Hereditary myopathy with lactic acidosis due to ISCU deficiency (ORPHA:43115)
A rare disorder of energy metabolism characterized clinically by myopathy with severe exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes, succinate dehydrogenase and aconitase.
Epidemiology
ISCU myopathy is an ultra-rare disease reported in approximately 20 individuals in the world. Most patients are of Swedish heritage, though patients from other ethnic backgrounds have also been identified.
Clinical description
The cardinal feature of this condition is childhood-onset exercise intolerance, with muscle fatigue, pain, tachycardia and dyspnea occurring within a few minutes of mild physical activity. More prolonged or substantial exertion can result in an episode of profound muscle weakness associated with lactic acidosis and severe rhabdomyolysis. Cardiomyopathy has also been reported in patients of non-Swedish ancestry.
Etiology
This genetic condition occurs due to bi-allelic variants in the gene ISCU (autosomal recessive inheritance). There is one report of a patient with a de novo heterozygous variant in ISCU, but thus far no other cases support an autosomal dominant inheritance pattern. The ISCU protein acts as a scaffold for iron-sulfur cluster assembly. Iron-sulfur clusters are essential components of various proteins, including some involved in mitochondrial function. Dysfunction of ISCU prevents mitochondria (particularly in muscle) from generating energy efficiently, resulting in exercise intolerance. All Swedish patients described to date are homozygous for the same genetic change in ISCU (c.418+382G>C).
Diagnostic methods
ISCU myopathy should be considered in patients with the above clinical features. High blood lactate levels are usually present at baseline: with exercise physiology testing, further elevations in lactate and pyruvate occur, significantly limiting VO2 max. Confirmation of the diagnosis is now primarily via molecular (genetic) testing: possibilities include targeted sequencing for the Swedish variant, a gene panel for myopathy, or a broader test such as whole exome sequencing. Specialized biochemical testing can add confidence to the diagnosis, especially if the molecular testing identifies variants of uncertain significance. Most patients have high plasma fibroblast growth factor 21 levels. Analysis of muscle biopsy specimens can identify deficiency of mitochondrial aconitase, succinate dehydrogenase and specific respiratory chain complexes (I, II and III), as well as histochemical evidence of mitochondrial iron accumulation.
Differential diagnosis
The differential diagnosis includes other mitochondrial disorders, muscle-specific glycogen storage diseases, fatty acid oxidation disorders, glycolytic pathway defects (eg. phosphoglycerate kinase deficiency), TANGO2 deficiency and other genetic myopathies.
Antenatal diagnosis
Antenatal diagnosis is possible if the disease-causing variants have been previously identified in an affected family member. The decision to undertake testing should be discussed with the couple with input from genetic counseling and obstetric teams.
Genetic counseling
Because this is a recessive condition, couples where each partner carries a pathogenic variant in ISCU have a 25% chance of having an affected child with each pregnancy. Specialized genetic counseling can help such couples contextualize this risk and understand their reproductive options.
Management and treatment
Currently, the focus of treatment for this condition is supportive management during episodes of rhabdomyolysis and a specialized exercise program to maintain muscle function without precipitating symptoms. Antisense oligonucleotide therapy has been trialled in vitro on patient myotubular cell lines. It appeared to correct the c.418+382G>C splicing abnormality, leading to improvements in biochemical abnormalities. However, there have been no subsequent clinical trials or other studies of such a treatment in humans.
Prognosis
Most patients live well into adulthood, with preserved quality of life despite their limited exercise tolerance. Acute decompensations with rhabdomyolysis and lactic acidosis can be fatal in rare instances, especially if supportive management is not initiated in these situations.

                            Last update: 
                            July 2024


                            - Expert reviewer(s): 
                            Dr Parayil Sankaran BINDU  - Dr Arthavan SELVANATHAN