rs121917746 — SPR Q119X

Nonsense variant in sepiapterin reductase that abolishes BH4 biosynthesis, causing dopamine and serotonin deficiency in the brain; homozygosity leads to DOPA-responsive dystonia (SPR deficiency, OMIM

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SPR Q119X — The Hidden Dystonia Gene

Inside every neuron that makes dopamine or serotonin, a small enzyme called sepiapterin reductase (SPR) performs the final step in synthesising tetrahydrobiopterin11 tetrahydrobiopterin
BH4 — an essential cofactor for three key enzymes in neurotransmitter production. Without sufficient BH4, the enzymes that convert tyrosine into dopamine and tryptophan into serotonin grind to a halt. The Q119X variant in SPR — a single nucleotide change that replaces glutamine at position 119 with a premature stop codon — creates a truncated, non-functional protein and is the cause of SPR deficiency (OMIM #612716), a rare but fully treatable neurological disorder.

The Mechanism

BH4 acts as a cofactor for phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH). TH and TPH are the rate-limiting enzymes for dopamine and serotonin synthesis respectively. SPR catalyses the reduction of 6-pyruvoyltetrahydropterin to BH4 in the final step of de novo synthesis22 SPR catalyses the reduction of 6-pyruvoyltetrahydropterin to BH4 in the final step of de novo synthesis
sepiapterin reductase is an aldo-keto reductase encoded on chromosome 2p13.2. The Q119X nonsense mutation (c.355C>T, NM_003124.5) truncates the protein at codon 119, abolishing enzyme activity in skin fibroblasts. Peripheral tissues can partially compensate via alternative reductases (aldose reductase, carbonyl reductase, dihydrofolate reductase), but the brain relies predominantly on SPR — explaining why SPR deficiency is neurologically devastating while plasma phenylalanine remains normal, causing it to be invisible to standard PKU neonatal screening33 invisible to standard PKU neonatal screening
SPR deficiency does not elevate blood phenylalanine, the marker used in universal newborn screening.

The Evidence

Bonafé et al. (2001)44 Bonafé et al. (2001) first characterised Q119X in a consanguineous Turkish family: a 14-year-old male homozygous for the variant had psychomotor retardation, spasticity, dystonia, and severely reduced CSF levels of the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), with elevated biopterin. Clinical improvement followed levodopa treatment.

Friedman et al. (2012)55 Friedman et al. (2012) described 38 patients with confirmed SPR deficiency across 11 countries. Average symptom onset was 7 months, but average time to diagnosis was 9.1 years — most patients were misdiagnosed as having cerebral palsy. The defining features were axial hypotonia, dystonia, oculogyric crises, and diurnal fluctuation (worse in the evening, better after sleep). Patients improved dramatically on levodopa/carbidopa, with further benefit from adding 5-hydroxytryptophan.

GeneReviews (Friedman & Galosi, updated 2025)66 GeneReviews (Friedman & Galosi, updated 2025) confirms autosomal recessive inheritance and notes that early treatment — ideally within the first year of life — can reverse developmental delay and prevent permanent cognitive impairment. Levodopa is dosed at 0.1–16 mg/kg/day combined with carbidopa or benserazide; 5-HTP at 1–6 mg/kg/day.

Heterozygous carriers of Q119X are clinically asymptomatic. A population study in Malta — where the carrier frequency reaches ~4–5% due to a founder effect — found that all carrier parents showed no clinical symptoms despite carrying one defective copy of the gene. Farrugia et al. 200777 Farrugia et al. 2007.

Practical Actions

For homozygous individuals (TT) the situation is a medical emergency requiring specialist care. The standard treatment is levodopa/carbidopa plus 5-HTP under neurological supervision, with remarkable outcomes when started early. For heterozygous carriers (CT), current evidence does not support any supplement protocol — carriers are phenotypically normal. The main practical value of knowing carrier status is for reproductive planning: two CT carriers have a 25% chance of an affected (TT) child per pregnancy.

Interactions

SPR deficiency shares its pathway with GTP cyclohydrolase I deficiency (GCH1 mutations, the dominant form of DOPA-responsive dystonia) and other BH4 biosynthesis disorders. All these conditions converge on the same downstream deficiency of dopamine and serotonin. SPR also interacts with the nitric oxide synthase pathway — BH4 is a cofactor for NOS enzymes, so severe SPR deficiency secondarily impairs nitric oxide production, contributing to autonomic dysfunction seen in roughly half of patients.

Nutrient Interactions

tetrahydrobiopterin (BH4) impaired_conversion
L-DOPA (levodopa) increased_need
5-hydroxytryptophan (5-HTP) increased_need

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

No SPR deficiency risk allele detected

You carry two copies of the common reference allele at rs121917746 and do not carry the Q119X nonsense mutation in sepiapterin reductase. Your SPR enzyme is expected to function normally, supporting adequate tetrahydrobiopterin (BH4) synthesis for dopamine and serotonin production. This is the genotype found in essentially the entire global population outside of affected families.

TT SPR Deficiency Deficient

Homozygous Q119X — high likelihood of SPR deficiency requiring immediate specialist evaluation

SPR deficiency (sepiapterin reductase deficiency, SRD) is a rare autosomal recessive inborn error of BH4 metabolism. Q119X (c.355C>T) was the first SPR mutation described, identified by Bonafé et al. (2001) in a Turkish family. Clinical features include: axial hypotonia, progressive dystonia, oculogyric crises, psychomotor retardation, diurnal symptom fluctuation (worse evenings, improved after sleep), and — in about half of patients — autonomic dysfunction (temperature dysregulation, excessive sweating or drooling). Unlike classic BH4 deficiency (GCH1 or PTPS deficiency), SPR deficiency does NOT cause elevated blood phenylalanine, so it escapes standard newborn PKU screening. Average diagnostic delay in the largest published cohort was 9.1 years, with most patients misdiagnosed as cerebral palsy.

Biochemical hallmarks: low CSF HVA and 5-HIAA, elevated CSF biopterin and dihydrobiopterin, normal urinary pterins, normal plasma phenylalanine. Diagnosis is confirmed by enzyme activity in skin fibroblasts and molecular genetic testing.

Treatment is highly effective: levodopa/carbidopa (0.1–16 mg/kg/day with a 4:1 levodopa:decarboxylase inhibitor ratio) restores dopamine signaling. Adding 5-HTP (1–6 mg/kg/day) addresses the serotonin deficit. Early treatment (within the first year of life) can reverse developmental delay; late treatment still achieves functional gains. BH4 supplementation raises CSF markers but typically provides no additional clinical benefit over the combination therapy.

CT Carrier Carrier

Heterozygous carrier of SPR Q119X — one functional copy retained

SPR encodes the enzyme sepiapterin reductase, which performs the final step in BH4 (tetrahydrobiopterin) biosynthesis. Q119X is a nonsense mutation creating a premature stop codon at position 119, producing a truncated, enzymatically inactive protein. One functional copy (CC, the common allele) is sufficient for normal BH4 levels and normal neurotransmitter synthesis. Two defective copies (TT) causes SPR deficiency (OMIM #612716) with dopamine and serotonin depletion in the brain. No clinical effects have been documented in heterozygous carriers. Carrier status has primary clinical relevance for reproductive planning when a partner is also a carrier.