Six-year prospective follow-up study in 151 carriers of the mitochondrial DNA 3243 A>G variant.

Autor:	de Laat P; Radboudumc Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands., Rodenburg RR; Radboudumc Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands., Roeleveld N; Department for Health Evidence, Radboudumc, Nijmegen, Gelderland, The Netherlands., Koene S; Radboudumc Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands., Smeitink JA; Radboudumc Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands., Janssen MC; Department of Internal Medicine, Radboudumc, Nijmegen, The Netherlands mirian.janssen@radboudumc.nl.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2021 Jan; Vol. 58 (1), pp. 48-55. Date of Electronic Publication: 2020 May 21.
DOI:	10.1136/jmedgenet-2019-106800
Abstrakt:	Background: The mitochondrial DNA (mDNA) 3243A>G variant is the most common pathogenic variant of the mDNA. To interpret results of clinical trials in mitochondrial disease, it is important to have a clear understanding of the natural course of disease. To obtain more insight into the disease burden and the progression of disease in carriers of the mDNA 3243 A>G variant, we followed a cohort of 151 carriers from 61 families prospectively for up to 6 years. Methods: The disease severity was scored using the Newcastle Mitochondrial Disease Adult Scale (NMDAS), including SF-36 quality of life (QoL) scores. Heteroplasmy levels were measured in urinary epithelial cells (UEC), leucocytes and saliva. The progression of the disease was studied using linear mixed model analysis. Results: One hundred twenty-four carriers (out of 151) were symptomatic. Four clinical groups were identified: 1) classical mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (n=7), 2) maternally inherited diabetes deafness syndrome (n=60), 3) 'other' (n=57) and 4) dormant carriers (n=27). A yearly increase of NMDAS score of 0.47 point was measured in the total group. Heteroplasmy levels in both leucocytes and UEC were only weakly correlated with disease severity. Physical QoL declined with age. The most important determinants of QoL decline were hearing loss, speech problems, exercise intolerance, gait instability, psychiatric problems and gastrointestinal involvement. Conclusion: The mDNA 3243 A>G variant causes a slowly progressive disease, with a yearly increase of NMDAS score of ~0.5 point overall with the clinical phenotype being the only determinant of disease progression. Competing Interests: Competing interests: PdL, RRR, NR, SK and MJ report no disclosures. JAS is founding CEO of Khondrion BV. (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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