ISCU Myopathy: Comprehensive Disease-Characteristics Report

Scope and evidence date. This report synthesizes retrieved literature through 2024. ISCU myopathy is ultra-rare; consequently, much of the evidence consists of Northern Swedish families, isolated case reports, patient muscle/cell studies, and engineered yeast or mouse systems rather than large cohorts. Frequencies, penetrance estimates, survival statistics, and treatment-response rates are generally unavailable. No disease-specific interventional trial was identified in the ClinicalTrials.gov search.

Executive summary

ISCU myopathy is principally an autosomal-recessive mitochondrial metabolic myopathy caused by deficient function of the iron–sulfur-cluster scaffold protein ISCU. Classical disease is strongly associated with the Northern Swedish founder variant ISCU c.418+382G>C, which activates cryptic splicing and causes muscle-predominant pseudoexon inclusion. Hallmarks are childhood-onset severe exercise intolerance, exertional tachycardia and dyspnea, lactic acidosis, and episodes of rhabdomyolysis/myoglobinuria. Muscle demonstrates profound succinate-dehydrogenase and aconitase deficiency and mitochondrial iron accumulation. No approved disease-modifying therapy exists; a splice-switching antisense oligonucleotide has corrected molecular and metabolic defects in patient cells but has not entered demonstrated clinical use. (mochel2008splicemutationin pages 1-2, selvanathan2022mitochondrialironsulfurcluster pages 3-4, holmeshampton2016useofantisense pages 1-2, holmeshampton2016useofantisense pages 7-7)

The following table is a compact knowledge-base-ready summary; the narrative thereafter provides qualifications and mechanistic detail.

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.

1. Disease information

Definition and identifiers

Preferred name: hereditary myopathy with lactic acidosis due to ISCU deficiency.
Major synonyms: ISCU myopathy; iron–sulfur cluster deficiency myopathy; Swedish myopathy; hereditary myopathy with lactic acidosis; myopathy with deficiency of succinate dehydrogenase and aconitase.

• MONDO: MONDO:0009706.
• OMIM phenotype: 255125.
• Gene: ISCU, OMIM *611911; Ensembl ENSG00000136003; approved name “iron-sulfur cluster assembly enzyme.” Open Targets reports one strongly supported ISCU–disease association, underpinned by human genetic literature including PMIDs 18296749, 19567699, 20206689, and 29079705. (OpenTargets Search: ISCU myopathy-ISCU)
• ICD/MeSH: no dedicated disease-specific ICD-10, ICD-11, or MeSH identifier was established in the retrieved evidence. Coding generally requires broader mitochondrial, metabolic-myopathy, lactic-acidosis, or rhabdomyolysis categories.

The evidence is aggregated disease-level information derived from published pedigrees, individual patients, muscle biopsies, physiological studies, and experimental systems; it is not an EHR-derived patient dataset.

2. Etiology, risk, and protective factors

The initiating cause is a germline pathogenic ISCU variant. In classical disease, biallelic loss of functional ISCU impairs mitochondrial Fe–S-cluster assembly. The Northern Swedish founder allele is c.418+382G>C, historically reported as g.7044G>C or IVS5+382G>C. It strengthens a cryptic splice acceptor, inserts pseudoexon 4A, introduces a premature termination signal, and markedly reduces functional transcript and protein in skeletal muscle. (mochel2008splicemutationin pages 2-4, holmeshampton2016useofantisense pages 1-2, rawcliffe2018ptbp1actsas pages 1-2)

Additional reported alleles include c.149G>A (p.Gly50Glu) in compound heterozygosity with the founder allele and a single de novo heterozygous p.Gly96Val allele. Yeast experiments supported pathogenicity and a dominant-negative action of p.Gly96Val, but dominant ISCU myopathy remains provisional because independent human cases have not substantiated it. (vanlander2018clinicalandgenetic pages 1-3, selvanathan2022mitochondrialironsulfurcluster pages 3-4, legati2017anovelde pages 5-7)

Risk factors: biallelic pathogenic variants, Northern Swedish ancestry, and family history are the only established disease-occurrence risks. Strenuous or unaccustomed exercise is a trigger for attacks, not a cause of the inherited disorder. Dehydration, fasting, intercurrent illness, and heat are clinically plausible metabolic stressors, but disease-specific quantitative interaction studies were not found.

