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Hereditary myopathy with lactic acidosis due to ISCU deficiency

Orpha number ORPHA43115
Synonym(s) Aconitase deficiency
ISCU myopathy
Iron-sulfur cluster deficiency myopathy
Myopathy with exercise intolerance, Swedish type
Prevalence <1 / 1 000 000
Inheritance
  • Autosomal recessive
Age of onset Childhood
ICD-10 -
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT -

Summary

Aconitase deficiency is characterised by myopathy with severe exercise intolerance and deficiencies of skeletal muscle succinate dehydrogenase and aconitase. It has been described in 19 individuals from nine families from northern Sweden. Onset of the exercise intolerance occurs during childhood. Mild physical activity is associated with cardiac palpitations, lactic acidosis, muscle fatigue and weakness, and dyspnoea. Intense physical activity may trigger acute episodes associated with profound muscle weakness with pain and swelling, myoglobinuria, and in severe cases, extensive muscle paralysis and circulatory shock. Hypertrophy of the calves was also noted in some patients. Myopathy with succinate dehydrogenase and aconitase deficiency is transmitted in an autosomal recessive manner and has recently been found to be caused by mutations in the gene encoding the iron-sulphur cluster scaffold protein (ISCU; 12q24.1). ISCU plays an important role in iron-sulphur cluster assembly and is therefore essential for the activity mitochondrial iron-sulphur proteins such as succinate dehydrogenase and aconitase. Diagnosis requires physiological, biochemical and histochemical analysis. Exercise tests reveal low physical work tolerance with reduced oxidative capacity, low maximal muscle oxygen extraction and a hyperkinetic circulatory response (exaggerated cardiac output relative to the rate of oxygen consumption). Increased work loads result in high lactate and pyruvate concentrations in the blood. Analysis of skeletal muscle biopsies reveals the deficiencies in succinate dehydrogenase and aconitase. Histochemical studies also reveal the presence of iron-rich inclusions in the mitochondria, indicative of mitochondrial iron overload. Identification of ISCU as the causative gene may now allow confirmation of the diagnosis by molecular analysis. At present, there is no treatment for the disease. The recent discovery of the genetic defect may lead to the development of new therapeutic approaches revolving around correction of the defect in intracellular iron homeostasis. The prognosis for patients is variable: acute attacks triggered by physical exertion have been associated with circulatory shock and a fatal outcome in some cases.

Expert reviewer(s)

  • Pr Pascale DE LONLAY

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Detailed information

Clinical genetics review
  • EN (2011)
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