Familial Creutzfeldt-Jakob disease in France: epidemiological implications.

Of 329 patients dying of Creutzfeldt-Jakob disease (CJD) in continental France between 1968 and 1982, 19 (6%) were familial cases. Genealogical investigation permitted the identification of 19 additional cases, bringing the total number of familial CJD cases reported here to 38. There are 6 definitely affected families, yielding an average of 6.3 cases per family. Mediterranean Jews account for one-third of all the cases, with Tunisian Jews constituting two-thirds of this ethnic group. Males and females are equally affected. The overall rate of occurrence (47.3%) is consistent with autosomal dominant transmission, but wide variations in individual pedigrees (26.7%-80%) leave this hypothesis open to scrutiny. Age at death is 10 to 15 years lower in familial than in sporadic CJD, suggesting the possible inheritance of "short incubation" genes in certain CJD families. Disease duration is longer in familial than in sporadic CJD, but this could be the effect of ascertainment bias. There is no evidence for maternal lineage. While members of a given family tend to die within the same age bracket, our data fail to discriminate between vertical transmission and common source exposure as hypothetical transmission mechanisms within affected families. CJD occurrence in a woman related by marriage to an unaffected branch of a CJD family, but who was raised in early childhood by the affected branch, argues in favor of horizontal transmission early in life. Analysis of death intervals and geographic/temporal separations suggests minimal incubation periods of up to 43 years. A family combining clinico-pathological features of CJD and the Gerstmann-Straüssler syndrome (GSS) indicates a nosological relationship between the two. The "genetic susceptibility" of members of CJD-affected families may be due to accelerated derepression of normally repressed host genes, coding for abnormal amyloid-type proteins. Accumulation of these proteins may play an important role in the pathogenesis of CJD and scrapie, and constitute a common pathogenetic mechanism in several neurological diseases, including Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT).