title: 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.
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. elsebet.oestergaard@rh.hosp.dk
authors.forename: Elsebet
authors.initials: E
authors.lastname: Ostergaard
authors.forename: Flemming J
authors.initials: FJ
authors.lastname: Hansen
authors.forename: Nicolina
authors.initials: N
authors.lastname: Sorensen
authors.forename: Morten
authors.initials: M
authors.lastname: Duno
authors.forename: John
authors.initials: J
authors.lastname: Vissing
authors.forename: Pernille L
authors.initials: PL
authors.lastname: Larsen
authors.forename: Oddmar
authors.initials: O
authors.lastname: Faeroe
authors.forename: Sigurdur
authors.initials: S
authors.lastname: Thorgrimsson
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.forename: Ernst
authors.initials: E
authors.lastname: Christensen
authors.forename: Marianne
authors.initials: M
authors.lastname: Schwartz
mesh_terms: D000293:Adolescent; D000328:Adult; D001266:Atlantic Islands / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000235:genetics; D005192:Family Health; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015994:Incidence; D008297:Male; D008764:Methylmalonic Acid / Q000032:analysis*; D018895:Microsatellite Repeats / Q000235:genetics; D017237:Mitochondrial Encephalomyopathies / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013389:Succinate-CoA Ligases / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D008764:Methylmalonic Acid; D013389:Succinate-CoA Ligases; C518788:SUCLA2 protein, human