Amyotrophic lateral sclerosis type 4

disease

On this page

Also known as ALS 4ALS4amyotrophic lateral sclerosis 4, juvenileamyotrophic lateral sclerosis caused by mutation in SETXdHMN with upper motor neuron signsdistal hereditary motor neuropathy with upper motor neuron signsSETX amyotrophic lateral sclerosis

Summary

Amyotrophic lateral sclerosis type 4 (MONDO:0011223) is a disease caused by SETX (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: SETX (GenCC Definitive)
Cohort genes: 1
ClinVar variants: 1,502
Phenotypes (HPO): 8
Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		70	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0001258	Spastic paraplegia	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 4
Mondo ID	MONDO:0011223
MeSH	C566550
OMIM	602433
Orphanet	357043
DOID	DOID:0060196
UMLS	C1865409
MedGen	355983
GARD	0010502
Is cancer (heuristic)	no

Also known as: ALS 4 · ALS4 · amyotrophic lateral sclerosis 4, juvenile · amyotrophic lateral sclerosis caused by mutation in SETX · dHMN with upper motor neuron signs · distal hereditary motor neuropathy with upper motor neuron signs · SETX amyotrophic lateral sclerosis

Data availability: 1,502 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › amyotrophic lateral sclerosis type 4

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:

182 likely benign, 168 uncertain significance, 151 conflicting classifications of pathogenicity, 64 benign, 15 benign/likely benign, 9 likely pathogenic, 9 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
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
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
2289	NM_015046.7(SETX):c.1166T>C (p.Leu389Ser)	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
1333867	NM_015046.7(SETX):c.1110G>A (p.Trp370Ter)	SETX	Likely pathogenic	criteria provided, single submitter
1341357	NM_015046.7(SETX):c.1165_1167del (p.Leu389del)	SETX	Likely pathogenic	criteria provided, single submitter
1490503	NM_015046.7(SETX):c.6842+1G>T	SETX	Likely pathogenic	criteria provided, single submitter
1685438	NM_015046.7(SETX):c.1167A>C (p.Leu389Phe)	SETX	Likely pathogenic	criteria provided, single submitter
1705107	NC_000009.11:g.(135164039_135171258)_(135176191_135187143)del	SETX	Likely pathogenic	criteria provided, single submitter
1803141	NM_015046.7(SETX):c.1011-2A>G	SETX	Likely pathogenic	criteria provided, single submitter
2136826	NM_015046.7(SETX):c.7100+2T>C	SETX	Likely pathogenic	criteria provided, single submitter
2290	NM_015046.7(SETX):c.8C>T (p.Thr3Ile)	SETX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2291	NM_015046.7(SETX):c.6407G>A (p.Arg2136His)	SETX	Likely pathogenic	criteria provided, single submitter
2684373	NM_015046.7(SETX):c.7200-3T>C	LOC126860782	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001860	NM_015046.7(SETX):c.4520A>C (p.Asp1507Ala)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001873	NM_015046.7(SETX):c.7005G>C (p.Lys2335Asn)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007876	NM_015046.7(SETX):c.3589G>A (p.Asp1197Asn)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1013339	NM_015046.7(SETX):c.382C>T (p.Arg128Cys)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024285	NM_015046.7(SETX):c.7439C>T (p.Ala2480Val)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1026940	NM_015046.7(SETX):c.4283A>G (p.His1428Arg)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031857	NM_015046.7(SETX):c.658A>C (p.Lys220Gln)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055753	NM_015046.7(SETX):c.7810G>A (p.Val2604Met)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1056497	NM_015046.7(SETX):c.7682C>T (p.Ser2561Leu)	SETX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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 dominant	amyotrophic lateral sclerosis type 4	6

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

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
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	gencc,clinvar

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.

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)
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C

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
calcaneal tendon	1
left testis	1
right testis	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETX	3,127

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of termination of DNA-templated transcription	1	16852.0×	0.001	SETX
positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled	1	5617.3×	0.002	SETX
positive regulation of DNA-templated transcription initiation	1	1872.4×	0.003	SETX
DNA-templated transcription termination	1	1532.0×	0.003	SETX
termination of RNA polymerase II transcription	1	1296.3×	0.003	SETX
positive regulation of RNA splicing	1	1053.2×	0.003	SETX
mRNA splice site recognition	1	802.5×	0.003	SETX
DNA recombination	1	337.0×	0.007	SETX
circadian rhythm	1	244.2×	0.008	SETX
cellular response to hydrogen peroxide	1	234.1×	0.008	SETX
RNA processing	1	218.9×	0.008	SETX
double-strand break repair	1	203.0×	0.008	SETX
cellular response to oxidative stress	1	154.6×	0.009	SETX
positive regulation of neuron projection development	1	137.0×	0.010	SETX
DNA damage response	1	53.5×	0.024	SETX
nervous system development	1	45.9×	0.026	SETX
spermatogenesis	1	35.2×	0.032	SETX
cell differentiation	1	29.1×	0.036	SETX
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	SETX

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SETX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

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	0
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
NCT04394871	Not specified	RECRUITING	Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing

Cohort genes: SETX