FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation

Sebastian Montealegre; Elise Lebigot; Hugo Debruge; Norma Romero; Bénédicte Héron; Pauline Gaignard; Antoine Legendre; Apolline Imbard; Stéphanie Gobin; Emmanuelle Lacène; Patrick Nusbaum; Arnaud Hubas; Isabelle Desguerre; Aude Servais; Pascal Laforêt; Peter van Endert; François Jérome Authier; Cyril Gitiaux; Pascale de Lonlay

doi:10.1212/NXG.0000000000000648

FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation

Neurol Genet. 2022 Jan 19;8(1):e648. doi: 10.1212/NXG.0000000000000648. eCollection 2022 Feb.

Authors

Sebastian Montealegre¹, Elise Lebigot¹, Hugo Debruge¹, Norma Romero¹, Bénédicte Héron¹, Pauline Gaignard¹, Antoine Legendre¹, Apolline Imbard¹, Stéphanie Gobin¹, Emmanuelle Lacène¹, Patrick Nusbaum¹, Arnaud Hubas¹, Isabelle Desguerre¹, Aude Servais¹, Pascal Laforêt¹, Peter van Endert¹, François Jérome Authier¹, Cyril Gitiaux¹, Pascale de Lonlay¹

Affiliation

¹ Inserm U1151 (S.M., H.D., P.E., P.d.L.), Institut Necker Enfants-Malades, Paris; Reference Center of Inherited Metabolic Diseases (S.M., A.I., A.S., P.d.L.), Necker-Enfants-Malades University Hospital, APHP, Imagine Institute, Paris University, Filière G2M; Biochemistry Laboratory (E. Lebigot, P.G.), Filière G2M, Bicêtre Hospital, APHP Paris Saclay, Le Kremlin Bicêtre; Sorbonne Universié (E. Lacène), UPMC, INSERM UMR974, Center for Research in Myology, Neuromuscular Morphology Unit, Myology Institute, AP-HP, East-Paris Reference Center of Neuromuscular Diseases, GHU Pitié-Salpêtrière; Neurology Unit (N.R., B.H.), Trousseau Hospital, APHP, Filière G2M; M3C-Necker (A.L.), Congenital and Pediatric Cardiology, Hôpital Universitaire Necker-Enfants Malades; Biochemistry Department (A.I.), Necker-Enfants-Malades University Hospital, APHP, Paris University; Genetics Department (S.G.), Necker-Enfants-Malades University Hospital, APHP; Genetics and Molecular Biology (P.N., A.H.), Laboratoire de Culture Cellulaire, Hôpital Cochin, Paris; Reference Center of Neuromuscular Diseases (I.D., C.G.), Necker-Enfants-Malades University Hospital, APHP, Filière Filnemus; Adult Nephrology & Transplantation (A.S.), Necker-Enfants-Malades University Hospital, APHP, Inserm U1163, Imagine Institute, Paris Descartes University; Department of Neurology (P.L.), Raymond-Poincaré Hospital, Garches, and Inserm U1179 Versailles Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux; and Reference Center for Neuromuscular Disorders (F.J.A., C.G.), Department de Pathologie, Henri Mondor Hospital, APHP, IMRB U955, Faculty of Medicine, Creteil, France.

Abstract

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.