Dopa-responsive dystonia due to sepiapterin reductase deficiency

Summary

Dopa-responsive dystonia due to sepiapterin reductase deficiency (MONDO:0012994) is a disease caused by SPR (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SPR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 76
• Phenotypes (HPO): 26
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		43	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000366	Abnormality of the nose	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002329	Drowsiness	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002509	Limb hypertonia	Frequent (30-79%)
HP:0005968	Temperature instability	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0010553	Oculogyric crisis	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0100021	Cerebral palsy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dopa-responsive dystonia due to sepiapterin reductase deficiency
Mondo ID	MONDO:0012994
MeSH	C562657
OMIM	612716
Orphanet	70594
DOID	DOID:0111168
SNOMED CT	45116002
UMLS	C0268468
MedGen	120642
GARD	0010365
NORD	1885
Is cancer (heuristic)	no

Also known as: autosomal recessive sepiapterin reductase-deficient DRD · dopa-responsive dystonia due to sepiapterin reductase deficiency · DRD due to SRD · DYT-SPR · Sepiapterin Reductase Deficiency · sepiapterin reductase deficiency · SPR deficiency · SRD

Data availability: 76 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › dopa-responsive dystonia › dopa-responsive dystonia due to sepiapterin reductase deficiency

Related subtypes (3): TH-deficient dopa-responsive dystonia, dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive, autosomal dominant dopa-responsive dystonia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

76 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 13 pathogenic, 12 conflicting classifications of pathogenicity, 9 likely pathogenic, 2 benign, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3775092	NM_003124.5(SPR):c.3G>A (p.Met1Ile)	LOC129934069	Pathogenic	criteria provided, single submitter
1162322	NM_003124.5(SPR):c.304+2_304+13del	SPR	Pathogenic	criteria provided, single submitter
12939	NM_003124.5(SPR):c.355C>T (p.Gln119Ter)	SPR	Pathogenic	no assertion criteria provided
12940	NM_003124.5(SPR):c.448_452del (p.Thr151fs)	SPR	Pathogenic	no assertion criteria provided
12941	NM_003124.5(SPR):c.448A>G (p.Arg150Gly)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
12943	NM_003124.5(SPR):c.488C>T (p.Pro163Leu)	SPR	Pathogenic	no assertion criteria provided
12944	NM_003124.5(SPR):c.751A>T (p.Lys251Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
1323647	NM_003124.5(SPR):c.544C>T (p.Gln182Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
235551	NM_003124.5(SPR):c.655C>T (p.Arg219Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
2720176	NM_003124.5(SPR):c.715C>T (p.Gln239Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
31917	NM_003124.5(SPR):c.304G>T (p.Gly102Cys)	SPR	Pathogenic	no assertion criteria provided
3384923	NM_003124.5(SPR):c.663del (p.Leu222fs)	SPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39869	NM_003124.5(SPR):c.596-2A>G	SPR	Pathogenic	criteria provided, single submitter
522878	NM_003124.4(SPR):c.596del	SPR	Pathogenic	criteria provided, single submitter
3065103	NM_003124.5(SPR):c.1A>G (p.Met1Val)	LOC129934069	Likely pathogenic	criteria provided, single submitter
3255615	NM_003124.5(SPR):c.43del (p.Ala15fs)	LOC129934069	Likely pathogenic	criteria provided, single submitter
3362269	NM_003124.5(SPR):c.86C>A (p.Ser29Ter)	LOC129934069	Likely pathogenic	criteria provided, single submitter
666329	NM_003124.5(SPR):c.18_19insGGGCGGGCTG (p.Arg7fs)	LOC129934069	Likely pathogenic	criteria provided, single submitter
1162323	NM_003124.5(SPR):c.512G>A (p.Cys171Tyr)	SPR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414432	NM_003124.5(SPR):c.596-2_602del	SPR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698420	NM_003124.5(SPR):c.1A>C (p.Met1Leu)	SPR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502832	NM_003124.5(SPR):c.631del (p.Glu211fs)	SPR	Likely pathogenic	no assertion criteria provided
2627381	NM_003124.5(SPR):c.560A>G (p.Glu187Gly)	SPR	Likely pathogenic	criteria provided, single submitter
239509	NM_003124.5(SPR):c.112G>A (p.Val38Ile)	LOC129934069	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336988	NM_003124.5(SPR):c.87G>C (p.Ser29=)	LOC129934069	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898835	NM_003124.5(SPR):c.120C>T (p.Ser40=)	LOC129934069	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1332715	NM_003124.5(SPR):c.262C>T (p.Arg88Trp)	SPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2436316	NM_003124.5(SPR):c.616C>T (p.Gln206Ter)	SPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336990	NM_003124.5(SPR):c.369C>T (p.Tyr123=)	SPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
660797	NM_003124.5(SPR):c.706G>A (p.Val236Met)	SPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SPR	Definitive	Autosomal recessive	dopa-responsive dystonia due to sepiapterin reductase deficiency	7
TACR1	Definitive	Autosomal recessive	dopa-responsive dystonia due to sepiapterin reductase deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPR	Orphanet:70594	Dopa-responsive dystonia due to sepiapterin reductase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPR	HGNC:11257	ENSG00000116096	P35270	Sepiapterin reductase	gencc,clinvar
TACR1	HGNC:11526	ENSG00000115353	P25103	Substance-P receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPR	Sepiapterin reductase	Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
TACR1	Substance-P receptor	Receptor for the tachykinin substance P, also able to bind and respond to tachynins neurokinin A/substance K and neurokinin B/neuromedin-K.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	12.0×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPR	Enzyme (other)	yes	1.1.1.153	SDR_fam, Sepiapterin_red, NAD(P)-bd_dom_sf
TACR1	GPCR	yes		NK1_rcpt, GPCR_Rhodpsn, Neurokn_rcpt

