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Inheritance

1

Autosomal recessive HP:0000007

Classic ISCU myopathy is autosomal recessive, with affected northern-Swedish patients homozygous for a shared deep-intronic founder haplotype. Both sexes are affected. The rarer compound-heterozygous and de novo dominant genotypes are recorded in the genetic block.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:19567699 SUPPORT Human Clinical

"the patients are homozygous for a deep intronic IVS5 + 382G>C splicing affecting mutation in ISCU, which encodes the differently spliced cytosolic and mitochondrial iron-sulphur cluster assembly protein IscU."

States the recessive founder genotype (homozygous deep-intronic ISCU variant) that defines classic disease.

PMID:20301757 SUPPORT Other

"Myopathy with deficiency of ISCU is inherited in an autosomal recessive manner."

GeneReviews states the autosomal recessive inheritance pattern.

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Discussions and Knowledge Gaps

2

Why is ISCU myopathy confined to skeletal muscle when ISCU is an essential Fe-S scaffold expressed in every energy-demanding tissue, and which splicing regulators set that restriction?

KNOWLEDGE GAP OPEN iscu_tissue_specific_splicing_muscle_restriction

Attached to

pathophysiology#Skeletal-Muscle-Predominant ISCU Protein Deficiency

The defining paradox of the disease is that a housekeeping defect produces an organ-restricted phenotype. The resolution is that the founder mutation's aberrant splicing is far more efficient in skeletal muscle (the highest fraction of mis-spliced transcript) than in heart or liver, so only muscle becomes severely ISCU-deficient while other tissues retain enough normal protein. The regulators implicated - low muscle levels of the repressor PTBP1, muscle-differentiation factor MyoD enhancing mis-splicing, and other candidate factors (RBM39/IGF2BP1, SRSF3) - explain part but not all of the tissue selectivity, and the quantitative determinants of who mis-splices how much remain incompletely defined. This matters clinically because it is why the heart and CNS are spared, and mechanistically because splice-modulating therapy works by shifting exactly this balance.

Proposed experiments

Tissue-resolved map of ISCU splicing regulators

iscu_splicing_regulator_map

Systematically quantify mis-splicing against levels/activity of PTBP1, MyoD, SRSF3 and candidate factors across human and humanized-mouse tissues to determine which regulators are rate-limiting for the muscle-selective pseudoexon inclusion, and whether modulating them corrects the defect.

Can a faithful in-vivo model of the human founder disease be built when the causal mutation lies in a human/primate-specific intronic sequence and complete Iscu loss is lethal in mice?

HUMAN MODEL MISMATCH OPEN iscu_human_specific_founder_allele_model_gap

Attached to

pathophysiology#ISCU Deep-Intronic Founder Splice Variant pathophysiology#Skeletal-Muscle-Predominant ISCU Protein Deficiency

Model evidence for the disease exists but its translational fidelity is genuinely uncertain. A conventional Iscu knockout is embryonic lethal, so it cannot model the viable muscle-restricted disease; human-ISCU transgenic mice reproduce the tissue-specific splicing but not the founder mutation in its native context, because the deep-intronic sequence that the mutation acts on is human-specific. Yeast (S. cerevisiae isu1) engineered with homologous residues supported pathogenicity and dominance of the missense alleles but cannot model human tissue-specific splicing at all. The open question is whether a humanized knock-in carrying the founder intronic allele can recapitulate the muscle-selective mis-splicing and the exertional metabolic phenotype, which is a prerequisite for testing muscle-directed splice correction in vivo.

Proposed experiments

Humanized ISCU founder-allele knock-in mouse

iscu_humanized_knockin_mouse

Engineer a mouse carrying the human ISCU intronic context with the c.418+382G>C founder variant and test for muscle-predominant pseudoexon inclusion, SDH-negative fibres, mitochondrial iron accumulation and an exertional metabolic phenotype, then use it to evaluate splice-switching ASO delivery and durability in vivo.

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Pathophysiology

11

ISCU Deep-Intronic Founder Splice Variant

The initiating lesion. A single deep-intronic transversion in ISCU, c.418+382G>C (historically IVS5+382G>C), lies well within intron 4/5 and lengthens a polypyrimidine tract, strengthening an otherwise weak cryptic splice acceptor site. Almost all patients are homozygous for this founder allele on a shared northern-Swedish haplotype.

ISCU hgnc:29882

Downstream

Cryptic Splice-Site Activation and Pseudoexon Inclusion The strengthened acceptor site permits inclusion of an aberrant pseudoexon in the processed transcript.

Show evidence (1 reference)

PMID:18304497 SUPPORT Human Clinical

"We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention."

Identifies the causal ISCU splice-acceptor-strengthening mutation, the initiating lesion of the chain.

Cryptic Splice-Site Activation and Pseudoexon Inclusion

The activated cryptic acceptor drives inclusion of a pseudoexon (reported as ~86-100 bp of intronic sequence) into most ISCU transcripts. The inserted sequence shifts the reading frame and introduces a premature stop codon, so the transcript encodes a truncated, non-functional ISCU protein.

aberrant pre-mRNA splicing of ISCU GO:0008380 ↑ INCREASED

Downstream

Skeletal-Muscle-Predominant ISCU Protein Deficiency Because the mis-splicing is far more efficient in skeletal muscle, the truncated transcript translates into severe loss of functional ISCU selectively in muscle.

Show evidence (1 reference)

PMID:19567699 SUPPORT Human Clinical

"The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon."

States that pseudoexon inclusion frameshifts the transcript and creates a premature stop codon.

Skeletal-Muscle-Predominant ISCU Protein Deficiency

ISCU protein is nearly undetectable in patient skeletal muscle while fibroblasts, heart and liver retain substantial normal protein. This tissue selectivity is the pivotal feature of the disease: it is created by the splicing machinery rather than by tissue-specific expression of ISCU, with the highest fraction of mis-spliced transcript in skeletal muscle. Low levels of the splicing repressor PTBP1 in muscle, and muscle-differentiation factors such as MyoD, enhance the mis-splicing; oxidative stress from muscle work further destabilises what little normal ISCU is made.

skeletal muscle fiber CL:0008002

skeletal muscle tissue UBERON:0001134

Animal models

Iscu-null mouse (complete knockout) Mouse fails to recapitulate Complete loss of ISCU is lethal, so the knockout cannot model the viable, muscle-selective partial deficiency that defines human ISCU myopathy.

Human-ISCU transgenic mouse Mouse partially recapitulates Reproduces the muscle-predominant mis-splicing and its inverse correlation with Ptbp1 levels, the mechanism restricting ISCU deficiency to muscle.

Downstream

Failure of Mitochondrial Fe-S Cluster Assembly Loss of the scaffold protein removes the platform on which nascent Fe-S clusters are built.

Show evidence (2 references)

PMID:21165651 SUPPORT Human Clinical

"The highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle, while the normal splice form predominated in patient heart."

Shows the mis-splicing, and hence ISCU deficiency, is concentrated in skeletal muscle and spares the heart.

PMID:23035118 SUPPORT In Vitro

"ISCU protein was nearly undetectable in patient skeletal muscle, but was higher in patient myoblasts, fibroblasts, and lymphoblasts."

Documents severe, muscle-selective loss of ISCU protein relative to other patient cell types.

Failure of Mitochondrial Fe-S Cluster Assembly

ISCU is the scaffold on which nascent iron-sulfur clusters are assembled in complex with the cysteine desulfurase NFS1, frataxin and other factors, then delivered to apoproteins. Severe ISCU loss in muscle therefore impairs assembly and delivery of Fe-S clusters to the enzymes that require them.

iron-sulfur cluster assembly GO:0016226 ↓ DECREASED

Downstream

Deficiency of Fe-S Cluster Enzymes (Aconitase and Complex II) Apoproteins that cannot receive a cluster lose activity, most severely the Fe-S enzymes aconitase and complex II.

Mitochondrial Iron Overload and Oxidative Stress Failed cluster assembly and loss of aconitase/IRP1 function dysregulate cellular iron handling, driving mitochondrial iron accumulation.

Show evidence (1 reference)

PMID:21165651 SUPPORT Human Clinical

"This results in a deficiency of Fe-S cluster proteins, affecting the TCA cycle and the respiratory chain."

States that the splicing defect produces a deficiency of Fe-S cluster proteins hitting the TCA cycle and respiratory chain.

Deficiency of Fe-S Cluster Enzymes (Aconitase and Complex II)

The Fe-S-dependent enzymes lose activity. The greatest deficiencies are in succinate dehydrogenase (respiratory complex II) and aconitase, with lesser impairment of complexes I and III and the Rieske protein. Histochemically this appears as succinate-dehydrogenase-negative muscle fibres.

aconitate hydratase activity GO:0003994 ↓ DECREASED succinate dehydrogenase (complex II) activity GO:0008177 ↓ DECREASED

Downstream

Impaired Oxidative Phosphorylation and TCA Cycle Flux Loss of complex II and aconitase blocks the TCA cycle and respiratory electron flow, limiting NADH-driven oxidative ATP production.

Show evidence (2 references)

PMID:1918374 SUPPORT Human Clinical

"Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase"

The original human description documents combined deficiency of complex II (SDH) and aconitase.

PMID:28007899 SUPPORT BACKGROUND Human Clinical

"The greater deficiencies were observed in succinate dehydrogenase (complex II) and aconitase and to a lesser extent in NADH dehydrogenase (complex I), cytochrome bc1 complex (complex III), and the Rieske protein"

Ranks the enzyme deficiencies, with SDH and aconitase most affected and complexes I/III less so. The sentence sits in this paper's introduction and restates the earlier human-muscle enzymology, so it is graded on the human evidence it describes and tagged as background.

Impaired Oxidative Phosphorylation and TCA Cycle Flux

With the TCA cycle and respiratory chain crippled, muscle mitochondria cannot extract oxygen or generate ATP normally. Exercise testing shows markedly reduced maximal oxygen uptake and impaired muscle oxygen extraction despite a hyperkinetic circulatory response.

oxidative phosphorylation GO:0006119 ↓ DECREASED tricarboxylic acid cycle GO:0006099 ↓ DECREASED

Downstream

Compensatory Glycolysis and Lactate Accumulation Blocked oxidative ATP production forces reliance on glycolysis, generating excess pyruvate and lactate during exertion.

Muscle Energy Failure on Exertion The oxidative deficit means ATP supply cannot meet demand once muscle is worked.

PGC-1alpha Remodeling and FGF21 Secretion Chronic mitochondrial energy starvation triggers a compensatory transcriptional remodeling program.

Show evidence (1 reference)

PMID:1918374 SUPPORT Human Clinical

"The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise"

Directly demonstrates the impaired oxidative metabolism (poor muscle oxygen extraction) that follows respiratory-chain enzyme deficiency.

Mitochondrial Iron Overload and Oxidative Stress

Disrupted Fe-S/aconitase-IRP1 iron sensing dysregulates iron homeostasis, producing intracellular and mitochondrial iron accumulation in muscle (visible as iron-positive fibres on Perls' staining) together with reactive oxygen species. Oxidative stress in turn destabilises residual ISCU, a feed-forward loop that worsens the deficiency. Iron-mediated oxidative injury is a biologically plausible contributor to myofiber damage but has not been demonstrated as the proximate cause of human myofiber necrosis.

intracellular iron ion homeostasis GO:0006879 ↓ DECREASED response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Exertional Rhabdomyolysis and Myoglobinuria Iron-mediated oxidative injury is a plausible contributor to the myofiber breakdown seen with severe exertion, though not proven as its proximate cause.

Show evidence (2 references)

PMID:18304497 SUPPORT Human Clinical

"A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease."

