Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations

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 beta 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.

Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

“…The patients, who were examined, had a respiratory chain SUCLA2 point mutation and 13q14 deletion S Matilainen et al defect and depletion of mtDNA. [6][7][8][9][10] Our two Finnish patients became symptomatic at the age of 5-6 months, similar to other reported patients, but showed clearly slower progression of the disease: at the current age of 9 and 20, they are able to walk with a walker, go to school and, despite a hearing deficit and inability to speak, are able to communicate using signs and gestures. The MRI findings of patient 1 have not progressed between the age of 2 and a half years and 7 years of age.…”

“…3,6 Over 20 patients and five different mutations in SUCLA2 have been described. [6][7][8][9][10] We report here molecular basis of mitochondrial encephalomyopathy, also combined with bilateral retinoblastoma, in patients with clinical symptoms or signs previously described in association with SUCLA2 mutations: encephalomyopathy with hearing deficit and methylmalonic aciduria.…”

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…Higher incidences have however been reported in specific populations in the Faroe Islands, 1:1700 (Ostergaard et al 2007) and Saguenay Lac-Saint-Jean region of Quebec, Canada, 1:2000 (Morin et al 1993) which have been attributable to founder mutations.…”

Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation

“…Western blot analysis was performed essentially as previously reported (Ostergaard et al 2007). The membrane was incubated with an antibody against ND1 (1:1000, H00004535-A01, Abnova.)…”