PT  - JOURNAL ARTICLE
AU  - Montealegre, Sebastian
AU  - Lebigot, Elise
AU  - Debruge, Hugo
AU  - Romero, Norma
AU  - Héron, Bénédicte
AU  - Gaignard, Pauline
AU  - Legendre, Antoine
AU  - Imbard, Apolline
AU  - Gobin, Stéphanie
AU  - Lacène, Emmanuelle
AU  - Nusbaum, Patrick
AU  - Hubas, Arnaud
AU  - Desguerre, Isabelle
AU  - Servais, Aude
AU  - Laforêt, Pascal
AU  - van Endert, Peter
AU  - Authier, François Jérome
AU  - Gitiaux, Cyril
AU  - de Lonlay, Pascale
TI  - FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation
AID  - 10.1212/NXG.0000000000000648
DP  - 2022 Feb 01
TA  - Neurology Genetics
PG  - e0648
VI  - 8
IP  - 1
4099  - http://ng.neurology.org/content/8/1/e0648.short
4100  - http://ng.neurology.org/content/8/1/e0648.full
SO  - Neurol Genet2022 Feb 01; 8
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