Late diagnosis of phenylketonuria with p.L48S/p.R408W genotype and late positive response to tetrahydrobiopterin – case presentation and literature review

Abstract

Phenylketonuria (PKU) is an autosomal recessive disease with important consequences on nervous system development, if not properly treated. Decrease of the antioxidative mechanisms, altered transport of amino acids through the blood-brain barrier, low brain protein synthesis, hypomyelination are the main contributors to the neural damage and central nervous system functional impairment. Diagnosis of PKU and hypothyroidism are part of the neonatal screening program for inborn diseases and an early diagnosis should be provided in order to prevent complications.
We are reporting here a case of a late-diagnosed PKU with a p.L48S/
p.R408W genotype, with a clinical evolution more severe than in cases with similar genotype, despite a particularly good late response to tetrahydrobiopterin (BH4) on the metabolic status. The severity of the evolution with persistent neuro-psychic impairment could be related to the associated subclinical hypothyroidism and the attention deficit hyperactivity disorder (ADHD) syndrome. Hypertrophic and hyperplasic obesity, cutis laxa and inverted nipples were also diagnosed and the BMI over the 99th percentile was maintained at those levels afterwards. In the discussion section, we review the literature covering the complexity of the mutual influences of these medical conditions in PKU patients.
Through this case presentation, we underline the importance of neonatal screening as a major preventive action of neurological impairment. We also highlight the importance of performing genotyping in PKU and of a complete (48h) sapropterin test in order to avoid missing the late responders, in PKU patients with p.L48S/p.R408W genotype.