Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: Diagnosis and genetics of DOPA-responsive dystonia and sepiapterin reductase deficiency

DOPA responsive dystonia (DRD) and sepiapterin reductase (SR) deficiency ar e inherited disorders of tetrahydrobiopterin (BH4) metabolism characterized by the signs and symptoms related to monoamine neurotransmitter deficiency . In contrast to classical forms of BH4 deficiency DRD and SR deficiency pr esent without hyperphenylalaninemia and thus cannot be detected by the neon atal screening for phenylketonuria (PKU). While DRD is mostly caused by aut osomal dominant mutations in the GTP cyclohydrolase I gene (GCH1), SR defic iency is an autosomal. recessive disease. The most important biochemical in vestigations for the diagnosis of these neurological diseases includes CSF investigations for neurotransmitter metabolites and pterins as well as neop terin and biopterin production in cytokine-stimulated fibroblasts. Discover y of SR deficiency opened new insights into alternative pathways of the cof actor BH4 via carbonyl, aldose, and dihydrofolate reductases. As a conseque nce of the low dihydrofolate reductase activity in the brain, dihydrobiopte rin intermediate accumulates and inhibits tyrosine and tryptophan hydroxyla ses and uncouples nitric oxide synthase (nNOS), leading to neurotransmitter deficiency and possibly also to neuronal cell death. (C) 2001 Academic Pre ss.