Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Summary

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (MONDO:0008045) is a disease caused by ASAH1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ASAH1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 60
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Obligate (100%)
HP:0001336	Myoclonus	Very frequent (80-99%)
HP:0002366	Abnormal lower motor neuron morphology	Very frequent (80-99%)
HP:0004302	Functional motor deficit	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002100	Recurrent aspiration pneumonia	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0010819	Atonic seizure	Frequent (30-79%)
HP:0011147	Typical absence seizure	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001757	High-frequency sensorineural hearing impairment	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0025097	Eyelid myoclonus	Occasional (5-29%)
HP:0025190	Bilateral tonic-clonic seizure with generalized onset	Occasional (5-29%)
HP:0032667	Myoclonic status epilepticus	Occasional (5-29%)
HP:0045084	Limb myoclonus	Occasional (5-29%)
HP:0001371	Flexion contracture	Excluded (0%)
HP:0001433	Hepatosplenomegaly	Excluded (0%)
HP:0001609	Hoarse voice	Excluded (0%)
HP:0200036	Skin nodule	Excluded (0%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0002015	Dysphagia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinal muscular atrophy-progressive myoclonic epilepsy syndrome
Mondo ID	MONDO:0008045
MeSH	C537563
OMIM	159950
Orphanet	2590
DOID	DOID:0111527
SNOMED CT	703524005
UMLS	C1834569
MedGen	371854
GARD	0003875
Is cancer (heuristic)	no

Also known as: hereditary myoclonus and progressive distal muscular atrophy · hereditary myoclonus-progressive distal muscular atrophy syndrome · Jankovic Rivera syndrome · Jankovic-Rivera syndrome · myoclonus hereditary progressive distal muscular atrophy · SMAPME · spinal muscular atrophy with progressive myoclonic epilepsy

Data availability: 60 ClinVar variants · 4 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 › spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Related subtypes (18): 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, infantile-onset X-linked spinal muscular atrophy, 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

60 retrieved; paginated sample, class counts are floors:

21 benign, 12 uncertain significance, 11 pathogenic, 7 pathogenic/likely pathogenic, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163018	NM_177924.5(ASAH1):c.3G>T (p.Met1Ile)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323941	NM_177924.5(ASAH1):c.186G>A (p.Trp62Ter)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180642	NM_177924.5(ASAH1):c.850G>T (p.Gly284Ter)	ASAH1	Pathogenic	no assertion criteria provided
180643	NM_177924.5(ASAH1):c.456A>C (p.Lys152Asn)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
2069383	NM_177924.5(ASAH1):c.185G>A (p.Trp62Ter)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
2413836	NM_177924.5(ASAH1):c.177C>A (p.Tyr59Ter)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
35544	NM_177924.5(ASAH1):c.125C>T (p.Thr42Met)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375548	NM_177924.5(ASAH1):c.410A>G (p.Tyr137Cys)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620456	NM_177924.5(ASAH1):c.147G>A (p.Trp49Ter)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
662497	NM_177924.5(ASAH1):c.125+1G>A	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
812470	NM_177924.5(ASAH1):c.177C>G (p.Tyr59Ter)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812480	NM_177924.5(ASAH1):c.518A>T (p.Asn173Ile)	ASAH1	Pathogenic	criteria provided, single submitter
812481	NM_177924.5(ASAH1):c.594_599dup (p.Phe199_Lys200insAsnPhe)	ASAH1	Pathogenic	criteria provided, single submitter
812482	NM_177924.5(ASAH1):c.77C>G (p.Pro26Arg)	ASAH1	Pathogenic	criteria provided, single submitter
812490	NM_177924.5(ASAH1):c.997C>T (p.Arg333Cys)	ASAH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812500	NM_177924.5(ASAH1):c.223_224insC (p.Val75fs)	ASAH1	Pathogenic	criteria provided, single submitter
812508	NM_177924.5(ASAH1):c.886C>T (p.Arg296Ter)	ASAH1	Pathogenic	criteria provided, multiple submitters, no conflicts
35545	NC_000008.11:g.(?18051554)(18107050_?)del	ASAH1-AS1	Pathogenic	no assertion criteria provided
1709286	NM_177924.5(ASAH1):c.1157G>A (p.Arg386Gln)	ASAH1	Likely pathogenic	criteria provided, single submitter
3896780	NM_177924.5(ASAH1):c.848_849delinsC (p.Leu283fs)	ASAH1	Likely pathogenic	criteria provided, single submitter
4813721	NM_177924.5(ASAH1):c.1042-4_1042-1delinsAAAACAC	ASAH1	Likely pathogenic	criteria provided, single submitter
812479	NM_177924.5(ASAH1):c.1096A>C (p.Lys366Gln)	ASAH1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
560955	NM_177924.5(ASAH1):c.124A>G (p.Thr42Ala)	ASAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560956	NM_177924.5(ASAH1):c.536C>T (p.Thr179Ile)	ASAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873542	NM_177924.5(ASAH1):c.118G>C (p.Gly40Arg)	ASAH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031749	NM_177924.5(ASAH1):c.556A>G (p.Thr186Ala)	ASAH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1388513	NM_177924.5(ASAH1):c.308G>C (p.Gly103Ala)	ASAH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1398318	NM_177924.5(ASAH1):c.784A>T (p.Ser262Cys)	ASAH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1431525	NM_177924.5(ASAH1):c.1169A>G (p.Asp390Gly)	ASAH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
362377	NM_177924.5(ASAH1):c.620A>T (p.Tyr207Phe)	ASAH1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
ASAH1	Definitive	Autosomal recessive	spinal muscular atrophy-progressive myoclonic epilepsy syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASAH1	Orphanet:2590	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome
ASAH1	Orphanet:333	Farber disease