Links ISCU loss to reduced IRP1 and intracellular iron overload in muscle.

PMID:23035118 SUPPORT In Vitro

"oxidative stress resulting from skeletal muscle work destabilizes the small amounts of normal ISCU protein generated in patient skeletal muscles."

Supports the feed-forward loop in which oxidative stress further destabilises residual ISCU.

Compensatory Glycolysis and Lactate Accumulation

Unable to burn substrate oxidatively, muscle shifts to glycolysis, so exertion produces disproportionate rises in venous lactate and pyruvate and, in severe episodes, systemic lactic acidosis.

glycolytic process GO:0006096 ↑ INCREASED

Downstream

Lactic acidosis Severe exertion drives lactate to life-threatening levels, the acidosis in the disease's historical name.

Increased circulating lactate concentration Elevated blood lactate is the routine biochemical correlate.

Show evidence (1 reference)

PMID:1918374 SUPPORT Human Clinical

"with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."

Documents the exaggerated exertional lactate/pyruvate rise arising from the oxidative block.

PGC-1alpha Remodeling and FGF21 Secretion

Chronic Fe-S/energy starvation elicits a coordinated adaptive response in muscle: a shift toward type I oxidative fibres and higher capillary density, up-regulation of PGC-1alpha and fatty-acid-oxidation and ketogenic genes, and secretion of FGF21, which is reflected by elevated circulating FGF21. This is a compensatory branch rather than a step toward injury, and FGF21 is a supportive but non-specific biomarker.

Show evidence (2 references)

PMID:23943793 SUPPORT Human Clinical

"muscle tissue from patients deficient in the Fe-S cluster scaffold protein ISCU showed a predominance of type I oxidative muscle fibers and higher capillary density, enhanced expression of transcriptional co-activator PGC-1α and increased mitochondrial fatty acid oxidation genes."

Documents the PGC-1alpha-driven compensatory remodeling in Fe-S-deficient patient muscle.

PMID:23943793 SUPPORT Human Clinical

"Enhanced muscle FGF21 expression was reflected by elevated circulating FGF21 levels in the patients"

Supports elevated circulating FGF21 as a systemic readout of the compensatory response.

Muscle Energy Failure on Exertion

The functional endpoint at tissue level: skeletal muscle cannot meet the ATP demand of even modest exertion. This produces premature fatigue, cramps and pain, and drives the disproportionate cardiovascular effort (tachycardia, dyspnea, palpitations) by which the body tries to compensate for the oxidative deficit.

Downstream

Exertional Rhabdomyolysis and Myoglobinuria Sustained or intense exertion beyond the muscle's oxidative capacity can break down myofibers.

Exercise intolerance

Exertional dyspnea

Tachycardia

Myalgia

Muscle weakness

Show evidence (1 reference)

PMID:1918374 SUPPORT Human Clinical

"We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations"

Describes the exertional energy-failure phenotype central to the disease.

Exertional Rhabdomyolysis and Myoglobinuria

Under severe or sustained exertion, energy-starved myofibers break down, releasing myoglobin into the circulation and urine. These episodes carry the disease's acute risk (acute kidney injury, hyperkalemia, severe acidosis), with typically full recovery of strength between attacks.

Downstream

Rhabdomyolysis

Myoglobinuria

Show evidence (1 reference)

PMID:21196119 SUPPORT Human Clinical

"Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria."

Names episodic myoglobinuria among the disease manifestations.

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Histopathology

3

Succinate dehydrogenase-negative muscle fibres

Histochemical SDH (complex II) staining is markedly reduced or absent across muscle fibres, the morphological hallmark of the disease and the direct tissue correlate of Fe-S enzyme loss. It is confirmed biochemically in isolated muscle mitochondria. In the single de novo dominant p.Gly96Val case, COX as well as SDH histochemistry was severely reduced, without ragged-red fibres. SDH activity can transiently normalise in regenerating fibres after rhabdomyolysis.

Show evidence (3 references)

PMID:21196119 SUPPORT Human Clinical

"Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease."

Names histochemical SDH deficiency as a morphological hallmark of the disease.

PMID:1918374 SUPPORT Human Clinical

"A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically."

The original description documents SDH deficiency both histochemically and biochemically.

PMID:29079705 SUPPORT Human Clinical

"The main feature was a severe reduction of the histochemical reaction for both COX and SDH, not associated with ragged red fibres."

In the dominant missense case the SDH (and COX) histochemical reduction was the main biopsy feature, without ragged-red fibres.

Iron accumulation in muscle fibres

Perls' (Prussian blue) staining shows punctate iron accumulation within muscle fibres, reflecting the muscle-restricted disturbance of iron homeostasis that follows ISCU loss and reduced IRP1. Iron accumulation is present in muscle but absent in other patient tissues, and is described as a feature that distinguishes ISCU deficiency from some other Fe-S biogenesis defects. Like SDH deficiency, it is minimal in regenerating muscle shortly after rhabdomyolysis.

Show evidence (3 references)

PMID:21196119 SUPPORT Human Clinical

"Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease."

Names iron accumulation in muscle fibres as a morphological hallmark of the disease.

PMID:21165651 SUPPORT Human Clinical

"loss of Fe-S cluster carrying enzymes and accumulation of iron were present in muscle, but absent in other tissues."

Shows the iron accumulation is confined to muscle, matching the tissue restriction of the splicing defect.

PMID:29079705 SUPPORT Human Clinical

"Perls staining demonstrating punctuate accumulation of iron in the patient’s muscle fibres."

Documents Perls-positive punctate iron in muscle fibres in the dominant missense case as well.

Type I oxidative fibre predominance with increased capillary density

Despite the oxidative defect, patient muscle shows a predominance of type I oxidative fibres and higher capillary density, together with up-regulated PGC-1alpha and fatty-acid-oxidation genes. This is read as a compensatory remodelling response to chronic mitochondrial energy starvation rather than as a degenerative change. No cached source quotes mitochondrial proliferation or ragged-red fibres in classic founder-allele disease, so that feature is not recorded here.

Show evidence (1 reference)

PMID:23943793 SUPPORT Human Clinical

"muscle tissue from patients deficient in the Fe-S cluster scaffold protein ISCU showed a predominance of type I oxidative muscle fibers and higher capillary density, enhanced expression of transcriptional co-activator PGC-1α and increased mitochondrial fatty acid oxidation genes."

Reports the type I fibre predominance and higher capillary density in ISCU-deficient muscle.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 1

Tachycardia VERY_FREQUENT HP:0001649

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles"

GeneReviews names exertional tachycardia among the cardinal features.

Genitourinary 1

Myoglobinuria FREQUENT HP:0002913

Show evidence (1 reference)

PMID:18304497 SUPPORT Human Clinical

"A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden"

Names myoglobinuria as a defining feature of the northern-Swedish disease.

Limbs 1

Calf muscle hypertrophy OCCASIONAL HP:0008981

Mechanism unsettled. No cached source links the large calves to a pathophysiology node, so no causal edge is drawn from the pathograph to this phenotype; it is recorded as an observed clinical feature only.

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"Affected individuals usually have near-normal strength; they can have large calves."

GeneReviews notes preserved strength and large calves.

Metabolism 2

Increased circulating lactate concentration HP:0002151

Show evidence (1 reference)

PMID:1918374 SUPPORT Human Clinical

"with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."

Documents the exaggerated exertional rise in blood lactate.

Lactic acidosis HP:0003128

Show evidence (1 reference)

PMID:19567699 SUPPORT Human Clinical

"life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur."

Documents severe metabolic (lactic) acidosis during episodes.

Musculoskeletal 2

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:19567699 SUPPORT Human Clinical

"life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur."

Documents episodic widespread weakness during metabolic crises.

Rhabdomyolysis FREQUENT HP:0003201

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe"

GeneReviews names exertional rhabdomyolysis as a recurrent episodic manifestation.

Respiratory 1

Exertional dyspnea VERY_FREQUENT HP:0002875

Show evidence (1 reference)

PMID:18296749 SUPPORT Human Clinical

"HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations."

Lists exertional dyspnea and palpitations as characteristic features.

Constitutional 2

Exercise intolerance VERY_FREQUENT HP:0003546

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"classically characterized by lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles"

GeneReviews names lifelong exercise intolerance as the classic defining feature.

Myalgia HP:0003326

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles"

GeneReviews names pain of active muscles (myalgia) as a cardinal feature.

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Genetic Associations

1

ISCU

Gene: ISCU hgnc:29882 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:18296749 SUPPORT Human Clinical

"our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family."

Establishes ISCU as the causal gene via the intronic splicing mutation.

PMID:19567699 SUPPORT Human Clinical

"The brothers were compound heterozygous for the deep intronic mutation and had a c.149 G>A missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate."

Documents the compound-heterozygous p.Gly50Glu genotype with a more severe phenotype.

PMID:24573684 SUPPORT In Vitro

"the G50E mutation results in compromised interaction with the sulfur donor NFS1 and the J-protein HSCB, thus impairing the rate of Fe-S cluster synthesis"

Provides the molecular loss-of-function mechanism of the G50E missense allele.

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Medical Actions

4

Avoidance of Sustained Fatiguing Exertion

Action: activity modification (exertion avoidance) Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

The mainstay of management is behavioral: avoiding sustained fatiguing physical exertion, which anecdotally prevents episodes of rhabdomyolysis and myoglobinuria. GeneReviews lists sustained fatiguing physical exertion as the circumstance to avoid.

Mechanism Target:

INHIBITS Exertional Rhabdomyolysis and Myoglobinuria — Avoiding the exertional trigger prevents the myofiber breakdown that causes rhabdomyolysis and its complications.

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"Anecdotal evidence suggests that episodes of rhabdomyolysis and myoglobinuria may be prevented by avoiding sustained fatiguing physical exertion."

GeneReviews states that avoiding sustained exertion may prevent rhabdomyolysis episodes.

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"Agents/circumstances to avoid: Sustained fatiguing physical exertion."

GeneReviews explicitly lists sustained fatiguing exertion as the circumstance to avoid.

Supportive Management of Rhabdomyolysis Episodes

Action: Supportive Care NCIT:C15747

Platform: Other

Acute episodes are managed as for other causes of rhabdomyolysis - hydration and attention to renal function, electrolytes (hyperkalemia) and acidosis - to prevent secondary complications including acute kidney injury from myoglobinuria.

Mechanism Target:

MODULATES Exertional Rhabdomyolysis and Myoglobinuria — Supportive care mitigates the systemic consequences of an episode rather than the underlying Fe-S defect.

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"Management is similar to that for other causes of rhabdomyolysis."

GeneReviews states episode management follows standard rhabdomyolysis care.

Splice-Switching Antisense Oligonucleotide (Experimental)

Action: Pharmacotherapy NCIT:C15986

Platform: Antisense oligonucleotide Splice modulation (exon skipping) Targeting: Unconjugated Chemistry: 2′-MOE

RNA target: ISCU hgnc:29882 ISCU intron 4 mutation site / cryptic splice acceptor (pseudoexon)

An experimental, mechanism-directed therapy. Antisense oligonucleotides targeted to the intronic mutation site block access of splicing factors, suppress pseudoexon inclusion and restore ISCU protein, with recovery of SDHB/complex II and aconitase activity in patient fibroblasts and myotubes. This is in-vitro evidence only; no ISCU-specific human trial exists. The oligonucleotide reported by Holmes-Hampton et al. (2016) is an 18-mer carrying mixed 2'-O-methoxyethyl and constrained-ethyl sugar modifications; the chemistry slot records the 2'-MOE component and the constrained-ethyl component is described here, as the schema asks for mixed-chemistry designs.

