Lewy body Parkinson's disease in a large pedigree with 77Parkin mutation carriers

Abstract

We report the clinical, genetic, and neuropathological findings of a seven generation-spanning pedigree with 196 individuals, 25 of whom had levodopa-responsive parkinsonism. Genetic analyses indicated Parkin mutations in 77 subjects. Among the 25 patients, 5 carried compound heterozygous mutations and met criteria for definite Parkinson's disease (PD) according to UK PD Society Brain Bank guidelines; 8 subjects carried only a heterozygous Parkin mutation. The mutational status of five deceased patients was unknown, and seven PD patients had no Parkin mutation. Survival analyses showed a significant difference in the age-at-onset distribution between patients with compound heterozygous mutations and the groups of heterozygous carriers and subjects without detectable Parkin mutations. Autopsy of a 73-year-old patient, who carried two mutant Parkin alleles (delExon7 + del1072T), showed PD-type cell loss, reactive gliosis, and alpha-synuclein-positive Lewy bodies in the substantia nigra and locus ceruleus. Surviving neurons were reactive with antibodies to the N terminus of Parkin but not the In-Between-RING ("IBR") domain, which had been deleted by both mutations. This large Parkin pedigree represents a unique opportunity to prospectively study the role of heterozygous Parkin mutations as a PD risk factor, to identify additional contributors to the expression of late-onset PD in heterozygous carriers, and to reexamine the role of Parkin in inclusion formation.

Parkin Protects against Mitochondrial Toxins and β-Amyloid Accumulation in Skeletal Muscle Cells

“…Preincubation with the immunizing peptide, but not the control peptide, led to a total elimination of parkin staining. Of note, the specificity of the HP2A antibody staining has also been recently confirmed in human brain specimens of a Parkin-mutant Parkinson disease case (33). Co-accumulation of both Parkin and ubiquitin, and of ␤-amyloid together with ubiquitin, occurred in a significantly increased proportion of myofibers staining for either (2 ϭ 47.4 and 90.8, respectively, p Ͻ0.05).…”

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…Subsequently, Lewy bodies were demonstrated in two patients with Parkin mutations [220,221], possibly reflecting mutations that did not result in complete loss of Parkin activity. To date, hundreds of cases with a wide variety of Parkin mutations, from large exon rearrangements to single base pair deletions and insertions, have been reported.…”

Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia

“…[3][4][5][6][7] However, the similarities between Parkinand PINK1-associated parkinsonism and idiopathic PD extend far beyond the clinical picture: for example, postmortem analysis of the index patient of a large Parkin pedigree (Family LA) revealed classic idiopathic PD-like findings including alphasynuclein-positive Lewy bodies. 8 Of note, asymptomatic carriers of a single mutant Parkin or PINK1 allele also display a latent abnormality of striatal dopaminergic function as revealed by 18 F-DOPA PET. 9,10 18 F-DOPA PET findings in asymptomatic carriers of a single mutant Parkin allele from the Family LA revealed a reduction of 18 F-DOPA uptake in the posterior dorsal putamen.…”