TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?

Eur J Hum Genet. 2010 Aug;18(8):948-52. doi: 10.1038/ejhg.2010.36. Epub 2010 Mar 17.


The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Amyloid Neuropathies, Familial / epidemiology
  • Amyloid Neuropathies, Familial / genetics*
  • DNA, Mitochondrial / genetics*
  • Female
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Penetrance*
  • Polymorphism, Genetic*
  • Portugal / epidemiology
  • Prealbumin / genetics*
  • Sweden / epidemiology


  • DNA, Mitochondrial
  • Prealbumin