Malignant Phenylketonuria (PKU) Due to Dihydropteridine Reductase (DHPR) Deficiency

Abstract DHPR deficiency is a rare autosomal recessively inherited metabolic disorder of tetrahydrobiopterin (BH4) regeneration. Clinical symptoms may comprise microcephaly, developmental delay, ataxia and seizures. BH4 is the cofactor for the enzyme phenylalanine (Phe)hydroxylase (PAH), and for tryptophan and tyrosine hydroxylases, both of which are essential for serotonin and dopamine biosynthesis. We present four patients in two families who are being treated at the National Centre for Inherited Metabolic Disorders (NCIMD). All are members of the Irish Traveller population. We have identified a homozygous mutation, c.353C>T, in the DHPR (QDPR) gene which, to the best of our knowledge, has not been previously described. The mainstay of treatment is a life-long Phe-restricted diet together with supplementation of L-dopa and 5-hydroxy tryptophan (5-HT) and folinic acid. In Ireland, there is neurological comorbidity in our adult DHPR patients, although the overall outcome is satisfactory and one affected female has three healthy children.