hereditary myopathy with lactic acidosis due to ISCU deficiency

Summary

hereditary myopathy with lactic acidosis due to ISCU deficiency (MONDO:0009706) is a disease caused by ISCU (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ISCU (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary myopathy with lactic acidosis due to ISCU deficiency
Mondo ID	MONDO:0009706
MeSH	C564972
OMIM	255125
Orphanet	43115
SNOMED CT	699268002
UMLS	C1850718
MedGen	342573
GARD	0016643
Is cancer (heuristic)	no

Also known as: aconitase deficiency · HML · iron-sulfur cluster deficiency myopathy · ISCU myopathy · myopathy with exercise intolerance, Swedish type · myopathy with lactic acidosis, hereditary

Data availability: 14 ClinVar variants · 4 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 › metabolic myopathy › hereditary myopathy with lactic acidosis due to ISCU deficiency

Related subtypes (3): metabolic myopathy due to lactate transporter defect, autosomal dominant mitochondrial myopathy with exercise intolerance, endocrine myopathy

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

14 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 5 benign, 1 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
223141	NM_213595.4(ISCU):c.418+382G>C	ISCU	Pathogenic	criteria provided, multiple submitters, no conflicts
783	NM_213595.4(ISCU):c.149G>A (p.Gly50Glu)	ISCU	Likely pathogenic	criteria provided, single submitter
214555	NM_213595.4(ISCU):c.10G>C (p.Ala4Pro)	ISCU	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1908029	NM_213595.4(ISCU):c.314C>G (p.Ala105Gly)	ISCU	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432876	NM_213595.4(ISCU):c.368_369del (p.Thr123fs)	ISCU	Uncertain significance	criteria provided, single submitter
2432877	NM_213595.4(ISCU):c.484G>T (p.Gly162Ter)	ISCU	Uncertain significance	criteria provided, single submitter
2578027	NM_213595.4(ISCU):c.418+702T>C	ISCU	Uncertain significance	criteria provided, single submitter
3896884	NM_213595.4(ISCU):c.376G>A (p.Ala126Thr)	ISCU	Uncertain significance	criteria provided, single submitter
1251487	NM_213595.4(ISCU):c.419-162C>T	ISCU	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
214554	NM_213595.4(ISCU):c.114+17dup	ISCU	Benign	criteria provided, multiple submitters, no conflicts
559220	NM_213595.4(ISCU):c.19_20delinsGG (p.Phe7Gly)	ISCU	Benign	criteria provided, multiple submitters, no conflicts
559221	NM_213595.4(ISCU):c.20T>G (p.Phe7Cys)	ISCU	Benign	criteria provided, multiple submitters, no conflicts
559222	NM_213595.4(ISCU):c.35C>T (p.Ala12Val)	ISCU	Benign	criteria provided, multiple submitters, no conflicts
768575	NM_213595.4(ISCU):c.19T>G (p.Phe7Val)	ISCU	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ISCU	Strong	Autosomal recessive	hereditary myopathy with lactic acidosis due to ISCU deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ISCU	Orphanet:43115	Hereditary myopathy with lactic acidosis due to ISCU deficiency

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
ISCU	HGNC:29882	ENSG00000136003	Q9H1K1	Iron-sulfur cluster assembly enzyme ISCU	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ISCU	Iron-sulfur cluster assembly enzyme ISCU	Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled.

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)
ISCU	Other/Unknown	no		NIF_FeS_clus_asmbl_NifU_N, ISCU

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
heart right ventricle	1
pons	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ISCU	301	ubiquitous	marker	heart right ventricle, pons, renal medulla

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ISCU	2,571

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ISCU	Q9H1K1	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Maturation of replicase proteins	1	11420.0×	1e-03	ISCU
Early SARS-CoV-2 Infection Events	1	1038.2×	0.003	ISCU
Mitochondrial iron-sulfur cluster biogenesis	1	815.7×	0.003	ISCU
Translation of Replicase and Assembly of the Replication Transcription Complex	1	815.7×	0.003	ISCU
Maturation of TCA enzymes and regulation of TCA cycle	1	571.0×	0.004	ISCU
Complex III assembly	1	439.2×	0.004	ISCU
SARS-CoV-2 Infection	1	80.4×	0.020	ISCU
SARS-CoV Infections	1	55.4×	0.025	ISCU
Viral Infection Pathways	1	30.8×	0.040	ISCU
Infectious disease	1	24.8×	0.044	ISCU
Disease	1	13.1×	0.076	ISCU

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
negative regulation of iron ion import across plasma membrane	1	16852.0×	4e-04	ISCU
positive regulation of mitochondrial electron transport, NADH to ubiquinone	1	5617.3×	5e-04	ISCU
[4Fe-4S] cluster assembly	1	3370.4×	6e-04	ISCU
[2Fe-2S] cluster assembly	1	1404.3×	0.001	ISCU
iron-sulfur cluster assembly	1	601.9×	0.002	ISCU
intracellular iron ion homeostasis	1	244.2×	0.004	ISCU

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
ISCU	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	ISCU

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)
ISCU	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.