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Hereditary myopathy with lactic acidosis due to ISCU deficiency

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Disease definition

A rare disease characterised by myopathy with severe exercise intolerance and deficiencies of skeletal muscle succinate dehydrogenase and aconitase.

ORPHA:43115

Classification level: Disorder

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: G71.3

ICD-11: 5C53.1

OMIM: 255125

UMLS: C1850718

MeSH: C564972

Summary
Epidemiology

It has been described in 19 individuals from nine families from northern Sweden.

Clinical description

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.

Etiology

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.

Diagnostic methods

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.

Management and treatment

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.

Prognosis

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.

Last update: April 2008 - Expert reviewer(s): Pr Pascale DE LONLAY
A summary on this disease is available in Français (2008) Español (2008) Deutsch (2008) Italiano (2008) Português (2008) Nederlands (2008)
Detailed information
General public
Article for general public
Svenska (2018) - Socialstyrelsen
Disease review articles
Clinical genetics review
English (2016) - GeneReviews

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