Mechanism Target:

INHIBITS Cryptic Splice-Site Activation and Pseudoexon Inclusion — The ASO blocks the splicing factors' access to the mutant intronic site, diminishing aberrant splicing and restoring normal ISCU transcript.

Show evidence (1 reference)

PMID:28007899 SUPPORT In Vitro

"We have shown that ASO treatment diminished aberrant splicing and increased ISCU protein levels in both patient fibroblasts and patient myotubes in a concentration dependent fashion."

Shows the ASO reduces aberrant splicing and restores ISCU protein.

RESTORES Deficiency of Fe-S Cluster Enzymes (Aconitase and Complex II) — Restored ISCU rebuilds Fe-S enzyme activity, recovering complex II (SDHB) and aconitase function.

Show evidence (1 reference)

PMID:28007899 SUPPORT In Vitro

"Mitochondrial and cytosolic aconitase activities increased significantly following ASO treatment in patient myotubes."

Shows recovery of aconitase activity after ASO correction.

Show evidence (2 references)

PMID:28007899 SUPPORT In Vitro

"The current study suggests that ASO treatment may serve as a viable approach to correcting ISCU myopathy in patients."

States the therapeutic rationale, while remaining a preclinical (in-vitro) result.

PMID:21196119 SUPPORT Human Clinical

"an increase of normally spliced ISCU by RNA modulating therapy may be a therapeutic possibility for these patients."

Independent support for RNA-modulating (splice-correcting) therapy as a rational strategy.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Given autosomal recessive inheritance and the founder allele, genetic counseling with carrier and prenatal testing is offered to at-risk families when the familial pathogenic variants are known.

Show evidence (1 reference)

PMID:20301757 SUPPORT Other

"Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased are possible if the pathogenic variants in the family have been identified."

GeneReviews describes carrier and prenatal testing for at-risk relatives.

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Biochemical Markers

4

Elevated lactate (INCREASED)

Context: Blood lactate and pyruvate rise disproportionately with exertion because impaired oxidative metabolism forces glycolytic ATP production; severe episodes produce systemic lactic acidosis.

Pathograph Readouts

Readout Of Compensatory Glycolysis and Lactate Accumulation Positive Diagnostic

Exertional lactate elevation reports the glycolytic shift downstream of the oxidative block.

Show evidence (1 reference)

PMID:1918374 SUPPORT Human Clinical

"with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."

Quantifies the exaggerated exertional lactate/pyruvate response on cycle testing.

Creatine kinase (INCREASED)

Context: Serum creatine kinase rises, particularly during and after rhabdomyolysis episodes; it is a routine but non-specific marker of the muscle breakdown in this disease. No exact-quote abstract source for a CK value was available in the cached references, so this entry carries context only.

Myoglobinuria (INCREASED)

Context: Myoglobin appears in the urine (dark urine) during rhabdomyolysis episodes, a historically noted feature of the Swedish patients.

Pathograph Readouts

Readout Of Exertional Rhabdomyolysis and Myoglobinuria Positive Diagnostic

Urinary myoglobin reports acute rhabdomyolysis.

Show evidence (1 reference)

PMID:21196119 SUPPORT Human Clinical

"Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria."

Names episodic myoglobinuria as a manifestation.

Elevated circulating FGF21 (INCREASED)

Context: Serum FGF21 is elevated in ISCU-deficient patients as the systemic reflection of the muscle-intrinsic energy-starvation response (PGC-1alpha, ketogenic enzyme and FGF21 up-regulation). It is a supportive marker of a mitochondrial myopathy, not a disease-specific test: FGF21 rises across many mitochondrial-disease classes and has not been formally validated as a diagnostic in ISCU myopathy.

Pathograph Readouts

Readout Of PGC-1alpha Remodeling and FGF21 Secretion Positive Diagnostic

Circulating FGF21 reports the compensatory muscle transcriptional program that secretes it.

Show evidence (1 reference)

PMID:23943793 SUPPORT Human Clinical

"Enhanced muscle FGF21 expression was reflected by elevated circulating FGF21 levels in the patients"

Reports elevated circulating FGF21 in ISCU-deficient patients, tied to the muscle expression that drives it.

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Diagnosis

4

Molecular Genetic Testing for Biallelic ISCU Variants

The primary diagnostic test. The diagnosis is established by finding biallelic pathogenic variants in ISCU; in a patient of northern-Swedish ancestry, targeted testing for the deep-intronic founder allele c.418+382G>C is the efficient first step. Because the founder allele lies ~380 bp inside an intron, routine exome capture can miss it, so the intronic region must be screened directly (or genome sequencing used) when exome sequencing is uninformative and suspicion remains; the dominant p.Gly96Val case is the worked example of an exome-first work-up that then screened the founder intronic region explicitly. Molecular confirmation also enables carrier testing of at-risk relatives.

molecular genetic testing (targeted ISCU intronic founder variant, panel, exome or genome sequencing) NCIT:C15709

Results: Identifies biallelic pathogenic ISCU variants, most often homozygosity for the c.418+382G>C founder allele

Show evidence (3 references)

PMID:20301757 SUPPORT Other

"The diagnosis of myopathy with deficiency of ISCU is established in a proband by the identification of biallelic pathogenic variants in ISCU by molecular genetic testing or, if molecular genetic testing is uninformative, by characteristic histochemical and biochemical findings on muscle biopsy."

GeneReviews states that molecular genetic testing for biallelic ISCU variants is the primary route to diagnosis, with muscle biopsy as the fallback.

PMID:29079705 SUPPORT Human Clinical

"We then screened our patient and his parents for the intronic region encompassing the common mutation present in all the previously described ISCU mutant patients but no variant was identified."

Shows that after exome sequencing the founder deep-intronic region was screened as a separate, targeted step, the practical consequence of an allele that exome capture does not cover.

PMID:29079705 SUPPORT Human Clinical

"To exclude that WES could have missed the presence of another deep intronic variant affecting the splicing"

States directly that whole-exome sequencing can miss deep-intronic splice-affecting variants, which is why transcript-level analysis was added to the work-up.

RNA Analysis for ISCU Pseudoexon Inclusion

Transcript analysis complements DNA testing when a deep-intronic allele is suspected but not captured, or when a variant of uncertain effect is found. RT-PCR of ISCU from patient muscle (or differentiated myotubes, where the mis-splicing is enhanced) shows the larger pseudoexon-containing transcript predominating over the normal mitochondrial isoform. Fibroblast RNA can be used to exclude a missed splicing variant but is a weaker substrate, because mis-splicing is far less efficient outside muscle.

ISCU transcript (RT-PCR) analysis for pseudoexon inclusion NCIT:C18473

Results: Aberrant ISCU transcript retaining intronic sequence (pseudoexon) predominates in muscle

Show evidence (3 references)

PMID:18296749 SUPPORT Human Clinical

"In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant."

Demonstrates that patient RNA shows a predominant larger (pseudoexon-containing) transcript, the readout this analysis relies on.

PMID:19567699 SUPPORT Human Clinical

"The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle."

Places the pseudoexon-inclusion readout specifically in muscle transcripts.

PMID:29079705 SUPPORT Human Clinical

"we further investigated patient’s specimen at the transcriptional level. No aberrant mRNA ISCU species was observed in PCR products obtained from fibroblast RNA"

Shows transcript analysis used to exclude a missed intronic splice variant; here fibroblast RNA was the substrate and was negative in the dominant missense case.

Muscle Biopsy with Histochemical and Biochemical Analysis

The fallback confirmatory test when molecular testing is uninformative, and historically the way the disease was defined. Histochemistry shows marked succinate dehydrogenase deficiency with iron accumulation in muscle fibres; biochemistry of isolated muscle mitochondria shows deficient complex II and aconitase activity. The combined histochemical and biochemical picture is described as probably pathognomonic for muscle Fe-S cluster deficiency. Timing matters: a biopsy taken shortly after rhabdomyolysis can show regenerating fibres with normal SDH activity and little iron, so a biopsy during regeneration can be falsely reassuring.

muscle biopsy with SDH histochemistry, iron staining and respiratory-chain enzymology NCIT:C51895

Results: SDH-negative fibres, iron-positive fibres on Perls' stain, deficient complex II and aconitase activity

Show evidence (4 references)

PMID:20301757 SUPPORT Other

"if molecular genetic testing is uninformative, by characteristic histochemical and biochemical findings on muscle biopsy."

GeneReviews positions muscle biopsy histochemistry and biochemistry as the diagnostic route when molecular testing is uninformative.

PMID:19567699 SUPPORT Human Clinical

"had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle iron-sulphur cluster deficiency"

Describes the biopsy phenotype as probably pathognomonic, supporting its confirmatory value.

PMID:21196119 SUPPORT Human Clinical

"A biopsy specimen from a patient, two months after a severe attack of rhabdomyolysis, revealed regenerating muscle with normal succinate dehydrogenase activity and only minor iron accumulation"

Documents the timing caveat, a post-rhabdomyolysis biopsy can lack the diagnostic hallmarks.

+ 1 more reference

Cycle Exercise Testing with Lactate and Oxygen-Uptake Measurement

Supportive physiological testing. Cardiopulmonary cycle exercise testing shows very low maximal oxygen uptake, exaggerated rises in venous lactate and pyruvate relative to oxygen uptake, and a hyperkinetic circulatory response with impaired muscle oxygen extraction, the functional signature of a muscle oxidative defect. It points to a mitochondrial myopathy but does not identify the gene.

cycle exercise testing with venous lactate/pyruvate and oxygen uptake measurement NCIT:C116517

Results: Low maximal oxygen uptake with exaggerated exertional lactate and pyruvate rise

Show evidence (2 references)

PMID:1918374 SUPPORT Human Clinical

"Cycle exercise testing revealed low maximal oxygen uptake"

Reports the low maximal oxygen uptake found on cycle exercise testing in the index patient.

PMID:1918374 SUPPORT Human Clinical

"with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."

Reports the exaggerated exertional lactate/pyruvate response that exercise testing is used to elicit.

📊

Prevalence

1

Northern Sweden (founder population)

Unknown Ultra Rare

An ultra-rare founder disease. Molecularly confirmed classic disease has been described essentially only in patients of northern-Swedish descent homozygous for the founder allele. A carrier frequency near 1:188 for northern Sweden has been cited in reviews but no exact-quote abstract source was available in the cached references, so no rate is recorded here; the measure subtype is left UNKNOWN.

Show evidence (1 reference)

PMID:19567699 SUPPORT Human Clinical

"The disease has so far only been identified in northern Sweden."

Supports the geographically restricted founder distribution underlying the ultra-rare classification.

🐁

Animal Models

2

Iscu-null mouse (complete knockout)

A conventional complete knockout of Iscu in mice is embryonic lethal, so it cannot reproduce the viable, muscle-restricted human disease. This is itself informative: it shows ISCU is essential in all tissues and that the human phenotype's tissue restriction must come from the partial, splicing-based deficiency rather than from tissue-limited ISCU function.

Species

Mouse

Genotype

Iscu homozygous null

Publication

PMID:21165651

Pathograph links

Skeletal-Muscle-Predominant ISCU Protein Deficiency fails to recapitulate fidelity: low observes: organism Complete loss of ISCU is lethal, so the knockout cannot model the viable, muscle-selective partial deficiency that defines human ISCU myopathy.

Limitations: Embryonic lethality precludes any adult muscle phenotype; the model tests essentiality of ISCU, not the human disease, whose tissue restriction depends on residual normal ISCU generated by tissue-specific splicing.

Show evidence (1 reference)

PMID:21165651 SUPPORT Model Organism

"complete loss of ISCU in mice results in early embryonic death"

Documents embryonic lethality of complete Iscu loss, the reason the knockout fails to model the disease.

