Enasidenib treatment in two individuals with D-2-hydroxyglutaric aciduria carrying a germline IDH2 mutation.

Abstract

D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. Here we report the results of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder.

• Authors: Birgit Geoerger, Manuel Schiff, Virginie Penard-Lacronique, Niklas Darin, Selim-Maria Saad, Clarisse Duchon, Antonin Lamazière, Aurore Desmons, Clément Pontoizeau, Pablo Berlanga, Stéphane Ducassou, Katharine Yen, Michael Su, David Schenkein, Chris Ottolenghi, Stéphane De Botton
• Journal: Nature medicine (Nat Med) Vol. 29 Issue 6 Pg. 1358-1363 (Jun 2023) ISSN: 1546-170X [Electronic] United States
• PMID: 37248298 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• enasidenib
• Enzyme Inhibitors
• Isocitrate Dehydrogenase

Topics

• Child
• Humans
• Cardiomyopathies (drug therapy, genetics)
• Enzyme Inhibitors (adverse effects)
• Germ Cells (metabolism)
• Isocitrate Dehydrogenase (metabolism)
• Mutation (genetics)