Parkinson’s disease is the second most common neurodegenerative disease, affecting around 2% of the general population aged 80 or more. Its precise origin is still a matter of debate, and its diagnosis relies upon clinical and pathological examination. While many environmental factors are
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Parkinson’s disease is the second most common neurodegenerative disease, affecting around 2% of the general population aged 80 or more. Its precise origin is still a matter of debate, and its diagnosis relies upon clinical and pathological examination. While many environmental factors are known to increase the risk for Parkinson’s disease, a genetic component has also long been suspected. Numerous studies have emphasised the importance of genetics in Parkinson’s disease, showing that one of the major risk factors for the development of the disease is a positive family history. Furthermore, although previously published work has yielded conflicting results regarding this issue, data from twin studies demonstrate that the concordance for Parkinson’s disease is higher in monozygotic twins compared with dizygotic twins, a pattern suggesting a genetic transmission of the disease. However, it is only recently that developments in molecular biology allowed several genes to be identified. Until now, 11 different loci have been described causing inherited parkinsonism, either dominant or recessive. Most of these genes have been discovered in large Parkinson’s disease families, with multigeneration pedigrees. While their relevance for the sporadic form of Parkinson’s disease needs to be further elucidated, studies have shown an association between genetic polymorphism of α-synuclein, ubiquitin-C terminal hydrolase and tau genes, and sporadic Parkinson’s disease. These studies therefore suggest a common cellular mechanism in neurodegenerative pathways in sporadic and familial forms of Parkinson’s disease. In addition, genes and loci have been described that are not linked to monogenic forms of Parkinson’s disease, but rather increase the lifetime risk of developing the disease, thus behaving like inherited risk factors. PARK 1, 3, 4, 5 and 8 are loci responsible for dominantly inherited parkinsonism.The mutation of the α-synuclein gene was the first to be described in 1997, but it is a very uncommon cause of Parkinson’s disease. While PARK 4 is associated with atypical features (dementia, myoclonus), the other dominantly inherited Parkinson’s diseases mimic more the sporadic form. Among the recessively inherited Parkinson’s diseases (PARK 2, 6, 7 and 9), PARK 2 is the most frequently encountered: numerous mutations have been described on the parkin gene located on chromosome 6.PARK 2 phenotype is an autosomal recessive juvenile parkinsonism, with a good response to levodopa but frequently associated with early dyskinesias. The manifestations of PARK 6 and 7 also share many clinical aspects with the sporadic form of the disease, while PARK 9 (Kufor- Rakeb syndrome) is associated with spasticity, dementia and oculomotor signs. Among “parkinson-plus” syndromes, frontotemporal dementia and parkinsonism linked with chromosome 17 (FTDP-17) is caused by mutations of the tau gene and dominantly inherited. The association of parkinsonism and dystonia characterises both DYT 12 (chromosome 19, dominant) and DYT 3 (X-linked recessive). Ataxia and parkinsonism are found in some of the dominantly inherited spino-cerebellar ataxias, and mutations of mitochondrial complex 1 cause parkinsonism with dementia, dystonia and oculomotor signs. This article reviews the studies and available evidences supporting a genetic cause of Parkinson’s disease and “parkinson-plus” syndromes, and discusses the main genes and loci that have been described until now.
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