Show evidence (1 reference)

PMID:21165651 SUPPORT Model Organism

"complete loss of ISCU in mice results in early embryonic death"

Establishes that complete Iscu knockout is not a viable disease model.

Human-ISCU transgenic mouse

Mice transgenic for human ISCU reproduce the tissue-specific mis-splicing seen in patients, with the highest levels of incorrect splicing and the lowest levels of the repressor Ptbp1 in slow (soleus) muscle. They model the splicing regulation that confines the disease to muscle, but not a full disease phenotype.

Species

Mouse

Genotype

Transgenic for human ISCU

Publication

PMID:30209894

Pathograph links

Skeletal-Muscle-Predominant ISCU Protein Deficiency partially recapitulates fidelity: moderate observes: molecular Reproduces the muscle-predominant mis-splicing and its inverse correlation with Ptbp1 levels, the mechanism restricting ISCU deficiency to muscle.

Limitations: The mouse does not carry the human founder mutation in its native context (the intronic sequence is human-specific) and models the splicing regulation rather than the clinical myopathy or metabolic crises.

Show evidence (1 reference)

PMID:30209894 SUPPORT Model Organism

"low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU."

Shows the transgenic-mouse tissue data linking low Ptbp1 to high ISCU mis-splicing.

Show evidence (1 reference)

PMID:30209894 SUPPORT Model Organism

"low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU."

Supports the transgenic mouse as a model of the tissue-specific splicing mechanism.

{ }

Source YAML

click to show

name: ISCU Myopathy
creation_date: "2026-09-04T23:23:40Z"
category: Mendelian
description: >-
  ISCU myopathy (hereditary myopathy with lactic acidosis; myopathy with
  deficiency of succinate dehydrogenase and aconitase; the "Swedish" myopathy
  with exercise intolerance) is an autosomal recessive mitochondrial myopathy of
  iron-sulfur (Fe-S) cluster biogenesis. Almost all patients described to date
  come from a founder population in northern Sweden and are homozygous for a
  single deep-intronic variant in ISCU, c.418+382G>C (historically IVS5+382G>C),
  which strengthens a weak cryptic splice acceptor site so that a pseudoexon
  carrying a premature stop codon is retained in the mature transcript. The
  result is a truncated, non-functional ISCU protein.

  The organising feature of the disease is that this splicing error is tissue
  specific. ISCU is the scaffold on which nascent Fe-S clusters are assembled,
  and it is expressed in every energy-demanding organ, yet aberrant splicing is
  far more efficient in skeletal muscle than in heart or liver. Muscle is
  therefore severely ISCU-deficient while other tissues are largely spared,
  which is why an essential housekeeping defect produces a myopathy rather than a
  multisystem mitochondrial disease. Loss of Fe-S clusters cripples the
  Fe-S-dependent enzymes aconitase and succinate dehydrogenase (respiratory
  complex II), with lesser impairment of complexes I and III, so the muscle
  cannot sustain oxidative phosphorylation.

  Clinically this manifests as lifelong exercise intolerance: minor exertion
  triggers premature fatigue, disproportionate tachycardia and dyspnea, and
  early lactate accumulation, while more intense or sustained exertion can
  precipitate rhabdomyolysis, myoglobinuria and life-threatening lactic
  acidosis, with near-normal strength between episodes. Muscle biopsy shows
  succinate-dehydrogenase-negative fibres and mitochondrial iron accumulation.
  The entry is built as a causal chain from the founder splice variant through
  Fe-S enzyme failure to the exertional phenotype, with the tissue-specific
  splicing step made explicit because it is what confines the disease to muscle.
disease_term:
  preferred_term: ISCU Myopathy
  term:
    id: MONDO:0009706
    label: hereditary myopathy with lactic acidosis due to ISCU deficiency
synonyms:
- Hereditary myopathy with lactic acidosis
- HML
- Myopathy with deficiency of succinate dehydrogenase and aconitase
- Myopathy with exercise intolerance, Swedish type
- Iron-sulfur cluster deficiency myopathy
- Aconitase deficiency
- Linderholm myopathy
- Larsson-Linderholm syndrome
parents:
- metabolic myopathy
- mitochondrial disease
- disorder of iron-sulfur cluster biogenesis
notes: >-
  Scope and lump/split. This is a single-gene (ISCU) autosomal recessive
  myopathy and is curated as one DISEASE entry. The overwhelming majority of
  reported patients carry the homozygous northern-Swedish founder variant
  c.418+382G>C; two rarer allelic presentations are recorded in the genetic
  block rather than split out, because they are the same gene and the same core
  Fe-S mechanism: the compound-heterozygous intronic + p.Gly50Glu genotype
  (more severe, with muscle wasting and cardiac involvement) and a single de
  novo dominant p.Gly96Val case with a broader, slowly progressive phenotype.
  The entry is written around the classic founder disease; where a claim comes
  only from a missense/dominant case it is attributed as such.

  Module conformance. No mechanism module was conformed to. mitochondrial_dysfunction
  is an aging-hallmark module and is not an appropriate conformance target for a
  Mendelian Fe-S biogenesis defect; no muscle-energy-failure module exists at
  time of writing. The pathophysiology is therefore curated in full here.

  GeneReviews. A GeneReviews chapter exists (PMID:20301757, "Myopathy with
  Deficiency of ISCU") but has been RETIRED and is flagged "FOR HISTORICAL
  REFERENCE ONLY". It remains the expert clinical baseline and is tagged
  GeneReviews in the top-level references; its retired status is noted here so
  the tag is not read as a current chapter.

