Monomelic amyotrophy

Summary

Monomelic amyotrophy (MONDO:0011224) is a disease with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 10
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002817	Abnormality of the upper limb	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0007149	Distal upper limb amyotrophy	Very frequent (80-99%)
HP:0002398	Degeneration of anterior horn cells	Frequent (30-79%)
HP:0003134	Abnormality of peripheral nerve conduction	Frequent (30-79%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002380	Fasciculations	Occasional (5-29%)
HP:0002715	Abnormality of the immune system	Occasional (5-29%)
HP:0100022	Abnormality of movement	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	monomelic amyotrophy
Mondo ID	MONDO:0011224
EFO	EFO:1001989
MeSH	C538253
OMIM	602440
Orphanet	65684
ICD-11	2090347823
UMLS	C1865384
MedGen	356265
GARD	0009697
MedDRA	10069681
Is cancer (heuristic)	no

Also known as: benign focal amyotrophy · Hirayama disease · JMADUE · juvenile muscular atrophy of distal upper extremity · juvenile muscular atrophy of the distal upper limb · spinal muscular atrophy juvenile nonprogressive

Data availability: 3 ClinVar variants.

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 › neurodegenerative disease › motor neuron disorder › acquired motor neuron disease › monomelic amyotrophy

Related subtypes (2): poliomyelitis, Mills syndrome

Subtypes (1): O’Sullivan-McLeod syndrome

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:

1 likely pathogenic, 1 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500146	NM_003061.3(SLIT1):c.2276T>A (p.Ile759Asn)	SLIT1	Likely pathogenic	no assertion criteria provided
2506387	NM_001385562.1(ARPP21):c.2325G>T (p.Gln775His)	ARPP21	Uncertain significance	no assertion criteria provided
707389	NM_001036.6(RYR3):c.4505G>T (p.Arg1502Leu)	RYR3	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR3	HGNC:10485	ENSG00000198838	Q15413	Ryanodine receptor 3	clinvar
SLIT1	HGNC:11085	ENSG00000187122	O75093	Slit homolog 1 protein	clinvar
ARPP21	HGNC:16968	ENSG00000172995	Q9UBL0	cAMP-regulated phosphoprotein 21	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RYR3	Ryanodine receptor 3	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction.
SLIT1	Slit homolog 1 protein	Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors.
ARPP21	cAMP-regulated phosphoprotein 21	Isoform 2 may act as a competitive inhibitor of calmodulin-dependent enzymes such as calcineurin in neurons.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Ion channel	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR3	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SLIT1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, LRRNT, Cys-rich_flank_reg_C
ARPP21	Other/Unknown	no		R3H_dom, SUZ, R3H_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
right hemisphere of cerebellum	1
sural nerve	1
cortical plate	1
middle temporal gyrus	1
orbitofrontal cortex	1
lateral globus pallidus	1
nucleus accumbens	1
putamen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR3	233	broad	marker	diaphragm, sural nerve, right hemisphere of cerebellum
SLIT1	186	broad	marker	cortical plate, middle temporal gyrus, orbitofrontal cortex
ARPP21	197	broad	marker	lateral globus pallidus, putamen, nucleus accumbens

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLIT1	2,414
RYR3	1,705
ARPP21	1,349

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RYR3	Q15413	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLIT1	O75093	80.28
ARPP21	Q9UBL0	52.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 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
Regulation of cortical dendrite branching	1	1142.0×	0.012	SLIT1
Regulation of commissural axon pathfinding by SLIT and ROBO	1	475.8×	0.015	SLIT1
Netrin-1 signaling	1	219.6×	0.021	SLIT1
Ion homeostasis	1	102.0×	0.034	RYR3
Stimuli-sensing channels	1	68.0×	0.036	RYR3
Signaling by ROBO receptors	1	62.1×	0.036	SLIT1
Cardiac conduction	1	54.4×	0.036	RYR3
Ion channel transport	1	48.0×	0.036	RYR3
Muscle contraction	1	38.6×	0.040	RYR3
Regulation of expression of SLITs and ROBOs	1	34.6×	0.040	SLIT1
Axon guidance	1	22.6×	0.054	SLIT1
Nervous system development	1	21.5×	0.054	SLIT1
Transport of small molecules	1	12.6×	0.084	RYR3
Developmental Biology	1	7.2×	0.134	SLIT1

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
dorsal/ventral axon guidance	1	2106.5×	0.004	SLIT1
tangential migration from the subventricular zone to the olfactory bulb	1	1685.2×	0.004	SLIT1
negative regulation of synapse assembly	1	1203.7×	0.004	SLIT1
cellular response to magnesium ion	1	1203.7×	0.004	RYR3
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	842.6×	0.004	RYR3
negative regulation of axon extension involved in axon guidance	1	842.6×	0.004	SLIT1
axon extension involved in axon guidance	1	766.0×	0.004	SLIT1
cellular response to caffeine	1	766.0×	0.004	RYR3
forebrain morphogenesis	1	702.2×	0.004	SLIT1
cellular response to ATP	1	443.5×	0.005	RYR3
striated muscle contraction	1	421.3×	0.005	RYR3
retinal ganglion cell axon guidance	1	383.0×	0.005	SLIT1
nuclear migration	1	366.4×	0.005	SLIT1
motor neuron axon guidance	1	351.1×	0.005	SLIT1
negative chemotaxis	1	324.1×	0.005	SLIT1
spinal cord development	1	255.3×	0.006	SLIT1
release of sequestered calcium ion into cytosol	1	172.0×	0.008	RYR3
protein homotetramerization	1	118.7×	0.011	RYR3
calcium ion transmembrane transport	1	105.3×	0.011	RYR3
cellular response to calcium ion	1	100.3×	0.011	RYR3
calcium ion transport	1	90.6×	0.012	RYR3
intracellular calcium ion homeostasis	1	72.6×	0.014	RYR3
axon guidance	1	45.3×	0.022	SLIT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RYR3	0	0
SLIT1	0	0
ARPP21	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RYR3	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	RYR3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLIT1, ARPP21

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR3	2	—
SLIT1	0	—
ARPP21	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05959980	Not specified	RECRUITING	Cervical Fixation Surgery Cervical Collar for Management of Hirayama Disease: A Randomized Study
NCT02574390	Not specified	COMPLETED	Answer ALS: Individualized Initiative for ALS Discovery