No validated genetic protective variants or modifier genes are known. PTBP1 represses aberrant ISCU splicing experimentally; its tissue-specific abundance may modify expression, but it is not an established protective genotype. Approximately 80% incorrect splicing in skeletal muscle versus 30% in heart and 10% in liver offers a mechanistic explanation for tissue selectivity. (rawcliffe2018ptbp1actsas pages 1-2)

Environmental toxins, infections, smoking, alcohol, occupation, radiation, and diet are not established causes. Hypoxia can suppress ISCU through the miR-210–ISCU axis in pulmonary vascular biology, but this acquired mechanism should not be conflated with inherited ISCU myopathy. (tong201710ironsulfurproteins pages 31-34)

3. Phenotypes

The classical phenotype begins in childhood and is chronic/lifelong. Severe intolerance to even modest exercise causes fatigue, muscle pain or cramps, dyspnea, tachycardia, and palpitations. More intense activity may cause acute weakness, painful swelling, rhabdomyolysis, myoglobinuria, and severe lactic acidosis. Maximal work and oxidative capacity are markedly reduced. Suggested terms include HP:0003546 exercise intolerance, HP:0003326 muscle weakness, HP:0001649 tachycardia, HP:0002094 dyspnea, HP:0002151 increased serum lactate, HP:0003201 rhabdomyolysis, and HP:0002913 myoglobinuria. (mochel2008splicemutationin pages 1-2, selvanathan2022mitochondrialironsulfurcluster pages 3-4, tong201710ironsulfurproteins pages 31-34)

Non-founder missense disease can broaden the phenotype. The p.Gly96Val patient had delayed walking, falls, hypotonia, wasting, absent reflexes, bilateral ptosis, distal weakness, elevated CK, anemia/leukopenia, and episodic inability to walk; progression was slow with partial recovery between episodes and preserved cognition. Suggested additional terms are HP:0000508 ptosis, HP:0003236 elevated CK, HP:0001252 hypotonia, and HP:0003202 muscle atrophy. (legati2017anovelde pages 2-3)

Reliable percentages for symptoms cannot be assigned because published cohorts are tiny and genotype-enriched. Classical disease is often relatively stable between metabolic attacks, whereas missense-associated cases may be slowly progressive. Quality-of-life instruments such as EQ-5D, SF-36, or PROMIS have not been systematically reported; nevertheless, profound restriction of walking, exercise, employment, and daily activity indicates substantial functional burden.

4. Genetic and molecular information

ISCU is a nuclear gene encoding a mitochondrial scaffold on which nascent [2Fe–2S] clusters are assembled before transfer to recipient proteins. Suggested annotation: GO:0016226 iron–sulfur cluster assembly and GO:0005739 mitochondrion. (vanlander2018clinicalandgenetic pages 1-3, tong201710ironsulfurproteins pages 31-34)

The founder and missense alleles are germline. The founder variant is a deep-intronic splice-altering loss-of-function allele; p.Gly50Glu impairs scaffold function; p.Gly96Val behaves dominantly in yeast, including impaired respiratory growth, reduced aconitase and complex-II activity, increased iron, and approximately 30% lower iron binding. Current gnomAD frequencies and variant-specific contemporary ClinVar classifications were not established from the retrieved texts and should be imported directly from those databases before production curation. (saha2014thepresenceof pages 1-2, legati2017anovelde pages 5-7)

No recurrent chromosomal abnormality, somatic ISCU lesion, germline mosaicism, anticipation, or disease-defining epigenetic signature is known. PTBP1, and experimentally IGF2BP1, regulate aberrant splicing and are candidate expression modifiers, not proven Mendelian modifier genes.

5. Environmental and lifestyle information

No environmental agent or pathogen causes ISCU myopathy. Exercise is physiologically beneficial in many mitochondrial myopathies but excessive exertion can precipitate rhabdomyolysis in ISCU deficiency. Therefore, lifestyle advice must balance avoidance of maximal exertion with carefully supervised, submaximal conditioning. (holmeshampton2016useofantisense pages 5-6, selvanathan2022mitochondrialironsulfurcluster pages 8-8)

There is no evidence that smoking cessation, alcohol avoidance, or a specific diet prevents the genotype, although general mitochondrial-care principles favor adequate hydration, avoidance of prolonged fasting, and prompt management of illness. These are expert-practice extrapolations rather than trial-proven ISCU interventions.