  Provenance. Built from an Edison/Falcon deep-research report
  (research/ISCU_Myopathy-deep-research-falcon.md), which cites by author-year
  and DOI keys. Every DOI was resolved to its PubMed record and all evidence is
  cited and verified against PMID abstracts/full text. Two PMIDs asserted in the
  report prose were wrong and were corrected before use: the report attributed
  the Mochel 2008 AJHG paper to PMID 18296749 (that PMID is actually Olsson 2008
  HMG) and the Holmes-Hampton 2016 ASO paper to PMID 27729411 (an unrelated
  potassium-channel paper); the correct PMIDs are 18304497 and 28007899
  respectively. Yeast (S. cerevisiae isu1) modelling of the missense alleles is
  described in the tissue-specific-splicing discussion rather than as an
  experimental_models block.
references:
- reference: PMID:20301757
  title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
- reference: PMID:18304497
  title: Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.
- reference: PMID:18296749
  title: Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect.
- reference: PMID:1918374
  title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Classic ISCU myopathy is autosomal recessive, with affected northern-Swedish
    patients homozygous for a shared deep-intronic founder haplotype. Both sexes
    are affected. The rarer compound-heterozygous and de novo dominant genotypes
    are recorded in the genetic block.
  evidence:
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients are homozygous for a deep intronic IVS5 + 382G>C splicing affecting mutation in ISCU, which encodes the differently spliced cytosolic and mitochondrial iron-sulphur cluster assembly protein IscU."
    explanation: States the recessive founder genotype (homozygous deep-intronic ISCU variant) that defines classic disease.
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myopathy with deficiency of ISCU is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the autosomal recessive inheritance pattern.
pathophysiology:
- name: ISCU Deep-Intronic Founder Splice Variant
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. A single deep-intronic transversion in ISCU,
    c.418+382G>C (historically IVS5+382G>C), lies well within intron 4/5 and
    lengthens a polypyrimidine tract, strengthening an otherwise weak cryptic
    splice acceptor site. Almost all patients are homozygous for this founder
    allele on a shared northern-Swedish haplotype.
  genes:
  - preferred_term: ISCU
    term:
      id: hgnc:29882
      label: ISCU
  evidence:
  - reference: PMID:18304497
    reference_title: Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention."
    explanation: Identifies the causal ISCU splice-acceptor-strengthening mutation, the initiating lesion of the chain.
  downstream:
  - target: Cryptic Splice-Site Activation and Pseudoexon Inclusion
    causal_link_type: DIRECT
    description: >-
      The strengthened acceptor site permits inclusion of an aberrant pseudoexon
      in the processed transcript.
    evidence:
    - reference: PMID:18296749
      reference_title: Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron."
      explanation: States that the mutation activates cryptic splicing and produces aberrant intron-containing mRNA.
- name: Cryptic Splice-Site Activation and Pseudoexon Inclusion
  biological_scale: MOLECULAR
  description: >-
    The activated cryptic acceptor drives inclusion of a pseudoexon (reported as
    ~86-100 bp of intronic sequence) into most ISCU transcripts. The inserted
    sequence shifts the reading frame and introduces a premature stop codon, so
    the transcript encodes a truncated, non-functional ISCU protein.
  biological_processes:
  - preferred_term: aberrant pre-mRNA splicing of ISCU
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: INCREASED
  evidence:
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon."
    explanation: States that pseudoexon inclusion frameshifts the transcript and creates a premature stop codon.
  downstream:
  - target: Skeletal-Muscle-Predominant ISCU Protein Deficiency
    causal_link_type: DIRECT
    description: >-
      Because the mis-splicing is far more efficient in skeletal muscle, the
      truncated transcript translates into severe loss of functional ISCU
      selectively in muscle.
- name: Skeletal-Muscle-Predominant ISCU Protein Deficiency
  biological_scale: MOLECULAR
  description: >-
    ISCU protein is nearly undetectable in patient skeletal muscle while
    fibroblasts, heart and liver retain substantial normal protein. This tissue
    selectivity is the pivotal feature of the disease: it is created by the
    splicing machinery rather than by tissue-specific expression of ISCU, with
    the highest fraction of mis-spliced transcript in skeletal muscle. Low
    levels of the splicing repressor PTBP1 in muscle, and muscle-differentiation
    factors such as MyoD, enhance the mis-splicing; oxidative stress from muscle
    work further destabilises what little normal ISCU is made.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:21165651
    reference_title: Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle, while the normal splice form predominated in patient heart."
    explanation: Shows the mis-splicing, and hence ISCU deficiency, is concentrated in skeletal muscle and spares the heart.
  - reference: PMID:23035118
    reference_title: "Tissue specificity of a human mitochondrial disease: differentiation-enhanced mis-splicing of the Fe-S scaffold gene ISCU renders patient cells more sensitive to oxidative stress in ISCU myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ISCU protein was nearly undetectable in patient skeletal muscle, but was higher in patient myoblasts, fibroblasts, and lymphoblasts."
    explanation: Documents severe, muscle-selective loss of ISCU protein relative to other patient cell types.
  downstream:
  - target: Failure of Mitochondrial Fe-S Cluster Assembly
    causal_link_type: DIRECT
    description: >-
      Loss of the scaffold protein removes the platform on which nascent Fe-S
      clusters are built.
- name: Failure of Mitochondrial Fe-S Cluster Assembly
  biological_scale: MOLECULAR
  description: >-
    ISCU is the scaffold on which nascent iron-sulfur clusters are assembled in
    complex with the cysteine desulfurase NFS1, frataxin and other factors, then
    delivered to apoproteins. Severe ISCU loss in muscle therefore impairs
    assembly and delivery of Fe-S clusters to the enzymes that require them.
  biological_processes:
  - preferred_term: iron-sulfur cluster assembly
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:21165651
    reference_title: Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This results in a deficiency of Fe-S cluster proteins, affecting the TCA cycle and the respiratory chain."
    explanation: States that the splicing defect produces a deficiency of Fe-S cluster proteins hitting the TCA cycle and respiratory chain.
  downstream:
  - target: Deficiency of Fe-S Cluster Enzymes (Aconitase and Complex II)
    causal_link_type: DIRECT
    description: >-
      Apoproteins that cannot receive a cluster lose activity, most severely the
      Fe-S enzymes aconitase and complex II.
  - target: Mitochondrial Iron Overload and Oxidative Stress
    causal_link_type: DIRECT
    description: >-
      Failed cluster assembly and loss of aconitase/IRP1 function dysregulate
      cellular iron handling, driving mitochondrial iron accumulation.
- name: Deficiency of Fe-S Cluster Enzymes (Aconitase and Complex II)
  biological_scale: MOLECULAR
  description: >-
    The Fe-S-dependent enzymes lose activity. The greatest deficiencies are in
    succinate dehydrogenase (respiratory complex II) and aconitase, with lesser
    impairment of complexes I and III and the Rieske protein. Histochemically
    this appears as succinate-dehydrogenase-negative muscle fibres.
  molecular_functions:
  - preferred_term: aconitate hydratase activity
    term:
      id: GO:0003994
      label: aconitate hydratase activity
    modifier: DECREASED
  - preferred_term: succinate dehydrogenase (complex II) activity
    term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    modifier: DECREASED
  evidence:
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase"
    explanation: The original human description documents combined deficiency of complex II (SDH) and aconitase.
  - reference: PMID:28007899
    reference_title: Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The greater deficiencies were observed in succinate dehydrogenase (complex II) and aconitase and to a lesser extent in NADH dehydrogenase (complex I), cytochrome bc1 complex (complex III), and the Rieske protein"
    explanation: Ranks the enzyme deficiencies, with SDH and aconitase most affected and complexes I/III less so. The sentence sits in this paper's introduction and restates the earlier human-muscle enzymology, so it is graded on the human evidence it describes and tagged as background.
  downstream:
  - target: Impaired Oxidative Phosphorylation and TCA Cycle Flux
    causal_link_type: DIRECT
    description: >-
      Loss of complex II and aconitase blocks the TCA cycle and respiratory
      electron flow, limiting NADH-driven oxidative ATP production.
- name: Impaired Oxidative Phosphorylation and TCA Cycle Flux
  biological_scale: CELLULAR
  description: >-
    With the TCA cycle and respiratory chain crippled, muscle mitochondria
    cannot extract oxygen or generate ATP normally. Exercise testing shows
    markedly reduced maximal oxygen uptake and impaired muscle oxygen extraction
    despite a hyperkinetic circulatory response.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: DECREASED
  evidence:
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise"
    explanation: Directly demonstrates the impaired oxidative metabolism (poor muscle oxygen extraction) that follows respiratory-chain enzyme deficiency.
  downstream:
  - target: Compensatory Glycolysis and Lactate Accumulation
    causal_link_type: DIRECT
    description: >-
      Blocked oxidative ATP production forces reliance on glycolysis, generating
      excess pyruvate and lactate during exertion.
  - target: Muscle Energy Failure on Exertion
    causal_link_type: DIRECT
    description: >-
      The oxidative deficit means ATP supply cannot meet demand once muscle is
      worked.
  - target: PGC-1alpha Remodeling and FGF21 Secretion
    causal_link_type: DIRECT
    description: >-
      Chronic mitochondrial energy starvation triggers a compensatory
      transcriptional remodeling program.
- name: Mitochondrial Iron Overload and Oxidative Stress
  biological_scale: CELLULAR
  description: >-
    Disrupted Fe-S/aconitase-IRP1 iron sensing dysregulates iron homeostasis,
    producing intracellular and mitochondrial iron accumulation in muscle
    (visible as iron-positive fibres on Perls' staining) together with reactive
    oxygen species. Oxidative stress in turn destabilises residual ISCU, a
    feed-forward loop that worsens the deficiency. Iron-mediated oxidative injury
    is a biologically plausible contributor to myofiber damage but has not been
    demonstrated as the proximate cause of human myofiber necrosis.
  biological_processes:
  - preferred_term: intracellular iron ion homeostasis
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    modifier: DECREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:18304497
    reference_title: Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease."
    explanation: Links ISCU loss to reduced IRP1 and intracellular iron overload in muscle.
  - reference: PMID:23035118
    reference_title: "Tissue specificity of a human mitochondrial disease: differentiation-enhanced mis-splicing of the Fe-S scaffold gene ISCU renders patient cells more sensitive to oxidative stress in ISCU myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "oxidative stress resulting from skeletal muscle work destabilizes the small amounts of normal ISCU protein generated in patient skeletal muscles."
    explanation: Supports the feed-forward loop in which oxidative stress further destabilises residual ISCU.
  downstream:
  - target: Exertional Rhabdomyolysis and Myoglobinuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Iron-mediated oxidative injury is a plausible contributor to the myofiber
      breakdown seen with severe exertion, though not proven as its proximate
      cause.
- name: Compensatory Glycolysis and Lactate Accumulation
  biological_scale: CELLULAR
  description: >-
    Unable to burn substrate oxidatively, muscle shifts to glycolysis, so
    exertion produces disproportionate rises in venous lactate and pyruvate and,
    in severe episodes, systemic lactic acidosis.
  biological_processes:
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: INCREASED
  evidence:
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."
    explanation: Documents the exaggerated exertional lactate/pyruvate rise arising from the oxidative block.
  downstream:
  - target: Lactic acidosis
    causal_link_type: DIRECT
    description: >-
      Severe exertion drives lactate to life-threatening levels, the acidosis in
      the disease's historical name.
  - target: Increased circulating lactate concentration
    causal_link_type: DIRECT
    description: >-
      Elevated blood lactate is the routine biochemical correlate.
- name: PGC-1alpha Remodeling and FGF21 Secretion
  biological_scale: CELLULAR
  description: >-
    Chronic Fe-S/energy starvation elicits a coordinated adaptive response in
    muscle: a shift toward type I oxidative fibres and higher capillary density,
    up-regulation of PGC-1alpha and fatty-acid-oxidation and ketogenic genes, and
    secretion of FGF21, which is reflected by elevated circulating FGF21. This is
    a compensatory branch rather than a step toward injury, and FGF21 is a
    supportive but non-specific biomarker.
  evidence:
  - reference: PMID:23943793
    reference_title: "Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle tissue from patients deficient in the Fe-S cluster scaffold protein ISCU showed a predominance of type I oxidative muscle fibers and higher capillary density, enhanced expression of transcriptional co-activator PGC-1α and increased mitochondrial fatty acid oxidation genes."
    explanation: Documents the PGC-1alpha-driven compensatory remodeling in Fe-S-deficient patient muscle.
  - reference: PMID:23943793
    reference_title: "Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enhanced muscle FGF21 expression was reflected by elevated circulating FGF21 levels in the patients"
    explanation: Supports elevated circulating FGF21 as a systemic readout of the compensatory response.
- name: Muscle Energy Failure on Exertion
  biological_scale: TISSUE
  description: >-
    The functional endpoint at tissue level: skeletal muscle cannot meet the ATP
    demand of even modest exertion. This produces premature fatigue, cramps and
    pain, and drives the disproportionate cardiovascular effort (tachycardia,
    dyspnea, palpitations) by which the body tries to compensate for the
    oxidative deficit.
  evidence:
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations"
    explanation: Describes the exertional energy-failure phenotype central to the disease.
  downstream:
  - target: Exertional Rhabdomyolysis and Myoglobinuria
    causal_link_type: DIRECT
    description: >-
      Sustained or intense exertion beyond the muscle's oxidative capacity can
      break down myofibers.
  - target: Exercise intolerance
    causal_link_type: DIRECT
  - target: Exertional dyspnea
    causal_link_type: DIRECT
  - target: Tachycardia
    causal_link_type: DIRECT
  - target: Myalgia
    causal_link_type: DIRECT
  - target: Muscle weakness
    causal_link_type: DIRECT
- name: Exertional Rhabdomyolysis and Myoglobinuria
  biological_scale: ORGANISM
  description: >-
    Under severe or sustained exertion, energy-starved myofibers break down,
    releasing myoglobin into the circulation and urine. These episodes carry the
    disease's acute risk (acute kidney injury, hyperkalemia, severe acidosis),
    with typically full recovery of strength between attacks.
  evidence:
  - reference: PMID:21196119
    reference_title: Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria."
    explanation: Names episodic myoglobinuria among the disease manifestations.
  downstream:
  - target: Rhabdomyolysis
    causal_link_type: DIRECT
  - target: Myoglobinuria
    causal_link_type: DIRECT
phenotypes:
- name: Exercise intolerance
  category: Musculoskeletal
  description: >-
    The cardinal, lifelong feature: even minor exertion causes premature fatigue
    and reduced maximal work capacity. Present from childhood.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "classically characterized by lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles"
    explanation: GeneReviews names lifelong exercise intolerance as the classic defining feature.
- name: Exertional dyspnea
  category: Respiratory
  description: >-
    Shortness of breath on trivial exertion, part of the disproportionate
