Neurodegeneration with ataxia and late-onset optic atrophy

Summary

Neurodegeneration with ataxia and late-onset optic atrophy (MONDO:0031006) is a disease caused by SDHA (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SDHA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 133

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with ataxia and late-onset optic atrophy
Mondo ID	MONDO:0031006
OMIM	619259
UMLS	C5543254
MedGen	1779901
GARD	0027269
Is cancer (heuristic)	no

Also known as: NDAXOA

Data availability: 133 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › neurodegeneration with ataxia and late-onset optic atrophy

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

133 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 36 conflicting classifications of pathogenicity, 17 pathogenic/likely pathogenic, 15 benign/likely benign, 6 benign, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066704	NM_004168.4(SDHA):c.778G>C (p.Gly260Arg)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070947	NM_004168.4(SDHA):c.1012del (p.Ala338fs)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
141876	NM_004168.4(SDHA):c.667del (p.Asp223fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
160358	NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209127	NM_004168.4(SDHA):c.223C>T (p.Arg75Ter)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
231173	NM_004168.4(SDHA):c.1663+1G>T	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
239647	NM_004168.4(SDHA):c.1432_1432+1del	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371794	NM_004168.4(SDHA):c.1A>T (p.Met1Leu)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371805	NM_004168.4(SDHA):c.1534C>T (p.Arg512Ter)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3892371	NM_004168.4(SDHA):c.1335_1337delinsTC (p.Val446fs)	SDHA	Pathogenic	criteria provided, single submitter
412346	NM_004168.4(SDHA):c.762_770+17del	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
422382	NM_004168.4(SDHA):c.2T>G (p.Met1Arg)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
472289	NM_004168.4(SDHA):c.1471G>T (p.Glu491Ter)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
472291	NM_004168.4(SDHA):c.688del (p.Glu230fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
568815	NM_004168.4(SDHA):c.1752_1753inv (p.Arg585Trp)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
653810	NM_004168.4(SDHA):c.1579del (p.Arg527fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
825001	NM_004168.4(SDHA):c.456+1G>A	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8744	NM_004168.4(SDHA):c.1A>C (p.Met1Leu)	SDHA	Pathogenic	criteria provided, multiple submitters, no conflicts
947042	NM_004168.4(SDHA):c.484del (p.Arg162fs)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956996	NM_004168.4(SDHA):c.1663+1G>A	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573516	NC_000005.9:g.(?218337)(235455_236542)del	SDHA	Likely pathogenic	criteria provided, single submitter
8742	NM_004168.4(SDHA):c.1660C>T (p.Arg554Trp)	SDHA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
141401	NM_004168.4(SDHA):c.818C>T (p.Thr273Ile)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
141767	NM_004168.4(SDHA):c.146A>G (p.Asp49Gly)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
142601	NM_004168.4(SDHA):c.91C>T (p.Arg31Ter)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222817	NM_004168.4(SDHA):c.830C>T (p.Thr277Met)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224948	NM_004168.4(SDHA):c.1368G>A (p.Ser456=)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224951	NM_004168.4(SDHA):c.136A>G (p.Lys46Glu)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224952	NM_004168.4(SDHA):c.17G>A (p.Gly6Asp)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224953	NM_004168.4(SDHA):c.822C>T (p.Gly274=)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 6 · 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
SDHA	Strong	Autosomal dominant	neurodegeneration with ataxia and late-onset optic atrophy	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis 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
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).

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)
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd

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
apex of heart	1
heart left ventricle	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SDHA	P31040	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Maturation of TCA enzymes and regulation of TCA cycle	1	571.0×	0.006	SDHA
Citric acid cycle (TCA cycle)	1	423.0×	0.006	SDHA
Respiratory electron transport	1	95.2×	0.014	SDHA
Aerobic respiration and respiratory electron transport	1	88.5×	0.014	SDHA
Metabolism	1	11.6×	0.086	SDHA

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
succinate metabolic process	1	3370.4×	9e-04	SDHA
mitochondrial electron transport, succinate to ubiquinone	1	3370.4×	9e-04	SDHA
respiratory electron transport chain	1	842.6×	0.002	SDHA
tricarboxylic acid cycle	1	510.7×	0.003	SDHA
proton motive force-driven mitochondrial ATP synthesis	1	263.3×	0.005	SDHA
nervous system development	1	45.9×	0.022	SDHA

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
SDHA	LINEZOLID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SDHA	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LINEZOLID	4	SDHA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SDHA	3	Binding:3

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)
LINEZOLID	4	SDHA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SDHA
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: 0.