6. Mechanism and pathophysiology

Ordered causal chain

1. Biallelic c.418+382G>C leads to activation of a cryptic splice acceptor and muscle-predominant pseudoexon 4A inclusion; alternatively, pathogenic missense variation leads to dysfunctional ISCU scaffold activity. (holmeshampton2016useofantisense pages 1-2, legati2017anovelde pages 1-2)
2. Aberrant transcript/protein results in reduced functional mitochondrial ISCU, especially in skeletal myofibers. (rawcliffe2018ptbp1actsas pages 1-2)
3. Reduced ISCU scaffold function leads to impaired assembly and delivery of Fe–S clusters to apoproteins. (tong201710ironsulfurproteins pages 31-34)
4. Fe–S-cluster deficiency results in severe loss of mitochondrial and cytosolic aconitase and complex-II/SDH activity, with lesser complex-I and complex-III/Rieske impairment. In founder-variant muscle, aconitase/complex-II activity was reported at roughly 10–20% of control. (crooks2014elevatedfgf21secretion pages 1-2, holmeshampton2016useofantisense pages 1-2)
5. Respiratory-chain failure leads to poor muscle oxygen extraction, reduced oxidative phosphorylation, and compensatory glycolytic flux. (tong201710ironsulfurproteins pages 31-34)
6. Increased reliance on glycolysis results in exercise-induced pyruvate and lactate accumulation and metabolic acidosis. (holmeshampton2016useofantisense pages 1-2, rawcliffe2018ptbp1actsas pages 1-2)
7. ATP insufficiency during exertion leads to fatigue, cramps, weakness, dyspnea, tachycardia, and—under severe stress—myofiber breakdown, rhabdomyolysis, and myoglobinuria. (mochel2008splicemutationin pages 1-2, crooks2014elevatedfgf21secretion pages 1-2)
8. Parallel branch: impaired aconitase/IRP1 and Fe–S homeostasis leads to dysregulated iron handling and mitochondrial iron accumulation; iron-mediated oxidative injury is biologically plausible but not fully demonstrated as the proximate cause of human myofiber necrosis. (montealegre2022fdx2andiscu pages 1-2, crooks2014elevatedfgf21secretion pages 3-4)
9. Compensatory branch: energetic stress results in PGC-1α-driven mitochondrial remodeling, increased capillarity/type-I fibers, fatty-acid oxidation and ketogenic enzymes, and FGF21 secretion. (crooks2014elevatedfgf21secretion pages 1-2, crooks2014elevatedfgf21secretion pages 3-4)

The primary cell is the skeletal myocyte/myofiber (CL:0000187 myocyte); mitochondria are the key compartment. Relevant processes include GO:0016226 Fe–S-cluster assembly, GO:0006120 mitochondrial electron transport, GO:0006096 glycolysis, GO:0006879 cellular iron-ion homeostasis, and GO:0008380 RNA splicing.

Human muscle transcriptomics showed induction of mitochondrial, fatty-acid-oxidation, sulfur-metabolism, PGC-1α, HMGCS2, and FGF21 programs, with reduced expression of some contraction/cytoskeletal genes. These are compensatory profiles, not validated diagnostic classifiers. No disease-specific single-cell, spatial-transcriptomic, lipidomic, epigenomic, CRISPR-screen, or integrated multi-omics study was identified. (crooks2014elevatedfgf21secretion pages 1-2, crooks2014elevatedfgf21secretion pages 3-4)

7. Anatomical structures affected

The principal organ is skeletal muscle (UBERON:0001134), especially oxidative myofibers. The relevant subcellular site is the mitochondrial matrix/inner-membrane respiratory machinery. Muscle may display type-I-fiber predominance, mitochondrial proliferation, increased capillary density, reduced SDH staining, and iron-positive mitochondrial inclusions. (mochel2008splicemutationin pages 1-2, crooks2014elevatedfgf21secretion pages 1-2)

The heart and vascular smooth muscle are relatively spared in classical founder disease, consistent with less aberrant splicing, although cardiomyopathy or pulmonary vascular dysfunction can occur in broader ISCU-associated phenotypes. There is no characteristic lateralization; weakness is systemic and generally bilateral. CNS involvement is not typical of classical Swedish disease. (mochel2008splicemutationin pages 1-2, selvanathan2022mitochondrialironsulfurcluster pages 3-4)

8. Temporal development

Onset is usually childhood, insidious, and exercise-linked. Classical disease is chronic and frequently described as nonprogressive or slowly changing between crises, but severe attacks are episodic. There is no formal staging system. Missense cases may progress from early fatigability and falls to ptosis, distal weakness, and wasting. (legati2017anovelde pages 1-2, legati2017anovelde pages 2-3)

Critical periods are metabolic stress episodes—strenuous activity, illness, dehydration, or fasting—when energy demand exceeds oxidative capacity. Recovery between attacks can be substantial, but cumulative disability and persistent exercise intolerance remain. Spontaneous molecular remission is not described.

9. Inheritance and population

Classical ISCU myopathy is autosomal recessive. Affected Northern Swedish families share a homozygous 12q haplotype, supporting a founder effect. A historical carrier estimate near 1:188 has been cited for Northern Sweden, but no contemporary population-based prevalence, incidence, global carrier frequency, or sex ratio is available. Both sexes can be affected. (mochel2008splicemutationin pages 1-2, saha2014thepresenceof pages 1-2, mochel2008splicemutationin pages 2-4)

Penetrance appears high among reported biallelic patients but has not been formally quantified. Expressivity varies by genotype and tissue-specific splicing. Anticipation has not been reported. Consanguinity is not required because the founder allele can produce homozygosity in an endogamous population.