    cardiopulmonary response to the muscle oxidative deficit.
  phenotype_term:
    preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:18296749
    reference_title: Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations."
    explanation: Lists exertional dyspnea and palpitations as characteristic features.
- name: Tachycardia
  category: Cardiovascular
  description: >-
    Disproportionate exertional tachycardia and palpitations, reflecting a
    hyperkinetic circulatory attempt to compensate for impaired muscle oxygen
    extraction.
  phenotype_term:
    preferred_term: Exertional tachycardia and palpitations
    term:
      id: HP:0001649
      label: Tachycardia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles"
    explanation: GeneReviews names exertional tachycardia among the cardinal features.
- name: Myalgia
  category: Musculoskeletal
  description: >-
    Pain of active muscles on exertion, with painful muscle swelling during
    severe episodes.
  phenotype_term:
    preferred_term: Exertional muscle pain
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles"
    explanation: GeneReviews names pain of active muscles (myalgia) as a cardinal feature.
- name: Muscle weakness
  category: Musculoskeletal
  description: >-
    Episodic, sometimes severe, weakness during metabolic crises, with
    near-normal strength between episodes; a progressive fixed weakness occurs
    mainly in the rarer compound-heterozygous and dominant genotypes.
  phenotype_term:
    preferred_term: Episodic muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur."
    explanation: Documents episodic widespread weakness during metabolic crises.
- name: Rhabdomyolysis
  category: Musculoskeletal
  description: >-
    Exertion-triggered breakdown of skeletal muscle during severe episodes,
    carrying risk of acute kidney injury and hyperkalemia.
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe"
    explanation: GeneReviews names exertional rhabdomyolysis as a recurrent episodic manifestation.
- name: Myoglobinuria
  category: Renal
  description: >-
    Dark urine from myoglobin release during rhabdomyolysis episodes; a
    historically noted feature ("dark urine") of the Swedish patients.
  phenotype_term:
    preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  frequency: FREQUENT
  evidence:
  - reference: PMID:18304497
    reference_title: Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden"
    explanation: Names myoglobinuria as a defining feature of the northern-Swedish disease.
- name: Increased circulating lactate concentration
  category: Laboratory
  description: >-
    Elevated blood lactate, especially after exertion, reflecting the shift to
    glycolytic metabolism.
  phenotype_term:
    preferred_term: Elevated blood lactate
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."
    explanation: Documents the exaggerated exertional rise in blood lactate.
- name: Lactic acidosis
  category: Laboratory
  description: >-
    Severe metabolic (lactic) acidosis during profound exertional episodes, the
    feature that gives the disease its "lactic acidosis" name.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur."
    explanation: Documents severe metabolic (lactic) acidosis during episodes.
- name: Calf muscle hypertrophy
  category: Musculoskeletal
  description: >-
    Affected individuals usually have near-normal strength and can have large
    calves.
  phenotype_term:
    preferred_term: Large calves
    term:
      id: HP:0008981
      label: Calf muscle hypertrophy
  frequency: OCCASIONAL
  notes: >-
    Mechanism unsettled. No cached source links the large calves to a
    pathophysiology node, so no causal edge is drawn from the pathograph to this
    phenotype; it is recorded as an observed clinical feature only.
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Affected individuals usually have near-normal strength; they can have large calves."
    explanation: GeneReviews notes preserved strength and large calves.
genetic:
- name: ISCU
  gene_term:
    preferred_term: ISCU
    term:
      id: hgnc:29882
      label: ISCU
  relationship_type: CAUSATIVE
  notes: >-
    ISCU encodes the iron-sulfur cluster scaffold protein, produced as cytosolic
    and mitochondrial isoforms. The classic disease allele is the homozygous
    deep-intronic founder variant c.418+382G>C (IVS5+382G>C) on a shared
    northern-Swedish haplotype, which activates a cryptic splice acceptor and
    causes pseudoexon inclusion, a frameshift, a premature stop codon and a
    truncated non-functional protein - a loss-of-function splicing allele. Two
    rarer allelic presentations are recorded rather than split out: compound
    heterozygosity for the intronic variant plus a c.149G>A (p.Gly50Glu) missense
    change, seen in two brothers of Swedish/Finnish origin with a more severe
    phenotype including muscle wasting and cardiomyopathy; and a single de novo
    heterozygous c.287G>T (p.Gly96Val) missense variant reported to act
    dominantly, with a broader slowly progressive multisystem phenotype.
  evidence:
  - reference: PMID:18296749
    reference_title: Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family."
    explanation: Establishes ISCU as the causal gene via the intronic splicing mutation.
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The brothers were compound heterozygous for the deep intronic mutation and had a c.149 G>A missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate."
    explanation: Documents the compound-heterozygous p.Gly50Glu genotype with a more severe phenotype.
  - reference: PMID:24573684
    reference_title: The presence of multiple cellular defects associated with a novel G50E iron-sulfur cluster scaffold protein (ISCU) mutation leads to development of mitochondrial myopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the G50E mutation results in compromised interaction with the sulfur donor NFS1 and the J-protein HSCB, thus impairing the rate of Fe-S cluster synthesis"
    explanation: Provides the molecular loss-of-function mechanism of the G50E missense allele.
biochemical:
- name: Elevated lactate
  presence: INCREASED
  context: >-
    Blood lactate and pyruvate rise disproportionately with exertion because
    impaired oxidative metabolism forces glycolytic ATP production; severe
    episodes produce systemic lactic acidosis.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  readouts:
  - target: Compensatory Glycolysis and Lactate Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Exertional lactate elevation reports the glycolytic shift downstream of the oxidative block.
  evidence:
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."
    explanation: Quantifies the exaggerated exertional lactate/pyruvate response on cycle testing.
- name: Creatine kinase
  presence: INCREASED
  context: >-
    Serum creatine kinase rises, particularly during and after rhabdomyolysis
    episodes; it is a routine but non-specific marker of the muscle breakdown in
    this disease. No exact-quote abstract source for a CK value was available in
    the cached references, so this entry carries context only.
  biomarker_term:
    preferred_term: creatine kinase
- name: Myoglobinuria
  presence: INCREASED
  context: >-
    Myoglobin appears in the urine (dark urine) during rhabdomyolysis episodes,
    a historically noted feature of the Swedish patients.
  biomarker_term:
    preferred_term: myoglobin
  readouts:
  - target: Exertional Rhabdomyolysis and Myoglobinuria
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Urinary myoglobin reports acute rhabdomyolysis.
  evidence:
  - reference: PMID:21196119
    reference_title: Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria."
    explanation: Names episodic myoglobinuria as a manifestation.
- name: Elevated circulating FGF21
  presence: INCREASED
  context: >-
    Serum FGF21 is elevated in ISCU-deficient patients as the systemic reflection
    of the muscle-intrinsic energy-starvation response (PGC-1alpha, ketogenic
    enzyme and FGF21 up-regulation). It is a supportive marker of a mitochondrial
    myopathy, not a disease-specific test: FGF21 rises across many
    mitochondrial-disease classes and has not been formally validated as a
    diagnostic in ISCU myopathy.
  specificity: Mitochondrial myopathy as a class; not specific to ISCU deficiency
  biomarker_term:
    preferred_term: Fibroblast Growth Factor 21 Measurement
    term:
      id: NCIT:C112280
      label: Fibroblast Growth Factor 21 Measurement
  readouts:
  - target: PGC-1alpha Remodeling and FGF21 Secretion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Circulating FGF21 reports the compensatory muscle transcriptional program that secretes it.
  evidence:
  - reference: PMID:23943793
    reference_title: "Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enhanced muscle FGF21 expression was reflected by elevated circulating FGF21 levels in the patients"
    explanation: Reports elevated circulating FGF21 in ISCU-deficient patients, tied to the muscle expression that drives it.
diagnosis:
- name: Molecular Genetic Testing for Biallelic ISCU Variants
  description: >-
    The primary diagnostic test. The diagnosis is established by finding
    biallelic pathogenic variants in ISCU; in a patient of northern-Swedish
    ancestry, targeted testing for the deep-intronic founder allele
    c.418+382G>C is the efficient first step. Because the founder allele lies
    ~380 bp inside an intron, routine exome capture can miss it, so the
    intronic region must be screened directly (or genome sequencing used) when
    exome sequencing is uninformative and suspicion remains; the dominant
    p.Gly96Val case is the worked example of an exome-first work-up that then
    screened the founder intronic region explicitly. Molecular confirmation
    also enables carrier testing of at-risk relatives.
  diagnosis_term:
    preferred_term: molecular genetic testing (targeted ISCU intronic founder variant, panel, exome or genome sequencing)
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Identifies biallelic pathogenic ISCU variants, most often homozygosity for the c.418+382G>C founder allele
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of myopathy with deficiency of ISCU is established in a proband by the identification of biallelic pathogenic variants in ISCU by molecular genetic testing or, if molecular genetic testing is uninformative, by characteristic histochemical and biochemical findings on muscle biopsy."
    explanation: GeneReviews states that molecular genetic testing for biallelic ISCU variants is the primary route to diagnosis, with muscle biopsy as the fallback.
  - reference: PMID:29079705
    reference_title: A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We then screened our patient and his parents for the intronic region encompassing the common mutation present in all the previously described ISCU mutant patients but no variant was identified."
    explanation: Shows that after exome sequencing the founder deep-intronic region was screened as a separate, targeted step, the practical consequence of an allele that exome capture does not cover.
  - reference: PMID:29079705
    reference_title: A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To exclude that WES could have missed the presence of another deep intronic variant affecting the splicing"
    explanation: States directly that whole-exome sequencing can miss deep-intronic splice-affecting variants, which is why transcript-level analysis was added to the work-up.
- name: RNA Analysis for ISCU Pseudoexon Inclusion
  description: >-
    Transcript analysis complements DNA testing when a deep-intronic allele is
    suspected but not captured, or when a variant of uncertain effect is found.
    RT-PCR of ISCU from patient muscle (or differentiated myotubes, where the
    mis-splicing is enhanced) shows the larger pseudoexon-containing transcript
    predominating over the normal mitochondrial isoform. Fibroblast RNA can be
    used to exclude a missed splicing variant but is a weaker substrate, because
    mis-splicing is far less efficient outside muscle.
  diagnosis_term:
    preferred_term: ISCU transcript (RT-PCR) analysis for pseudoexon inclusion
    term:
      id: NCIT:C18473
      label: RNA Analysis
  results: Aberrant ISCU transcript retaining intronic sequence (pseudoexon) predominates in muscle
  evidence:
  - reference: PMID:18296749
    reference_title: Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant."
    explanation: Demonstrates that patient RNA shows a predominant larger (pseudoexon-containing) transcript, the readout this analysis relies on.
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle."
    explanation: Places the pseudoexon-inclusion readout specifically in muscle transcripts.
  - reference: PMID:29079705
    reference_title: A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we further investigated patient’s specimen at the transcriptional level. No aberrant mRNA ISCU species was observed in PCR products obtained from fibroblast RNA"
    explanation: Shows transcript analysis used to exclude a missed intronic splice variant; here fibroblast RNA was the substrate and was negative in the dominant missense case.
- name: Muscle Biopsy with Histochemical and Biochemical Analysis
  description: >-
    The fallback confirmatory test when molecular testing is uninformative, and
    historically the way the disease was defined. Histochemistry shows marked
    succinate dehydrogenase deficiency with iron accumulation in muscle fibres;
    biochemistry of isolated muscle mitochondria shows deficient complex II and
    aconitase activity. The combined histochemical and biochemical picture is
    described as probably pathognomonic for muscle Fe-S cluster deficiency.
    Timing matters: a biopsy taken shortly after rhabdomyolysis can show
    regenerating fibres with normal SDH activity and little iron, so a biopsy
    during regeneration can be falsely reassuring.
  diagnosis_term:
    preferred_term: muscle biopsy with SDH histochemistry, iron staining and respiratory-chain enzymology
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  results: SDH-negative fibres, iron-positive fibres on Perls' stain, deficient complex II and aconitase activity
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "if molecular genetic testing is uninformative, by characteristic histochemical and biochemical findings on muscle biopsy."
    explanation: GeneReviews positions muscle biopsy histochemistry and biochemistry as the diagnostic route when molecular testing is uninformative.
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle iron-sulphur cluster deficiency"
    explanation: Describes the biopsy phenotype as probably pathognomonic, supporting its confirmatory value.
  - reference: PMID:21196119
    reference_title: Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A biopsy specimen from a patient, two months after a severe attack of rhabdomyolysis, revealed regenerating muscle with normal succinate dehydrogenase activity and only minor iron accumulation"
    explanation: Documents the timing caveat, a post-rhabdomyolysis biopsy can lack the diagnostic hallmarks.
  - reference: PMID:21196119
    reference_title: Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results have implications for diagnosis of the disease based on muscle biopsy findings"
    explanation: The authors draw the diagnostic implication explicitly.
- name: Cycle Exercise Testing with Lactate and Oxygen-Uptake Measurement
  description: >-
    Supportive physiological testing. Cardiopulmonary cycle exercise testing
    shows very low maximal oxygen uptake, exaggerated rises in venous lactate and
    pyruvate relative to oxygen uptake, and a hyperkinetic circulatory response
    with impaired muscle oxygen extraction, the functional signature of a muscle
    oxidative defect. It points to a mitochondrial myopathy but does not identify
    the gene.
  diagnosis_term:
    preferred_term: cycle exercise testing with venous lactate/pyruvate and oxygen uptake measurement
    term:
      id: NCIT:C116517
      label: Cardiopulmonary Exercise Testing
  results: Low maximal oxygen uptake with exaggerated exertional lactate and pyruvate rise
  evidence:
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cycle exercise testing revealed low maximal oxygen uptake"
    explanation: Reports the low maximal oxygen uptake found on cycle exercise testing in the index patient.
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise."
    explanation: Reports the exaggerated exertional lactate/pyruvate response that exercise testing is used to elicit.
histopathology:
- name: Succinate dehydrogenase-negative muscle fibres
  description: >-
    Histochemical SDH (complex II) staining is markedly reduced or absent across
    muscle fibres, the morphological hallmark of the disease and the direct
    tissue correlate of Fe-S enzyme loss. It is confirmed biochemically in
    isolated muscle mitochondria. In the single de novo dominant p.Gly96Val
