1. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness
- Author
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Eva Morava, Simona Lucioli, Rosalba Carrozzo, Carlo Dionisi-Vici, Barbara Franke, Enrico Bertini, Filippo M. Santorelli, Richard J. Rodenburg, Maria Chiara Meschini, René Santer, Diana Vermunt-de Koning, Fiorella Piemonte, Leo A. J. Kluijtmans, Ulrike Steuerwald, Federica Deodato, Cristiano Rizzo, Sivia Di Giandomenico, Ron A. Wevers, and Arno van Rooij
- Subjects
Male ,Candidate gene ,Genetics and epigenetic pathways of disease [NCMLS 6] ,SUCLA2 ,DNA Mutational Analysis ,Methylmalonic acid ,Methylmalonic acidemia ,Neuroinformatics [DCN 3] ,Deafness ,chemistry.chemical_compound ,Gene Frequency ,Succinate-CoA Ligases ,Perception and Action [DCN 1] ,Determinants in Health and Disease [EBP 1] ,Atlantic Islands ,education.field_of_study ,Brain ,Magnetic Resonance Imaging ,Pedigree ,Mitochondrial medicine [IGMD 8] ,Lactic acidosis ,Muscle Hypotonia ,Female ,Leigh Disease ,Functional Neurogenomics [DCN 2] ,medicine.medical_specialty ,Energy and redox metabolism [NCMLS 4] ,Population ,Biology ,DNA, Mitochondrial ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Cognitive neurosciences [UMCN 3.2] ,Mitochondrial Encephalomyopathies ,Internal medicine ,Carnitine ,medicine ,Humans ,education ,Muscle, Skeletal ,Family Health ,Infant ,Glycostation disorders [IGMD 4] ,medicine.disease ,Neuromuscular development and genetic disorders [UMCN 3.1] ,Endocrinology ,chemistry ,Methylmalonic aciduria ,Genetic defects of metabolism [UMCN 5.1] ,Inborn error of metabolism ,Mutation ,Neurology (clinical) ,Methylmalonic Acid - Abstract
Contains fulltext : 53236.pdf (Publisher’s version ) (Closed access) 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.
- Published
- 2007