Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

Summary

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (MONDO:0011801) is a disease caused by TDP1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TDP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 97
• Phenotypes (HPO): 20
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000640	Gaze-evoked nystagmus	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002283	Global brain atrophy	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002503	Spinocerebellar tract degeneration	Frequent (30-79%)
HP:0003073	Hypoalbuminemia	Frequent (30-79%)
HP:0003124	Hypercholesterolemia	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0006855	Cerebellar vermis atrophy	Frequent (30-79%)
HP:0006858	Impaired distal proprioception	Frequent (30-79%)
HP:0007021	Pain insensitivity	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0009053	Distal lower limb muscle weakness	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001249	Intellectual disability	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
Mondo ID	MONDO:0011801
MeSH	C537313
OMIM	607250
Orphanet	94124
DOID	DOID:0090115
SNOMED CT	765091006
UMLS	C4759870
MedGen	1683470
GARD	0010000
NORD	1730
Is cancer (heuristic)	no

Also known as: autosomal recessive spinocerebellar ataxia with axonal neuropathy · SCAN1 · spinocerebellar ataxia autosomal recessive with axonal neuropathy · spinocerebellar ataxia type 1 with axonal neuropathy · Spinocerebellar Ataxia with Axonal Neuropathy · spinocerebellar ataxia with axonal neuropathy · spinocerebellar ataxia, autosomal recessive, with axonal neuropathy · spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

Data availability: 97 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

Related subtypes (64): giant axonal neuropathy, Finnish type amyloidosis, familial amyloid neuropathy, carpal tunnel syndrome, congenital trigeminal anesthesia, familial recurrent peripheral facial palsy, meralgia paraesthetica, familial, amyotrophic neuralgia, hereditary neuropathy with liability to pressure palsies, abetalipoproteinemia, VPS13A-related neurodegenerative disease, mitochondrial DNA depletion syndrome 4a, oxoglutaricaciduria, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, homocystinuria due to methylene tetrahydrofolate reductase deficiency, Krabbe disease, beta-mannosidosis, biotinidase deficiency, Leigh syndrome, hereditary sensory and autonomic neuropathy with spastic paraplegia, ornithine aminotransferase deficiency, adult polyglucosan body disease, Sandhoff disease, Tay-Sachs disease, methylmalonic aciduria and homocystinuria type cblC, familial isolated deficiency of vitamin E, Kearns-Sayre syndrome, NARP syndrome, Charcot-Marie-Tooth disease type 5, hereditary motor and sensory neuropathy, Okinawa type, fumaric aciduria, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, Niemann-Pick disease type B, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, primary CD59 deficiency, PHARC syndrome, progressive demyelinating neuropathy with bilateral striatal necrosis, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, ataxia - oculomotor apraxia type 4, adrenomyeloneuropathy, neuropathy with hearing impairment, hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, Charcot-Marie-Tooth disease, infantile axonal neuropathy, mitochondrial neurogastrointestinal encephalomyopathy, attenuated Chédiak-Higashi syndrome, coenzyme Q10 deficiency, familial episodic pain syndrome, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, metachromatic leukodystrophy, distal hereditary motor neuropathy, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, proximal spinal muscular atrophy, pyruvate dehydrogenase deficiency, peroxisome biogenesis disorder, neurodegeneration with brain iron accumulation 2A, neuropathy, congenital hypomelinating, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, EMILIN-1-related connective tissue disease, PRPS1 deficiency disorder, neuropathy, hereditary sensory and autonomic, type IId, peripheral motor neuropathy, childhood-onset, biotin-responsive

