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Research paper
mtDNA copy number associated with age of onset in familial amyloid polyneuropathy
  1. Diana Santos1,2,3,
  2. Maria João Santos4,5,
  3. Miguel Alves-Ferreira1,2,3,
  4. Teresa Coelho6,
  5. Jorge Sequeiros1,2,3,7,
  6. Isabel Alonso1,2,7,3,
  7. Pedro Oliveira3,8,
  8. Alda Sousa1,2,3,
  9. Carolina Lemos1,2,3,
  10. Manuela Grazina4,5
  1. 1 i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  2. 2 UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal
  3. 3 Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
  4. 4 Centre for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics (LGB), Universidade de Coimbra, Coimbra, Portugal
  5. 5 Faculdade de Medicina da Universidade de Coimbra (FMUC), Coimbra, Portugal
  6. 6 Unidade Corino de Andrade (UCA), Centro Hospitalar do Porto (CHP), Porto, Portugal
  7. 7 Centro de Genética Preditiva e Preventiva (CGPP), Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
  8. 8 Instituto de Saúde Pública (ISPUP), Universidade do Porto, Porto, Portugal
  1. Correspondence to Dr Carolina Lemos, ICBAS, UnIGENe, IBMC and i3S, University Porto, Rua Alfredo Allen, n 208, 4200-135 Porto, Portugal; clclemos{at}


Background Transthyretin-related familial amyloid polyneuropathy (TTR-FAP Val30Met) shows a wide variation in age-at-onset (AO) between generations and genders, as in Portuguese families, where women display a later onset and a larger anticipation (>10 years). Mitochondrial DNA (mtDNA) copy number was assessed to clarify whether it has a modifier effect on AO variability in Portuguese patients.

Methods The mtDNA copy number of 262 samples (175 Val30Met TTR carriers and 87 controls (proven Val30Val)) was quantified by quantitative real-time PCR. Statistical analysis was performed using IBM SPSS V.23 software.

Results This study shows that Val30Met TTR carriers have a significantly higher (p<0.001) mean mtDNA copy number than controls. Furthermore, the highest mtDNA copy number mean was observed in early-onset patients (AO <40 years). Importantly, early-onset offspring showed a significant increase (p=0.002) in the mtDNA copy number, when compared with their late AO parents.

Conclusions The present findings suggest, for the first time, that mtDNA copy number may be associated with earlier events and may therefore be further explored as a potential biomarker for follow-up of TTR-FAP Val30Met carriers.

  • genetics

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  • CL and MG contributed equally.

  • Contributors Conception and design of the study: AS, CL, MG. Acquisition and analysis of data: TC, DS, MA-F, PO, AS, CL. Drafting a significant portion of the manuscript or figures: DS, MJS, AS, CL, MG. Critical revision of the manuscript for important intellectual content: MJS, TC, MA-F, PO, JS, IA, AS. Statistical expertise: PO, AS, CL. Obtaining funding: TC, JS, IA, AS, CL. Administrative, technical or material support: MA-F, IA, CL. Study supervision: AS, CL, MG.

  • Funding DS and MA-F are recipients of an FCT fellowship (SFRH/BD /91160/2012 and SFRH/BD/101352/2014, respectively). Our funding sources supported the data collection and analysis, but did not play a role in the study design, in interpretation of data, in the writing of the report or in the decision to submit the paper for publication.

  • Competing interests DS has received research support from an FCT fellowship (SFRH/BD /91160/2012). TC’s institution has received support from FoldRx Pharmaceuticals, which was acquired by Pfizer in October 2010; TC has served on the scientific advisory board of Pfizer and received funding from Pfizer for scientific meeting expenses (travel, accommodations and registration). She currently serves on the THAOS (natural history disease registry) scientific advisory board. MA-F has received research support from an FCT fellowship (SFRH/BD/101352/2014). MJS, JS, PO, IA, AS, CL and MG report no disclosures.

  • Ethics approval The Ethics Committee of Hospital de Santo António (HAS-CHP, Porto) approved the study.

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

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