Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Summary

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (MONDO:0018996) is a disease caused by SETX (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 1 000 000 (France) [Orphanet-validated]
• Causal gene: SETX (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,533
• Phenotypes (HPO): 22
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.11	France	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0006855	Cerebellar vermis atrophy	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0000640	Gaze-evoked nystagmus	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001152	Saccadic smooth pursuit	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0006254	Elevated alpha-fetoprotein	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002174	Postural tremor	Occasional (5-29%)
HP:0002346	Head tremor	Occasional (5-29%)
HP:0002839	Urinary bladder sphincter dysfunction	Occasional (5-29%)
HP:0003073	Hypoalbuminemia	Occasional (5-29%)
HP:0003124	Hypercholesterolemia	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
Mondo ID	MONDO:0018996
MeSH	C537308
OMIM	606002
Orphanet	64753
DOID	DOID:0050755
NCIT	C165500
SNOMED CT	725408001
UMLS	C1853761
MedGen	340052
GARD	0012860
Is cancer (heuristic)	no

Also known as: AOA2 · ataxia with oculomotor apraxia type 2 · ataxia-ocular apraxia 2 · ataxia-oculomotor apraxia 2 · ataxia-oculomotor apraxia type 2 · autosomal recessive spinocerebellar ataxia-1 · SCAN 2 · SCAN2 · SCAR1 · spinocerebellar ataxia with axonal neuropathy type 2 · spinocerebellar ataxia, autosomal recessive 1 · spinocerebellar ataxia, autosomal recessive type 1

Data availability: 1,533 ClinVar variants · 4 GenCC gene-disease records · 14 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Related subtypes (64): giant axonal neuropathy, Finnish type amyloidosis, familial amyloid neuropathy, carpal tunnel syndrome, congenital trigeminal anesthesia, familial recurrent peripheral facial palsy, meralgia paraesthetica, familial, amyotrophic neuralgia, hereditary neuropathy with liability to pressure palsies, abetalipoproteinemia, VPS13A-related neurodegenerative disease, mitochondrial DNA depletion syndrome 4a, oxoglutaricaciduria, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, homocystinuria due to methylene tetrahydrofolate reductase deficiency, Krabbe disease, beta-mannosidosis, biotinidase deficiency, Leigh syndrome, hereditary sensory and autonomic neuropathy with spastic paraplegia, ornithine aminotransferase deficiency, adult polyglucosan body disease, Sandhoff disease, Tay-Sachs disease, methylmalonic aciduria and homocystinuria type cblC, familial isolated deficiency of vitamin E, Kearns-Sayre syndrome, NARP syndrome, Charcot-Marie-Tooth disease type 5, hereditary motor and sensory neuropathy, Okinawa type, fumaric aciduria, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, Niemann-Pick disease type B, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, primary CD59 deficiency, PHARC syndrome, progressive demyelinating neuropathy with bilateral striatal necrosis, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, ataxia - oculomotor apraxia type 4, adrenomyeloneuropathy, neuropathy with hearing impairment, hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, Charcot-Marie-Tooth disease, infantile axonal neuropathy, mitochondrial neurogastrointestinal encephalomyopathy, attenuated Chédiak-Higashi syndrome, coenzyme Q10 deficiency, familial episodic pain syndrome, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, metachromatic leukodystrophy, distal hereditary motor neuropathy, proximal spinal muscular atrophy, pyruvate dehydrogenase deficiency, peroxisome biogenesis disorder, neurodegeneration with brain iron accumulation 2A, neuropathy, congenital hypomelinating, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, EMILIN-1-related connective tissue disease, PRPS1 deficiency disorder, neuropathy, hereditary sensory and autonomic, type IId, peripheral motor neuropathy, childhood-onset, biotin-responsive

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

600 retrieved; paginated sample, class counts are floors:

