Sepiapterin Reductase (SPR) Deficiency
Sepiapterin reductase catalyzes the NADPH-dependent reduction of carbonyl derivatives, including pteridines, and plays an important role in BH4 biosynthesis. Somewhat surprisingly, the first identified cases had normal plasma phenylalanine and urine pterin levels. Blau et al have hypothesized that peripheral tissues can use alternative carbonyl, aldose, and dihydrofolate reductases to perform the last two steps in BH4 biosynthesis. Therefore, BH4 levels in the liver are likely to be normal, probably explaining the absence of hyperphenylalaninemia in these patients. In addition, it is likely that low dihydrofolate reductase activity in the brain allows accumulation of dihydrobiopterin that inhibits tyrosine and tryptophan hydroxylases, and uncouples nitric oxide synthase (nNOS), leading to neurotransmitter deficiency and neuronal cell death. Thus, identification of low CSF neurotransmitter levels and the presence of elevated CSF dihyrobiopterin is crucial for making the diagnosis in these patients.
Few patients have been reported to date. Dystonic posturing, oculogyric crises, spasticity, tremor, and ataxia with recurrent falls were reported in one 9-year-old boy. He also had a depressed affect, aggressive behavior, and psychomotor retardation. Another child had psychomotor retardation, microcephaly, growth deficiency, spasticity, and dystonia. Blau et al recently confirmed this diagnosis in a 22-year-old woman with cerebral palsy; and lifelong cognitive impairment and a gait disorder, who had been having increasing difficulties with head control, excessive fatigue and dystonia, with associated parkinsonian features including gait instability, hypophonia, and pallilalia. She had significant diurnal variation of symptoms, with symptoms much worse in the evenings. She benefited greatly with supplemental 5-hydroxytryptophan (HTP) and L-dopa/carbidopa, but later discontinued both due to side effects. She remains on treatment with selegeline, an MAO-B inhibitor which prolongs half-life of dopamine at the synapse.
CSF neurotransmitter metabolite and pterin analysis reveals low levels of HVA and 5-HIAA, and high levels of biopterin and dihydrobiopterin. Diagnosis can be confirmed by documenting low SPR activity in skin fibroblast cultures.
