Evidence for sodium valproate toxicity in mitochondrial diseases: a systematic analysis

Abstract

BackgroundWe aimed to determine whether sodium valproate (VPA) should be contraindicated in all mitochondrial diseases, due to known VPA-induced severe hepatotoxicity in some mitochondrial diseases.MethodsWe systematically reviewed the published literature for mitochondrial DNA (mtDNA) and common nuclear genotypes of mitochondrial diseases using PubMed, Ovid Embase, Ovid Medline and MitoPhen databases. We extracted patient-level data from peer-reviewed articles, published until July 2022, using the Human Phenotype Ontology to manually code clinical presentations for 156 patients with genetic diagnoses from 90 publications.ResultsThere were no fatal adverse drug reactions (ADRs) in the mtDNA disease group (35 patients), and only 1 out of 54 patients with a non-POLGmitochondrial disease developed acute liver failure. There were fatal outcomes in 53/102 (52%)POLGVPA-exposed patients who all harboured recessive mutations.ConclusionsOur findings confirm the high risk of severe ADRs in any patient with recessivePOLGvariants irrespective of the phenotype, and therefore recommend that VPA is contraindicated in this group. However, there was limited evidence of toxicity to support a similar recommendation in other genotypes of mitochondrial diseases.