Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations

TLDR

Mitochondrial encephalomyopathy with elevated methylmalonic acid occurs at a high frequency in the Faroe Islands (1 in 1700) and is linked to SUCLA2 mutations, which encode the ATP‑forming β subunit of succinyl‑CoA ligase. Homozygosity mapping pinpointed a 13q14 region containing SUCLA2, and loss of its ATP‑forming β subunit leads to succinyl‑CoA accumulation that blocks methylmalonyl‑CoA conversion, causing elevated methylmalonic acid. In 12 autosomal recessive patients the disorder manifested as hypotonia, muscle atrophy, hyperkinesia, severe hearing loss, growth retardation, demyelination, basal ganglia atrophy, and Leigh‑syndrome features, all accompanied by elevated urinary and plasma methylmalonic acid and a novel IVS4+1G→A splice‑site mutation causing exon 4 skipping.

Abstract

We have identified 12 patients with autosomal recessive mitochondrial encephalomyopathy with elevated methylmalonic acid. The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33. The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation. Neuroimaging showed demyelination and central and cortical atrophy, including atrophy of the basal ganglia, and some of the patients fulfilled the criteria for Leigh syndrome. Urine and plasma methylmalonic acid were elevated. Homozygosity mapping with the Affymetrix 10 K array revealed a homozygous region on chromosome 13q14 harbouring the SUCLA2 gene. Mutations in SUCLA2 were recently shown to cause a similar disorder in a small Israeli family. Mutation analysis identified a novel splice site mutation in SUCLA2, IVS4 + 1G → A, leading to skipping of exon 4. The SUCLA2 gene encodes the ATP-forming β subunit of the Krebs cycle enzyme succinyl-CoA ligase. The hallmark of the condition, elevated methylmalonic acid, can be explained by an accumulation of the substrate of the enzyme, succinyl-CoA, which in turn leads to elevated methylmalonic acid, because the conversion of methylmalonyl-CoA to succinyl-CoA is inhibited.