177 likely benign, 164 uncertain significance, 151 conflicting classifications of pathogenicity, 61 benign, 17 pathogenic, 15 benign/likely benign, 9 likely pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027519	NM_015046.7(SETX):c.7292dup (p.Asn2431fs)	SETX	Pathogenic	criteria provided, single submitter
1048755	NM_015046.7(SETX):c.3247T>C (p.Phe1083Leu)	SETX	Pathogenic	no assertion criteria provided
1328975	NM_015046.7(SETX):c.5332C>T (p.Arg1778Ter)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333209	NM_015046.7(SETX):c.4931_4932del (p.Ile1644fs)	SETX	Pathogenic	criteria provided, single submitter
1359217	NM_015046.7(SETX):c.1484T>C (p.Leu495Pro)	SETX	Pathogenic	criteria provided, single submitter
1449878	NM_015046.7(SETX):c.3681T>A (p.Cys1227Ter)	SETX	Pathogenic	criteria provided, single submitter
1459833	NC_000009.11:g.(?135201691)(135210134_?)del	SETX	Pathogenic	criteria provided, single submitter
1693382	NM_015046.7(SETX):c.5320C>T (p.Gln1774Ter)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183294	NM_015046.7(SETX):c.5222dup (p.Asp1742fs)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2034975	NM_015046.7(SETX):c.3288_3291del (p.His1096fs)	SETX	Pathogenic	criteria provided, single submitter
2071447	NM_015046.7(SETX):c.331C>T (p.Arg111Ter)	SETX	Pathogenic	criteria provided, multiple submitters, no conflicts
209188	NM_015046.7(SETX):c.5821_5830del (p.Ala1941fs)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2159109	NM_015046.7(SETX):c.4890dup (p.Ile1631fs)	SETX	Pathogenic	criteria provided, single submitter
2159483	NM_015046.7(SETX):c.6422dup (p.Ser2142fs)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2284	NM_015046.7(SETX):c.4087C>T (p.Arg1363Ter)	SETX	Pathogenic	criteria provided, multiple submitters, no conflicts
2285	NM_015046.7(SETX):c.2602C>T (p.Gln868Ter)	SETX	Pathogenic	no assertion criteria provided
2287	NM_015046.7(SETX):c.2967_2971del (p.Arg989fs)	SETX	Pathogenic	no assertion criteria provided
2288	NM_015046.7(SETX):c.994C>T (p.Arg332Trp)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2289	NM_015046.7(SETX):c.1166T>C (p.Leu389Ser)	SETX	Pathogenic	criteria provided, multiple submitters, no conflicts
2292	NM_015046.7(SETX):c.5927T>G (p.Leu1976Arg)	SETX	Pathogenic	criteria provided, multiple submitters, no conflicts
2296	NM_015046.7(SETX):c.1027G>T (p.Glu343Ter)	SETX	Pathogenic	no assertion criteria provided
243082	NM_015046.7(SETX):c.6322C>T (p.Gln2108Ter)	SETX	Pathogenic	criteria provided, multiple submitters, no conflicts
280027	NM_015046.7(SETX):c.4816C>T (p.Arg1606Ter)	SETX	Pathogenic	criteria provided, multiple submitters, no conflicts
1184554	NM_015046.7(SETX):c.6106G>C (p.Gly2036Arg)	SETX	Likely pathogenic	no assertion criteria provided
1339062	NM_015046.7(SETX):c.6859C>T (p.Arg2287Ter)	SETX	Likely pathogenic	criteria provided, single submitter
1490503	NM_015046.7(SETX):c.6842+1G>T	SETX	Likely pathogenic	criteria provided, single submitter
1526214	NM_015046.7(SETX):c.6694C>T (p.Arg2232Cys)	SETX	Likely pathogenic	criteria provided, single submitter
209189	NM_015046.7(SETX):c.6038T>G (p.Val2013Gly)	SETX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136826	NM_015046.7(SETX):c.7100+2T>C	SETX	Likely pathogenic	criteria provided, single submitter
2297	NM_015046.7(SETX):c.340CTT[1] (p.Leu115del)	SETX	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
SETX	Definitive	Autosomal recessive	spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	6
PIK3R5	Supportive	Autosomal recessive	spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SETX	Orphanet:357043	Amyotrophic lateral sclerosis type 4
SETX	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2
PIK3R5	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	gencc,clinvar
PIK3R5	HGNC:30035	ENSG00000141506	Q8WYR1	Phosphoinositide 3-kinase regulatory subunit 5	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
PIK3R5	Phosphoinositide 3-kinase regulatory subunit 5	Regulatory subunit of the PI3K gamma complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
PIK3R5	Other/Unknown	no		PIK3R5/6

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
left testis	1
right testis	1
blood	1
granulocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis
PIK3R5	193	broad	marker	granulocyte, blood, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETX	3,127
PIK3R5	1,380

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIK3R5	Q8WYR1	71.39
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 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
Co-stimulation by ICOS	1	1038.2×	0.005	PIK3R5
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.005	PIK3R5
G beta:gamma signalling through PI3Kgamma	1	439.2×	0.006	PIK3R5
CD28 dependent PI3K/Akt signaling	1	393.8×	0.006	PIK3R5
GPVI-mediated activation cascade	1	308.6×	0.006	PIK3R5
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	PIK3R5
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.010	PIK3R5
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.012	PIK3R5
PIP3 activates AKT signaling	1	66.8×	0.015	PIK3R5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of termination of DNA-templated transcription	1	8426.0×	0.003	SETX
positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled	1	2808.7×	0.004	SETX
positive regulation of DNA-templated transcription initiation	1	936.2×	0.008	SETX
DNA-templated transcription termination	1	766.0×	0.008	SETX
termination of RNA polymerase II transcription	1	648.1×	0.008	SETX
positive regulation of RNA splicing	1	526.6×	0.008	SETX
phosphatidylinositol metabolic process	1	443.5×	0.008	PIK3R5
mRNA splice site recognition	1	401.2×	0.008	SETX
positive regulation of MAP kinase activity	1	324.1×	0.009	PIK3R5
DNA recombination	1	168.5×	0.015	SETX
circadian rhythm	1	122.1×	0.016	SETX
cellular response to hydrogen peroxide	1	117.0×	0.016	SETX
RNA processing	1	109.4×	0.016	SETX
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	105.3×	0.016	PIK3R5
double-strand break repair	1	101.5×	0.016	SETX
cellular response to oxidative stress	1	77.3×	0.020	SETX
positive regulation of neuron projection development	1	68.5×	0.021	SETX
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.035	PIK3R5
DNA damage response	1	26.8×	0.049	SETX
immune response	1	23.5×	0.051	PIK3R5
nervous system development	1	23.0×	0.051	SETX
G protein-coupled receptor signaling pathway	1	18.1×	0.061	PIK3R5
spermatogenesis	1	17.6×	0.061	SETX
cell differentiation	1	14.6×	0.070	SETX
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	SETX

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3R5	4	3
SETX	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DACTOLISIB	3	PIK3R5
BUPARLISIB	3	PIK3R5
PICTILISIB	2	PIK3R5
ROGINOLISIB	2	PIK3R5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PIK3R5	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 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)
DACTOLISIB	3	PIK3R5
BUPARLISIB	3	PIK3R5
PICTILISIB	2	PIK3R5
ROGINOLISIB	2	PIK3R5

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	PIK3R5
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SETX

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SETX	0	—

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