Myopathy with Lactic Acidosis via the ISCU Gene

Myopathy with lactic acidosis is a mitochondrial myopathy that presents with lifelong exercise intolerance, muscle fatigue, shortness of breath, and tachycardia with low levels of physical exertion (Mochel et al. 2008; Olsson et al. 2008; Kollberg et al. 2009). Muscle tenderness, cramping, and myoglobinuria may also be present. Patients show a low work and oxidative capacity in additional to deficiency in the succinate dehydrogenase and aconitase enzymes. Onset is typically noticed in childhood with episodes of rhabdomyolysis and myoglobinuria occurring during or after the second decade of life (Mochel and Haller 2016). Two brothers with early onset of a slowly progressive severe muscle weakness, severe exercise intolerance, and cardiomyopathy have also been reported (Kollberg et al. 2009; Saha et al. 2014).

Myopathy with lactic acidosis is inherited in an autosomal recessive manner due to pathogenic variants in ISCU, located on chromosome 12q24.1. The ISCU gene encodes the iron-sulfur cluster scaffold protein (ISCU). The common pathogenic Swedish c.418+382G>C intronic variant results in aberrant splicing and a premature stop codon in the penultimate exon (Mochel et al. 2008; Olsson et al. 2008). This change alters the C-terminus of the ISCU protein and results in decreased levels of ISCU protein which results in deficiency of multiple iron-sulfer containing mitochondrial enzymes including succinate dehydrogenase, aconitase, and respiratory chain complexes I and III (Mochel et al. 2008; Olsson et al. 2008). The only pathogenic variants reported to date are the c.418+382G>C intronic variant and a missense variant (c.149G>A). The c.149G>A variant in the compound heterozygous state with the c.418+382G>C was reported in two brothers with a more severe phenotype (Kollberg et al. 2009; Saha et al. 2014).

Many types of mitochondrial myopathies exist and may be difficult to distinguish from ISCU-related myopathy. The clinical sensitivity is uncertain; however, patients of Swedish descent with reduced activity of succinate dyhydrogenase and aconitase on muscle biopsy are most likely to harbor ISCU variants. Analytical sensitivity should be high as all reported pathogenic variants are detected by sequencing.

This test provides full coverage of all coding exons of the ISCU gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

This test also includes coverage of the common Swedish c.418+382G>C intronic variant.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).