| Knowledge-base field | Curated ISCU-myopathy entry | Ontology suggestions | Evidence type and key references |
|---|---|---|---|
| Disease identity and identifiers | **Hereditary myopathy with lactic acidosis due to ISCU deficiency**; synonyms: **ISCU myopathy**, **iron–sulfur cluster deficiency myopathy**, **Swedish myopathy**, **myopathy with deficiency of succinate dehydrogenase and aconitase**. **MONDO:** MONDO:0009706; **OMIM phenotype:** #255125. Dedicated ICD-10/ICD-11 and MeSH disease codes were not identified; broader mitochondrial/metabolic-myopathy coding is required. Information is aggregated disease-level evidence derived from published patients, families, biopsies, and experimental models—not individual EHR data. | MONDO:0009706 | Curated disease–gene association and human genetic studies (pqac-00000000, pqac-00000002, pqac-00000005). Mochel et al., 2008, PMID:18296749, DOI:10.1016/j.ajhg.2007.12.012. |
| Causal gene and inheritance | **ISCU** (iron–sulfur cluster assembly enzyme; OMIM *611911; Ensembl ENSG00000136003), encoding the mitochondrial scaffold on which nascent Fe–S clusters are assembled. Classical Swedish disease is **autosomal recessive**. A single **de novo heterozygous** p.Gly96Val case supports a possible dominant-negative form, but dominant inheritance remains **provisional** because independent cases are lacking. | GO:0016226 iron–sulfur cluster assembly; GO:0005739 mitochondrion | Human pedigrees, patient tissue, and yeast functional validation (pqac-00000000, pqac-00000005, pqac-00000013, pqac-00000029). Legati et al., 2017, PMID:29079705, DOI:10.1136/jmedgenet-2017-104822. |
| Principal pathogenic variants | **c.418+382G>C** (historically g.7044G>C or IVS5+382G>C): deep-intronic Northern Swedish founder variant; strengthens a cryptic splice acceptor, inserts pseudoexon 4A, creates a premature stop, and markedly lowers functional ISCU in muscle. **c.149G>A (p.Gly50Glu):** recessive missense allele reported in compound heterozygosity with the founder variant. **p.Gly96Val:** heterozygous de novo missense variant with yeast-supported dominant-negative activity; classification/inheritance should remain provisional. Population allele frequencies and current ClinVar assertion details were not established from the retrieved evidence. All are germline. | Sequence Ontology: intron_variant, splice_region_variant, missense_variant | Human molecular genetics and functional studies (pqac-00000001, pqac-00000003, pqac-00000006, pqac-00000008, pqac-00000029). Saha et al., 2014, DOI:10.1074/jbc.M113.526665; Legati et al., 2017, PMID:29079705. |
| Hallmark phenotypes | Usually **childhood-onset**, lifelong severe exercise intolerance with early fatigue, exertional myalgia/cramps, dyspnea, tachycardia or palpitations, and markedly reduced oxidative/work capacity. More strenuous activity can precipitate episodic weakness, rhabdomyolysis, myoglobinuria, and severe lactic acidosis. Weakness may be stable/nonprogressive in classical Swedish disease but slowly progressive with ptosis and wasting in non-founder missense cases. Published samples are too small for defensible percentages; these features are qualitatively common or characteristic. | HP:0003546 exercise intolerance; HP:0003326 muscle weakness; HP:0008947 infantile/childhood muscular weakness; HP:0003323 progressive muscle weakness; HP:0002151 increased serum lactate; HP:0003201 rhabdomyolysis; HP:0002913 myoglobinuria; HP:0001649 tachycardia; HP:0002094 dyspnea; HP:0000508 ptosis; HP:0003236 elevated creatine kinase | Human clinical cohorts and case reports (pqac-00000002, pqac-00000004, pqac-00000005, pqac-00000007, pqac-00000016). Mochel et al., 2008, PMID:18296749; Kollberg et al., 2009, PMID:19567699; Montealegre et al., 2022, DOI:10.1212/NXG.0000000000000648. |
| Tissue specificity and anatomy | Skeletal muscle is the principal affected tissue. For the founder allele, incorrect splicing was approximately **80% in skeletal muscle, 30% in heart, and 10% in liver**, explaining predominant myopathy and relative cardiac/hepatic sparing. Slow-fiber soleus showed especially high mis-splicing in a transgenic system. Cardiac involvement is uncommon in classical disease but has been reported with non-founder variants; exercise-induced pulmonary vascular dysfunction was reported in one homozygous woman. | UBERON:0001134 skeletal muscle tissue; CL:0000187 myocyte; CL:0000748 cardiac muscle cell; GO:0005739 mitochondrion | Human tissue and transgenic/cardiopulmonary evidence (pqac-00000002, pqac-00000012, pqac-00000025). Rawcliffe et al., 2018, DOI:10.1002/mgg3.413. |