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
right adrenal gland	1
right lobe of liver	1
endocervix	1
male germ line stem cell (sensu Vertebrata) in testis	1
subcutaneous adipose tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPR	255	ubiquitous	marker	mucosa of transverse colon, right lobe of liver, right adrenal gland
TACR1	183	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, endocervix, subcutaneous adipose tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPR	3,029
TACR1	1,350

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TACR1	P25103	15
SPR	P35270	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of nitric oxide: NOS3 activation and regulation	1	1142.0×	0.004	SPR
Tachykinin receptors bind tachykinins	1	951.7×	0.004	TACR1
Metabolism of cofactors	1	951.7×	0.004	SPR
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	571.0×	0.004	SPR
eNOS activation	1	439.2×	0.005	SPR
Metabolism of vitamins and cofactors	1	58.3×	0.027	SPR
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.027	TACR1
Clathrin-mediated endocytosis	1	42.6×	0.029	TACR1
G alpha (q) signalling events	1	28.7×	0.038	TACR1
Metabolism	1	5.8×	0.165	SPR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
angiotensin-mediated drinking behavior	1	2808.7×	0.003	TACR1
aggressive behavior	1	2106.5×	0.003	TACR1
phospholipase C-activating tachykinin receptor signaling pathway	1	2106.5×	0.003	TACR1
smooth muscle contraction involved in micturition	1	2106.5×	0.003	TACR1
detection of abiotic stimulus	1	1685.2×	0.003	TACR1
response to ozone	1	1685.2×	0.003	TACR1
positive regulation of synaptic transmission, cholinergic	1	1685.2×	0.003	TACR1
sperm ejaculation	1	1685.2×	0.003	TACR1
tetrahydrobiopterin biosynthetic process	1	1203.7×	0.003	SPR
regulation of smooth muscle cell migration	1	1203.7×	0.003	TACR1
operant conditioning	1	1203.7×	0.003	TACR1
positive regulation of action potential	1	1053.2×	0.003	TACR1
positive regulation of uterine smooth muscle contraction	1	1053.2×	0.003	TACR1
tachykinin receptor signaling pathway	1	936.2×	0.003	TACR1
positive regulation of lymphocyte proliferation	1	936.2×	0.003	TACR1
positive regulation of hormone secretion	1	842.6×	0.003	TACR1
positive regulation of vascular permeability	1	648.1×	0.003	TACR1
regulation of smooth muscle cell proliferation	1	648.1×	0.003	TACR1
positive regulation of flagellated sperm motility	1	648.1×	0.003	TACR1
positive regulation of blood pressure	1	526.6×	0.004	TACR1
