Brain Advance Access originally published online on February 14, 2007
Brain 2007 130(3):862-874; doi:10.1093/brain/awl389
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SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness
1Unit of Molecular Medicine, 2Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy, 3Department of Occupational and Public Health, Torshavn, Faroe Islands, 4Department of Pediatrics and Genetics, 5Laboratory of Pediatrics and Neurology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands and 6Molecular Genetics Laboratory, University Children's Hospital, Hamburg, Germany
Corresponding author: Carlo Dionisi-Vici, Division of Metabolism, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy; Ron A. Wevers, Radboud University Nijmegen Medical Centre, Laboratory of Pediatrics and Neurology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands E-mail: dionisi{at}opbg.net; r.wevers{at}cukz.umcn.nl
One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported.
We have studied 14 patients with mild ‘unlabelled’ methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G 
A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.
Key Words: methylmalonic aciduria; succinylcarnitine; mtDNA depletion; succinyl-CoA synthetase; TCA cycle defect
Abbreviations: MIM, Mendelian Inheritance in Man database; MMA, methylmalonic aciduria; mtDNA, mitochondrial DNA; SCS-A, ADP-forming succinyl-CoA synthetase; SCS-G, GDP-forming succinyl-CoA synthetase; SUCLA2, gene coding for the ß-subunit of ADP-forming succinyl-CoA synthetase; TCA, tricarboxylic acid; GC–MS, gas chromatography/mass spectrometry; MSMS, tandem mass spectrometry
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Received September 22, 2006. Revised November 26, 2006. Accepted December 20, 2006.
Rosalba Carrozzo and Carlo Dionisi-Vici equally contributed to the design and preparation of the manuscript.
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