Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early
fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe
metabolic acidosis and
rhabdomyolysis may occur. The disease has so far only been identified in northern Sweden. The clinical, histochemical and biochemical phenotype is very homogenous and 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.
Iron-sulphur cluster containing
proteins are essential for
iron homeostasis and respiratory chain function, with
IscU being among the most conserved
proteins in evolution. We identified a shared homozygous segment of only 405,000 base pair with the deep intronic mutation in eight patients with a phenotype consistent with the original description of the disease. Two other patients, two brothers, had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle
iron-sulphur cluster deficiency, but they presented with a disease where the clinical phenotype was characterized by early onset of a slowly progressive severe
muscle weakness, severe exercise intolerance and
cardiomyopathy. 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. The missense mutation was inherited from their mother who was of Finnish descent. 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. In western blot analysis of
protein extracts from fibroblasts, there was no pronounced reduction of
IscU in any of the patients, but the analysis revealed that the species corresponding to mitochondrial
IscU migrates slower than a species present only in whole cells. In
protein extracted from isolated skeletal muscle mitochondria the western blot analysis revealed a severe deficiency of
IscU in the homozygous patients and appearance of a faint new fraction that could represent a truncated
protein. There was only a slight reduction of mitochondrial
IscU in the compound heterozygotes, despite their severe phenotype, indicating that the
IscU expressed in these patients is non-functional.