Key result
FDX2 variants link to more severe rhabdomyolysis than ISCU variants without skeletal muscle iron accumulation.
Why the study?
Common clinical and biological traits in individuals with biallelic ISCU or FDX2 variants causing severe and recurrent rhabdomyolysis and lactic acidosis were not well characterized.
Do FDX2 and ISCU gene variations lead to distinct clinical and biological phenotypes in individuals with rhabdomyolysis?
Case Report (n=2)
Do FDX2 and ISCU gene variations lead to distinct clinical and biological phenotypes in individuals with rhabdomyolysis?
FDX2 and ISCU variants cause a similar muscle phenotype of rhabdomyolysis but differ in clinical severity and skeletal muscle iron accumulation.
May indicate distinct FDX2 versus ISCU phenotypes warranting genotype-specific evaluation in rhabdomyolysis; leaves open confirmation in larger cohorts.
Background and Objectives To determine common clinical and biological traits in 2 individuals with variants in ISCU and FDX2, displaying severe and recurrent rhabdomyolyses and lactic acidosis. Methods We performed a clinical characterization of 2 distinct individuals with biallelic ISCU or FDX2 variants from 2 separate families and a biological characterization with muscle and cells from those patients. Results The individual with FDX2 variants was clinically more affected than the individual with ISCU variants. Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities, associated with high levels of blood FGF21. ISCU individual fibroblasts showed no oxidative phosphorylation deficiency and moderate increase of blood FGF21 levels relative to controls. The severity of the FDX2 individual was not due to dysfunctional autophagy. Iron was excessively accumulated in ISCU-deficient skeletal muscle, which was accompanied by a downregulation of IRP1 and mitoferrin2 genes and an upregulation of frataxin (FXN) gene expression. This excessive iron accumulation was absent from FDX2 affected muscle and could not be correlated with variable gene expression in muscle cells. Discussion We conclude that FDX2 and ISCU variants result in a similar muscle phenotype, that differ in severity and skeletal muscle iron accumulation. ISCU and FDX2 are not involved in mitochondrial iron influx contrary to frataxin.
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A 2022 study conducted a case report in Severe and recurrent rhabdomyolyses and lactic acidosis (n=2). ISCU and FDX2 gene variants vs. Controls was evaluated on Clinical and biological traits including muscle phenotype and iron regulation. FDX2 and ISCU variants caused similar rhabdomyolysis phenotypes, but the FDX2 variant led to greater clinical severity without the skeletal muscle iron accumulation seen with ISCU variants.
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