: A total of 166 different PAH variants were reviewed; of those, seven variants were identified as not previously described in literature. Most frequently reported variant was p.Ala403Val, followed by p.Arg261Gln, p.Val245Ala, IVS10-11 g>a, p.Tyr414Cys and p.Leu48Ser. Phenotype prediction, based on APV/GPV, matched the actual phenotype in most cases, but not always.

Conclusion/discussion: The cohort of patients included in this study constitute a representative sample of the HPA population worldwide. Studies on this sample may allow to improve clinical and genetic evaluation performances for affected patients, consequently to develop personalized medicine interventions and provide more precise indications on the correct treatment approach based on the accumulated evidence, also in light of a prognostically reliable but not always conclusive APV/GPV system.

Keywords: PAH; PKU; genotype; hyperphenylalaninemia; phenotype; phenylketonuria.

FIGURE 1

Distribution of patients based on type of hyperphenylalaninemia and demographics characteristics. Distribution of patients affected by any type of HPA and in follow up at the Clinical Department of Paediatrics, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Italy, along with indications about gender and age distribution. Abbreviations: HPAs = hyperphenylalaninemias; PTPS = 6‐Pyruvoyl‐Tetrahydropterin Synthase Deficiency; DHPR = Dihydropteridine Reductase Deficiency; PCD = Pterin‐4 alpha‐carbinolamine dehydratase (PCD) deficiency.

FIGURE 2

Distribution of according to GPV. Distribution of patients is represented with data expressed as absolute values, based on identified GPV value and classified in different forms of hyperphenylalaninemia (mild PKU, hyperphenylalaninemia = HPA and classic PKU). Calculation of expected phenotype was obtained from the site www.biopku.org.

FIGURE 3

Discrepancies in ‘expected’ vs. ‘presenting’ phenotype based on type of HPAs. Evidence of relevant discrepancies between type of HPA prediction and reality: on the left, the distribution of the expected phenotypes according to the GPV; on the right, the distribution of actual presenting phenotype based on pre‐treatment Phe levels, divided according to Blau's classification.