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

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;107:234250, 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).