The tau locus is not significantly associated with pathologically confirmed sporadic Parkinson's disease.

Mutations of the tau gene in frontotemporal dementia with parkinsonism and genetic association of the tau locus with progressive supranuclear palsy and corticobasal degeneration directly implicate the tau gene in the aetiology of these tauopathies. Three studies have also shown an association of the tau locus with clinically diagnosed Parkinson's disease. Noting the significant incidence of clinical misdiagnosis of Parkinson's disease, we investigated this tau gene association in a series of 157 pathologically confirmed cases of brain stem Lewy body Parkinson's disease by analysing their tau haplotype status. Although H1H1 homozygotes are elevated in the Parkinson's disease cases (63.1%) compared to controls (56.1%) this difference is not significant (P=0.22). These results indicate that any association must either be weak (with an odds ratio of less than 2) or that previous positive associations were due to contamination of clinically diagnosed cases with other diagnostic clinico-pathological entities such as neurofibrillary tangle Parkinson's syndrome.

PARK6-linked parkinsonism occurs in several European families.

The Parkin gene on 6q25.2-27 is responsible for about 50% of autosomal recessive juvenile parkinsonism and less than 20% of sporadic early-onset cases. We recently mapped a novel locus for early-onset parkinsonism (PARK6) on chromosome 1p35-p36 in a large family from Sicily. We now confirm linkage to PARK6 in eight additional families with Parkin-negative autosomal recessive juvenile parkinsonism from four different European countries. The maximum cumulative pairwise LOD score was 5.39 for marker D1S478. Multipoint linkage analysis gave the highest cumulative LOD score of 6.29 for marker D1S478. Haplotype construction and determination of the smallest region of homozygosity in one consanguineous family has reduced the candidate interval to a 9cM region between markers D1S483 and D1S2674. No common haplotype could be detected, excluding a common founder effect. These families share some clinical features with the phenotype reported for European Parkin-positive cases, with a wide range of ages at onset (up to 68 yrs) and slow progression. However, features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6-linked families, thus making the clinical presentation of late-onset cases indistinguishable from idiopathic Parkinson's disease. PARK6 appears to be an important locus for early-onset parkinsonism in European Parkin-negative patients.