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

97 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 20 benign, 5 benign/likely benign, 5 likely benign, 2 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3424	NM_018319.4(TDP1):c.1478A>G (p.His493Arg)	TDP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1030645	NM_018319.4(TDP1):c.910C>T (p.Arg304Ter)	TDP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4845733	NM_018319.4(TDP1):c.629G>A (p.Trp210Ter)	TDP1	Likely pathogenic	criteria provided, single submitter
314822	NM_018319.4(TDP1):c.15C>T (p.Gly5=)	LOC126862019	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1176334	NM_018319.4(TDP1):c.16G>A (p.Asp6Asn)	LOC126862019	Uncertain significance	criteria provided, multiple submitters, no conflicts
196488	NM_018319.4(TDP1):c.208T>A (p.Ser70Thr)	LOC126862019	Uncertain significance	criteria provided, multiple submitters, no conflicts
2524953	NM_018319.4(TDP1):c.194T>A (p.Phe65Tyr)	LOC126862019	Uncertain significance	criteria provided, multiple submitters, no conflicts
314823	NM_018319.4(TDP1):c.19T>C (p.Tyr7His)	LOC126862019	Uncertain significance	criteria provided, multiple submitters, no conflicts
3576879	NM_018319.4(TDP1):c.544G>T (p.Ala182Ser)	LOC126862019	Uncertain significance	criteria provided, multiple submitters, no conflicts
4685848	NM_018319.4(TDP1):c.394G>A (p.Ala132Thr)	LOC126862019	Uncertain significance	criteria provided, single submitter
805648	NM_018319.4(TDP1):c.137A>G (p.Tyr46Cys)	LOC126862019	Uncertain significance	criteria provided, multiple submitters, no conflicts
805649	NM_018319.4(TDP1):c.236G>C (p.Ser79Thr)	LOC126862019	Uncertain significance	criteria provided, multiple submitters, no conflicts
885078	NM_018319.4(TDP1):c.25A>G (p.Arg9Gly)	LOC126862019	Uncertain significance	criteria provided, single submitter
885079	NM_018319.4(TDP1):c.68C>T (p.Pro23Leu)	LOC126862019	Uncertain significance	criteria provided, single submitter
885080	NM_018319.4(TDP1):c.84A>G (p.Pro28=)	LOC126862019	Uncertain significance	criteria provided, single submitter
885996	NM_018319.4(TDP1):c.353C>T (p.Ala118Val)	LOC126862019	Uncertain significance	criteria provided, single submitter
1032036	NM_018319.4(TDP1):c.764T>G (p.Leu255Trp)	TDP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1330989	NM_018319.4(TDP1):c.1793C>T (p.Pro598Leu)	TDP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
314810	NM_018319.3(TDP1):c.-292G>T	TDP1	Uncertain significance	criteria provided, single submitter
314812	NM_018319.3(TDP1):c.-278C>T	TDP1	Uncertain significance	criteria provided, single submitter
314813	NM_018319.3(TDP1):c.-275C>G	TDP1	Uncertain significance	criteria provided, single submitter
314819	NM_018319.4(TDP1):c.-76T>C	TDP1	Uncertain significance	criteria provided, single submitter
314820	NM_018319.4(TDP1):c.-55C>G	TDP1	Uncertain significance	criteria provided, single submitter
314827	NM_018319.4(TDP1):c.716A>G (p.His239Arg)	TDP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
314828	NM_018319.4(TDP1):c.789C>T (p.His263=)	TDP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
314829	NM_018319.4(TDP1):c.884+5G>A	TDP1	Uncertain significance	criteria provided, single submitter
314830	NM_018319.4(TDP1):c.885-15T>C	TDP1	Uncertain significance	criteria provided, single submitter
314836	NM_018319.4(TDP1):c.1342C>T (p.Arg448Trp)	TDP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
314837	NM_018319.4(TDP1):c.1343G>A (p.Arg448Gln)	TDP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
314840	NM_018319.4(TDP1):c.1747A>G (p.Ser583Gly)	TDP1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TDP1	Strong	Autosomal recessive	spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TDP1	Orphanet:94124	Spinocerebellar ataxia with axonal neuropathy type 1

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TDP1	HGNC:18884	ENSG00000042088	Q9NUW8	Tyrosyl-DNA phosphodiesterase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TDP1	Tyrosyl-DNA phosphodiesterase 1	DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3’-phosphodiester bond, giving rise to DNA with a free 3’ phosphate.

