Rare presentation of FDX2-related disorder and untargeted global metabolomics findings

We present the case of a 20-year-old male with a history of myopathy and multiple episodes of rhabdomyolysis, and lactic acidosis. He needed hemodialysis for severe rhabdomyolysis-related acute renal failure at the time of initial presentation (age 10 years). Exome sequencing detected a homozygous likely pathogenic variant in FDX2 (c.12G>T, p.M4I). The FDX2 gene encodes a mitochondrial protein, ferredoxin 2, that is involved in the biogenesis of Fe-S clusters. Biallelic pathogenic variants in FDX2 have previously been associated with episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy. Only two cases with FDX2-related rhabdomyolysis as a predominant feature have been reported in medical literature. Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis. He does not have optic atrophy or leukoencephalopathy. This is the oldest patient reported with FDX2-related disorder and he has significantly elevated CK during episodes of rhabdomyolysis. In addition, we describe untargeted global metabolomic findings during an episode of metabolic decompensation, shedding light on the biochemical pathway perturbation associated with this ultra-rare genetic disorder.