10. Diagnostics

Clinical suspicion arises from childhood exercise intolerance, disproportionate exertional tachycardia/dyspnea, lactate elevation, and episodic rhabdomyolysis. Useful measurements include CK, lactate/pyruvate at rest and after controlled exercise, renal function and electrolytes during attacks, urine/blood myoglobin, cardiopulmonary exercise testing, and possibly FGF21. FGF21 is supportive but neither specific nor formally validated for ISCU myopathy. (selvanathan2022mitochondrialironsulfurcluster pages 3-4, crooks2014elevatedfgf21secretion pages 1-2, holmeshampton2016useofantisense pages 5-6)

Muscle biopsy may show absent or markedly reduced SDH staining, aconitase deficiency, iron-positive mitochondria on Perls’ staining, and respiratory-chain defects. Fibroblast respiration can be normal and therefore does not exclude disease. (selvanathan2022mitochondrialironsulfurcluster pages 3-4, montealegre2022fdx2andiscu pages 1-2)

Genetic strategy: targeted c.418+382G>C testing is efficient with Northern Swedish ancestry. Otherwise, use a mitochondrial/metabolic-myopathy panel or WES, but recognize that routine exome capture may miss deep-intronic alleles; WGS plus RNA analysis is preferable when suspicion remains high. Muscle or differentiated-myotube RNA can demonstrate pseudoexon inclusion. CMA, karyotyping, FISH, repeat-expansion testing, and mtDNA-only analysis are not first-line for a classic ISCU phenotype. (legati2017anovelde pages 2-3, selvanathan2022mitochondrialironsulfurcluster pages 3-4, mochel2008splicemutationin pages 2-4)

Differentials include fatty-acid oxidation disorders, glycogenoses such as McArdle disease, LPIN1/RYR1-related rhabdomyolysis, mitochondrial respiratory-chain disorders, FDX2-related episodic mitochondrial myopathy, and other Fe–S biogenesis defects including FXN, FDX2, NFU1, BOLA3, GLRX5, and CIAO1 disorders. FDX2 disease can resemble ISCU deficiency but may be more severe and lacks the characteristic ISCU-associated muscle iron accumulation. (montealegre2022fdx2andiscu pages 1-2)

No population newborn-screening program or standardized society diagnostic criteria were identified.

11. Outcome and prognosis

Classical disease usually permits survival into adulthood but causes lifelong exercise limitation and recurrent risk of severe metabolic crises. Potential acute complications include rhabdomyolysis, electrolyte abnormalities, acute kidney injury from myoglobinuria, and severe acidosis. Quantitative five- or ten-year survival, mortality, life expectancy, validated disability scales, and quality-of-life scores are unavailable. (legati2017anovelde pages 1-2, mochel2008splicemutationin pages 1-2)

Genotype may be prognostic: founder-associated disease is often relatively stable, while non-founder missense disease can be more progressive and multisystemic. Candidate monitoring markers include CK, lactate/pyruvate, FGF21, exercise capacity, and attack frequency, but none is a validated prognostic model.

12. Treatment and current implementation

There is no approved pharmacotherapy, gene therapy, cell therapy, or surgery that corrects ISCU deficiency. Care is supportive and individualized: activity pacing, avoidance of unaccustomed maximal exertion, specialist-supervised submaximal aerobic conditioning, physical and occupational therapy, and phenotype-directed cardiac/respiratory surveillance. Suggested NCIt concepts include Supportive Care, Physical Therapy, Rehabilitation, and Exercise Therapy. (holmeshampton2016useofantisense pages 5-6, selvanathan2022mitochondrialironsulfurcluster pages 8-8)

Acute rhabdomyolysis requires standard urgent management: stop exertion, assess CK, creatinine, urine output, potassium and acid-base status, provide appropriate hydration, and treat electrolyte disturbances or acidosis. These measures are standard-of-care extrapolations; ISCU-specific comparative trials are absent.