| Diagnostic biomarkers and functional tests | Resting or exertional **lactate and pyruvate elevation**, elevated CK during muscle injury, myoglobinuria during attacks, and low peak oxygen uptake/poor muscle oxygen extraction support a metabolic myopathy. **FGF21** may be elevated and is a candidate monitoring biomarker, but it is not disease-specific or formally validated. EMG may be myopathic; normal fibroblast respiration does not exclude disease. | HP:0002151 increased serum lactate; HP:0003236 elevated serum CK; HP:0002913 myoglobinuria; HP:0012378 abnormal circulating enzyme concentration | Human physiology, blood biomarkers, and cell studies (pqac-00000005, pqac-00000007, pqac-00000010, pqac-00000017). Crooks et al., 2014, PMID:23933728, DOI:10.1093/hmg/ddt393. |
| Muscle pathology and biochemical diagnosis | Muscle may show markedly diminished/absent **succinate dehydrogenase (complex II)** staining, severe mitochondrial and cytosolic aconitase deficiency, lesser complex-I and complex-III/Rieske defects, mitochondrial proliferation/type-I-fiber predominance, increased capillary density, and iron-positive mitochondrial inclusions. In studied founder-variant muscle, SDH/complex-II and aconitase activities were approximately **10–20% of control**. Perls’ Prussian-blue staining can demonstrate iron accumulation. | HP:0003737 mitochondrial myopathy; HP:0011924 abnormal mitochondrial morphology; HP:0003548 abnormality of mitochondrial metabolism; GO:0000104 succinate dehydrogenase activity; GO:0003994 aconitate hydratase activity | Human biopsy, histochemistry, enzyme assays, and transcriptomics (pqac-00000002, pqac-00000009, pqac-00000010, pqac-00000014). Mochel et al., 2008, PMID:18296749; Crooks et al., 2014, PMID:23933728. |
| Molecular mechanism | Pathogenic splicing or missense dysfunction **reduces functional ISCU scaffold activity → impairs mitochondrial Fe–S-cluster assembly/transfer → destabilizes Fe–S enzymes, especially aconitase and complex II, with lesser complexes I/III effects → reduces oxidative phosphorylation and oxygen utilization → increases glycolytic pyruvate/lactate production → causes exertional energy failure, pain, weakness, and rhabdomyolysis**. A parallel branch disrupts IRP1/iron regulation and causes mitochondrial iron accumulation; whether iron directly drives myofiber injury is incompletely demonstrated. Tissue-specific splicing is regulated partly by PTBP1. | GO:0016226 iron–sulfur cluster assembly; GO:0006120 mitochondrial electron transport; GO:0006096 glycolytic process; GO:0006879 cellular iron-ion homeostasis; GO:0008380 RNA splicing; GO:0006979 response to oxidative stress | Human muscle, patient myoblasts, biochemical assays, and mechanistic cell studies (pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000012, pqac-00000015). Rawcliffe et al., 2018, DOI:10.1002/mgg3.413. |
| Molecular profiling | Patient-muscle transcriptomics showed induction of **PGC-1α**, mitochondrial biogenesis, fatty-acid oxidation, ketogenic enzyme **HMGCS2**, sulfur-metabolism genes, and **FGF21**, with downregulation of some cytoskeletal/contraction genes. Iron-homeostasis transcripts were altered. These findings indicate compensatory metabolic remodeling rather than a validated diagnostic signature. No disease-specific single-cell, spatial-transcriptomic, lipidomic, epigenomic, or large multi-omics dataset was identified. | GO:0007005 mitochondrion organization; GO:0033539 fatty-acid beta-oxidation using acyl-CoA dehydrogenase; GO:0042776 mitochondrial ATP synthesis coupled proton transport | Human biopsy transcriptomics and cultured-myotube experiments (pqac-00000010, pqac-00000014). Crooks et al., 2014, PMID:23933728, DOI:10.1093/hmg/ddt393. |
| Diagnostic strategy | Confirm with **biallelic ISCU testing** in the classical phenotype: targeted c.418+382G>C analysis is efficient in Northern Swedish ancestry; otherwise use a metabolic/mitochondrial-myopathy panel, WES, or preferably WGS because deep-intronic variants may be missed by routine exome capture. RNA studies from muscle or differentiated myotubes can demonstrate pseudoexon inclusion. Muscle biopsy/enzyme assays are supportive but genetic confirmation is preferred. CMA, karyotype, FISH, mtDNA-only testing, and repeat-expansion testing are not first-line unless another diagnosis is suspected. | NCIT:C15709 genetic testing; NCIT:C101294 whole-genome sequencing; NCIT:C101295 whole-exome sequencing; NCIT:C15189 muscle biopsy | Human diagnostic studies and expert reviews (pqac-00000004, pqac-00000005, pqac-00000008). Mochel et al., 2008, PMID:18296749. |
| Management | No approved disease-modifying treatment exists. Current care is supportive: individualized activity pacing; avoidance of unaccustomed maximal exertion, dehydration, and prolonged fasting; specialist-supervised submaximal aerobic conditioning where tolerated; physical/occupational therapy; and monitoring of CK, renal function, electrolytes, lactate, cardiac status, and respiratory function according to phenotype. Acute rhabdomyolysis requires standard urgent management with cessation of exertion, hydration, electrolyte/renal surveillance, and treatment of acidosis. Disease-specific controlled outcome data are unavailable. | NCIT:C15311 supportive care; NCIT:C94626 physical therapy; NCIT:C15367 rehabilitation; NCIT:C15368 exercise therapy | Expert review and clinical-practice extrapolation; direct ISCU trial evidence is absent (pqac-00000017, pqac-00000023). |
