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Brain Advance Access originally published online on February 7, 2007
Brain 2007 130(3):853-861; doi:10.1093/brain/awl383
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations

Elsebet Ostergaard1, Flemming J. Hansen2, Nicolina Sorensen3, Morten Duno1, John Vissing4, Pernille L. Larsen1, Oddmar Faeroe5, Sigurdur Thorgrimsson6, Flemming Wibrand1,7, Ernst Christensen1 and Marianne Schwartz1

1Department of Clinical Genetics, 2Department of Pediatrics, 3Department of Pediatrics, Hillerod Hospital, 4Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, 5John F. Kennedy Institute, Glostrup, Denmark, 6Landssjukrahusid, Department of Paediatrics, Torshavn, Faroe Islands and 7The University Hospital of Iceland, Reykjavik, Iceland

Corresponding author: Dr Elsebet Ostergaard, Department of Clinical Genetics 4062, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark E-mail: elsebet.oestergaard{at}rh.hosp.dk

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 ß 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.

Key Words: Methylmalonic acid; Leigh syndrome; mitochondrial encephalomyopathies; mitochondrial diseases

Abbreviations: MMA, methylmalonic acid; PDH, pyruvate dehydrogenase

Received May 22, 2006. Revised December 5, 2006. Accepted December 19, 2006.


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