Protein-family classification

Druggable: 1 · 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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TDP1	Enzyme (other)	yes	3.1.4.1	Tdp1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
right testis	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TDP1	210	ubiquitous	marker	oocyte, secondary oocyte, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TDP1	1,678

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TDP1	Q9NUW8	48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nonhomologous End-Joining (NHEJ)	1	167.9×	0.006	TDP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
single strand break repair	1	1404.3×	0.002	TDP1
double-strand break repair	1	203.0×	0.007	TDP1
DNA repair	1	63.8×	0.016	TDP1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 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
TDP1	LEVODOPA

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TDP1	313	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVODOPA	4	TDP1
PHENYLBUTAZONE	4	TDP1
CEFOTAXIME SODIUM	4	TDP1
CLOTRIMAZOLE	4	TDP1
FLUORESCEIN	4	TDP1
AMIODARONE HYDROCHLORIDE	4	TDP1
VALPROIC ACID	4	TDP1
INDIGOTINDISULFONATE	4	TDP1
SULFAPHENAZOLE	4	TDP1
ARIPIPRAZOLE	4	TDP1
AMOXAPINE	4	TDP1
RALOXIFENE HYDROCHLORIDE	4	TDP1
BISMUTH SUBSALICYLATE	4	TDP1
CISPLATIN	4	TDP1
TRIMETREXATE	4	TDP1
NICARDIPINE HYDROCHLORIDE	4	TDP1
SULCONAZOLE NITRATE	4	TDP1
PYRITHIONE ZINC	4	TDP1
DEMECLOCYCLINE HYDROCHLORIDE	4	TDP1
DICYCLOMINE HYDROCHLORIDE	4	TDP1
AVOBENZONE	4	TDP1
CEFAZOLIN SODIUM	4	TDP1
CEFOXITIN SODIUM	4	TDP1
OXYMETHOLONE	4	TDP1
CHLOROXINE	4	TDP1
OLMESARTAN MEDOXOMIL	4	TDP1
AMPICILLIN SODIUM	4	TDP1
PHENOXYBENZAMINE HYDROCHLORIDE	4	TDP1
OXICONAZOLE NITRATE	4	TDP1
THIORIDAZINE HYDROCHLORIDE	4	TDP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TDP1	109	Binding:105, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TDP1	3.1.4.1	phosphodiesterase I

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TDP1	109

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
LEVODOPA	4	TDP1
PHENYLBUTAZONE	4	TDP1
CEFOTAXIME SODIUM	4	TDP1
CLOTRIMAZOLE	4	TDP1
FLUORESCEIN	4	TDP1
AMIODARONE HYDROCHLORIDE	4	TDP1
VALPROIC ACID	4	TDP1
INDIGOTINDISULFONATE	4	TDP1
SULFAPHENAZOLE	4	TDP1
ARIPIPRAZOLE	4	TDP1
AMOXAPINE	4	TDP1
RALOXIFENE HYDROCHLORIDE	4	TDP1
BISMUTH SUBSALICYLATE	4	TDP1
CISPLATIN	4	TDP1
TRIMETREXATE	4	TDP1
NICARDIPINE HYDROCHLORIDE	4	TDP1
SULCONAZOLE NITRATE	4	TDP1
PYRITHIONE ZINC	4	TDP1
DEMECLOCYCLINE HYDROCHLORIDE	4	TDP1
DICYCLOMINE HYDROCHLORIDE	4	TDP1
AVOBENZONE	4	TDP1
CEFAZOLIN SODIUM	4	TDP1
CEFOXITIN SODIUM	4	TDP1
OXYMETHOLONE	4	TDP1
CHLOROXINE	4	TDP1
OLMESARTAN MEDOXOMIL	4	TDP1
AMPICILLIN SODIUM	4	TDP1
PHENOXYBENZAMINE HYDROCHLORIDE	4	TDP1
OXICONAZOLE NITRATE	4	TDP1
THIORIDAZINE HYDROCHLORIDE	4	TDP1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TDP1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford