Spinocerebellar ataxia, autosomal recessive 23

Summary

Spinocerebellar ataxia, autosomal recessive 23 (MONDO:0014846) is a disease caused by TDP2 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TDP2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 6
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia, autosomal recessive 23
Mondo ID	MONDO:0014846
OMIM	616949
Orphanet	404493
DOID	DOID:0111613
UMLS	C4750914
MedGen	1667331
GARD	0017677
Is cancer (heuristic)	no

Also known as: autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome due to TUD deficiency · SCAR23 · spinocerebellar ataxia autosomal recessive type 23 · spinocerebellar ataxia, autosomal recessive 23 · spinocerebellar ataxia, autosomal recessive type 23

Data availability: 6 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome › spinocerebellar ataxia, autosomal recessive 23

Related subtypes (2): autosomal recessive spinocerebellar ataxia 12, autosomal recessive spinocerebellar ataxia 15

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

6 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323684	NM_016614.3(TDP2):c.650del (p.Gly217fs)	TDP2	Pathogenic	criteria provided, single submitter
226424	NM_016614.3(TDP2):c.425+1G>A	TDP2	Pathogenic	no assertion criteria provided
226425	NM_016614.3(TDP2):c.413_414delinsAA (p.Ser138Ter)	TDP2	Pathogenic	no assertion criteria provided
2442386	NM_016614.3(TDP2):c.949C>T (p.Arg317Ter)	TDP2	Pathogenic	criteria provided, single submitter
1325184	NM_016614.3(TDP2):c.635_636+2del	TDP2	Likely pathogenic	criteria provided, single submitter
1030570	NM_016614.3(TDP2):c.97G>T (p.Ala33Ser)	LOC113174982	Uncertain significance	criteria provided, single submitter

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
TDP2	Strong	Autosomal recessive	spinocerebellar ataxia, autosomal recessive 23	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TDP2	Orphanet:404493	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency

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
TDP2	HGNC:17768	ENSG00000111802	O95551	Tyrosyl-DNA phosphodiesterase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TDP2	Tyrosyl-DNA phosphodiesterase 2	DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5’-phosphodiester bond, giving rise to DNA with a free 5’ 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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TDP2	Phosphatase	yes		Endo/exonuclease/phosphatase, UBA-like_sf, Endo/exonu/phosph_ase_sf

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
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TDP2	292	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TDP2	1,312

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TDP2	O95551	5

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	TDP2

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
neuron development	1	255.3×	0.007	TDP2
double-strand break repair	1	203.0×	0.007	TDP2
cell surface receptor signaling pathway	1	64.1×	0.016	TDP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TDP2	3	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	TDP2
LAPACHONE	2	TDP2
LMP-744	1	TDP2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TDP2	30	Binding:30

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

3 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)
SURAMIN	3	TDP2
LAPACHONE	2	TDP2
LMP-744	1	TDP2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	TDP2
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