    case, COX as well as SDH histochemistry was severely reduced, without
    ragged-red fibres. SDH activity can transiently normalise in regenerating
    fibres after rhabdomyolysis.
  finding_term:
    preferred_term: histochemical succinate dehydrogenase deficiency in muscle fibres
  diagnostic: true
  evidence:
  - reference: PMID:21196119
    reference_title: Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease."
    explanation: Names histochemical SDH deficiency as a morphological hallmark of the disease.
  - reference: PMID:1918374
    reference_title: Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically."
    explanation: The original description documents SDH deficiency both histochemically and biochemically.
  - reference: PMID:29079705
    reference_title: A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main feature was a severe reduction of the histochemical reaction for both COX and SDH, not associated with ragged red fibres."
    explanation: In the dominant missense case the SDH (and COX) histochemical reduction was the main biopsy feature, without ragged-red fibres.
- name: Iron accumulation in muscle fibres
  description: >-
    Perls' (Prussian blue) staining shows punctate iron accumulation within
    muscle fibres, reflecting the muscle-restricted disturbance of iron
    homeostasis that follows ISCU loss and reduced IRP1. Iron accumulation is
    present in muscle but absent in other patient tissues, and is described as a
    feature that distinguishes ISCU deficiency from some other Fe-S biogenesis
    defects. Like SDH deficiency, it is minimal in regenerating muscle shortly
    after rhabdomyolysis.
  finding_term:
    preferred_term: intracellular (mitochondrial) iron accumulation in muscle fibres on Perls' stain
  diagnostic: true
  evidence:
  - reference: PMID:21196119
    reference_title: Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease."
    explanation: Names iron accumulation in muscle fibres as a morphological hallmark of the disease.
  - reference: PMID:21165651
    reference_title: Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss of Fe-S cluster carrying enzymes and accumulation of iron were present in muscle, but absent in other tissues."
    explanation: Shows the iron accumulation is confined to muscle, matching the tissue restriction of the splicing defect.
  - reference: PMID:29079705
    reference_title: A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Perls staining demonstrating punctuate accumulation of iron in the patient’s muscle fibres."
    explanation: Documents Perls-positive punctate iron in muscle fibres in the dominant missense case as well.
- name: Type I oxidative fibre predominance with increased capillary density
  description: >-
    Despite the oxidative defect, patient muscle shows a predominance of type I
    oxidative fibres and higher capillary density, together with up-regulated
    PGC-1alpha and fatty-acid-oxidation genes. This is read as a compensatory
    remodelling response to chronic mitochondrial energy starvation rather than
    as a degenerative change. No cached source quotes mitochondrial proliferation
    or ragged-red fibres in classic founder-allele disease, so that feature is
    not recorded here.
  finding_term:
    preferred_term: type I muscle fibre predominance with increased capillary density
  diagnostic: false
  evidence:
  - reference: PMID:23943793
    reference_title: "Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle tissue from patients deficient in the Fe-S cluster scaffold protein ISCU showed a predominance of type I oxidative muscle fibers and higher capillary density, enhanced expression of transcriptional co-activator PGC-1α and increased mitochondrial fatty acid oxidation genes."
    explanation: Reports the type I fibre predominance and higher capillary density in ISCU-deficient muscle.
treatments:
- name: Avoidance of Sustained Fatiguing Exertion
  description: >-
    The mainstay of management is behavioral: avoiding sustained fatiguing
    physical exertion, which anecdotally prevents episodes of rhabdomyolysis and
    myoglobinuria. GeneReviews lists sustained fatiguing physical exertion as the
    circumstance to avoid.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: activity modification (exertion avoidance)
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Exertional Rhabdomyolysis and Myoglobinuria
    treatment_effect: INHIBITS
    description: >-
      Avoiding the exertional trigger prevents the myofiber breakdown that
      causes rhabdomyolysis and its complications.
    evidence:
    - reference: PMID:20301757
      reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Anecdotal evidence suggests that episodes of rhabdomyolysis and myoglobinuria may be prevented by avoiding sustained fatiguing physical exertion."
      explanation: GeneReviews states that avoiding sustained exertion may prevent rhabdomyolysis episodes.
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Agents/circumstances to avoid: Sustained fatiguing physical exertion."
    explanation: GeneReviews explicitly lists sustained fatiguing exertion as the circumstance to avoid.
- name: Supportive Management of Rhabdomyolysis Episodes
  description: >-
    Acute episodes are managed as for other causes of rhabdomyolysis - hydration
    and attention to renal function, electrolytes (hyperkalemia) and acidosis -
    to prevent secondary complications including acute kidney injury from
    myoglobinuria.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Exertional Rhabdomyolysis and Myoglobinuria
    treatment_effect: MODULATES
    description: >-
      Supportive care mitigates the systemic consequences of an episode rather
      than the underlying Fe-S defect.
    evidence:
    - reference: PMID:20301757
      reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Management is similar to that for other causes of rhabdomyolysis."
      explanation: GeneReviews states episode management follows standard rhabdomyolysis care.
- name: Splice-Switching Antisense Oligonucleotide (Experimental)
  description: >-
    An experimental, mechanism-directed therapy. Antisense oligonucleotides
    targeted to the intronic mutation site block access of splicing factors,
    suppress pseudoexon inclusion and restore ISCU protein, with recovery of
    SDHB/complex II and aconitase activity in patient fibroblasts and myotubes.
    This is in-vitro evidence only; no ISCU-specific human trial exists. The
    oligonucleotide reported by Holmes-Hampton et al. (2016) is an 18-mer
    carrying mixed 2'-O-methoxyethyl and constrained-ethyl sugar modifications;
    the chemistry slot records the 2'-MOE component and the constrained-ethyl
    component is described here, as the schema asks for mixed-chemistry designs.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: SPLICE_MODULATION_EXON_SKIPPING
    target_gene:
      preferred_term: ISCU
      term:
        id: hgnc:29882
        label: ISCU
    target_transcript: ISCU intron 4 mutation site / cryptic splice acceptor (pseudoexon)
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: UNCONJUGATED
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Cryptic Splice-Site Activation and Pseudoexon Inclusion
    treatment_effect: INHIBITS
    description: >-
      The ASO blocks the splicing factors' access to the mutant intronic site,
      diminishing aberrant splicing and restoring normal ISCU transcript.
    evidence:
    - reference: PMID:28007899
      reference_title: Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We have shown that ASO treatment diminished aberrant splicing and increased ISCU protein levels in both patient fibroblasts and patient myotubes in a concentration dependent fashion."
      explanation: Shows the ASO reduces aberrant splicing and restores ISCU protein.
  - target: Deficiency of Fe-S Cluster Enzymes (Aconitase and Complex II)
    treatment_effect: RESTORES
    description: >-
      Restored ISCU rebuilds Fe-S enzyme activity, recovering complex II (SDHB)
      and aconitase function.
    evidence:
    - reference: PMID:28007899
      reference_title: Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mitochondrial and cytosolic aconitase activities increased significantly following ASO treatment in patient myotubes."
      explanation: Shows recovery of aconitase activity after ASO correction.
  evidence:
  - reference: PMID:28007899
    reference_title: Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The current study suggests that ASO treatment may serve as a viable approach to correcting ISCU myopathy in patients."
    explanation: States the therapeutic rationale, while remaining a preclinical (in-vitro) result.
  - reference: PMID:21196119
    reference_title: Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an increase of normally spliced ISCU by RNA modulating therapy may be a therapeutic possibility for these patients."
    explanation: Independent support for RNA-modulating (splice-correcting) therapy as a rational strategy.
- name: Genetic Counseling
  description: >-
    Given autosomal recessive inheritance and the founder allele, genetic
    counseling with carrier and prenatal testing is offered to at-risk families
    when the familial pathogenic variants are known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301757
    reference_title: "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased are possible if the pathogenic variants in the family have been identified."
    explanation: GeneReviews describes carrier and prenatal testing for at-risk relatives.
prevalence:
- population: Northern Sweden (founder population)
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    An ultra-rare founder disease. Molecularly confirmed classic disease has been
    described essentially only in patients of northern-Swedish descent
    homozygous for the founder allele. A carrier frequency near 1:188 for
    northern Sweden has been cited in reviews but no exact-quote abstract source
    was available in the cached references, so no rate is recorded here; the
    measure subtype is left UNKNOWN.
  evidence:
  - reference: PMID:19567699
    reference_title: Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease has so far only been identified in northern Sweden."
    explanation: Supports the geographically restricted founder distribution underlying the ultra-rare classification.
animal_models:
- name: Iscu-null mouse (complete knockout)
  species: Mouse
  genotype: Iscu homozygous null
  publication: PMID:21165651
  description: >-
    A conventional complete knockout of Iscu in mice is embryonic lethal, so it
    cannot reproduce the viable, muscle-restricted human disease. This is itself
    informative: it shows ISCU is essential in all tissues and that the human
    phenotype's tissue restriction must come from the partial, splicing-based
    deficiency rather than from tissue-limited ISCU function.
  modeled_mechanisms:
  - target: Skeletal-Muscle-Predominant ISCU Protein Deficiency
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Complete loss of ISCU is lethal, so the knockout cannot model the viable,
      muscle-selective partial deficiency that defines human ISCU myopathy.
    limitations: >-
      Embryonic lethality precludes any adult muscle phenotype; the model tests
      essentiality of ISCU, not the human disease, whose tissue restriction
      depends on residual normal ISCU generated by tissue-specific splicing.
    evidence:
    - reference: PMID:21165651
      reference_title: Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "complete loss of ISCU in mice results in early embryonic death"
      explanation: Documents embryonic lethality of complete Iscu loss, the reason the knockout fails to model the disease.
  evidence:
  - reference: PMID:21165651
    reference_title: Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "complete loss of ISCU in mice results in early embryonic death"
    explanation: Establishes that complete Iscu knockout is not a viable disease model.
- name: Human-ISCU transgenic mouse
  species: Mouse
  genotype: Transgenic for human ISCU
  publication: PMID:30209894
  description: >-
    Mice transgenic for human ISCU reproduce the tissue-specific mis-splicing
    seen in patients, with the highest levels of incorrect splicing and the
    lowest levels of the repressor Ptbp1 in slow (soleus) muscle. They model the
    splicing regulation that confines the disease to muscle, but not a full
    disease phenotype.
  modeled_mechanisms:
  - target: Skeletal-Muscle-Predominant ISCU Protein Deficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Reproduces the muscle-predominant mis-splicing and its inverse correlation
      with Ptbp1 levels, the mechanism restricting ISCU deficiency to muscle.
    limitations: >-
      The mouse does not carry the human founder mutation in its native context
      (the intronic sequence is human-specific) and models the splicing
      regulation rather than the clinical myopathy or metabolic crises.
    evidence:
    - reference: PMID:30209894
      reference_title: PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU."
      explanation: Shows the transgenic-mouse tissue data linking low Ptbp1 to high ISCU mis-splicing.
  evidence:
  - reference: PMID:30209894
    reference_title: PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU."
    explanation: Supports the transgenic mouse as a model of the tissue-specific splicing mechanism.
discussions:
- discussion_id: iscu_tissue_specific_splicing_muscle_restriction
  prompt: >-
    Why is ISCU myopathy confined to skeletal muscle when ISCU is an essential
    Fe-S scaffold expressed in every energy-demanding tissue, and which splicing
    regulators set that restriction?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Skeletal-Muscle-Predominant ISCU Protein Deficiency
  rationale: >-
    The defining paradox of the disease is that a housekeeping defect produces an
    organ-restricted phenotype. The resolution is that the founder mutation's
    aberrant splicing is far more efficient in skeletal muscle (the highest
    fraction of mis-spliced transcript) than in heart or liver, so only muscle
    becomes severely ISCU-deficient while other tissues retain enough normal
    protein. The regulators implicated - low muscle levels of the repressor
    PTBP1, muscle-differentiation factor MyoD enhancing mis-splicing, and other
    candidate factors (RBM39/IGF2BP1, SRSF3) - explain part but not all of the
    tissue selectivity, and the quantitative determinants of who mis-splices how
    much remain incompletely defined. This matters clinically because it is why
    the heart and CNS are spared, and mechanistically because splice-modulating
    therapy works by shifting exactly this balance.
  proposed_experiments:
  - experiment_id: iscu_splicing_regulator_map
    name: Tissue-resolved map of ISCU splicing regulators
    description: >-
      Systematically quantify mis-splicing against levels/activity of PTBP1,
      MyoD, SRSF3 and candidate factors across human and humanized-mouse tissues
      to determine which regulators are rate-limiting for the muscle-selective
      pseudoexon inclusion, and whether modulating them corrects the defect.
- discussion_id: iscu_human_specific_founder_allele_model_gap
  prompt: >-
    Can a faithful in-vivo model of the human founder disease be built when the
    causal mutation lies in a human/primate-specific intronic sequence and
    complete Iscu loss is lethal in mice?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#ISCU Deep-Intronic Founder Splice Variant
  - pathophysiology#Skeletal-Muscle-Predominant ISCU Protein Deficiency
  rationale: >-
    Model evidence for the disease exists but its translational fidelity is
    genuinely uncertain. A conventional Iscu knockout is embryonic lethal, so it
    cannot model the viable muscle-restricted disease; human-ISCU transgenic mice
    reproduce the tissue-specific splicing but not the founder mutation in its
    native context, because the deep-intronic sequence that the mutation acts on
    is human-specific. Yeast (S. cerevisiae isu1) engineered with homologous
    residues supported pathogenicity and dominance of the missense alleles but
    cannot model human tissue-specific splicing at all. The open question is
    whether a humanized knock-in carrying the founder intronic allele can
    recapitulate the muscle-selective mis-splicing and the exertional metabolic
    phenotype, which is a prerequisite for testing muscle-directed splice
    correction in vivo.
  proposed_experiments:
  - experiment_id: iscu_humanized_knockin_mouse
    name: Humanized ISCU founder-allele knock-in mouse
    description: >-
      Engineer a mouse carrying the human ISCU intronic context with the
      c.418+382G>C founder variant and test for muscle-predominant pseudoexon
      inclusion, SDH-negative fibres, mitochondrial iron accumulation and an
      exertional metabolic phenotype, then use it to evaluate splice-switching
      ASO delivery and durability in vivo.

