Familial aggregation of nephropathy in FAP-I ATTRV30M
Familial amyloid polyneuropathy (FAP-I or ATTRV30M) is a dominant form of amyloidosis, first described by Andrade, in Portugal, in 1952. Early descriptions of patients from northern Portugal consisted mainly of a progressive sensitive-motor and autonomic neuropathy, occurring during the 3rd or 4th decades of life. It was not until very recently that much later-onset cases and nephropathy were recognized as part of its clinical picture. For the past 10 years, we have been observing patients presenting mild nephropathy to end-stage renal disease (ESRD).
We now studied (a) risk factors and (b) familial aggregation in nephropathy. We performed a binary logistic regression analysis in 147 nephropatic and 256 non-nephropatic FAP-I patients, taking gender, age-at-onset, previous family history of nephropathy and district of origin, as risk factors. (1) Women, (2) patients with onset at or after age 40 yrs, and (3) previous family history of nephropathy, were all found to be significant, when adjusting for the other risk factors.
In 60 families with ESRD, a total of 276 patients were evaluated for nephropathy: age-at-onset was higher (mean, 41.7 yrs; s.d. 12.9) in patients with ESRD, than in patients who did not progress to ESRD (mean 33.7 yrs; s.d. 9.7). In order to evaluate familial aggregation of nephropathy, we compared its frequency in families with at least one ESRD patient, versus families without any case of ESRD.
Relatives of ESRD "probands" proved to have a two-fold risk of nephropathy, when compared to those from non-ESRD families. When considering the degree of kinship, relative risk would vary accordingly; sibs were found to have a four-fold risk. These results proved familial aggregation of nephropathy.
We hypothesize that genetic factors associated with gender and with variation in age-at-onset may have a role in renal tissue damage. The study of families with nephropathy and with ESRD will thus be a valuable approach to find modifier genes for FAP-I.