infantile-onset X-linked spinal muscular atrophy

Summary

infantile-onset X-linked spinal muscular atrophy (MONDO:0010532) is a disease caused by UBA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: UBA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 593
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0002033	Poor suck	Very frequent (80-99%)
HP:0002398	Degeneration of anterior horn cells	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003445	EMG: neuropathic changes	Very frequent (80-99%)
HP:0004303	Abnormal muscle fiber morphology	Very frequent (80-99%)
HP:0006802	Abnormal anterior horn cell morphology	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000773	Short ribs	Frequent (30-79%)
HP:0000887	Cupped ribs	Frequent (30-79%)
HP:0001220	Interphalangeal joint contracture of finger	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002425	Anarthria	Frequent (30-79%)
HP:0002804	Arthrogryposis multiplex congenita	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0003273	Hip contracture	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0006380	Knee flexion contracture	Frequent (30-79%)
HP:0006466	Ankle flexion contracture	Frequent (30-79%)
HP:0007269	Spinal muscular atrophy	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0009071	Inflammatory myopathy	Frequent (30-79%)
HP:0020110	Bone fracture	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001308	Tongue fasciculations	Occasional (5-29%)
HP:0002009	Potter facies	Occasional (5-29%)
HP:0002460	Distal muscle weakness	Occasional (5-29%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0003324	Generalized muscle weakness	Occasional (5-29%)
HP:0007178	Motor polyneuropathy	Occasional (5-29%)
HP:0008180	Mildly elevated creatine kinase	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0100543	Cognitive impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile-onset X-linked spinal muscular atrophy
Mondo ID	MONDO:0010532
MeSH	C535380
OMIM	301830
Orphanet	1145
DOID	DOID:0111827
SNOMED CT	719836007
UMLS	C1844934
MedGen	337123
GARD	0008521
Is cancer (heuristic)	no

Also known as: SMAX2 · spinal muscular atrophy with arthrogryposis · spinal muscular atrophy, X-linked 2 · spinal muscular atrophy, X-linked 2, infantile, X-linked recessive · spinal muscular atrophy, X-linked type 2 · X-linked distal arthrogryposis multiplex congenita · X-linked spinal muscular atrophy type 2

Data availability: 593 ClinVar variants · 5 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 › spinal muscular atrophy › infantile-onset X-linked spinal muscular atrophy

Related subtypes (18): spinal muscular atrophy-progressive myoclonic epilepsy syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, facioscapulohumeral type, adult-onset proximal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, segmental, spinal muscular atrophy, Ryukyuan type, scapuloperoneal spinal muscular atrophy, autosomal recessive, X-linked distal spinal muscular atrophy type 3, autosomal recessive distal spinal muscular atrophy 1, autosomal recessive distal spinal muscular atrophy 2, neuronopathy, distal hereditary motor, autosomal recessive 3, neuronopathy, distal hereditary motor, autosomal recessive 4, neuronopathy, distal hereditary motor, autosomal recessive 5, neuronopathy, distal hereditary motor, autosomal dominant, bulbospinal muscular atrophy, spinal muscular atrophy with respiratory distress type 2, proximal spinal muscular atrophy, spinal muscular atrophy type 0

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

593 retrieved; paginated sample, class counts are floors:

