Genetic Counseling for Phenylketonuria Complicated by Undiagnosed Parental Hyperphenylalaninemia in a Single Family

Introduction

Phenylketonuria, characterized by significant hyperphenylalaninemia is one of the most important and common inherited metabolic diseases. Its incidence ranges from 1 in 4500 to 125000 live births, and Turkey is one of the countries with the highest incidence rates 1/2600-1/4370 (Hillert A et al., Am J Hum Genet. 2020;107:234-250, El-Metwally A et al., Biomed Res Int. 2018 :7697210, van Spronsen FJ et al., Nat Rev Dis Primers. 2021;7:36). It is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase (PAH), responsible for the first step of the degradation of phenylalanine (Phe); namely, its conversion into tyrosine. As a result of its deficiency, phenylalanine levels increase in the blood and brain, causing global developmental delay, intellectual disability, hypopigmentation, eczematous rash, seizure, motor deficits, ataxia, autism and other behavioral problems, if left untreated. Deficiencies of the cofactor (tetrahydrobiopterin [BH4]) and co-chaperone (DNAJC12 protein) of PAH are responsible for approximately 1–2 percent of cases of persistent hyperphenylalaninemia, which present with neurotransmitter deficiencies in addition to hyperphenylalaninemia due to the impairment of other aromatic amino acid (tyrosine and tryptophan) hydroxylases (van Spronsen FJ et al., Nat Rev Dis Primers. 2021;7:36, van Wegberg AMJ et al., Orphanet J Rare Dis. 2017;12:162).

Residual PAH activity is the major determinant of blood Phe levels, which is closely related to the clinical phenotype. Based on untreated Phe levels (30–120 μmol/L in healthy individuals), PAH deficiency can be classified as mild hyperphenylalaninaemia (mHPA; blood Phe=120–600 μmol/L), mild phenylketonuria (mPKU; blood Phe=600–1200 μmol/L) and classical phenylketonuria (cPKU; blood Phe>1200 μmol/L). It is universally accepted that Phe levels above 360 μmol/L require treatment before the age of 12 years, after which treatment targets differ among European and North American guidelines (600 vs. 360 μmol/L). PAH deficiency is caused by biallelic pathogenic variants in PAH gene on chromosome 12q22–24.1 (van Spronsen FJ et al., Nat Rev Dis Primers. 2021;7:36, van Wegberg AMJ et al., Orphanet J Rare Dis. 2017;12:162). More than 1000 variants and approximately 2500 different genotypes have been reported in the PAH gene. PAH residual activity and thus the clinical phenotype can be predicted from a large number of PAH variants. Genotype-based phenotype prediction may be useful for clinical decision-making and for genetic counseling. In fact, the allelic phenotype value (APV) and genotypic phenotype value (GPV) are extremely successful in predicting the phenotype. APVs and GPVs range between 0 and 10, with the following classifying definitions cPKU (APV: 0–2.7), mPKU (APV:2.8–6.6), and mHPA (APV: 6.7–10). GPV of an individual is equal to the APV of the one of the two alleles harbored by the individual, whichever has the greater APV. GPV-based phenotype prediction was found to be 99% correct for cPKU, 46% for mPKU and 90% for mHPA within a cohort of>9000 patients with PAH deficiency (Garbade SF et al., Genet Med. 2019;21:580–590).

Here we present two siblings with discordant phenotypes, which led to the diagnosis of PAH deficiency in one of the parents.

Publikationsverlauf

Artikel online veröffentlicht:
20. Dezember 2022