RT Journal Article
SR Electronic
T1 FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e0648
DO 10.1212/NXG.0000000000000648
VO 8
IS 1
A1 Montealegre, Sebastian
A1 Lebigot, Elise
A1 Debruge, Hugo
A1 Romero, Norma
A1 Héron, Bénédicte
A1 Gaignard, Pauline
A1 Legendre, Antoine
A1 Imbard, Apolline
A1 Gobin, Stéphanie
A1 Lacène, Emmanuelle
A1 Nusbaum, Patrick
A1 Hubas, Arnaud
A1 Desguerre, Isabelle
A1 Servais, Aude
A1 Laforêt, Pascal
A1 van Endert, Peter
A1 Authier, François Jérome
A1 Gitiaux, Cyril
A1 de Lonlay, Pascale
YR 2022
UL http://ng.neurology.org/content/8/1/e0648.abstract
AB 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.ATP=adenosine triphosphate; BSA=bovine serum albumin; CK=creatine kinase; EBSS=Earle's balanced salt solution; Fe-S=iron-sulfur; FRDA=Friedreich ataxia; FXN=frataxin; OXPHOS=oxidative phosphorylation; RM=rhabdomyolysis; SDH=succinyl dehydrogenase