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ASAH1	HGNC:735	ENSG00000104763	Q13510	Acid ceramidase	gencc,clinvar
ASAH1-AS1	HGNC:55603	ENSG00000245281		ASAH1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASAH1	Acid ceramidase	Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH.

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)
ASAH1	Enzyme (other)	yes	3.5.1.23	Acid_ceramidase-like, Acid_ceramidase_N, CBAH/NAAA_C
ASAH1-AS1	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
heart right ventricle	1
pancreatic ductal cell	1
visceral pleura	1
bone marrow cell	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASAH1	302	ubiquitous	marker	heart right ventricle, visceral pleura, pancreatic ductal cell
ASAH1-AS1	134		yes	male germ line stem cell (sensu Vertebrata) in testis, cortical plate, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASAH1	2,633
ASAH1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASAH1	Q13510	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	671.8×	0.014	ASAH1
Glycosphingolipid metabolism	1	300.5×	0.014	ASAH1
Glycosphingolipid catabolism	1	292.8×	0.014	ASAH1
MITF-M-dependent gene expression	1	181.3×	0.014	ASAH1
Sphingolipid metabolism	1	167.9×	0.014	ASAH1
MITF-M-regulated melanocyte development	1	114.2×	0.018	ASAH1
Metabolism of lipids	1	31.6×	0.054	ASAH1
Innate Immune System	1	25.5×	0.058	ASAH1
Neutrophil degranulation	1	23.1×	0.058	ASAH1
Developmental Biology	1	14.5×	0.083	ASAH1
Immune System	1	13.0×	0.084	ASAH1
Metabolism	1	11.6×	0.086	ASAH1

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
regulation of programmed necrotic cell death	1	16852.0×	5e-04	ASAH1
ceramide catabolic process	1	2407.4×	0.002	ASAH1
regulation of steroid biosynthetic process	1	1532.0×	0.002	ASAH1
sphingosine biosynthetic process	1	1053.2×	0.002	ASAH1
ceramide biosynthetic process	1	421.3×	0.004	ASAH1
keratinocyte differentiation	1	247.8×	0.005	ASAH1
fatty acid metabolic process	1	193.7×	0.006	ASAH1
cellular response to tumor necrosis factor	1	163.6×	0.006	ASAH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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
ASAH1	1	2
ASAH1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARMOFUR	2	ASAH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ASAH1	111	Binding:108, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASAH1	3.5.1.23	ceramidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ASAH1	111

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)
CARMOFUR	2	ASAH1

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	ASAH1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ASAH1-AS1

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)
ASAH1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.