The leading experimental treatment is a splice-switching 18-mer ASO, sequence GATTCTGAAATGAAAGAT, with 2′-MOE/constrained-ethyl chemistry. In patient fibroblasts, approximately 25–30 nM restored ISCU protein; myotubes required about 200 nM. Treatment increased correct transcript and ISCU protein, restored SDHB/complex-II and aconitase activity, and normalized excess succinate. This is mechanistically strong in-vitro evidence, not patient efficacy. (holmeshampton2016useofantisense pages 7-7, holmeshampton2016useofantisense pages 1-2, holmeshampton2016useofantisense pages 2-3)

A 2024 review continued to identify splice-modulating ASOs as promising for inherited metabolic diseases, including ISCU myopathy, but no ISCU-specific human trial, response rate, safety dataset, or regulatory approval was found. The expert assessment is therefore that the founder allele is unusually tractable for precision splice correction, while delivery to widespread skeletal muscle, durability, toxicity, and an ultra-rare trial design remain major barriers.

13. Prevention

The inherited genotype cannot be prevented through lifestyle modification. Secondary prevention consists of early molecular diagnosis, family cascade testing, and avoidance of diagnostic delay. Tertiary prevention includes education about rhabdomyolysis warning signs, hydration, avoidance of prolonged fasting and unaccustomed maximal exertion, and prompt treatment of metabolic crises.

For two heterozygous parents, each pregnancy has a 25% affected, 50% carrier, and 25% unaffected/non-carrier probability. Carrier testing, prenatal diagnosis, and PGT-M are technically feasible after familial variants are established. No vaccine, prophylactic drug, newborn-screening program, or population-wide carrier program is available.

14. Other species and natural disease

No well-established naturally occurring ISCU-myopathy syndrome, affected veterinary breed, or zoonotic issue was identified. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), and Saccharomyces cerevisiae (4932). The Fe–S pathway is evolutionarily conserved, but the common human founder mutation lies in a human/primate-specific intronic sequence, limiting direct cross-species modeling. (holmeshampton2016useofantisense pages 5-6)

15. Model organisms and experimental systems

Patient-derived myoblasts differentiated into myotubes are the most disease-relevant model: they reproduce muscle-selective mis-splicing, low ISCU, complex-II/aconitase defects, excess succinate, and ASO rescue. Fibroblasts are easier to use but show milder and sometimes normal oxidative phenotypes, limiting negative-result interpretation. (holmeshampton2016useofantisense pages 1-1, holmeshampton2016useofantisense pages 5-6)

In S. cerevisiae, ISU1/ISU2 double deletion is lethal. Engineered homologous variants permit testing of respiratory growth, Fe–S enzymes, iron handling, and dominance. The isu1-G97V model supported pathogenicity and a dominant-negative action corresponding to human p.Gly96Val. Limitations include differences in targeting sequences, expression, protein conservation, and inability to model human tissue-specific splicing. (saha2014thepresenceof pages 2-3, berti2021thepowerof pages 6-7, legati2017anovelde pages 5-7)

Complete mouse Iscu loss is embryonic lethal. Human-ISCU transgenic mice have been useful for studying tissue-specific splicing, including high mis-splicing in slow-fiber soleus, but a conventional knock-in of the Swedish allele is difficult because its intronic context is human-specific. No validated disease-specific zebrafish, organoid, or spontaneous animal model was identified. (rawcliffe2018ptbp1actsas pages 1-2, holmeshampton2016useofantisense pages 5-6)

Recent developments and evidence gaps

Research published in 2023–2024 primarily advanced the broader Fe–S-biogenesis and splice-therapeutics fields rather than producing new ISCU patient cohorts. The most directly relevant recent development is continued recognition of ISCU pseudoexon correction as an actionable ASO strategy. Important unmet needs are an international natural-history registry, standardized exercise and attack outcomes, current allele-frequency analysis, systematic cardiopulmonary surveillance, patient-reported quality-of-life data, a humanized in-vivo model, and first-in-human muscle-directed splice-correction studies.

