Lewy bodies and parkinsonism in families with <i>parkin</i> mutations

TLDR

Early‑onset, autosomal recessive parkinsonism caused by compound or homozygous loss‑of‑function parkin mutations is known to involve dopaminergic neuron loss without Lewy body pathology. The authors sequenced parkin in 38 early‑onset Parkinson’s patients, followed two probands, and performed haplotype analysis, RNA and protein expression studies, and blinded clinical evaluations. A novel 40‑bp exon 3 deletion cosegregated with disease, an additional exon 7 R275W mutation was found on an alternate transcript, and Lewy body pathology was observed in one proband, indicating that compound heterozygous parkin mutations can cause early‑onset parkinsonism with Lewy bodies while hemizygous mutations may increase susceptibility to typical Parkinson’s disease.

Abstract

Abstract Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early‐onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early‐onset Parkinson's disease (&lt;41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2‐27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinson's disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early‐onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinson's disease.