Familial parkinsonism with anticipation may be more common than classical dominant and recessive subtypes combined. In our clinic population, among 487 patients studied, 145 had a first or second degree relative with PD; that is 30% which is in line with the published figures for other referral clinics. Among the 145 familial cases, 110 had parkinsonism in consecutive generations, which is compatible with autosomal dominant inheritance, and 35 had an affected sibling or cousin, which is suggestive of recessive inheritance. However, among the 110, only 26 were compatible with a classical dominant pattern (i.e., <10 years intergenerational variation in onset); while 63 exhibited 10–68 years of anticipation, and 7 had 10–17 years of reverse anticipation (14/110 had unknown onset ages). Our clinic is a referral center, which explains the relatively high proportions of early-onset and familial cases. The interesting finding was the relative proportions of autosomal dominant, autosomal recessive and anticipation cases within the familial subtype. Despite its relatively high prevalence, at least in our clinic, familial parkinsonism with anticipation has been largely overlooked in genetic research. A few parkinsonism families have been attributed to expansions in known SCA loci, but in the majority of the kindreds, the cause remains unknown. The more obvious possibilities are mitochondrial inheritance, modifier genes, parent-child exposure to environmental triggers, as yet unidentified triplet repeats or dominant genes with dosage effect, and in some cases, artifactual appearance of anticipation due to ascertainment bias. None of these are mutually exclusive; more than one may be true and operative in different families.
The current parkin
literature suggest that possessing two parkin
mutations is fully penetrant and leads to early-onset parkinsonism, whereas having only one mutation may be incompletely penetrant and lead to later disease onset. While the causative link to early-onset parkinsonism is widely accepted, the association of parkin
with late-onset parkinsonism remains controversial [9
]. We postulated that, if parkin
heterozygotes are at risk for late-onset disease, then some parkin
families should exhibit intergenerational variation in age at onset resembling anticipation, where heterozygous parents develop late-onset parkinsonism and children who inherit two mutations develop early-onset parkinsonism. We hoped to explain the appearance of anticipation in relation to parkin
dosage, but the findings do not support this postulate. While the results rule out a link between parkin
and anticipation in these families, they do not negate the association of parkin
with late-onset parkinsonism.