Tetrahydrobiopterin Disorders In Ireland: A Case Series Of 7 Patients

Background Classical Phenylketonuria (PKU) is an autosomal recessively inherited disorder in phenylalanine metabolism caused by profound deficiency of the enzyme phenylalanine hydroxylase (PAH). Newborn screening for PKU was introduced in Ireland in 1966. A low phenylalanine diet is the well-established standard treatment for patients with Classical PKU. However, approximately 1% of all cases in Ireland are caused by an inborn metabolic defect of the cofactor of PAH, tetrahydrobiopterin (BH4). BH4 is an essential cofactor for various metabolic pathways, including phenylalanine, Dopa and 5-OH-Tryptophan metabolism. This subgroup of ultra-rare neurometabolic diseases is referred to as ‘Malignant/Atypical Phenylketonuria’, as most of these patients have raised phenylalanine blood levels and develop profound neurological symptoms despite adequate dietary restriction of phenylalanine, if not treated with additional medications to prevent neurotransmitter deficiencies. Methods We describe diagnostic approaches, biochemical findings and mutational spectrum, clinical presentation, treatment and outcomes in a case series of 7 patients diagnosed with either 6-pyruvoyl-tetrahydrobiopterin synthase (PTPS) deficiency (n=2), a defect in BH4 biosynthesis, or dihydropteridine reductase (DHPR) deficiency (n=5), a defect in BH4 regeneration. Results Seven patients aged 2 to 33 years were included in this study after ethics approval was obtained. Six patients were diagnosed in the newborn period; all five patients with DHPR deficiency were diagnosed following detection of an elevated phenylalanine on newborn screening. Four patients had developmental delay and one patient with DHPR deficiency had epilepsy. All five patients with DHPR deficiency were homozygous for c.353C>T mutation in the QDPR gene. One patient with PTPS deficiency was diagnosed at age 3 years and 9 months when he presented with developmental delay and oculogyric crises, his sibling was subsequently diagnosed as a newborn and is neurologically normal at age 2 years, neither required dietary therapy as their hyperphenylalaninaemia is mild. Both patients with PTPS deficiency are homozygous for c.84–3C>G mutation in the PTS gene. All patients have been treated with neurotransmitter replacement. Conclusion Some disorders of BH4 metabolism such as DHPR deficiency may mimic Classical Phenylketonuria biochemically with a raised blood phenylalanine level, in others, such as PTPS deficiency, the hyperphenylananinaemia may be mild. However, early differential diagnosis is crucial to commence appropriate treatment in a timely manner to improve outcomes in patients with a rare ‘Atypical PKU’. These cases demonstrate the importance of BH4 measurement in patients with a positive PKU newborn screening result and also when evaluating children with unexplained neurological deterioration such as oculogyric crises.