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Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

BACKGROUND: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel...

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Autores principales: Danhelovska, Tereza, Kolarova, Hana, Zeman, Jiri, Hansikova, Hana, Vaneckova, Manuela, Lambert, Lukas, Kucerova-Vidrova, Vendula, Berankova, Kamila, Honzik, Tomas, Tesarova, Marketa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988306/
https://www.ncbi.nlm.nih.gov/pubmed/31996177
http://dx.doi.org/10.1186/s12887-020-1912-x
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author Danhelovska, Tereza
Kolarova, Hana
Zeman, Jiri
Hansikova, Hana
Vaneckova, Manuela
Lambert, Lukas
Kucerova-Vidrova, Vendula
Berankova, Kamila
Honzik, Tomas
Tesarova, Marketa
author_facet Danhelovska, Tereza
Kolarova, Hana
Zeman, Jiri
Hansikova, Hana
Vaneckova, Manuela
Lambert, Lukas
Kucerova-Vidrova, Vendula
Berankova, Kamila
Honzik, Tomas
Tesarova, Marketa
author_sort Danhelovska, Tereza
collection PubMed
description BACKGROUND: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. METHODS: The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. RESULTS: In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-(14)C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. CONCLUSIONS: Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-(14)C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.
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spelling pubmed-69883062020-01-31 Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I Danhelovska, Tereza Kolarova, Hana Zeman, Jiri Hansikova, Hana Vaneckova, Manuela Lambert, Lukas Kucerova-Vidrova, Vendula Berankova, Kamila Honzik, Tomas Tesarova, Marketa BMC Pediatr Research Article BACKGROUND: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. METHODS: The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. RESULTS: In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-(14)C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. CONCLUSIONS: Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-(14)C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis. BioMed Central 2020-01-29 /pmc/articles/PMC6988306/ /pubmed/31996177 http://dx.doi.org/10.1186/s12887-020-1912-x Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Danhelovska, Tereza
Kolarova, Hana
Zeman, Jiri
Hansikova, Hana
Vaneckova, Manuela
Lambert, Lukas
Kucerova-Vidrova, Vendula
Berankova, Kamila
Honzik, Tomas
Tesarova, Marketa
Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
title Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
title_full Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
title_fullStr Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
title_full_unstemmed Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
title_short Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
title_sort multisystem mitochondrial diseases due to mutations in mtdna-encoded subunits of complex i
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988306/
https://www.ncbi.nlm.nih.gov/pubmed/31996177
http://dx.doi.org/10.1186/s12887-020-1912-x
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