rs121917747 — SPR

SPR Lys251Ter — Sepiapterin Reductase Deficiency and BH4-Dependent Neurotransmitter Loss

Deep inside the brain's dopamine- and serotonin-producing neurons lies a biochemical chokepoint that few people have heard of: tetrahydrobiopterin¹¹ tetrahydrobiopterin
BH4 — an essential cofactor for the rate-limiting enzymes of dopamine, serotonin, and norepinephrine synthesis (phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase). Without BH4, these neurons cannot produce their neurotransmitters regardless of how much dietary tyrosine or tryptophan is available. The SPR gene encodes sepiapterin reductase, the final enzyme in the BH4 de novo synthesis pathway, and the c.751A>T variant (rs121917747) introduces a premature stop codon at lysine 251 that truncates the last 11 amino acids of the protein — reducing residual enzyme activity to less than 1%.

The Mechanism

The de novo BH4 synthesis pathway runs through three enzymes: GTP cyclohydrolase I (GCH1), 6-pyruvoyltetrahydropterin synthase (PTS), and finally sepiapterin reductase (SPR), which converts sepiapterin to BH4. The p.Lys251Ter truncation removes the C-terminal region of the SPR enzyme. ClinVar documents that this variant "disrupts the last 11 amino acids" while being "unlikely to trigger nonsense-mediated mRNA decay," meaning truncated protein is produced but is enzymatically non-functional — functional studies confirm less than 1% residual SPR enzyme activity in affected homozygotes²² functional studies confirm less than 1% residual SPR enzyme activity in affected homozygotes. The metabolic consequence is sepiapterin accumulation in CSF and urine (the diagnostic marker) and BH4 depletion in dopaminergic and serotonergic neurons, collapsing monoamine neurotransmitter synthesis.

Unlike GCH1 and PTS deficiencies, SPR deficiency does not cause hyperphenylalaninemia — the liver's alternative BH4 recycling pathway (via QDPR/dihydropteridine reductase) maintains enough BH4 for hepatic phenylalanine hydroxylase. Neurological symptoms predominate³³ Neurological symptoms predominate because brain tissue is more dependent on de novo BH4 synthesis and has less access to the salvage pathway.

The Evidence

The pathogenicity of p.Lys251Ter is established at the highest evidence tier: ClinVar VCV000012944 carries four-star review status (criteria provided, multiple submitters, no conflicts) with nine independent laboratory submissions all classifying the variant as pathogenic for dopa-responsive dystonia due to sepiapterin reductase deficiency.

The variant was confirmed in two Greek siblings in a homozygous state by Verbeek et al. (2008)⁴⁴ Verbeek et al. (2008), who documented undetectable sepiapterin reductase activity in cultured fibroblasts, markedly reduced CSF HVA and 5-HIAA (dopamine and serotonin metabolites), and elevated CSF sepiapterin. Both patients showed impressive clinical response to L-dopa therapy.

The broader clinical spectrum of SPR deficiency was characterized in the GeneReviews reference entry (Friedman & Galosi, 2015/2025)⁵⁵ GeneReviews reference entry (Friedman & Galosi, 2015/2025): affected individuals present in early infancy with axial hypotonia, oculogyric crises, dystonia, autonomic dysfunction, and diurnal fluctuation of symptoms (worse in the afternoon — reflecting dopamine depletion accumulating across the day). Cognitive outcomes are tightly linked to diagnostic timing: patients identified and treated in the first year of life have the best chance of normal cognitive development.

A murine SPR knockout model⁶⁶ murine SPR knockout model confirmed the biochemical cascade: Spr-null mice showed greatly diminished brain dopamine, norepinephrine, and serotonin, plus growth failure; all reversed by oral BH4 and neurotransmitter precursor supplementation. The mouse phenotype mirrors human disease.

Practical Actions

First-line treatment is L-DOPA/carbidopa (0.1–16 mg/kg/day, ratio 4:1) combined with 5-HTP (1–6 mg/kg/day), providing substrate for depleted dopamine and serotonin synthesis respectively. Early initiation — ideally in the first year of life — can reverse developmental delay and restore near-normal motor function. Motor symptoms typically respond better than cognitive manifestations. Some clinicians also add folinic acid, which supports CSF neurotransmitter synthesis through the folate–BH4 metabolic connection, though this is not yet standard across all centers.

For heterozygous carriers (AT genotype), one functional SPR allele is generally sufficient for adequate BH4 production. Published literature does not describe a clinical SPR deficiency syndrome in heterozygotes. However, carriers benefit from knowing their status for reproductive planning purposes and should seek genetic counseling if their partner may also carry a pathogenic SPR variant.

Interactions

SPR deficiency (biallelic) produces the same neurotransmitter-deficiency profile as GCH1 recessive deficiency and PTS deficiency, through different points in the same BH4 synthesis cascade. When other BH4 pathway SNPs are present alongside heterozygous SPR carrier status, the combined effect on BH4 availability in specific tissues warrants clinical evaluation if neurological symptoms develop. The folinic acid recommendation seen in some treatment protocols reflects the inter-dependence of the folate cycle and BH4 synthesis: folinic acid (reduced tetrahydrofolate) is a substrate in steps that feed into the pterin pathway and can partially compensate for BH4 insufficiency in the CNS.