positive regulation of leukocyte migration	1	495.6×	0.004	TACR1
positive regulation of synaptic transmission, GABAergic	1	495.6×	0.004	TACR1
positive regulation of ossification	1	468.1×	0.004	TACR1
behavioral response to pain	1	443.5×	0.004	TACR1
response to auditory stimulus	1	366.4×	0.005	TACR1
nitric oxide biosynthetic process	1	351.1×	0.005	SPR
response to electrical stimulus	1	324.1×	0.005	TACR1
eating behavior	1	300.9×	0.005	TACR1
positive regulation of vasoconstriction	1	300.9×	0.005	TACR1
response to progesterone	1	247.8×	0.006	TACR1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TACR1	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TACR1	42	4
SPR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	TACR1
ARIPIPRAZOLE	4	TACR1
AMOXAPINE	4	TACR1
THIOTHIXENE	4	TACR1
FIDAXOMICIN	4	TACR1
APREPITANT	4	TACR1
CYCLOSPORINE	4	TACR1
RITONAVIR	4	TACR1
TERFENADINE	4	TACR1
NETUPITANT	4	TACR1
NILOTINIB	4	TACR1
BOSUTINIB	4	TACR1
ASTEMIZOLE	4	TACR1
ROLAPITANT	4	TACR1
LANSOPRAZOLE	4	TACR1
PAROXETINE	4	TACR1
DEXTROMETHORPHAN	4	TACR1
HALOPERIDOL	4	TACR1
ACLIDINIUM BROMIDE	4	TACR1
TRAZODONE	4	TACR1
NEFAZODONE	4	TACR1
ITRACONAZOLE	4	TACR1
DOXAZOSIN	4	TACR1
CARVEDILOL	4	TACR1
ECONAZOLE	4	TACR1
TAMOXIFEN	4	TACR1
MICONAZOLE	4	TACR1
CASOPITANT	3	TACR1
SAREDUTANT	3	TACR1
SERLOPITANT	3	TACR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TACR1	620	Binding:506, Functional:111, ADMET:3
SPR	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPR	1.1.1.153	sepiapterin reductase (L-erythro-7,8-dihydrobiopterin-forming)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TACR1	620

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CLOTRIMAZOLE	4	TACR1
ARIPIPRAZOLE	4	TACR1
AMOXAPINE	4	TACR1
THIOTHIXENE	4	TACR1
FIDAXOMICIN	4	TACR1
APREPITANT	4	TACR1
CYCLOSPORINE	4	TACR1
RITONAVIR	4	TACR1
TERFENADINE	4	TACR1
NETUPITANT	4	TACR1
NILOTINIB	4	TACR1
BOSUTINIB	4	TACR1
ASTEMIZOLE	4	TACR1
ROLAPITANT	4	TACR1
LANSOPRAZOLE	4	TACR1
PAROXETINE	4	TACR1
DEXTROMETHORPHAN	4	TACR1
HALOPERIDOL	4	TACR1
ACLIDINIUM BROMIDE	4	TACR1
TRAZODONE	4	TACR1
NEFAZODONE	4	TACR1
ITRACONAZOLE	4	TACR1
DOXAZOSIN	4	TACR1
CARVEDILOL	4	TACR1
ECONAZOLE	4	TACR1
TAMOXIFEN	4	TACR1
MICONAZOLE	4	TACR1
CASOPITANT	3	TACR1
SAREDUTANT	3	TACR1
SERLOPITANT	3	TACR1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TACR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SPR	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening