Autosomal recessive ataxia due to ubiquinone deficiency

Summary

Autosomal recessive ataxia due to ubiquinone deficiency (MONDO:0012784) is a disease caused by COQ8A (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COQ8A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 189
• Phenotypes (HPO): 24
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		31	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001272	Cerebellar atrophy	Very frequent (80-99%)
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0004696	Talipes cavus equinovarus	Frequent (30-79%)
HP:0012752	Focal T2 hypointense basal ganglia lesion	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Occasional (5-29%)
HP:0002490	Increased CSF lactate	Occasional (5-29%)
HP:0003128	Lactic acidosis	Occasional (5-29%)
HP:0003457	EMG abnormality	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)
HP:0012758	Neurodevelopmental delay	Occasional (5-29%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0000771	Gynecomastia	Very rare (<1-4%)
HP:0001332	Dystonia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive ataxia due to ubiquinone deficiency
Mondo ID	MONDO:0012784
MeSH	C567436
OMIM	612016
Orphanet	139485
DOID	DOID:0070241
SNOMED CT	725394006
UMLS	C2677589
MedGen	436985
GARD	0010294
Is cancer (heuristic)	no

Also known as: ARCA2 · autosomal recessive ataxia due to coenzyme Q10 deficiency · autosomal recessive cerebellar ataxia type 2 · autosomal recessive spinocerebellar ataxia 9 · autosomal recessive spinocerebellar ataxia type 9 · coenzyme Q10 deficiency, primary, 4 · coenzyme Q10 deficiency, primary, type 4 · COQ10D4 · SCAR9

Data availability: 189 ClinVar variants · 2 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 ataxia due to ubiquinone deficiency

Related subtypes (28): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

189 retrieved; paginated sample, class counts are floors:

49 uncertain significance, 41 conflicting classifications of pathogenicity, 29 pathogenic, 23 likely pathogenic, 17 benign, 17 benign/likely benign, 12 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
217876	NM_020247.4(ADCK3):c.[1042C>T;1651G>A]		Pathogenic	no assertion criteria provided
1027504	NM_020247.5(COQ8A):c.589-3C>G	COQ8A	Pathogenic	criteria provided, multiple submitters, no conflicts
1027505	NM_020247.5(COQ8A):c.127del (p.Leu43fs)	COQ8A	Pathogenic	criteria provided, single submitter
1186913	NM_020247.5(COQ8A):c.127_128delinsA (p.Leu43fs)	COQ8A	Pathogenic	criteria provided, multiple submitters, no conflicts
1417235	NM_020247.5(COQ8A):c.478C>T (p.Arg160Ter)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183336	NM_020247.5(COQ8A):c.1744dup (p.Ser582fs)	COQ8A	Pathogenic	criteria provided, single submitter
210096	NM_020247.5(COQ8A):c.1334_1335del (p.Thr445fs)	COQ8A	Pathogenic	criteria provided, multiple submitters, no conflicts
214046	NM_020247.5(COQ8A):c.1844dup (p.Ser616fs)	COQ8A	Pathogenic	criteria provided, multiple submitters, no conflicts
225002	NM_020247.5(COQ8A):c.1015G>A (p.Ala339Thr)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225030	NM_020247.5(COQ8A):c.1665G>A (p.Met555Ile)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242458	NM_020247.5(COQ8A):c.1042C>T (p.Arg348Ter)	COQ8A	Pathogenic	criteria provided, multiple submitters, no conflicts
281924	NM_020247.5(COQ8A):c.638_645del (p.Arg213fs)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
286407	NM_020247.5(COQ8A):c.1742dup (p.Ser582fs)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2875719	NM_020247.5(COQ8A):c.1315dup (p.Ser439fs)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062181	NM_020247.5(COQ8A):c.1579dup (p.Arg527fs)	COQ8A	Pathogenic	criteria provided, single submitter
3254972	NM_020247.5(COQ8A):c.210del (p.Asn71fs)	COQ8A	Pathogenic	criteria provided, single submitter
3637	NM_020247.5(COQ8A):c.637C>T (p.Arg213Trp)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3638	NM_020247.5(COQ8A):c.815G>T (p.Gly272Val)	COQ8A	Pathogenic	criteria provided, single submitter
3639	NM_020247.5(COQ8A):c.815G>A (p.Gly272Asp)	COQ8A	Pathogenic	no assertion criteria provided
3640	NM_020247.5(COQ8A):c.1813dup (p.Glu605fs)	COQ8A	Pathogenic	no assertion criteria provided
3641	NM_020247.5(COQ8A):c.1398+2T>C	COQ8A	Pathogenic	criteria provided, single submitter
3642	NM_020247.5(COQ8A):c.500_521delinsTTG (p.Gln167fs)	COQ8A	Pathogenic	criteria provided, single submitter
3643	NM_020247.5(COQ8A):c.1541A>G (p.Tyr514Cys)	COQ8A	Pathogenic	no assertion criteria provided
3644	NM_020247.5(COQ8A):c.1747ACC[1] (p.Thr584del)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372655	NM_020247.5(COQ8A):c.895C>T (p.Arg299Trp)	COQ8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375329	NM_020247.5(COQ8A):c.1136T>A (p.Leu379Ter)	COQ8A	Pathogenic	criteria provided, single submitter
375330	NM_020247.5(COQ8A):c.1844G>A (p.Gly615Asp)	COQ8A	Pathogenic	criteria provided, single submitter
375331	NM_020247.5(COQ8A):c.1523T>C (p.Phe508Ser)	COQ8A	Pathogenic	criteria provided, single submitter
375332	NC_000001.10:g.227150977_227195656del44680	COQ8A	Pathogenic	no assertion criteria provided
3775925	NM_020247.5(COQ8A):c.512_521del (p.Gly171fs)	COQ8A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
COQ8A	Definitive	Autosomal recessive	autosomal recessive ataxia due to ubiquinone deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COQ8A	Orphanet:139485	Autosomal recessive ataxia due to ubiquinone 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
COQ8A	HGNC:16812	ENSG00000163050	Q8NI60	Atypical kinase COQ8A, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COQ8A	Atypical kinase COQ8A, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COQ8A	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom

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
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COQ8A	134	ubiquitous	marker	gastrocnemius, skeletal muscle tissue, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COQ8A	1,765

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COQ8A	Q8NI60	4

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
Ubiquinol biosynthesis	1	878.5×	0.001	COQ8A

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
phosphorylation	1	1296.3×	0.001	COQ8A
ubiquinone biosynthetic process	1	936.2×	0.001	COQ8A

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
COQ8A	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COQ8A	14	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	COQ8A
VANDETANIB	4	COQ8A
DASATINIB	4	COQ8A
ERLOTINIB	4	COQ8A
SARACATINIB	3	COQ8A
CANERTINIB	3	COQ8A
TG100-115	2	COQ8A
GALUNISERTIB	2	COQ8A
OSI-632	2	COQ8A
R-406	2	COQ8A
MILCICLIB	2	COQ8A
R-1487	1	COQ8A
CYC-116	1	COQ8A
AEW-541	1	COQ8A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
COQ8A	93	Binding:93

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

14 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)
FEDRATINIB	4	COQ8A
VANDETANIB	4	COQ8A
DASATINIB	4	COQ8A
ERLOTINIB	4	COQ8A
SARACATINIB	3	COQ8A
CANERTINIB	3	COQ8A
TG100-115	2	COQ8A
GALUNISERTIB	2	COQ8A
OSI-632	2	COQ8A
R-406	2	COQ8A
MILCICLIB	2	COQ8A
R-1487	1	COQ8A
CYC-116	1	COQ8A
AEW-541	1	COQ8A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	COQ8A
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