Key publications and URLs

• Mochel et al. March 2008, American Journal of Human Genetics, PMID 18296749, DOI: https://doi.org/10.1016/j.ajhg.2007.12.012. The study identified the shared ISCU splice mutation and stated that it “causes myopathy with exercise intolerance.” (mochel2008splicemutationin pages 1-2)
• Kollberg et al. August 2009, Brain, PMID 19567699, DOI: https://doi.org/10.1093/brain/awp152. Clinical/genetic expansion of ISCU deficiency, including a new mutation.
• Crooks et al. 2014; advance publication 13 August 2013, Human Molecular Genetics, PMID 23933728, DOI: https://doi.org/10.1093/hmg/ddt393. The authors identified “elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression” as hallmarks of Fe–S depletion in human skeletal muscle. (crooks2014elevatedfgf21secretion pages 1-2)
• Saha et al. 11 April 2014, Journal of Biological Chemistry, DOI: https://doi.org/10.1074/jbc.M113.526665. The abstract concluded that reduced respiration from diminished Fe–S-cluster synthesis produces muscle weakness. (saha2014thepresenceof pages 1-2)
• Holmes-Hampton et al. December 2016, Human Molecular Genetics, PMID 27729411, DOI: https://doi.org/10.1093/hmg/ddw338. The authors reported ASO correction of the splicing error in patient cell lines, with restoration of Fe–S-dependent biochemical functions. (holmeshampton2016useofantisense pages 7-7, holmeshampton2016useofantisense pages 2-3)
• Legati et al. 2017, Journal of Medical Genetics 54:815–824, PMID 29079705, DOI: https://doi.org/10.1136/jmedgenet-2017-104822. First reported de novo heterozygous p.Gly96Val case; dominant inheritance remains provisional. (legati2017anovelde pages 1-2)
• Rawcliffe et al. September 2018, Molecular Genetics & Genomic Medicine, DOI: https://doi.org/10.1002/mgg3.413. PTBP1 was shown to repress aberrant tissue-specific ISCU splicing. (rawcliffe2018ptbp1actsas pages 1-2)
• Montealegre et al. February 2022, Neurology Genetics 8:e648, DOI: https://doi.org/10.1212/NXG.0000000000000648. Human comparison of ISCU and FDX2 rhabdomyolysis highlighted distinct severity and muscle iron regulation. (montealegre2022fdx2andiscu pages 1-2)
• Chen et al. January 2024, BioDrugs 38:177–203, DOI: https://doi.org/10.1007/s40259-024-00644-7. Contemporary review of splice-modulating ASOs for inherited metabolic disease; ISCU remains a promising preclinical candidate rather than an approved therapy.

References

1. (mochel2008splicemutationin pages 1-2): Fanny Mochel, Melanie A. Knight, Wing-Hang Tong, Dena Hernandez, Karen Ayyad, Tanja Taivassalo, Peter M. Andersen, Andrew Singleton, Tracey A. Rouault, Kenneth H. Fischbeck, and Ronald G. Haller. Splice mutation in the iron-sulfur cluster scaffold protein iscu causes myopathy with exercise intolerance. American journal of human genetics, 82 3:652-60, Mar 2008. URL: https://doi.org/10.1016/j.ajhg.2007.12.012, doi:10.1016/j.ajhg.2007.12.012. This article has 278 citations and is from a highest quality peer-reviewed journal.

2. (selvanathan2022mitochondrialironsulfurcluster pages 3-4): Arthavan Selvanathan and Bindu Parayil Sankaran. Mitochondrial iron-sulfur cluster biogenesis and neurological disorders. Jan 2022. URL: https://doi.org/10.1016/j.mito.2021.10.004, doi:10.1016/j.mito.2021.10.004. This article has 22 citations and is from a peer-reviewed journal.

3. (holmeshampton2016useofantisense pages 1-2): Gregory P. Holmes-Hampton, Daniel R. Crooks, Ronald G. Haller, Shuling Guo, Susan M. Freier, Brett P. Monia, and Tracey A. Rouault. Use of antisense oligonucleotides to correct the splicing error in iscu myopathy patient cell lines. Human molecular genetics, 25 23:5178-5187, Dec 2016. URL: https://doi.org/10.1093/hmg/ddw338, doi:10.1093/hmg/ddw338. This article has 14 citations and is from a domain leading peer-reviewed journal.

4. (holmeshampton2016useofantisense pages 7-7): Gregory P. Holmes-Hampton, Daniel R. Crooks, Ronald G. Haller, Shuling Guo, Susan M. Freier, Brett P. Monia, and Tracey A. Rouault. Use of antisense oligonucleotides to correct the splicing error in iscu myopathy patient cell lines. Human molecular genetics, 25 23:5178-5187, Dec 2016. URL: https://doi.org/10.1093/hmg/ddw338, doi:10.1093/hmg/ddw338. This article has 14 citations and is from a domain leading peer-reviewed journal.

5. (OpenTargets Search: ISCU myopathy-ISCU): Open Targets Query (ISCU myopathy-ISCU, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

6. (legati2017anovelde pages 1-2): Andrea Legati, Aurelio Reyes, Camilla Ceccatelli Berti, Oliver Stehling, Silvia Marchet, Costanza Lamperti, Alberto Ferrari, Alan J Robinson, Ulrich Mühlenhoff, Roland Lill, Massimo Zeviani, Paola Goffrini, and Daniele Ghezzi. A novel de novo dominant mutation in iscu associated with mitochondrial myopathy. JournalArticle, Feb 2017. URL: https://doi.org/10.17863/cam.18560, doi:10.17863/cam.18560. This article has 45 citations.

