Clinical approach to monogenic Parkinson’s disease

Abstract Monogenic Parkinson’s disease refers to the Parkinson’s disease phenotype caused by mutations in genes that generally follow a mendelian pattern of inheritance. Though this is a rare entity in comparison to idiopathic Parkinson’s disease, they provide an opportunity to understand the pathophysiological basis of this neurodegenerative disease. Monogenic forms include those caused by pathogenic variants in PRKN, PINK1 and DJ1 , which have an autosomal recessive mode of inheritance and those in LRRK2, SNCA and VPS35 , which have an autosomal dominant inheritance pattern. Some of these mutation carriers ( PRKN, PINK1, DJ1, LRRK2, SNCA, VPS35 ) have a simple parkinsonian phenotype resembling idiopathic Parkinson’s disease, whereas certain other monogenic forms (e.g. ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, SYNJ1 ) can have a complex or atypical parkinsonian phenotype. Despite significant overlap in various clinical features and insufficient data in literature, characteristic phenotype can be identified for several monogenic forms of Parkinson’s disease. Establishing genotype-phenotype correlation helps in creation of specific disease cohorts for enrolling in future clinical trials involving gene-based target therapies. In this review article, we provide a pragmatic clinical approach to evaluate a suspected case of monogenic Parkinson’s disease.