Familial amyloidotic polyneuropathy (FAP-type I) was first described in Portugal by Andrade in 1952, a time when 54 among 64 patients (belonging to 25 families) originated from Póvoa do Varzim or its surrounding districts. Since then, a total of 1,233 patients, belonging to 489 pedigrees (so far unrelated), have been diagnosed at Centro de Estudos de Paramiloidose, Porto, Portugal. Although age-of-onset showed a wide range (17 to 78 years), 87% of these 1,233 patients developed symptoms before 40 years of age (mean 33.5, SD 9.4 years). Among all patients, 432 belong to 140 families originating from the area of Póvoa do Varzim/Vila do Conde, 330 of whom lived in that area at the time of diagnosis; age-of-onset was, on average, lower than in the overall group of patients (mean 31.1, SD 6.7 years), and no patient had onset after 57 years (versus 3.3% in the global sample). As in previous studies, women were found to have a later onset (33.7) than men (29.0) years. In 1991, the crude prevalence rate was 90.3 x 10(-5) (one in every 1,108 inhabitants), and the frequency of gene carriers was estimated to be 186 x 10(-5) (one in every 538); about 48.4% of these carriers had manifested symptoms by 1991. Female patients had a significantly higher number of children (mean 3.7, SD 2.6) than male patients (mean 2.7, SD 2.1) and the length of their reproductive period (mean 8.4, SD 5.8 yr) was also greater than for men (mean 5.6, SD 4.4 yr). Altogether, the 122 patients who ever reproduced contributed 457 children to the next generation, a mean fertility of 3.7. Further studies using a control groups may answer the question of whether this is the result of a specific high fertility of these patients or just their belonging to a population in natural expansion.

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Familial amyloidotic polyneuropathy (FAP) in Swedish patients is associated with the same transthyretin mutation (TTR^Met30) as in Portuguese, Japanese, Brazilian and Majorcan patients. Yet, the age of onset of FAP is much later in Sweden than in other populations. We have studied 239 cases of FAP from northern Sweden, their geographical distribution, differences in age of onset, and estimated prevalence and incidence rates. Cases and families concentrate mainly in two areas, around the towns of Skellefteå and Piteå. Mean age of onset was found to be later in the Piteå (58.8 ± 10.8) than in the Skellefteå area (54.4 ± 13.5). Unusually high figures were found for prevalence rates (91 × 10^–5 and 104 × 10^–5, respectively) in 1985. Mean yearly incidences were 3.1 × 10^–5 and 4.4 × 10^–5, respectively, over the period 1985–1989.

Familial amyloid polyneuropathy type I is an autosomal dominant disorder caused by mutations in the transthyretin (TTR) gene; however, carriers of the same mutation exhibit variability in penetrance and clinical expression. We analyzed alleles of candidate genes encoding non-fibrillar components of TTR amyloid deposits and a molecule metabolically interacting with TTR [retinol-binding protein (RBP)], for possible associations with age of disease onset and/or susceptibility in a Portuguese population sample with the TTR V30M mutation and unrelated controls. We show that the V30M carriers represent a distinct subset of the Portuguese population. Estimates of genetic distance indicated that the controls and the classical-onset group were furthest apart, whereas the late-onset group appeared to differ from both. Importantly, the data also indicate that genetic interactions among the multiple loci evaluated, rather than single-locus effects, are more likely to determine differences in the age of disease onset. Multifactor dimensionality reduction indicated that the best genetic model for classical onset group versus controls involved the APCS gene, whereas for late-onset cases, one APCS variant (APCSv1) and two RBP variants (RBPv1 and RBPv2) are involved. Thus, although the TTR V30M mutation is required for the disease in Portuguese patients, different genetic factors may govern the age of onset, as well as the occurrence of anticipation.

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