PARK6-Linked Parkinsonism
Abstract & Commentary
Source: Valente EM, et al. Park6-linked parkinsonism occurs in several European families. Ann Neurol. 2002;51: 14-18.
There have been several major advances in the last 5 years in the quest to unravel the genetics of Parkinson’s disease (PD). Three genes have been identified to cause dopa-responsive adult-onset familial parkinsonism: alpha-synuclein, the parkin gene, and ubiquitin C terminal hydrolase L1. Mutations in alpha-synuclein (chromosome 4q) produce a syndrome of autosomal dominant dopa-responsive parkinsonism with early age of onset (average age, 46 years). At autopsy, Lewy bodies are abundant in the substantia nigra, and they are indistinguishable from Lewy bodies that occur in sporadic PD. Aside from the original description in one Italian family (the "Contursi" kindred) and one other German family, mutations in alpha-synuclein have not been found to be responsible for sporadic or familial PD.
The gene called parkin (chromosome 6q) was originally discovered in several Japanese families with autosomal recessive parkinsonism. In the last several years, mutations in the parkin gene have been reported in many other families with early-onset PD throughout the world. The disease usually begins in the third decade, and is characterized by an excellent response to levodopa and early development of dopa-induced dyskinesias. Pathologically there is severe neuronal loss in the substantia nigra pars compacta, without Lewy bodies or inclusions. The third gene causing parkinsonism is ubiquitin C terminal hydrolase L1 (chromosome 4p); a mutation in this gene has been reported in 2 siblings of 1 family with typical adult-onset PD. No autopsies are available, and it is unknown if patients with sporadic PD also carry mutations in this gene.
At least 4 other genetic loci have been reported in familial PD: PARK3 (chromosome 2p, autosomal dominant), PARK4 (chromosome 4p, autosomal dominant), PARK 6 (chromosome 1p, autosomal recessive), and PARK 7 (chromosome 1p, autosomal recessive). In the current report, Valente and colleagues report their progress in the search for the gene encoding PARK6 in 8 European families. Of these families, 3 were Dutch, 2 German, 2 Italian, and 1 English. Mean age of onset was 42 years, however, 4 patients developed symptoms after age 45 and 1 patient presented at age 68! Clinical features were indistinguishable from patients with mutations in the parkin gene, with an excellent response to levodopa, and development of levodopa-induced dyskinesias in half of the patients. Using linkage analysis in these 8 families, Valente et al mapped the PARK6 gene to a 9 centiMorgan region of chromosome 1p35-36. There was no evidence of a founder effect, suggesting that distinct mutations in the gene arose spontaneously.
Commentary
It is not known whether mutations in the PARK6 gene are responsible for sporadic adult-onset PD. However, this is a distinct possibility, particularly since PARK6 mutations have been identified in multiple European kindreds and the clinical phenotype is similar to adult-onset sporadic PD. Even if PARK6 mutations are not found to be responsible for sporadic PD, identifying the PARK6 gene and understanding its function will assist in identifying the pathways that lead to selective dopaminergic neuronal demise. —Steven Frucht.
Frucht, MD, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, is Assistant Editor of Neurology Alert.
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