238 uncertain significance, 224 likely benign, 62 benign, 42 benign/likely benign, 27 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1168624	NM_003334.4(UBA1):c.253G>A (p.Val85Met)	LOC126863253	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914750	NM_003334.4(UBA1):c.105G>A (p.Ser35=)	LOC126863253	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
965290	NM_003334.4(UBA1):c.122T>C (p.Met41Thr)	LOC126863253	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
981654	NM_003334.4(UBA1):c.121A>C (p.Met41Leu)	LOC126863253	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006087	NM_003334.4(UBA1):c.1150C>T (p.Arg384Trp)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016899	NM_003334.4(UBA1):c.2933A>G (p.Tyr978Cys)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1094057	NM_003334.4(UBA1):c.2554-6T>C	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1118440	NM_003334.4(UBA1):c.2647-9_2647-6del	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1167115	NM_003334.4(UBA1):c.1328A>G (p.Lys443Arg)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1440941	NM_003334.4(UBA1):c.3133G>A (p.Gly1045Ser)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1465397	NM_003334.4(UBA1):c.242G>A (p.Arg81Gln)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1490238	NM_003334.4(UBA1):c.521G>A (p.Arg174Gln)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1590296	NM_003334.4(UBA1):c.1294C>T (p.Leu432Phe)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2197867	NM_003334.4(UBA1):c.2273A>G (p.Asn758Ser)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2571366	NM_003334.4(UBA1):c.1432G>T (p.Ala478Ser)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2901755	NM_003334.4(UBA1):c.2365A>G (p.Thr789Ala)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
368337	NM_003334.4(UBA1):c.1486G>A (p.Glu496Lys)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533611	NM_003334.4(UBA1):c.574C>T (p.Arg192Trp)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
578608	NM_003334.4(UBA1):c.1049G>A (p.Arg350His)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
647851	NM_003334.4(UBA1):c.1151G>A (p.Arg384Gln)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
753846	NM_003334.4(UBA1):c.1243G>A (p.Gly415Arg)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
836983	NM_003334.4(UBA1):c.121A>G (p.Met41Val)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
913157	NM_003334.4(UBA1):c.1683T>C (p.Asp561=)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
938029	NM_003334.4(UBA1):c.1189A>G (p.Ile397Val)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
939520	NM_003334.4(UBA1):c.954G>A (p.Thr318=)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
971382	NM_003334.4(UBA1):c.904A>G (p.Ser302Gly)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9782	NM_003334.4(UBA1):c.1731C>T (p.Asn577=)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424674	NC_000023.10:g.(?47058202)(47074328_?)del	INE1	Uncertain significance	criteria provided, single submitter
2424675	NC_000023.10:g.(?47058202)(47074328_?)dup	INE1	Uncertain significance	criteria provided, single submitter
1006955	NM_003334.4(UBA1):c.241C>T (p.Arg81Trp)	LOC126863253	Uncertain significance	criteria provided, single submitter

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
UBA1	Strong	X-linked	infantile-onset X-linked spinal muscular atrophy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UBA1	Orphanet:1145	Infantile-onset X-linked spinal muscular atrophy
UBA1	Orphanet:596753	VEXAS syndrome

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
UBA1	HGNC:12469	ENSG00000130985	P22314	Ubiquitin-like modifier-activating enzyme 1	gencc,clinvar
INE1	HGNC:6060	ENSG00000224975	O15225	Putative inactivation escape 1 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBA1	Ubiquitin-like modifier-activating enzyme 1	Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UBA1	Enzyme (other)	yes	2.3.2.23	UBQ/SUMO-activ_enz_E1-like, ThiF_NAD_FAD-bd, UBQ-activ_enz_E1_CS
INE1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
pharyngeal mucosa	1
renal medulla	1
granulocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBA1	292	ubiquitous	marker	endometrium epithelium, renal medulla, pharyngeal mucosa
INE1	172		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UBA1	4,870
INE1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBA1	P22314	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
INE1	O15225	50.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	368.4×	0.006	UBA1
Dengue Virus Attachment and Entry	1	259.6×	0.006	UBA1
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	UBA1

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
ubiquitin-dependent protein catabolic process	1	74.2×	0.024	UBA1
DNA damage response	1	53.5×	0.024	UBA1
protein ubiquitination	1	41.4×	0.024	UBA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
UBA1	0	0
INE1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
UBA1	38	Binding:38

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UBA1	2.3.2.23, 6.2.1.45, 6.2.1.64	E2 ubiquitin-conjugating enzyme, E1 ubiquitin-activating enzyme, E1 NEDD8-activating enzyme

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

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	1	UBA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	INE1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
UBA1	38	—
INE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.