Progressive muscular atrophy

Summary

Progressive muscular atrophy (MONDO:0018687) is a disease with 2 cohort genes and 14 clinical trials. Top therapeutic interventions include levetiracetam.

At a glance

• Cohort genes: 2
• ClinVar variants: 3
• Clinical trials: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive muscular atrophy
Mondo ID	MONDO:0018687
Orphanet	454706
DOID	DOID:318
ICD-11	1282359533
NCIT	C85027
SNOMED CT	88923002
UMLS	C4082951
MedGen	906831
GARD	0021891
Is cancer (heuristic)	no

Also known as: PMA

Data availability: 3 ClinVar variants · 94 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

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 › progressive muscular atrophy

Related subtypes (3): familial amyotrophic lateral sclerosis, sporadic amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with polyglucosan bodies

Subtypes (1): adult progressive spinal muscular atrophy, Aran Duchenne type

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
17621	NM_000070.3(CAPN3):c.550del (p.Thr184fs)	CAPN3	Pathogenic	reviewed by expert panel
92408	NM_000070.3(CAPN3):c.1746-20C>G	CAPN3	Pathogenic	reviewed by expert panel
3383314	NM_021982.3(SEC24A):c.2071C>T (p.Leu691Phe)	SEC24A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CAPN3	Orphanet:267	Calpain-3-related limb-girdle muscular dystrophy R1
CAPN3	Orphanet:565909	Calpain-3-related limb-girdle muscular dystrophy D4

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
SEC24A	HGNC:10703	ENSG00000113615	O95486	Protein transport protein Sec24A	clinvar
CAPN3	HGNC:1480	ENSG00000092529	P20807	Calpain-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEC24A	Protein transport protein Sec24A	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
CAPN3	Calpain-3	Calcium-regulated non-lysosomal thiol-protease.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Protease	1	18.3×	0.108
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEC24A	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
CAPN3	Protease	yes	3.4.22.54	Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom

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
jejunal mucosa	1
mucosa of sigmoid colon	1
oocyte	1
C1 segment of cervical spinal cord	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEC24A	288	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, oocyte
CAPN3	134	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAPN3	1,977
SEC24A	1,946

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SEC24A	O95486	20
CAPN3	P20807	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	196.9×	0.055	SEC24A
Cargo concentration in the ER	1	167.9×	0.055	SEC24A
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.055	SEC24A
COPII-mediated vesicle transport	1	81.6×	0.055	SEC24A
Metabolism of steroids	1	68.8×	0.055	SEC24A
ER to Golgi Anterograde Transport	1	66.4×	0.055	SEC24A
SARS-CoV-2-host interactions	1	59.5×	0.055	SEC24A
Degradation of the extracellular matrix	1	58.9×	0.055	CAPN3
Transport to the Golgi and subsequent modification	1	51.4×	0.055	SEC24A
MHC class II antigen presentation	1	44.6×	0.055	SEC24A
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.055	SEC24A
SARS-CoV-2 Infection	1	40.2×	0.056	SEC24A
Class I MHC mediated antigen processing & presentation	1	35.0×	0.059	SEC24A
Extracellular matrix organization	1	31.6×	0.059	CAPN3
Asparagine N-linked glycosylation	1	30.1×	0.059	SEC24A
SARS-CoV Infections	1	27.7×	0.060	SEC24A
Membrane Trafficking	1	18.5×	0.085	SEC24A
Vesicle-mediated transport	1	17.4×	0.085	SEC24A
Metabolism of lipids	1	15.8×	0.085	SEC24A
Viral Infection Pathways	1	15.4×	0.085	SEC24A
Adaptive Immune System	1	14.9×	0.085	SEC24A
Infectious disease	1	12.4×	0.097	SEC24A
Post-translational protein modification	1	9.6×	0.119	SEC24A
Disease	1	6.5×	0.160	SEC24A
Immune System	1	6.5×	0.160	SEC24A
Metabolism of proteins	1	6.2×	0.161	SEC24A
Metabolism	1	5.8×	0.165	SEC24A

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
calcium-dependent self proteolysis	1	8426.0×	0.004	CAPN3
positive regulation of satellite cell activation involved in skeletal muscle regeneration	1	4213.0×	0.004	CAPN3
cellular response to salt stress	1	2106.5×	0.005	CAPN3
G1 to G0 transition involved in cell differentiation	1	1404.3×	0.005	CAPN3
regulation of cholesterol transport	1	1203.7×	0.005	SEC24A
regulation of myoblast differentiation	1	1203.7×	0.005	CAPN3
negative regulation of protein sumoylation	1	766.0×	0.005	CAPN3
self proteolysis	1	766.0×	0.005	CAPN3
muscle structure development	1	702.2×	0.005	CAPN3
myofibril assembly	1	561.7×	0.006	CAPN3
COPII-coated vesicle cargo loading	1	495.6×	0.006	SEC24A
positive regulation of proteolysis	1	401.2×	0.007	CAPN3
muscle cell cellular homeostasis	1	324.1×	0.008	CAPN3
protein localization to membrane	1	300.9×	0.008	CAPN3
response to muscle activity	1	290.6×	0.008	CAPN3
positive regulation of release of sequestered calcium ion into cytosol	1	247.8×	0.008	CAPN3
regulation of canonical NF-kappaB signal transduction	1	240.7×	0.008	CAPN3
sarcomere organization	1	191.5×	0.010	CAPN3
positive regulation of protein secretion	1	172.0×	0.010	SEC24A
response to calcium ion	1	159.0×	0.010	CAPN3
protein destabilization	1	145.3×	0.011	CAPN3
protein catabolic process	1	118.7×	0.013	CAPN3
cellular response to calcium ion	1	100.3×	0.014	CAPN3
muscle organ development	1	83.4×	0.016	CAPN3
cholesterol homeostasis	1	78.0×	0.017	SEC24A
endoplasmic reticulum to Golgi vesicle-mediated transport	1	68.0×	0.019	SEC24A
protein-containing complex assembly	1	56.9×	0.021	CAPN3
intracellular protein transport	1	32.4×	0.036	SEC24A
negative regulation of apoptotic process	1	17.4×	0.063	CAPN3
proteolysis	1	17.1×	0.063	CAPN3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
SEC24A	0	0
CAPN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAPN3	3.4.22.54, 3.4.22.56	calpain-3, caspase-3

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	CAPN3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SEC24A

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)
SEC24A	0	—
CAPN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	12
PHASE2	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00324454	PHASE2	COMPLETED	Levetiracetam for Cramps, Spasticity and Neuroprotection in Motor Neuron Disease
NCT03067857	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Therapy for Motor Neuron Disease
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT03489278	Not specified	RECRUITING	Clinical Procedures to Support Research in ALS
NCT03912987	Not specified	ACTIVE_NOT_RECRUITING	TRIAL READY (Clinical Trial Readiness)
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT05204017	Not specified	RECRUITING	Comprehensive Analysis Platform To Understand, Remedy and Eliminate ALS
NCT05271435	Not specified	ACTIVE_NOT_RECRUITING	Digital Tools for Assessment of Motor Functions and Falls in ALS
NCT06315673	Not specified	RECRUITING	Digital Assessment of Speech and Fine Motor Control in ALS
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT02574390	Not specified	COMPLETED	Answer ALS: Individualized Initiative for ALS Discovery
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT03464903	Not specified	COMPLETED	Study of ALS Reversals 2: Genetic Analyses
NCT03706391	Not specified	COMPLETED	Study of ALS Reversals 4: LifeTime Exposures

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEVETIRACETAM	4	1