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

Abstract

Mitochondrial myopathy is a severe metabolic myopathy related to nuclear or mitochondrial DNA dysfunction. We present a rare case of mitochondrial myopathy, presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis (CPK 319,990 U/L, lactic acid 22.31 mmol/L, and GFR 3.82 mL/min/1.73m2). She was hospitalized in the pediatric intensive care unit due to acute kidney injury, elevated blood pressure, and deterioration of respiratory and cardiac function. Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies. Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) and a heterozygous variant of uncertain significance in MSTO1 (ENST00000538143:p.Leu137Pro/c.410 T > C). After Sanger sequencing, the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister. Recently, pathogenic variants in the FDX2 gene have been associated with mitochondrial myopathy, lactic acidosis, optic atrophy, and leukoencephalopathy. Only four reports of FDX2‐related rhabdomyolysis have been described before, but none of the previous patients had hyperammonemia. This is a rare case of severe mitochondrial myopathy in a pediatric patient related to a pathogenic FDX2 variant, suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies.

Clinical, biochemical and molecular characterization of a new case with FDX2‐related mitochondrial disorder: Potential biomarkers and treatment options

“…Previous study showed that patient with FDX2 ‐related disorder is sensitive to high dextrose fluid, leading to increased lactate production. 10 , 11 The proband also demonstrated increased blood lactate with the increase of glucose infusion rate. This phenomenon has been known in PDH deficiency, and in fact, the patients with PDH deficiency responded to ketogenic diet.…”

“… 9 The previously reported patients with predominant muscular presentation harbor the variants affecting the initiator codon. 6 , 7 , 8 , 10 , 11 The proband is the first reported patient with compound heterozygous variants. The patients harboring missense variants affecting initiator codon did not demonstrate extramuscular involvement.…”

“… 6 To date, 10 patients from 6 families have been reported with FDX2 ‐related disorder. 6 , 7 , 8 , 9 , 10 , 11 Clinical phenotype included progressive myopathy, rhabdomyolysis with variable onset and severity, peripheral neuropathy, and reversible leukoencephalopathy. Optic atrophy, neurodevelopmental abnormalities, microcytic anemia, neutropenia, hypothyroidism have been reported in some patients.…”

“…Biochemical abnormalities include lactic acidosis, and hyperexcretion of lactate, ketones, tricarboxylic acid (TCA) cycle metabolites, and 3‐methylglutaconic acid in urine organic acid analysis. 6 , 7 , 10 , 11 Mitochondrial respiratory chain analysis revealed decreased activities of several mitochondrial complexes and mitochondrial aconitase. 6 …”