Hereditary myopathy with lactic acidosis due to Iron-Sulfur Cluster Assembly Enzyme (ISCU) deficiency is a rare disorder of energy metabolism characterized clinically by myopathy with exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes. ISCU protein plays an important role in iron-sulphur clusters (Fe-S) assembly and is therefore essential for the activity of mitochondrial Fe-S proteins such as succinate dehydrogenase and aconitase. Recessive hypomorphic ISCU alleles have been associated with hereditary myopathy with lactic acidosis, also known as Swedish-type myopathy. To date, only one heterozygous dominant variant (c.287G>T, p.Gly96Val) in the ISCU gene has been reported as pathogenic. Functional studies have shown that this variant has a detrimental, dominant effect on activity of Fe-S-dependent enzymes. Whole exome sequencing performed in an adult female patient with progressive muscle weakness led to the identification of a novel heterozygous variant c.399del (p.Val134Ter) in the ISCU gene. This variant is localized in the functional IscU_like domain of the ISCU protein, with bioinformatics prediction of damaging effects on protein function. Moreover, the same variant was also found in a few family members, who present signs of myopathy. This novel variant segregates with the disease and results in a phenotype reminiscent of the recessive disease previously reported. Yeast Saccharomyces cerevisiae is a widely used tool able to assess the impact of the VUS in a quick and efficient way, therefore functional studies were performed on this model system. The results obtained not only confirm the pathogenetic effect of the variant, but also support its dominant inheritance.

Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron-sulfur (Fe-S) clusters. A single Scandinavian family was identified with a different mutation, a missense change in compound heterozygosity with the common intronic mutation. The aim of the study was to identify the genetic defect in our proband. A next-generation sequencing (NGS) approach was carried out on an Italian male who presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. Patient's specimens and yeast models were investigated. Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. We identified a single heterozygous mutation p.Gly96Val in ISCU, which was absent in DNA from his parents indicating a possible de novo dominant effect in the patient. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense mutation. We describe the first heterozygous dominant mutation in ISCU which results in a phenotype reminiscent of the recessive disease previously reported.