sepiapterin and Dystonia

Sepiapterin reductase deficiency (SRD) causes central nervous system symptoms due to dopamine and serotonin depletion because sepiapterin reductase plays an important role in tetrahydrobiopterin biosynthesis. SRD cannot be detected by newborn screening because of the absent hyperphenylalaninemia. To diagnose SRD biochemically, confirmation of reduced monoamine metabolites and elevated sepiapterin in the cerebrospinal fluid (CSF) has been considered necessary, because a past study showed no elevation of urine sepiapterin. Recently, however, the elevation of urine sepiapterin in SRD was reported.. We developed a fast method to measure sepiapterin and creatinine simultaneously using high-performance liquid chromatography with fluorescence and ultraviolet detection. Urine sepiapterin and creatinine were measured in three SRD patients, two SRD carriers, four SRD siblings, and 103 non-SRD patients.. In the three SRD cases, concentrations of urine sepiapterin were 1086, 914, and 575 µmol/mol creatinine (upper limit: 101.7 µmol/mol creatinine), and were markedly higher than those in other groups. CSF sepiapterin concentration was also measured in one SRD case and it was 4.1 nmol/L (upper limit: 0.5 nmol/L).. The simultaneous determination of urine sepiapterin and creatinine appears helpful for the diagnosis of SRD. This assay system can also be used to measure sepiapterin in the CSF.

Topics: Creatinine; Dystonia; Humans; Infant, Newborn; Metabolism, Inborn Errors; Psychomotor Disorders; Pterins

Sepiapterin reductase deficiency is a rare, under-recognized, autosomal recessively inherited disorder of neurotransmitter metabolism.. Five new patients from 3 unrelated Saudi consanguineous families are reported. Symptoms began at 6 months, with delay to diagnosis averaging 8 years. All 5 patients presented with severe symptoms including axial hypotonia, dystonia, and cognitive impairment, associated with hyper-reflexia (4 patients), spasticity (4 patients), bulbar dysfunction (4 patients), and oculogyric crisis (2 patients) with diurnal fluctuation and sleep benefit. Cerebrospinal fluid neurotransmitters analysis showed a typical pattern with increased sepiapterin and increased 7,8-dihydrobiopterin. Analysis of the SPR gene identified 3 novel mutations: c.1A > G, c.370T > C, and c.527C > T. Patient one, with early diagnosis, is currently developing within the normal range. The 4 other patients showed significant improvement in their motor function, but only mild improvement in their cognitive dysfunction.. Our cases illustrate the difficulties in the diagnosis of sepiapterin reductase deficiency in infancy, and the importance of early recognition and management.

Topics: Adolescent; Alcohol Oxidoreductases; Biopterins; Child; Delayed Diagnosis; Dystonia; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Mutation; Psychomotor Disorders; Pterins

Sepiapterin reductase deficiency (SRD) causes depletion of biogenic amines in the brain, early onset motor disorder, and intellectual disability. The diagnostic marker for this rare disease is increased sepiapterin and biopterin in CSF. Through a new analytic methodology we demonstrated accumulation of sepiapterin in urine of four SRD patients several times greater than that found in healthy controls and carriers, regardless of age or treatment. Our findings suggest a new interpretation of current theories of peripheral pterin metabolism and provide a new noninvasive diagnostic tool for children with early onset cryptogenetic developmental delay and/or movement disorder.

Topics: Biomarkers; Dystonia; Humans; Infant; Metabolism, Inborn Errors; Prognosis; Psychomotor Disorders; Pterins

Tetrahydrobiopterin (BH(4)) deficiency is a cause of dystonia at birth. We hypothesized that BH(4) is a developmental factor determining vulnerability of the immature fetal brain to hypoxic-ischemic injury and subsequent motor deficits in newborns.. Pregnant rabbits were subjected to 40-minute uterine ischemia, and fetal brains were investigated for global and focal changes in BH(4). Newborn kits were assessed by neurobehavioral tests following vehicle and sepiapterin (BH(4) analog) treatment of dams.. Naive fetal brains at 70% gestation (E22) were severely deficient for BH(4) compared with maternal and other fetal tissues. BH(4) concentration rapidly increased normally in the perinatal period, with the highest concentrations found in the thalamus compared with basal ganglia, frontal, occipital, hippocampus, and parietal cortex. Global sustained 40-minute hypoxia-ischemia depleted BH(4) in E22 thalamus and to a lesser extent in basal ganglia, but not in the frontal, occipital, and parietal regions. Maternal supplementation prior to hypoxia-ischemia with sepiapterin increased BH(4) in all brain regions and especially in the thalamus, but did not increase the intermediary metabolite, 7,8-BH(2). Sepiapterin treatment also reduced incidence of severe motor deficits and perinatal death following E22 hypoxia-ischemia.. We conclude that early developmental BH(4) deficiency plays a critical role in hypoxic-ischemic brain injury. Increasing brain BH(4) via maternal supplementation may be an effective strategy in preventing motor deficits from antenatal hypoxia-ischemia.

Topics: Animals; Animals, Newborn; Biopterins; Brain; Brain Chemistry; Disease Models, Animal; Dystonia; Female; Fetal Development; Fetal Hypoxia; Gestational Age; Humans; Hypoxia-Ischemia, Brain; Maternal-Fetal Exchange; Muscle Hypertonia; Nitric Oxide Synthase; Pregnancy; Pterins; Rabbits