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Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias
BACKGROUND: Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. METHODS: This study...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016503/ https://www.ncbi.nlm.nih.gov/pubmed/24059531 http://dx.doi.org/10.1186/1750-1172-8-148 |
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author | Nizon, Mathilde Ottolenghi, Chris Valayannopoulos, Vassili Arnoux, Jean-Baptiste Barbier, Valérie Habarou, Florence Desguerre, Isabelle Boddaert, Nathalie Bonnefont, Jean-Paul Acquaviva, Cécile Benoist, Jean-François Rabier, Daniel Touati, Guy de Lonlay, Pascale |
author_facet | Nizon, Mathilde Ottolenghi, Chris Valayannopoulos, Vassili Arnoux, Jean-Baptiste Barbier, Valérie Habarou, Florence Desguerre, Isabelle Boddaert, Nathalie Bonnefont, Jean-Paul Acquaviva, Cécile Benoist, Jean-François Rabier, Daniel Touati, Guy de Lonlay, Pascale |
author_sort | Nizon, Mathilde |
collection | PubMed |
description | BACKGROUND: Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. METHODS: This study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. RESULTS: Patients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 μmol/L versus 70 μmol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 μmol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 μmol/mmol of creatinine versus 34.6 μmol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 μmol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene. CONCLUSION: Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients. |
format | Online Article Text |
id | pubmed-4016503 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40165032014-05-11 Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias Nizon, Mathilde Ottolenghi, Chris Valayannopoulos, Vassili Arnoux, Jean-Baptiste Barbier, Valérie Habarou, Florence Desguerre, Isabelle Boddaert, Nathalie Bonnefont, Jean-Paul Acquaviva, Cécile Benoist, Jean-François Rabier, Daniel Touati, Guy de Lonlay, Pascale Orphanet J Rare Dis Research BACKGROUND: Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. METHODS: This study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. RESULTS: Patients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 μmol/L versus 70 μmol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 μmol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 μmol/mmol of creatinine versus 34.6 μmol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 μmol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene. CONCLUSION: Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients. BioMed Central 2013-09-23 /pmc/articles/PMC4016503/ /pubmed/24059531 http://dx.doi.org/10.1186/1750-1172-8-148 Text en Copyright © 2013 Nizon et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Nizon, Mathilde Ottolenghi, Chris Valayannopoulos, Vassili Arnoux, Jean-Baptiste Barbier, Valérie Habarou, Florence Desguerre, Isabelle Boddaert, Nathalie Bonnefont, Jean-Paul Acquaviva, Cécile Benoist, Jean-François Rabier, Daniel Touati, Guy de Lonlay, Pascale Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias |
title | Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias |
title_full | Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias |
title_fullStr | Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias |
title_full_unstemmed | Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias |
title_short | Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias |
title_sort | long-term neurological outcome of a cohort of 80 patients with classical organic acidurias |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016503/ https://www.ncbi.nlm.nih.gov/pubmed/24059531 http://dx.doi.org/10.1186/1750-1172-8-148 |
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