Genetics of Parkinson's disease
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REVIEW ARTICLE
Genetics of Parkinson’s disease Ajith Cherian1 · K. P. Divya1 Received: 7 May 2020 / Accepted: 11 August 2020 © Belgian Neurological Society 2020
Abstract Less than a quarter century after the discovery of SNCA as the first attributable gene in Parkinson’s disease (PD), our knowledge of the genetic architecture underlying this disease has improved by leaps and bounds. About 5–10% of all patients suffer from a monogenic form of PD where mutations in autosomal-dominant (AD) genes—SNCA, LRRK2, and VPS35 and autosomal recessive (AR) genes—PINK1, DJ-1, and Parkin cause the disease. Whole-exome sequencing has described AR DNAJC6 mutations not only in predominantly atypical, but also in patients with typical PD. Majority of PD is genetically complex, caused by the combination of common genetic variants in concert with environmental factors. Genome-wide association studies have identified twenty six PD risk loci till date; however, these show only moderate effects on the risk for PD. The validation of novel genes and its association with PD remains extremely challenging as families harboring rare genetic variants are sparse and globally widespread. This review article aims to provide a comprehensive overview on PD genetics. Keywords Lewy body · Tremor · α-synuclein · Parkin · Ubiquitin · Mutation · Bradykinesia
Parkinson’s disease—phenotype and pathology of the prototypic disease Parkinson’s disease (PD) is a debilitating neurodegenerative disorder with worldwide incidence rates of 8–18 per 100,000 person-years [1]. PD increases with age affecting more than 1% of the population over 60 years of age, making it the most prevalent movement disorder and the most common neurodegenerative disorder, only second to Alzheimer’s dementia [2]. The defining characteristics of PD include bradykinesia with one of tremor, rigidity or postural instability. PD is associated with a myriad of non‐motor symptoms including disorders of mood and affect like apathy, anhedonia and depression, cognitive dysfunction in the form of working memory deficits and complex behavioral disorders. Sensory dysfunction with hyposmia or pain is quite common, as are disturbances of sleep–wake cycle. Autonomic dysfunction like orthostatic hypotension, urogenital dysfunction and constipation is also present in a majority of patients. Many of the non‐motor symptoms can antedate the occurrence of * K. P. Divya [email protected] 1
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India 695011
motor signs or become increasingly prevalent with advancing disease. Symptoms such as loss of smell, constipation, anxiety/depression and rapid eye movement sleep behavioral disorders (RBD) have been described up to a decade or more prior to the onset of the typical disease [3]. PD occurs more in men (prevalence = 2.865/1000; incidence = 0.490/1000 person-years) than women (prevalence = 1.934/1000; incidence = 0.328/1000 person-years). The overall male:female (M:F) ratio was 1.48 for preva
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