Genotype-phenotype correlation in dihydropteridine reductase deficiency.

Abstract

Inherited deficiency of dihydropteridine reductase (DHPR, EC 1.66.99.7) impairs the regeneration of tetrahydrobiopterin (BH 4 ), the essential cofactor of phenylalanine (Phe) (PAH, EC 1.14.16.1), tyrosine (Tyr) (TYH, EC 1.14.16.2) and tryptophan (Trp) (TRH, EC 1.14.16.4) hydroxylases, which is oxidized to qBH 2 during a coupled reaction with these enzymes. The main metabolic derangements caused by DHPR deficiency (McKusick 261630) are hyperphenylalaninaemia and impaired production of monoamine neurotransmitters derived from Tyr and Trp dopamine, noradrenaline and serotonin. Untreated patients can early develop a severe and progressive neurological picture (Blau et al 1996a). The control of hyperphenylalaninaemia and biogenic amine deficiency is necessary to improve their prognosis, together with folinic acid supplementation to avoid folate depletion (Spada et al 1996). However, in some DHPR patients a milder phenotype has been described characterized by absent neurological signs. These patients respond to a BH 4 monotherapy or do not require any treatment (Blau et al 1992). The DHPR gene (QDPR), on 4p15.3, includes seven exons (Dianzani et al 1998). It encodes for a protein of 244 amino acids, active as a homodimer. So far, 21 mutations have been described in QDPR uniformly scattered throughout the coding region (Dianzani et al 1998; Smooker et al 1999), with different mutations having different effects on the protein, as determined by in vitro studies (Smooker et al 1993; Zhang et al 1996). Most mutations have been found in single chromosomes. So far, only five of them have been identified more than once (de Sanctis et al 1996). In the present study we evaluated genotype-phenotype correlation in 21 completely characterized DHPR patients. Molecular, biochemical and clinical data on DHPR-deficient patients are stored in the BIOMDB and BIODEF database (Blau et al 1996b).