Spinocerebellar ataxia with epilepsy

Summary

Spinocerebellar ataxia with epilepsy (MONDO:0016809) is a disease with 1 cohort gene and 2 clinical trials.

At a glance

• Cohort genes: 1
• ClinVar variants: 8
• Phenotypes (HPO): 28
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000182	Movement abnormality of the tongue	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0000640	Gaze-evoked nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0002448	Progressive encephalopathy	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003348	Hyperalaninemia	Frequent (30-79%)
HP:0003390	Sensory axonal neuropathy	Frequent (30-79%)
HP:0006554	Acute hepatic failure	Frequent (30-79%)
HP:0007334	Bilateral tonic-clonic seizure with focal onset	Frequent (30-79%)
HP:0012377	Hemianopia	Frequent (30-79%)
HP:0012692	Focal T2 hyperintense thalamic lesion	Frequent (30-79%)
HP:0025722	Cerebral infarct	Frequent (30-79%)
HP:0033720	EEG with occipital epileptiform discharges	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia with epilepsy
Mondo ID	MONDO:0016809
MeSH	C564395
Orphanet	254881
ICD-11	1238648682
UMLS	C1843852
MedGen	334510
GARD	0017229
Is cancer (heuristic)	no

Also known as: mitochondrial spinocerebellar ataxia with epilepsy · MSCAE · SCAE

Data availability: 8 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › sensory ataxic neuropathy, dysarthria, and ophthalmoparesis › spinocerebellar ataxia with epilepsy

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

8 retrieved; paginated sample, class counts are floors:

4 pathogenic/likely pathogenic, 2 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13496	NM_002693.3(POLG):c.1399G>A (p.Ala467Thr)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13507	NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13513	NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279961	NM_002693.3(POLG):c.2740A>C (p.Thr914Pro)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
640935	NM_002693.3(POLG):c.3255dup (p.Ser1086fs)	POLG	Pathogenic	criteria provided, single submitter
206548	NM_002693.3(POLG):c.3139C>T (p.Arg1047Trp)	POLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13510	NM_002693.3(POLG):c.1491G>C (p.Gln497His)	POLG	Uncertain significance	criteria provided, multiple submitters, no conflicts
195591	NM_002693.3(POLG):c.3425G>A (p.Arg1142Gln)	POLG	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 8 · 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
POLG	Supportive	Autosomal recessive	spinocerebellar ataxia with epilepsy	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome

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
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_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
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36

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
Strand-asynchronous mitochondrial DNA replication	1	1142.0×	9e-04	POLG

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
DNA replication proofreading	1	5617.3×	0.001	POLG
mitochondrial DNA replication	1	1532.0×	0.001	POLG
base-excision repair, gap-filling	1	1123.5×	0.001	POLG
DNA metabolic process	1	1053.2×	0.001	POLG
DNA-templated DNA replication	1	561.7×	0.002	POLG
base-excision repair	1	468.1×	0.002	POLG

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
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLG	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1

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

1 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)
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

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
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders