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Original research
Six-year prospective follow-up study in 151 carriers of the mitochondrial DNA 3243 A>G variant
  1. Paul de Laat1,
  2. Richard R Rodenburg1,
  3. Nel Roeleveld2,
  4. Saskia Koene1,
  5. Jan A Smeitink1,
  6. Mirian CH Janssen3
  1. 1 Radboudumc Amalia Children’s Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands
  2. 2 Department for Health Evidence, Radboudumc, Nijmegen, Gelderland, The Netherlands
  3. 3 Department of Internal Medicine, Radboudumc, Nijmegen, The Netherlands
  1. Correspondence to Dr Mirian CH Janssen, Department of internal medicine, Radboudumc, Nijmegen, Netherlands; mirian.janssen{at}


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.

  • genetics
  • metabolic disorders

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  • Contributors PdL: design of protocol logistics, clinical coordinator, clinical evaluation of patients, writing of manuscript. RRR: DNA analysis, data interpretation, correction of manuscript. NR: data interpretation, correction of manuscript. SK: clinical evaluation of patients, data interpretation, correction of manuscript. JAS: design of protocol, data interpretation, correction of manuscript. MJ: protocol design, clinical evaluation of patients, data interpretation, writing of manuscript.

  • Funding Part of this work was supported by grants from ZonMW (The Netherlands Organization for Health Research and Development) PM-Rare Grant (113302003), the Stichting Energy4All and the Tim Star Foundation awarded to JAS.

  • Competing interests PdL, RRR, NR, SK and MJ report no disclosures. JAS is founding CEO of Khondrion BV.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Regional Committee on Research involving Human Subjects Arnhem-Nijmegen (NL32683.091.10, METC nr 2010/183).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. Data are available on request from