7. (legati2017anovelde pages 5-7): Andrea Legati, Aurelio Reyes, Camilla Ceccatelli Berti, Oliver Stehling, Silvia Marchet, Costanza Lamperti, Alberto Ferrari, Alan J Robinson, Ulrich Mühlenhoff, Roland Lill, Massimo Zeviani, Paola Goffrini, and Daniele Ghezzi. A novel de novo dominant mutation in iscu associated with mitochondrial myopathy. JournalArticle, Feb 2017. URL: https://doi.org/10.17863/cam.18560, doi:10.17863/cam.18560. This article has 45 citations.

8. (vanlander2018clinicalandgenetic pages 1-3): A. V. Vanlander and R. Van Coster. Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway. Journal of Biological Inorganic Chemistry, 23:495-506, Apr 2018. URL: https://doi.org/10.1007/s00775-018-1550-z, doi:10.1007/s00775-018-1550-z. This article has 33 citations and is from a peer-reviewed journal.

9. (saha2014thepresenceof pages 1-2): Prasenjit Prasad Saha, S.K.Praveen Kumar, Shubhi Srivastava, Devanjan Sinha, Gautam Pareek, and Patrick D'Silva. The presence of multiple cellular defects associated with a novel g50e iron-sulfur cluster scaffold protein (iscu) mutation leads to development of mitochondrial myopathy. Journal of Biological Chemistry, 289(15):10359-10377, Apr 2014. URL: https://doi.org/10.1074/jbc.m113.526665, doi:10.1074/jbc.m113.526665. This article has 43 citations and is from a domain leading peer-reviewed journal.

10. (mochel2008splicemutationin pages 2-4): Fanny Mochel, Melanie A. Knight, Wing-Hang Tong, Dena Hernandez, Karen Ayyad, Tanja Taivassalo, Peter M. Andersen, Andrew Singleton, Tracey A. Rouault, Kenneth H. Fischbeck, and Ronald G. Haller. Splice mutation in the iron-sulfur cluster scaffold protein iscu causes myopathy with exercise intolerance. American journal of human genetics, 82 3:652-60, Mar 2008. URL: https://doi.org/10.1016/j.ajhg.2007.12.012, doi:10.1016/j.ajhg.2007.12.012. This article has 278 citations and is from a highest quality peer-reviewed journal.

11. (legati2017anovelde pages 2-3): Andrea Legati, Aurelio Reyes, Camilla Ceccatelli Berti, Oliver Stehling, Silvia Marchet, Costanza Lamperti, Alberto Ferrari, Alan J Robinson, Ulrich Mühlenhoff, Roland Lill, Massimo Zeviani, Paola Goffrini, and Daniele Ghezzi. A novel de novo dominant mutation in iscu associated with mitochondrial myopathy. JournalArticle, Feb 2017. URL: https://doi.org/10.17863/cam.18560, doi:10.17863/cam.18560. This article has 45 citations.

12. (montealegre2022fdx2andiscu pages 1-2): Sebastian Montealegre, Elise Lebigot, Hugo Debruge, Norma Romero, Bénédicte Héron, Pauline Gaignard, Antoine Legendre, Apolline Imbard, Stéphanie Gobin, Emmanuelle Lacène, Patrick Nusbaum, Arnaud Hubas, Isabelle Desguerre, Aude Servais, Pascal Laforêt, Peter van Endert, François Jérome Authier, Cyril Gitiaux, and Pascale de Lonlay. Fdx2 and iscu gene variations lead to rhabdomyolysis with distinct severity and iron regulation. Feb 2022. URL: https://doi.org/10.1212/nxg.0000000000000648, doi:10.1212/nxg.0000000000000648. This article has 17 citations.

13. (rawcliffe2018ptbp1actsas pages 1-2): Denise F. R. Rawcliffe, Lennart Österman, Angelica Nordin, and Monica Holmberg. Ptbp1 acts as a dominant repressor of the aberrant tissue‐specific splicing of iscu in hereditary myopathy with lactic acidosis. Molecular Genetics & Genomic Medicine, 6:887-897, Sep 2018. URL: https://doi.org/10.1002/mgg3.413, doi:10.1002/mgg3.413. This article has 8 citations and is from a peer-reviewed journal.

14. (crooks2014elevatedfgf21secretion pages 1-2): Daniel R. Crooks, Thanemozhi G. Natarajan, Suh Young Jeong, Chuming Chen, Sun Young Park, Hongzhan Huang, Manik C. Ghosh, Wing-Hang Tong, Ronald G. Haller, Cathy Wu, and Tracey A. Rouault. Elevated fgf21 secretion, pgc-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. Human molecular genetics, 23 1:24-39, Aug 2014. URL: https://doi.org/10.1093/hmg/ddt393, doi:10.1093/hmg/ddt393. This article has 81 citations and is from a domain leading peer-reviewed journal.