📚

References & Deep Research

References

4

PMID:20301757

Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

No top-level findings curated for this source.

PMID:18304497

Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.

No top-level findings curated for this source.

PMID:18296749

Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect.

No top-level findings curated for this source.

PMID:1918374

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Scope and lump/split. This is a single-gene (ISCU) autosomal recessive myopathy and is curated as one DISEASE entry. The overwhelming majority of reported patients carry the homozygous northern-Swedish founder variant c.418+382G>C; two rarer allelic presentations are recorded in the genetic block rather than split out, because they are the same gene and the same core Fe-S mechanism: the compound-heterozygous intronic + p.Gly50Glu genotype (more severe, with muscle wasting and cardiac involvement) and a single de novo dominant p.Gly96Val case with a broader, slowly progressive phenotype. The entry is written around the classic founder disease; where a claim comes only from a missense/dominant case it is attributed as such. Module conformance. No mechanism module was conformed to. mitochondrial_dysfunction is an aging-hallmark module and is not an appropriate conformance target for a Mendelian Fe-S biogenesis defect; no muscle-energy-failure module exists at time of writing. The pathophysiology is therefore curated in full here. GeneReviews. A GeneReviews chapter exists (PMID:20301757, "Myopathy with Deficiency of ISCU") but has been RETIRED and is flagged "FOR HISTORICAL REFERENCE ONLY". It remains the expert clinical baseline and is tagged GeneReviews in the top-level references; its retired status is noted here so the tag is not read as a current chapter. Provenance. Built from an Edison/Falcon deep-research report (research/ISCU_Myopathy-deep-research-falcon.md), which cites by author-year and DOI keys. Every DOI was resolved to its PubMed record and all evidence is cited and verified against PMID abstracts/full text. Two PMIDs asserted in the report prose were wrong and were corrected before use: the report attributed the Mochel 2008 AJHG paper to PMID 18296749 (that PMID is actually Olsson 2008 HMG) and the Holmes-Hampton 2016 ASO paper to PMID 27729411 (an unrelated potassium-channel paper); the correct PMIDs are 18304497 and 28007899 respectively. Yeast (S. cerevisiae isu1) modelling of the missense alleles is described in the tissue-specific-splicing discussion rather than as an experimental_models block.

Create: ISCU Myopathy (MONDO:0009706) · 2026-09-18T01:55:51Z · View source

De novo curation of ISCU myopathy (hereditary myopathy with lactic acidosis; myopathy with deficiency of SDH and aconitase; Swedish exercise-intolerance myopathy), autosomal recessive Fe-S cluster biogenesis defect. Node chain: ISCU deep-intronic founder splice variant (c.418+382G>C) -> cryptic splice-site activation and pseudoexon inclusion (truncated ISCU) -> skeletal-muscle-predominant ISCU protein deficiency (tissue-specific mis-splicing; PTBP1/MyoD) -> failure of mitochondrial Fe-S cluster assembly -> deficiency of Fe-S enzymes aconitase and complex II (SDH) -> impaired OXPHOS/TCA flux -> (branches) compensatory glycolysis and lactate accumulation; mitochondrial iron overload and oxidative stress; PGC-1alpha remodeling and FGF21 secretion -> muscle energy failure on exertion -> exertional rhabdomyolysis and myoglobinuria; edges to phenotypes exercise intolerance, exertional dyspnea, tachycardia, myalgia, muscle weakness, lactic acidosis, elevated lactate, rhabdomyolysis, myoglobinuria. Lump/split: single DISEASE entry; the rarer compound-het intronic+p.Gly50Glu (Kollberg 2009/Saha 2014) and de novo dominant p.Gly96Val (Legati 2017) alleles recorded in genetic notes, not split. No module conformance (mitochondrial_dysfunction is an aging module; not appropriate). Provider: Edison/Falcon deep-research report (research/ISCU_Myopathy-deep-research-falcon.md); it cites by author-year/DOI. DOIs resolved to PMIDs via idconv; two report-prose PMIDs were WRONG and corrected before use (Mochel 2008 AJHG is 18304497 not 18296749 which is Olsson 2008 HMG; Holmes-Hampton 2016 ASO is 28007899 not 27729411 which is an unrelated K-channel paper). GeneReviews PMID:20301757 used as clinical baseline and tagged GeneReviews with retired-status noted. PMIDs used: 20301757, 18304497, 18296749, 19567699, 21196119, 21165651, 23035118, 23943793, 24573684, 28007899, 30209894, 1918374. Unsourced/contentious: no exact-quote abstract for the ~1:188 carrier frequency or a serum CK value, so prevalence rate is left UNKNOWN/ULTRA_RARE with a notes caveat and CK biochemical carries context only. Validation: just validate PASS; count-verified-snippets 46/46; validate-terms PASS; check-entity-refs OK; check-causal-targets OK (no new); check-duplicate-keys/enum-values OK; validate-disorders 46/46 PASS; folded-hyphens/snippet-length/title-snippets/snippet-grading not flagged for this file; pytest test_data.py -k ISCU 23 passed; compliance 78.4%.

Falcon ▸

ISCU Myopathy: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 37 citations 2026-09-04T23:34:02.053059

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.

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 (OpenTargets Search: ISCU myopathy-ISCU, mochel2008splicemutationin pages 1-2, selvanathan2022mitochondrialironsulfurcluster pages 3-4). 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 (OpenTargets Search: ISCU myopathy-ISCU, selvanathan2022mitochondrialironsulfurcluster pages 3-4, legati2017anovelde pages 1-2, legati2017anovelde pages 5-7). 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 (legati2017anovelde pages 1-2, vanlander2018clinicalandgenetic pages 1-3, saha2014thepresenceof pages 1-2, mochel2008splicemutationin pages 2-4, legati2017anovelde pages 5-7). 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 (mochel2008splicemutationin pages 1-2, legati2017anovelde pages 2-3, selvanathan2022mitochondrialironsulfurcluster pages 3-4, montealegre2022fdx2andiscu pages 1-2). 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 (mochel2008splicemutationin pages 1-2, rawcliffe2018ptbp1actsas pages 1-2). 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 (selvanathan2022mitochondrialironsulfurcluster pages 3-4, montealegre2022fdx2andiscu pages 1-2, crooks2014elevatedfgf21secretion pages 1-2, holmeshampton2016useofantisense pages 5-6). 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 (mochel2008splicemutationin pages 1-2, tong201710ironsulfurproteins pages 31-34, crooks2014elevatedfgf21secretion pages 1-2, crooks2014elevatedfgf21secretion pages 3-4). 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 (tong201710ironsulfurproteins pages 31-34, crooks2014elevatedfgf21secretion pages 1-2, holmeshampton2016useofantisense pages 1-2, rawcliffe2018ptbp1actsas pages 1-2, holmeshampton2016useofantisense pages 1-1). 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 (crooks2014elevatedfgf21secretion pages 1-2, crooks2014elevatedfgf21secretion pages 3-4). 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 (legati2017anovelde pages 2-3, selvanathan2022mitochondrialironsulfurcluster pages 3-4, mochel2008splicemutationin pages 2-4). 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 (holmeshampton2016useofantisense pages 5-6, selvanathan2022mitochondrialironsulfurcluster pages 8-8).
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 (holmeshampton2016useofantisense pages 1-1, holmeshampton2016useofantisense pages 7-7, holmeshampton2016useofantisense pages 1-2, holmeshampton2016useofantisense pages 2-3). 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 (mochel2008splicemutationin pages 1-2, vanlander2018clinicalandgenetic pages 1-3, saha2014thepresenceof pages 1-2, mochel2008splicemutationin pages 2-4). 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 (legati2017anovelde pages 1-2, legati2017anovelde pages 2-3, selvanathan2022mitochondrialironsulfurcluster pages 3-4). 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 (vanlander2018clinicalandgenetic pages 1-3, selvanathan2022mitochondrialironsulfurcluster pages 3-4).
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 (rawcliffe2018ptbp1actsas pages 1-2, holmeshampton2016useofantisense pages 5-6, saha2014thepresenceof pages 2-3, berti2021thepowerof pages 6-7, legati2017anovelde pages 5-7, holmeshampton2016useofantisense pages 1-1). 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.

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

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)
Aberrant transcript/protein results in reduced functional mitochondrial ISCU, especially in skeletal myofibers. (rawcliffe2018ptbp1actsas pages 1-2)
Reduced ISCU scaffold function leads to impaired assembly and delivery of Fe–S clusters to apoproteins. (tong201710ironsulfurproteins pages 31-34)
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)
Respiratory-chain failure leads to poor muscle oxygen extraction, reduced oxidative phosphorylation, and compensatory glycolytic flux. (tong201710ironsulfurproteins pages 31-34)
Increased reliance on glycolysis results in exercise-induced pyruvate and lactate accumulation and metabolic acidosis. (holmeshampton2016useofantisense pages 1-2, rawcliffe2018ptbp1actsas pages 1-2)
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)
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)
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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.

Outcome	Count
References checked	21
Resolved	21
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	21
On topic	7
Off topic	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.

Outcome	Count
Terms checked	52
Resolved	48
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	3

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.

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ISCU Myopathy: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

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2. Etiology, risk, and protective factors

3. Phenotypes

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6. Mechanism and pathophysiology

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11. Outcome and prognosis

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