SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness
One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA 2 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 ac...
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fthighwire:oai:open-archive.highwire.org:brain:130/3/862 2023-05-15T16:10:44+02:00 SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness Carrozzo, Rosalba Dionisi-Vici, Carlo Steuerwald, Ulrike Lucioli, Simona Deodato, Federica Di Giandomenico, Sivia Bertini, Enrico Franke, Barbara Kluijtmans, Leo A. J. Meschini, Maria Chiara Rizzo, Cristiano Piemonte, Fiorella Rodenburg, Richard Santer, René Santorelli, Filippo M. van Rooij, Arno Vermunt-de Koning, Diana Morava, Eva Wevers, Ron A. 2007-03-01 00:00:00.0 text/html http://brain.oxfordjournals.org/cgi/content/short/130/3/862 https://doi.org/10.1093/brain/awl389 en eng Oxford University Press http://brain.oxfordjournals.org/cgi/content/short/130/3/862 http://dx.doi.org/10.1093/brain/awl389 Copyright (C) 2007, Oxford University Press Original Articles TEXT 2007 fthighwire https://doi.org/10.1093/brain/awl389 2015-02-28T22:27:18Z One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA 2 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 SUCLA 2 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 ... Text Faroe Islands HighWire Press (Stanford University) Faroe Islands Brain 130 3 862 874 |
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Original Articles Carrozzo, Rosalba Dionisi-Vici, Carlo Steuerwald, Ulrike Lucioli, Simona Deodato, Federica Di Giandomenico, Sivia Bertini, Enrico Franke, Barbara Kluijtmans, Leo A. J. Meschini, Maria Chiara Rizzo, Cristiano Piemonte, Fiorella Rodenburg, Richard Santer, René Santorelli, Filippo M. van Rooij, Arno Vermunt-de Koning, Diana Morava, Eva Wevers, Ron A. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness |
topic_facet |
Original Articles |
description |
One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA 2 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 SUCLA 2 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 ... |
format |
Text |
author |
Carrozzo, Rosalba Dionisi-Vici, Carlo Steuerwald, Ulrike Lucioli, Simona Deodato, Federica Di Giandomenico, Sivia Bertini, Enrico Franke, Barbara Kluijtmans, Leo A. J. Meschini, Maria Chiara Rizzo, Cristiano Piemonte, Fiorella Rodenburg, Richard Santer, René Santorelli, Filippo M. van Rooij, Arno Vermunt-de Koning, Diana Morava, Eva Wevers, Ron A. |
author_facet |
Carrozzo, Rosalba Dionisi-Vici, Carlo Steuerwald, Ulrike Lucioli, Simona Deodato, Federica Di Giandomenico, Sivia Bertini, Enrico Franke, Barbara Kluijtmans, Leo A. J. Meschini, Maria Chiara Rizzo, Cristiano Piemonte, Fiorella Rodenburg, Richard Santer, René Santorelli, Filippo M. van Rooij, Arno Vermunt-de Koning, Diana Morava, Eva Wevers, Ron A. |
author_sort |
Carrozzo, Rosalba |
title |
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness |
title_short |
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness |
title_full |
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness |
title_fullStr |
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness |
title_full_unstemmed |
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness |
title_sort |
sucla2 mutations are associated with mild methylmalonic aciduria, leigh-like encephalomyopathy, dystonia and deafness |
publisher |
Oxford University Press |
publishDate |
2007 |
url |
http://brain.oxfordjournals.org/cgi/content/short/130/3/862 https://doi.org/10.1093/brain/awl389 |
geographic |
Faroe Islands |
geographic_facet |
Faroe Islands |
genre |
Faroe Islands |
genre_facet |
Faroe Islands |
op_relation |
http://brain.oxfordjournals.org/cgi/content/short/130/3/862 http://dx.doi.org/10.1093/brain/awl389 |
op_rights |
Copyright (C) 2007, Oxford University Press |
op_doi |
https://doi.org/10.1093/brain/awl389 |
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Brain |
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130 |
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3 |
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862 |
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874 |
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