Genetic study of transthyretin amyloid neuropathies: carrier risks among French and Portuguese families.

INTRODUCTION Among the hereditary systemic amyloidosis, transthyretin (TTR) neuropathies (OMIM #176300) are devastating disorders with an autosomal dominant transmission, expressed mainly as a progressive fibre length dependent sensorimotor polyneuropathy and life threatening autonomic dysfunction. Initially, the condition was recognised in northern Portugal, in the area of Povoa de Varzim, where the prevalence has been estimated at 1/1000. 3 Other important clusters of families were subsequently reported in Japan, initially in two limited geographic areas (the districts of Arao and Ogawa), and in the north of Sweden. The condition is now known throughout the world, including various European countries. Among the 75 pathogenic TTR variants identified so far, Val30Met is the most frequent, and is virtually the only one described in Portugal and Sweden. 8 By contrast, in Japan, the TTR point mutations are highly heterogeneous, with more than 20 different substitutions, including Val30Met, described. In France, a previous study found a similar heterogeneity. Depending on the geographic origin, the mean age of onset ranges from 30 to 70 years. A variable clinical expression is also observed, with restrictive cardiomyopathy, carpal tunnel syndrome, and vitreous opacities often encountered, whereas renal involvement is less common. These manifestations, along with the discrepancy in age of onset, account for phenotypic variations. However, virtually no genotype–phenotype correlation seems to exist. To supply the main source of mutant TTR, liver transplantation has been proposed as a treatment for the disease for the last 10 years, with promising results. In the Val30Met patients, it virtually suppresses the production of the mutant TTR in the serum and slows the progression of the neurological symptoms that otherwise have a fatal outcome in less than 10 years. Another important aspect of the management of affected families is the recent availability of predictive molecular genetic diagnosis. Before the availability of liver transplantation, the presymptomatic or prenatal testing in relatives of patients raised many ethical issues. Nowadays, it is more widely performed in the frame of genetic counselling. Estimation of the risk for mutation carriers of being affected is essential. In order to support the choice of the family members, precise information is required on the clinical and genetic epidemiological background of the condition in the different geographical areas. After the historical study of Andrade, which concluded that inheritance is dominant with very high penetrance, some genealogical studies suggested that penetrance was probably incomplete and variable among families. 12–16 To gain more insight into the subject and to obtain penetrance estimates necessary for both genetic counselling and a better understanding of underlying mechanisms, and to test for possible differences between individuals, we performed a genetic study of TTR amyloid neuropathy in two separate populations, of French and Portuguese origins respectively. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .