Variant of dihydropteridine reductase deficiency without hyperphenylalaninaemia: effect of oral phenylalanine loading.

Abstract

Dihydropteridine reductase (DHPR; EC 1.6.99.7) deficiency (McKusick 261630), the second most common form of tetrahydrobiopterin (BH 4 ) deficiency, presents phenotypically with hyperphenylalaninaemia (HPA) and neurotransmitter deficiency (Blau et al 2000). The clinical course of the illness is similar to that seen in severe forms of GTP cyclohydrolase I and 6-pyruvoyltetrahydropterin synthase deficiencies. Common but variable symptoms are mental retardation, convulsions, disturbance of tone and posture, abnormal movements, hypersalivation and swallowing difficulties. In addition, extensive neuronal loss, calcification and abnormal vascular proliferation have been noted in the central cortex, white matter, basal ganglia, and thalamus. So far, more than 110 patients have been detected through newborn phenylketonuria screening and by selective screening of urinary pterins and DHPR activity on Guthrie cards. However, absence of HPA does not exclude BH 4 deficiency. Recently, a new variant of DHPR deficiency affecting only the central nervous system that does not lead to HPA was described (Blau et al 1998). A similar metabolic phenotype was described for the dominant form of GTP cyclohydrolase I deficiency (dopa-responsive dystonia) (Hyland et al 1996). Although presenting without HPA, these patients show an abnormal phenylalanine-to-tyrosine ratio after oral phenylalanine challenge, indicating abnormal hepatic phenylalanine turnover (Hyland et al 1997). Here we describe similar observations in two patients with a newly recognized variant of DHPR deficiency, one of which has been reported previously (Blau et al 1998). We investigated plasma phenylalaninine, tyrosine, neopterin and biopterin concentrations after oral administration of phenylalanine (100 mg/kg) with and without BH 4 (20 mg/kg).