15. (holmeshampton2016useofantisense pages 5-6): Gregory P. Holmes-Hampton, Daniel R. Crooks, Ronald G. Haller, Shuling Guo, Susan M. Freier, Brett P. Monia, and Tracey A. Rouault. Use of antisense oligonucleotides to correct the splicing error in iscu myopathy patient cell lines. Human molecular genetics, 25 23:5178-5187, Dec 2016. URL: https://doi.org/10.1093/hmg/ddw338, doi:10.1093/hmg/ddw338. This article has 14 citations and is from a domain leading peer-reviewed journal.

16. (tong201710ironsulfurproteins pages 31-34): Wing-Hang Tong and T. Rouault. 10 Iron-sulfur proteins and human diseases, pages 227-306. De Gruyter, Sep 2017. URL: https://doi.org/10.1515/9783110479850-010, doi:10.1515/9783110479850-010. This article has 0 citations.

17. (crooks2014elevatedfgf21secretion pages 3-4): Daniel R. Crooks, Thanemozhi G. Natarajan, Suh Young Jeong, Chuming Chen, Sun Young Park, Hongzhan Huang, Manik C. Ghosh, Wing-Hang Tong, Ronald G. Haller, Cathy Wu, and Tracey A. Rouault. Elevated fgf21 secretion, pgc-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. Human molecular genetics, 23 1:24-39, Aug 2014. URL: https://doi.org/10.1093/hmg/ddt393, doi:10.1093/hmg/ddt393. This article has 81 citations and is from a domain leading peer-reviewed journal.

18. (holmeshampton2016useofantisense pages 1-1): Gregory P. Holmes-Hampton, Daniel R. Crooks, Ronald G. Haller, Shuling Guo, Susan M. Freier, Brett P. Monia, and Tracey A. Rouault. Use of antisense oligonucleotides to correct the splicing error in iscu myopathy patient cell lines. Human molecular genetics, 25 23:5178-5187, Dec 2016. URL: https://doi.org/10.1093/hmg/ddw338, doi:10.1093/hmg/ddw338. This article has 14 citations and is from a domain leading peer-reviewed journal.

19. (selvanathan2022mitochondrialironsulfurcluster pages 8-8): Arthavan Selvanathan and Bindu Parayil Sankaran. Mitochondrial iron-sulfur cluster biogenesis and neurological disorders. Jan 2022. URL: https://doi.org/10.1016/j.mito.2021.10.004, doi:10.1016/j.mito.2021.10.004. This article has 22 citations and is from a peer-reviewed journal.

20. (holmeshampton2016useofantisense pages 2-3): Gregory P. Holmes-Hampton, Daniel R. Crooks, Ronald G. Haller, Shuling Guo, Susan M. Freier, Brett P. Monia, and Tracey A. Rouault. Use of antisense oligonucleotides to correct the splicing error in iscu myopathy patient cell lines. Human molecular genetics, 25 23:5178-5187, Dec 2016. URL: https://doi.org/10.1093/hmg/ddw338, doi:10.1093/hmg/ddw338. This article has 14 citations and is from a domain leading peer-reviewed journal.

21. (saha2014thepresenceof pages 2-3): Prasenjit Prasad Saha, S.K.Praveen Kumar, Shubhi Srivastava, Devanjan Sinha, Gautam Pareek, and Patrick D'Silva. The presence of multiple cellular defects associated with a novel g50e iron-sulfur cluster scaffold protein (iscu) mutation leads to development of mitochondrial myopathy. Journal of Biological Chemistry, 289(15):10359-10377, Apr 2014. URL: https://doi.org/10.1074/jbc.m113.526665, doi:10.1074/jbc.m113.526665. This article has 43 citations and is from a domain leading peer-reviewed journal.

22. (berti2021thepowerof pages 6-7): Camilla Ceccatelli Berti, Giulia di Punzio, Cristina Dallabona, Enrico Baruffini, Paola Goffrini, Tiziana Lodi, and Claudia Donnini. The power of yeast in modelling human nuclear mutations associated with mitochondrial diseases. Feb 2021. URL: https://doi.org/10.3390/genes12020300, doi:10.3390/genes12020300. This article has 31 citations.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:23933728 (3 mentions) - Synchronized dynamics of Tipula paludosa metapopulation in a southwestern Scotland agroecosystem: linking pattern to process.
• shared terms: none

Weighed against this report's own most characteristic terms: disease, iscu, gene, genetic, human, clinical, mitochondrial, myopathy, muscle, include, exercise, protein, model, cell, variant, rhabdomyolysis, affected, metabolic, molecular, phenotype.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• NCIT:C15368 (Treatment) (1 mention)

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Taxon.

48 of 52 terms resolved to a current term; the rest could not be looked up either way.