Genetic Insights into Early-onset Parkinson’s Disease
Genetic Insights into Early-onset Parkinson’s Disease
European Neurological Review 2010; 5(1): 30–3
US Neurology, 2010;6(1):41–4
Abstract
Early-onset Parkinson’s disease (EOPD) is defined as disease onset before 40 or 50 years of age. The clinical characteristics of EOPD are very similar to those of late-onset PD, but dystonia is more often a presenting symptom, dementia is rare and disease progression may be slower. Mutations in several genes have been described in cases with EOPD, often with strong family history, including mutations in α-synuclein (SNCA), DJ-1, PTEN-induced kinase-1 (PINK-1) and ATP13A2. However, the most common mutations identified in EOPD are in Parkin (PRKN), leucinerich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA). With the exception of SNCA and ATP13A2 carriers, mutation carriers are oftenindistinguishable from non-carriers. Large series of EOPD cases that are not ascertained by family history estimate mutation frequency at 4–16%. Given that the frequency of positive family history is much higher, we believe that many genetic risk factors are yet to be discovered.
Keywords
Parkin, SNCA, DJ1, PINK1, LRRK2, GBA, phenotype, early-onset Parkinson’s disease (EOPD)
Disclosure: The authors have no conflicts of interest to declare.
Received: 2 May 2010 Accepted: 28 June 2010 Citation: European Neurological Review, 2010;5(1):30–33
Correspondence: Roy N Alcalay, Department of Neurology, Columbia University Medical Center, 710 West 168th Street, New York, NY 10032, US. E: rna2104@columbia.edu
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting up to 1.5% of the American population.1 It has been estimated that up to 10% of the affected population develops the disease by 40 years of age.2 The definition of early-onset PD (EOPD) varies among studies, and usually ranges between 40 and 50 years of age.2–4 While familial clustering of PD has been well described,5,6 it is only as recently as 19977 that the first gene associated with PD was identified. To date, all of the genes associated with PD have also been identified in people who developed PD before 50 years of age (i.e. EOPD) and, with the exception of the leucine-rich repeat kinase 2 (LRRK2), mutations are more often identified in people who develop EOPD rather than late-onset PD.
EOPD is considered to be a complex disorder, which means that it is associated with the effects of multiple genes in combination with lifestyle and environmental factors. In EOPD, traditional genetic definitions of autosomal dominant and autosomal recessive may not fully apply. Most of the carriers of autosomal dominant mutations do not develop the disease, i.e. incomplete penetrance (e.g. LRRK2 and possibly synuclein), and some of the autosomal recessive genes may actually increase the risk of EOPD even when only a single copy of the mutated gene is inherited (e.g. Parkin [PRKN], PTEN-induced kinase 1 [PINK-1]).8 Several genes and chromosomal loci have been associated with EOPD and were designated PARK1 to PARK14 (see Table 1). In this article we will summarise the available data on each separate gene.
PARK1, PARK4 – α-synuclein
α-synuclein (SNCA) was the first gene identified as a cause of EOPD in 1997.7 The gene encodes for synuclein, which has since been found to comprise a major component of Lewy bodies,9 which are the pathological hallmark of PD and EOPD. Gain-of-function mutations, duplications and triplications have all been found in EOPD patients, most often in those with a strong family history.10 However, very few cases have been described in the literature and penetrance estimations vary. Only 33% of duplication carriers in a single family developed PD in one report.10 Unfortunately, carriers of gain-of-function mutations and copy number variation (CNV) in the gene may also develop dementia.10
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Parkin, SNCA, DJ1, PINK1, LRRK2, GBA, phenotype, early-onset Parkinson’s disease (EOPD)
