Proximal myopathy with extrapyramidal signs

Summary

Proximal myopathy with extrapyramidal signs (MONDO:0014300) is a disease caused by MICU1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MICU1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 22
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002310	Orofacial dyskinesia	Frequent (30-79%)
HP:0002322	Resting tremor	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003687	Centrally nucleated skeletal muscle fibers	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0007153	Progressive extrapyramidal movement disorder	Frequent (30-79%)
HP:0007158	Progressive extrapyramidal muscular rigidity	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Frequent (30-79%)
HP:0030230	Central core regions in muscle fibers	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0008180	Mildly elevated creatine kinase	Occasional (5-29%)
HP:0000365	Hearing impairment	Excluded (0%)
HP:0000831	Insulin-resistant diabetes mellitus	Excluded (0%)
HP:0001638	Cardiomyopathy	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	proximal myopathy with extrapyramidal signs
Mondo ID	MONDO:0014300
OMIM	615673
Orphanet	401768
DOID	DOID:0111335
UMLS	C3810285
MedGen	816615
GARD	0012978
Is cancer (heuristic)	no

Also known as: MPXPS · myopathy with extrapyramidal signs

Data availability: 22 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › proximal myopathy with extrapyramidal signs

Related subtypes (31): polyglucosan body myopathy, muscular atrophy, myopathy of extraocular muscle, acute quadriplegic myopathy, myofascial pain syndrome, myopathy with abnormal lipid metabolism, proximal myopathy with focal depletion of mitochondria, Brody myopathy, rippling muscle disease, myopathy due to myoadenylate deaminase deficiency, intermediate nemaline myopathy, hereditary inclusion-body myopathy, hereditary continuous muscle fiber activity, congenital myopathy, muscular dystrophy, metabolic myopathy, myositis disease, collagen 6-related myopathy, myopathy caused by variation in CRPPA, drug-induced myopathy, myopathy caused by variation in FKRP, myopathy caused by variation in FKTN, myopathy caused by variation in POMGNT1, myopathy caused by variation in POMGNT2, myopathy caused by variation in POMT1, myopathy caused by variation in POMT2, myopathy caused by variation in GMPPB, FHL1-related myopathy, myopathy, sarcoplasmic body, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis

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

22 retrieved; paginated sample, class counts are floors:

8 pathogenic, 6 pathogenic/likely pathogenic, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 uncertain significance, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
101045	NM_001195518.2(MICU1):c.1072-1G>C	MICU1	Pathogenic	criteria provided, multiple submitters, no conflicts
101046	NM_001195518.2(MICU1):c.735+1G>A	MICU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027817	NM_001195518.2(MICU1):c.460C>T (p.Arg154Ter)	MICU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033066	NM_001195518.2(MICU1):c.310del (p.Ser104fs)	MICU1	Pathogenic	criteria provided, single submitter
1174136	NM_001195518.2(MICU1):c.52C>T (p.Arg18Ter)	MICU1	Pathogenic	criteria provided, multiple submitters, no conflicts
1174137	NG_033179.1:g.(5183_64397)_(64560_68128)_del	MICU1	Pathogenic	no assertion criteria provided
1699954	NM_001195518.2:g.(?74326370)(74326571_?)del	MICU1	Pathogenic	criteria provided, single submitter
2631843	NM_001195518.2(MICU1):c.553C>T (p.Arg185Ter)	MICU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279993	NM_001195518.2(MICU1):c.386G>C (p.Arg129Pro)	MICU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431145	NM_001195518.2(MICU1):c.1042C>T (p.Gln348Ter)	MICU1	Pathogenic	criteria provided, single submitter
431146	NM_001195518.2(MICU1):c.40del (p.Ala14fs)	MICU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431921	NM_001195518.2(MICU1):c.355C>T (p.Arg119Ter)	MICU1	Pathogenic	criteria provided, multiple submitters, no conflicts
916533	MICU1, EX9-10DUP	MICU1	Pathogenic	no assertion criteria provided
992285	NM_001195518.2(MICU1):c.161+1G>A	MICU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690642	NM_001195518.2(MICU1):c.765dup (p.Met256fs)	MICU1	Likely pathogenic	criteria provided, single submitter
3382200	NM_001195518.2(MICU1):c.156G>A (p.Trp52Ter)	MICU1	Likely pathogenic	criteria provided, single submitter
3774390	NM_001195518.2(MICU1):c.736-1G>A	MICU1	Likely pathogenic	no assertion criteria provided
1520093	NM_001195518.2(MICU1):c.1A>G (p.Met1Val)	MICU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265243	NM_001195518.2(MICU1):c.547C>T (p.Gln183Ter)	MICU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709115	NM_001195518.2(MICU1):c.538-20G>A	MICU1	Uncertain significance	criteria provided, single submitter
2074118	NM_001195518.2(MICU1):c.88C>T (p.Arg30Trp)	MICU1	Uncertain significance	criteria provided, multiple submitters, no conflicts
559182	NM_001195518.2(MICU1):c.538-4A>G	MICU1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
MICU1	Definitive	Autosomal recessive	proximal myopathy with extrapyramidal signs	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MICU1	Orphanet:401768	Proximal myopathy with extrapyramidal signs

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
MICU1	HGNC:1530	ENSG00000107745	Q9BPX6	Calcium uptake protein 1, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MICU1	Calcium uptake protein 1, mitochondrial	Calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which senses calcium level via its EF-hand domains.

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)
MICU1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

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
cerebellar cortex	1
cerebellar hemisphere	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MICU1	283	ubiquitous	marker	calcaneal tendon, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MICU1	1,246

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MICU1	Q9BPX6	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 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
Processing of SMDT1	1	634.4×	0.003	MICU1
Mitochondrial calcium ion transport	1	543.8×	0.003	MICU1
Transport of small molecules	1	25.1×	0.040	MICU1

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 cristae formation	1	5617.3×	0.001	MICU1
cellular response to calcium ion starvation	1	4213.0×	0.001	MICU1
regulation of cellular hyperosmotic salinity response	1	3370.4×	0.001	MICU1
positive regulation of mitochondrial calcium ion concentration	1	1685.2×	0.002	MICU1
calcium import into the mitochondrion	1	1203.7×	0.002	MICU1
mitochondrial calcium ion transmembrane transport	1	991.3×	0.002	MICU1
mitochondrial calcium ion homeostasis	1	991.3×	0.002	MICU1
calcium ion import	1	802.5×	0.002	MICU1
defense response	1	216.1×	0.005	MICU1
cellular response to calcium ion	1	200.6×	0.005	MICU1
protein homooligomerization	1	122.1×	0.008	MICU1

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
MICU1	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	MICU1

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)
MICU1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.