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

• Published in: European journal of human genetics : EJHG 2010-08, Vol.18 (8), p.948-952
• Main Authors: Bonaïti, Bernard, Olsson, Malin, Hellman, Urban, Suhr, Ole, Bonaïti-Pellié, Catherine, Planté-Bordeneuve, Violaine
• Format: Article
• Language: English
• Subjects: 631/208/726/649; 692/699/375/365; Adult; Age; Age of Onset; Amyloid; Amyloid Neuropathies, Familial - epidemiology; Amyloid Neuropathies, Familial - genetics; Amyloidosis; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Clinical genetics; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Cytogenetics; Deoxyribonucleic acid; Dermatologi och venerologi, klinisk genetik, invärtesmedicin; Dermatology and venerology,clinical genetics, internal medicine; Disease transmission; DNA; DNA, Mitochondrial - genetics; Female; Fundamental and applied biological sciences. Psychology; Gender; Gene Expression; Gene polymorphism; General aspects. Genetic counseling; Genetic testing; Genetics; Genetics of eukaryotes. Biological and molecular evolution; genetik; Haplotypes; Heredity; Human Genetics; Humans; Hypotheses; Klinisk genetik; Male; Maternal inheritance; Medical genetics; Medical sciences; MEDICIN; MEDICINE; Middle Aged; mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial DNA; Molecular and cellular biology; Mutation; Nervous system (semeiology, syndromes); Neurology; parent-of-origin; Penetrance; Phenotypic variations; Polymorphism, Genetic; Polyneuropathy; Portugal - epidemiology; Prealbumin - genetics; Sweden - epidemiology; Transthyretin; transthyretin amyloid polyneuropathy
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/ejhg.2010.36

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.