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Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment
Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912785/ https://www.ncbi.nlm.nih.gov/pubmed/31683770 http://dx.doi.org/10.3390/jcm8111811 |
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author | Bravo-Alonso, Irene Navarrete, Rosa Vega, Ana Isabel Ruíz-Sala, Pedro García Silva, María Teresa Martín-Hernández, Elena Quijada-Fraile, Pilar Belanger-Quintana, Amaya Stanescu, Sinziana Bueno, María Vitoria, Isidro Toledo, Laura Couce, María Luz García-Jiménez, Inmaculada Ramos-Ruiz, Ricardo Martín, Miguel Ángel Desviat, Lourdes R. Ugarte, Magdalena Pérez-Cerdá, Celia Merinero, Begoña Pérez, Belén Rodríguez-Pombo, Pilar |
author_facet | Bravo-Alonso, Irene Navarrete, Rosa Vega, Ana Isabel Ruíz-Sala, Pedro García Silva, María Teresa Martín-Hernández, Elena Quijada-Fraile, Pilar Belanger-Quintana, Amaya Stanescu, Sinziana Bueno, María Vitoria, Isidro Toledo, Laura Couce, María Luz García-Jiménez, Inmaculada Ramos-Ruiz, Ricardo Martín, Miguel Ángel Desviat, Lourdes R. Ugarte, Magdalena Pérez-Cerdá, Celia Merinero, Begoña Pérez, Belén Rodríguez-Pombo, Pilar |
author_sort | Bravo-Alonso, Irene |
collection | PubMed |
description | Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic condition remains low. The present work reports our group’s experience of using a clinical/biochemical analysis system in conjunction with genetic findings that facilitates the taking of timely clinical decisions with minimum need for invasive procedures. The system’s workflow combines different metabolomics datasets and phenotypic information with the results of clinical exome sequencing and/or RNA analysis. The system’s use detected genetic variants in 64% of a cohort of 39 CLA-patients; these variants, 14 of which were novel, were found in 19 different nuclear and two mitochondrial genes. For patients with variants of unknown significance, the genetic analysis was combined with functional genetic and/or bioenergetics analyses in an attempt to detect pathogenicity. Our results warranted subsequent testing of antisense therapy to rescue the abnormal splicing in cultures of fibroblasts from a patient with a defective GFM1 gene. The discussed system facilitates the diagnosis of CLA by avoiding the need to use invasive techniques and increase our knowledge of the causes of this condition. |
format | Online Article Text |
id | pubmed-6912785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69127852020-01-02 Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment Bravo-Alonso, Irene Navarrete, Rosa Vega, Ana Isabel Ruíz-Sala, Pedro García Silva, María Teresa Martín-Hernández, Elena Quijada-Fraile, Pilar Belanger-Quintana, Amaya Stanescu, Sinziana Bueno, María Vitoria, Isidro Toledo, Laura Couce, María Luz García-Jiménez, Inmaculada Ramos-Ruiz, Ricardo Martín, Miguel Ángel Desviat, Lourdes R. Ugarte, Magdalena Pérez-Cerdá, Celia Merinero, Begoña Pérez, Belén Rodríguez-Pombo, Pilar J Clin Med Article Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic condition remains low. The present work reports our group’s experience of using a clinical/biochemical analysis system in conjunction with genetic findings that facilitates the taking of timely clinical decisions with minimum need for invasive procedures. The system’s workflow combines different metabolomics datasets and phenotypic information with the results of clinical exome sequencing and/or RNA analysis. The system’s use detected genetic variants in 64% of a cohort of 39 CLA-patients; these variants, 14 of which were novel, were found in 19 different nuclear and two mitochondrial genes. For patients with variants of unknown significance, the genetic analysis was combined with functional genetic and/or bioenergetics analyses in an attempt to detect pathogenicity. Our results warranted subsequent testing of antisense therapy to rescue the abnormal splicing in cultures of fibroblasts from a patient with a defective GFM1 gene. The discussed system facilitates the diagnosis of CLA by avoiding the need to use invasive techniques and increase our knowledge of the causes of this condition. MDPI 2019-11-01 /pmc/articles/PMC6912785/ /pubmed/31683770 http://dx.doi.org/10.3390/jcm8111811 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bravo-Alonso, Irene Navarrete, Rosa Vega, Ana Isabel Ruíz-Sala, Pedro García Silva, María Teresa Martín-Hernández, Elena Quijada-Fraile, Pilar Belanger-Quintana, Amaya Stanescu, Sinziana Bueno, María Vitoria, Isidro Toledo, Laura Couce, María Luz García-Jiménez, Inmaculada Ramos-Ruiz, Ricardo Martín, Miguel Ángel Desviat, Lourdes R. Ugarte, Magdalena Pérez-Cerdá, Celia Merinero, Begoña Pérez, Belén Rodríguez-Pombo, Pilar Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment |
title | Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment |
title_full | Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment |
title_fullStr | Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment |
title_full_unstemmed | Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment |
title_short | Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment |
title_sort | genes and variants underlying human congenital lactic acidosis—from genetics to personalized treatment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912785/ https://www.ncbi.nlm.nih.gov/pubmed/31683770 http://dx.doi.org/10.3390/jcm8111811 |
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