Neurodegenerative Disease Parkinson’s Disease Genetic Insights into Early-onset Parkinson’s Disease Roy N Alcalay1 and Cheryl Waters2


1. Assistant Professor; 2. Albert B and Judith L Glickman Professor, Division of Movement Disorders, Department of Neurology, Columbia University Medical Center


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), leucine- rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA). With the exception of SNCA and ATP13A2 carriers, mutation carriers are often indistinguishable 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):30–3 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 neuro- degenerative 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


it is only as recently as 19977


While familial clustering of PD has been well described,5,6 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


30


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


Unfortunately, carriers of gain-of-function mutations and copy number variation (CNV) in the gene may also develop dementia.10


Gene dosage may dictate the severity of the EOPD phenotype according to one report. Carriers of triplications were more likely to develop EOPD and dementia, while carriers of duplications were more likely to develop late-onset PD.11


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


Interestingly, single-nucleotide polymorphisms (SNPs) in the promoter region of SNCA were implicated by genome-wide association studies (GWAS) in the pathogenesis of PD.12–14 SNPs are also associated with EOPD is unknown.


Whether these


PARK2 – Parkin Mutations in the PRKN gene15,16


are the most common genetic risk


factors for EOPD. The relationship between PRKN mutations and EOPD was discovered in 1998.15 familial cases of EOPD,17


PRKN mutations were initially identified in which were usually indistinguishable from


The gene encodes for synuclein, which has since been found to


idiopathic PD. PRKN-associated EOPD was initially thought to present with dystonia and brisk reflexes. Subsequent studies comparing PRKN carriers with other patients with EOPD demonstrated that carriers develop the disease at a younger age compared with non-carriers,18 require less levodopa treatment and present with a similar frequency of brisk reflexes or dystonia to non-carriers after adjustment for age at onset.19


Therefore, presentation with dystonia was associated with © TOUCH BRIEFINGS 2010


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