The diagnosis and long-term effects of treatment of two cases of sepiapterin reductase deficiency (SRD) are reported from Service de Neuropediatrie, CHU Montpellier, France; University de Sherbrooke, Quebec, Canada; and centers in Germany and Switzerland. Patient 1, a male with first-cousin Turkish parents, presented with a prolonged afebrile seizure at 6 months of age. Progressive global delay, intermittent dystonic movements, and oculogyric crises followed. EEG, MRI, and routine metabolic tests were normal. At 18 months he had developed generalized spasticity, and by 7 years of age, symptoms showed a diurnal variation, with ability to walk in the mornings and requiring a wheelchair by afternoon. Patient 2, a female born of nonconsanguineous Caucasian parents, presented with delayed psychomotor signs at 5 months, generalized hypotonia, and oculogyric crises. At one year dystonic movements and swallowing difficulties developed. She walked at 3 years, hypotonia was replaced by spasticity, and her IQ was measured at 46. Oculogyric crises stopped at 10 years, the head circumference remained at the 50th percentile, and EEG and MRI were normal. A diagnosis of cerebral palsy was suspected until a CSF neurotransmitter study at 13 years of age confirmed a SRD encephalopathy. CSF sepiapterin levels were elevated, and a phenylalanine loading test showed a marked increase in phenylalanine. Plasma serotonin levels were decreased and plasma prolactin was increased. Sepiapterin reductase activity was deficient in fibroblasts from both patients, a homozygous mutation in the SPR gene was found in patient 1, and a homozygous nonsense mutation in patient 2. Treatment was started at 7 and 12 years of age, initially with levodopa and later, with the addition of 5-hydroxytryptophan. Response was dramatic, with resolution of pyramidal signs, dystonic gait, and tremor, muscle tone becoming normal within 2 years. After 5 year follow-up, patients were in school, language and motor development were improved, mild dystonia persisted, and IQ remained subnormal. CSF sepiapterin and 5-OH-tryptophan and plasma prolactin levels, used to monitor progress, had not completely normalized. [1]

COMMENT. Sepiapterin reductase deficiency, an autosomal recessive, dopa-responsive, neurotransmitter disease, presents as an infantile encephalopathy between 2 and 6 months of age with delayed developmental milestones, hypotonia, later replaced by spasticity, oculogyric crises, and dystonic movements, with diurnal variation of motor abnormalities. Diagnosis, often mislabeled as cerebral palsy, is confirmed by CSF examination of neurotransmitters. Treatment consists of levodopa, carbidopa and 5-OH tryptophan. Response is dramatic with improvement in motor function and control of oculogyric crises, but persistence of moderately impaired cognitive function and learning. Neville BGR and colleagues at Great Ormond Street Hospital, London, previously reported 7 cases of SRD from Malta, with similar findings and response to therapy (Ped Neur Briefs Oct 2005;19:78) [2]. The clinical manifestations of SRD resemble the autosomal dominant dopa responsive, Segawa disease [3]. Infants with unexplained cerebral palsy should be screened for SRD, and patients with action dystonia and/or oculogyric crises should receive a trial of L-dopa.