| Experimental therapy | A mutation-directed **18-mer splice-switching ASO** (sequence GATTCTGAAATGAAAGAT; 2′-MOE/constrained-ethyl chemistries) reduced pseudoexon inclusion and restored ISCU protein in patient fibroblasts at roughly **25–30 nM** and myotubes at about **200 nM**. It improved SDHB/complex-II and aconitase activities and normalized excess succinate. This is compelling **in-vitro rescue only**: no ISCU-specific human trial, clinical response rate, safety dataset, regulatory approval, gene therapy, or cell therapy was identified. A 2024 review continues to describe this approach as a promising candidate rather than clinical therapy. | NCIT:C178220 antisense oligonucleotide therapy; NCIT:C179456 splice-switching oligonucleotide | Patient-derived cell experiments and 2024 therapeutic review (pqac-00000015, pqac-00000018, pqac-00000021, pqac-00000022). Holmes-Hampton et al., 2016, PMID:27729411, DOI:10.1093/hmg/ddw338. |
| Epidemiology and population genetics | Ultra-rare, with most classical cases originating in **Northern Sweden** and sharing a founder haplotype; isolated Scandinavian and non-Scandinavian cases carry other genotypes. A historical Northern Swedish carrier estimate of about **1:188** has been reported in the literature, but a contemporary population-based prevalence, incidence, sex ratio, and validated global carrier frequency are **unavailable**. Both sexes are affected. Penetrance appears high in reported biallelic cases, but formal age-dependent estimates are lacking; expressivity varies, especially across genotypes. | Orphan disease; founder variant | Founder mapping, published families, and reviews (pqac-00000002, pqac-00000003, pqac-00000006, pqac-00000008). Mochel et al., 2008, PMID:18296749. |
| Prognosis | Classical founder-associated disease is chronic and often described as relatively nonprogressive between attacks, but produces substantial lifelong exercise limitation and episodic risk of severe weakness, acidosis, rhabdomyolysis, and renal complications. Missense-associated disease may be more progressive and include ptosis, distal weakness, wasting, anemia, or cardiac involvement. Survival rates, life expectancy, mortality rates, validated quality-of-life scores, and prognostic models are **not available**. | HP:0031796 episodic; HP:0003676 progressive disorder | Human clinical series and case reports (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000016). Legati et al., 2017, PMID:29079705. |
| Prevention and counseling | Primary prevention after conception is not available. Secondary/tertiary prevention includes molecular diagnosis, cascade testing, education about rhabdomyolysis warning signs, personalized exertion plans, hydration, and early treatment of metabolic crises. Autosomal-recessive counseling gives a **25% affected, 50% carrier, 25% unaffected/non-carrier** risk per pregnancy when both parents are carriers. Carrier testing, prenatal diagnosis, and PGT-M are technically feasible once familial variants are known. No newborn-screening program, vaccine, prophylactic drug, or public-health screening program exists. | NCIT:C15278 genetic counseling; NCIT:C92844 carrier testing; NCIT:C17004 prenatal genetic testing; NCIT:C116463 preimplantation genetic testing | Mendelian-risk inference plus established molecular diagnosis; no disease-specific prevention trial identified (pqac-00000003, pqac-00000005). |
| Models and comparative biology | **Patient myoblasts/myotubes** best reproduce muscle-selective mis-splicing, low ISCU, complex-II/aconitase defects, and ASO rescue; fibroblast abnormalities are milder. **Saccharomyces cerevisiae** engineered variants model respiratory growth, Fe–S-enzyme defects, iron accumulation, and p.Gly96Val dominance; ISU1/ISU2 double loss is lethal. Complete mouse Iscu loss is embryonic lethal; human-ISCU transgenic mice model tissue-specific splicing, but the founder intronic sequence is human/primate-specific, limiting conventional knock-in modeling. No well-established naturally occurring veterinary ISCU myopathy, affected breed, zoonotic transmission, organoid model, or disease-specific zebrafish model was identified. | NCBI Taxon:9606 Homo sapiens; NCBI Taxon:10090 Mus musculus; NCBI Taxon:4932 Saccharomyces cerevisiae; CL:0000187 myocyte | Patient-cell, transgenic-mouse, and engineered-yeast evidence (pqac-00000025, pqac-00000026, pqac-00000027, pqac-00000028, pqac-00000029, pqac-00000031). Saha et al., 2014, DOI:10.1074/jbc.M113.526665; Holmes-Hampton et al., 2016, PMID:27729411. |


*Table: Compact evidence table covering identity, genetics, phenotype, mechanism, diagnosis, management, epidemiology, and experimental models. Quantitative findings and evidence limitations are explicitly labeled for knowledge-base curation.*