Recessive mitochondrial ataxia syndrome

Summary

Recessive mitochondrial ataxia syndrome (MONDO:0019791) is a disease with 1 cohort gene and 3 clinical trials.

At a glance

• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 22
• Clinical trials: 3

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000602	Ophthalmoplegia	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000872	Hashimoto thyroiditis	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002403	Positive Romberg sign	Frequent (30-79%)
HP:0002406	Limb dysmetria	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003390	Sensory axonal neuropathy	Frequent (30-79%)
HP:0003542	Increased serum pyruvate	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0012079	Abnormality of central motor conduction	Frequent (30-79%)
HP:0012251	ST segment elevation	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0001260	Dysarthria	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	recessive mitochondrial ataxia syndrome
Mondo ID	MONDO:0019791
Orphanet	94125
UMLS	C4760799
MedGen	1683676
GARD	0019251
Is cancer (heuristic)	no

Also known as: MIRAS

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › ataxia neuropathy spectrum › recessive mitochondrial ataxia syndrome

Related subtypes (1): sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

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

2 retrieved; paginated sample, class counts are floors:

1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
206556	NM_002693.3(POLG):c.3286C>T (p.Arg1096Cys)	POLG	Likely pathogenic	reviewed by expert panel
167522	NM_002693.3(POLG):c.126GCA[12] (p.Gln55dup)	POLG	Benign/Likely benign	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	Definitive	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	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: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

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
NCT07315737	Not specified	COMPLETED	Could miRNAs be Used as Markers for Distinguishing Undescended Testicles From Retractile Testicles