rs121917747 — SPR

Nonsense variant in sepiapterin reductase creating a premature stop codon (p.Lys251Ter) that abolishes BH4 synthesis, causing dopa-responsive dystonia with severe neurotransmitter depletion when inherited biallelically

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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.

Nutrient Interactions

tetrahydrobiopterin impaired_conversion
levodopa increased_need

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-Carrier Normal

Normal sepiapterin reductase — full BH4 synthesis capacity

With two intact SPR alleles, the de novo BH4 synthesis pathway functions without interruption. BH4 is available as a cofactor for tyrosine hydroxylase (dopamine/norepinephrine synthesis), tryptophan hydroxylase (serotonin synthesis), and phenylalanine hydroxylase (hepatic phenylalanine clearance). You do not carry a pathogenic allele that could cause sepiapterin reductase deficiency in offspring — your children can only inherit the Lys251Ter allele if your partner also carries one. No specific surveillance or supplementation is warranted based on this variant.

TT Homozygous Deficient

Homozygous Lys251Ter — sepiapterin reductase deficiency; BH4 synthesis abolished, severe neurotransmitter deficit

With two copies of Lys251Ter, neither SPR allele can produce functional sepiapterin reductase. ClinVar documents less than 1% residual enzyme activity in homozygotes. The metabolic consequence is accumulation of sepiapterin in CSF and urine (the diagnostic hallmark) and collapse of BH4-dependent neurotransmitter synthesis in the central nervous system.

Clinical presentation typically begins in the first year of life with axial hypotonia, oculogyric crises, and dystonia that fluctuates diurnally — worse in the afternoon as dopamine stores are depleted through the day and partially restored after sleep. Additional features include autonomic dysfunction, sleep disturbances, and developmental delay. Unlike PKU-associated BH4 deficiency, blood phenylalanine is normal because the liver uses an alternative BH4 recycling pathway.

CSF analysis is diagnostic: markedly reduced HVA and 5-HIAA (dopamine and serotonin metabolites), elevated sepiapterin and biopterin, and normal to slightly elevated neopterin. Urinary sepiapterin is a non-invasive biomarker that can supplement CSF analysis.

Treatment is L-DOPA/carbidopa (0.1–16 mg/kg/day at a 4:1 ratio) combined with 5-HTP (1–6 mg/kg/day). Early initiation — ideally within the first year of life — dramatically improves motor and cognitive outcomes. Motor responses are usually more complete than cognitive recovery, particularly when treatment is delayed past infancy. Some treatment centers also add folinic acid to support CSF neurotransmitter cofactor availability. Lifelong treatment is required.

AT Carrier Carrier

Heterozygous carrier of Lys251Ter — single-allele status, no BH4 deficiency syndrome

One functional SPR allele supports normal de novo BH4 synthesis under typical physiological conditions. Parents of confirmed SPR-deficient children — who are obligate heterozygotes — do not develop dystonia or neurotransmitter deficiency themselves. Clinical SPR deficiency is not expected from carrier status.

The primary clinical significance of heterozygous carrier status is reproductive: autosomal recessive inheritance means that if both parents carry a pathogenic SPR variant, each pregnancy has a 25% chance of producing a child with biallelic pathogenic variants and SPR deficiency. Genetic counseling and partner carrier testing are recommended before or during pregnancy when a carrier is identified.

There is no published evidence that heterozygous SPR carriers have measurably reduced BH4 levels, reduced neurotransmitter synthesis, or increased risk of neurological conditions under normal physiological conditions.