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Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset

Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C...

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Autores principales: Capiau, Sara, Smet, Joél, De Paepe, Boel, Yildiz, Yilmaz, Arslan, Mutluay, Stevens, Olivier, Verschoore, Maxime, Stepman, Hedwig, Seneca, Sara, Vanlander, Arnaud
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834419/
https://www.ncbi.nlm.nih.gov/pubmed/35159298
http://dx.doi.org/10.3390/cells11030489
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author Capiau, Sara
Smet, Joél
De Paepe, Boel
Yildiz, Yilmaz
Arslan, Mutluay
Stevens, Olivier
Verschoore, Maxime
Stepman, Hedwig
Seneca, Sara
Vanlander, Arnaud
author_facet Capiau, Sara
Smet, Joél
De Paepe, Boel
Yildiz, Yilmaz
Arslan, Mutluay
Stevens, Olivier
Verschoore, Maxime
Stepman, Hedwig
Seneca, Sara
Vanlander, Arnaud
author_sort Capiau, Sara
collection PubMed
description Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C variant in MT-ATP6. Patient 1 presented as a toddler with severe motor and speech delay and spastic ataxia without extra-neurologic involvement. Patient 2 presented in adolescence with ataxia and ophthalmoplegia without cognitive or motor impairment. Respiratory chain complex activities were normal in cultured skin fibroblasts from both patients when calculated as ratios over citrate synthase activity. Native gels found presence of subcomplexes of complex V in fibroblast and/or skeletal muscle. Bioenergetic measurements in fibroblasts from both patients detected reduced spare respiratory capacities and altered extracellular acidification rates, revealing a switch from mitochondrial respiration to glycolysis to uphold ATP production. Thus, in contrast to the differing disease presentation, biochemical evidence of mitochondrial deficiency turned out quite similar. We conclude that biochemical analysis remains a valuable tool to confirm the genetic diagnosis of mitochondrial disease, especially in patients with new gene variants or atypical clinical presentation.
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spelling pubmed-88344192022-02-12 Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset Capiau, Sara Smet, Joél De Paepe, Boel Yildiz, Yilmaz Arslan, Mutluay Stevens, Olivier Verschoore, Maxime Stepman, Hedwig Seneca, Sara Vanlander, Arnaud Cells Article Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C variant in MT-ATP6. Patient 1 presented as a toddler with severe motor and speech delay and spastic ataxia without extra-neurologic involvement. Patient 2 presented in adolescence with ataxia and ophthalmoplegia without cognitive or motor impairment. Respiratory chain complex activities were normal in cultured skin fibroblasts from both patients when calculated as ratios over citrate synthase activity. Native gels found presence of subcomplexes of complex V in fibroblast and/or skeletal muscle. Bioenergetic measurements in fibroblasts from both patients detected reduced spare respiratory capacities and altered extracellular acidification rates, revealing a switch from mitochondrial respiration to glycolysis to uphold ATP production. Thus, in contrast to the differing disease presentation, biochemical evidence of mitochondrial deficiency turned out quite similar. We conclude that biochemical analysis remains a valuable tool to confirm the genetic diagnosis of mitochondrial disease, especially in patients with new gene variants or atypical clinical presentation. MDPI 2022-01-30 /pmc/articles/PMC8834419/ /pubmed/35159298 http://dx.doi.org/10.3390/cells11030489 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Capiau, Sara
Smet, Joél
De Paepe, Boel
Yildiz, Yilmaz
Arslan, Mutluay
Stevens, Olivier
Verschoore, Maxime
Stepman, Hedwig
Seneca, Sara
Vanlander, Arnaud
Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset
title Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset
title_full Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset
title_fullStr Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset
title_full_unstemmed Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset
title_short Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset
title_sort clinical heterogeneity in mt-atp6 pathogenic variants: same genotype—different onset
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834419/
https://www.ncbi.nlm.nih.gov/pubmed/35159298
http://dx.doi.org/10.3390/cells11030489
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