ISCU myopathy

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ISCU myopathy in short

A rare energy metabolism disorder marked by myopathy with pronounced exercise intolerance, and biochemically defined by deficiencies in mitochondrial respiratory chain enzymes in skeletal muscle, particularly succinate dehydrogenase and aconitase.

Prevalence: <1 / 1 000 000

Inheritance: Autosomal recessive

Age of onset: Childhood

ISCU myopathy is an extremely rare condition, documented in only about 20 individuals worldwide. While the majority of cases have been reported in individuals of Swedish descent, patients from other ethnic backgrounds have also been diagnosed.

The hallmark of this condition is exercise intolerance beginning in childhood, marked by rapid onset of muscle fatigue, pain, rapid heartbeat, and shortness of breath within minutes of even mild physical activity.
More intense or sustained exertion may trigger episodes of profound muscle weakness, accompanied by lactic acidosis and severe rhabdomyolysis.
Cases of cardiomyopathy have also been observed, particularly among patients of non-Swedish descent.

This genetic disorder is caused by bi-allelic variants in the ISCU gene and follows an autosomal recessive inheritance pattern.
Although a single case involving a de novo heterozygous variant has been reported, there is currently no strong evidence supporting autosomal dominant inheritance.
The ISCU protein serves as a scaffold for assembling iron-sulfur clusters, which are vital components of many proteins, including those essential for mitochondrial function.
When ISCU is defective, mitochondria—particularly in muscle cells—are unable to produce energy efficiently, leading to exercise intolerance. All Swedish patients identified to date share the same homozygous mutation in ISCU (c.418+382G>C).

ISCU myopathy should be suspected in individuals presenting with the clinical features described above. Elevated resting blood lactate levels are typically observed, and exercise physiology testing often reveals further increases in both lactate and pyruvate, along with a marked reduction in VO₂ max.
Diagnosis is primarily confirmed through molecular genetic testing, which may involve targeted analysis for the common Swedish variant, a myopathy gene panel, or broader approaches such as whole exome sequencing. Additional biochemical tests can help support the diagnosis, particularly when genetic findings include variants of uncertain significance.
Most affected individuals also exhibit elevated plasma levels of fibroblast growth factor 21 (FGF21). Muscle biopsy analysis may show deficiencies in mitochondrial aconitase, succinate dehydrogenase, and respiratory chain complexes I, II, and III, as well as histochemical evidence of mitochondrial iron accumulation.

The differential diagnosis includes

Antenatal diagnosis can be performed if the pathogenic variants have already been identified in a previously affected family member.
The decision to proceed with testing should involve thorough discussions with the couple, supported by input from genetic counseling and obstetric care teams.

As ISCU myopathy follows an autosomal recessive inheritance pattern, couples in which both partners are carriers of a pathogenic ISCU variant have a 25% chance of having an affected child with each pregnancy.
Genetic counseling is essential to help these couples understand the implications of this risk and explore available reproductive options.

At present, treatment for this condition is primarily supportive, focusing on the management of rhabdomyolysis episodes and the implementation of a tailored exercise program designed to preserve muscle function without triggering symptoms.
In vitro studies using patient-derived myotubular cell lines have explored the use of antisense oligonucleotide therapy, which showed promise in correcting the c.418+382G>C splicing defect and improving associated biochemical abnormalities.
However, no clinical trials or further investigations in humans have been conducted to date.

Most individuals with this condition live well into adulthood and maintain a good quality of life, despite limitations in exercise tolerance.
However, acute episodes of decompensation—marked by rhabdomyolysis and lactic acidosis—can be life-threatening in rare cases, particularly if timely supportive care is not provided.