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

Abstract

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.

Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin‐2 (FDX2) gene

“…Significant increase in urine ketone bodies and lactate was also detected. As already mentioned by Aggarwal et al (2022), our patient had myopathy with lactic acidosis that was deteriorated after the administration of high concentration of dextrose, setting the suspicion of mitochondrial and tricarboxylic acid cycle dysfunction. Our patient's severe increase in lactate without the proportional increase in pyruvate, leads us away from the diagnosis of pyruvate dehydrogenase complex deficiency, but raises the suspicion of fatty acid oxidation disorders, especially of carnitine palmitoyltransferase 2 (CPT2) deficiency.…”

“…However, no supplementation with alpha‐lipoic acid was needed, compared to the Aggarwal et al's (2022) patient. Finally, it is worth mentioning that there are only four cases reported with the same homozygous pathogenic variant in FDX2 (p.M4L; Aggarwal et al, 2022; Lebigot et al, 2017; Montealegre et al, 2022; Spiegel et al, 2014). Additionally, the case of Gurgel‐Giannetti et al (2018) ( p .P144L/c.431C > T) is the only case of FDX2 ‐related myopathy combined with optic atrophy and brain MRI findings.…”

“…In our patient, severe rhabdomyolysis, especially the persistent lactic acidosis combined with the history of exercise intolerance and hyperammonemia raised the suspicion for an inherited metabolic disorder and more specifically of a mitochondrial disorder (Nance & Mammen, 2015; Scalco et al, 2015). There are few published cases, describing patients with recurrent episodes of rhabdomyolysis and lactic acidosis related to FDX2 myopathy (Aggarwal et al, 2022; Gurgel‐Giannetti et al, 2018; Lebigot et al, 2017; Montealegre et al, 2022; Spiegel et al, 2014; Table 2). This is the first reported case of FDX2 myopathy with elevated plasma ammonia levels in the acute phase of the initial presentation.…”

“…Recently, a few patients with mitochondrial myopathy caused by a homozygous mutation in the ferredoxin‐2 ( FDX2 ) gene have been reported with homozygous pathogenic variant ENST00000541276:p.Met4Leu/c.10A > T being related to myopathy, lactic acidosis, and rhabdomyolysis (Aggarwal et al, 2022; Gurgel‐Giannetti et al, 2018; Lebigot et al, 2017; Montealegre et al, 2022; Spiegel et al, 2014). FDX2 along with FDX1 play a key role in steroidogenesis and iron–sulfur cluster biosynthesis (Sheftel et al, 2010).…”

Recent advances in our understanding of genetic rhabdomyolysis

“…This difference has been explained by tissue-specific splicing of the latter [55]. However, FDX2 patients with a phenotype where severe rhabdomyolysis episodes predominate without apparent extramuscular involvement, have also recently been described [56]. ISCs are conserved across almost all organisms from bacteria, and plants to mammals.…”