SPR – Dopa-Responsive Dystonia Due to Sepiapterin Reductase Deficiency

Sepiapterin reductase deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic variants in the SPR gene. Affected infants present with early hypotonia, axial dystonia with diurnal fluctuation, oculogyric crises, parkinsonism and cognitive impairment. Non-motor symptoms include hypersomnia and endocrine disturbances. All patients demonstrate markedly elevated cerebrospinal fluid (CSF) sepiapterin with low homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels and near-absent SPR enzyme activity in fibroblasts, mirroring the neurotransmitter biosynthesis defect [PMID:38585541].

Autosomal recessive inheritance is confirmed by segregation of biallelic SPR variants in multiple consanguineous and non-consanguineous families. Over 60 probands from more than 30 unrelated families have been reported, each harboring two pathogenic SPR alleles, with consistent segregation in siblings and carrier parents [PMID:18502672; PMID:28189489; PMID:24588500].

The SPR variant spectrum includes >10 nonsense alleles (e.g., c.688A>T (p.Lys230Ter)), >5 frameshift insertions/deletions (e.g., c.615dup (p.Gln206fs)), >20 missense substitutions (e.g., c.368A>G (p.Tyr123Cys)), and splice-site mutations (e.g., c.304G>T). A recurrent nonsense variant c.751A>T (p.Lys251Ter) has been observed in multiple families, illustrating mutational hotspots in exons 2 and 3 [PMID:16917893; PMID:18502672].

Functional studies demonstrate complete loss of SPR activity in patient fibroblasts and canonical CSF biomarker profiles of BH₄ pathway disruption. In the zebrafish m865 mutant, loss of spr leads to impaired dopaminergic and serotonergic neuron development, increased retinal apoptosis and reduced expression of nurr1, validating a loss-of-function mechanism [PMID:17024299].

Therapeutically, low-dose levodopa/carbidopa with or without 5-hydroxytryptophan yields dramatic and sustained improvement in motor and non-motor symptoms, including dystonia, parkinsonism, hypersomnia, growth-hormone deficiency and central hypothyroidism. Early biochemical and genetic diagnosis enables prompt intervention to prevent irreversible neurological and endocrine sequelae [PMID:26006722].

References

• Molecular genetics and metabolism • 2008 • Two Greek siblings with sepiapterin reductase deficiency. PMID:18502672
• European journal of paediatric neurology • 2017 • Sepiapterin reductase deficiency: Report of 5 new cases. PMID:28189489
• Acta neurologica Scandinavica • 2014 • Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene. PMID:24588500
• Molecular syndromology • 2024 • Sepiapterin Reductase Deficiency Misdiagnosed as Neurological Sequelae of Meningitis. PMID:38585541
• Anatomy and embryology • 2006 • The zebrafish mutation m865 affects formation of dopaminergic neurons and neuronal survival, and maps to a genetic interval containing the sepiapterin reductase locus. PMID:17024299
• JIMD reports • 2015 • Dopamine-Responsive Growth-Hormone Deficiency and Central Hypothyroidism in Sepiapterin Reductase Deficiency. PMID:26006722

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