Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure

We report on 3 siblings (2 females and 1 male) with chronic progressive ext ernal ophthalmoplegia (CPEO), compatible with inherited mitochondrial cytop athy. The younger of the two sisters died at the age of 37 due to progressi ve respiratory failure. The older one presented with a status epilepticus a t the age of 39 and was treated with valproate. Five months after the start of treatment, she developed fulminant liver failure and died. The brother has suffered from CPEO since early childhood but has had so far no other sy mptoms of a mitochondrial disease. A muscle biopsy from the younger sister revealed ragged-red fibers and decreased activities of complex I and IV of the respiratory chain but no pathogenic mutations in the mitochondrial tRNA genes or in several locations in the coding region of the mitochondrial ge nome. In the older sister's liver (obtained post-mortem), mitochondrial DNA was fragmented and could not be investigated. The clinical presentation an d the biochemical findings suggest that all 3 siblings suffered from a mito chondrial cytopathy. Since mitochondrial cytopathies and valproate-induced fulminant liver failure are both rare events, an association between them i s likely. Mitochondrial diseases should therefore be considered as a risk f actor for valproate-induced liver failure and be excluded before treatment with valproate.