Parkinson Disease Genetics: A 'Continuum' from Mendelian to Multifactorial Inheritance

摘要

Parkinson Disease (PD) is a common neurodegenerative disorder of intricate etiology, caused by progressive loss of aminergic neurons and accumulation of Lewy bodies. The predominant role of genetics in the etiology of the disease has emerged since the identification of the first pathogenetic mutation in SNCA (alpha-synuclein) gene, back in 1997. Mendelian parkinsonisms, a minority among all PD forms, have been deeply investigated, with 19 loci identified. More recently, genome wide association studies have provided convincing evidence that variants in some of these genes, as well as in other genes, may confer an increased risk for late onset, sporadic PD. Moreover, the finding that heterozygous mutations in the GBA gene (mutated in Gaucher disease) are among the strongest genetic susceptibility factors for PD, has widened the scenario of PD genetic background to enclose a number of genes previously associated to distinct disorders, such as genes causative of spinocerebellar ataxias, mitochondrial disorders and fragile X syndrome. At present, the genetic basis of PD defines a continuum from purely mendelian forms (such as those caused by autosomal recessive genes) to multifactorial inheritance, resulting from the variable interplay of many distinct genetic variants and environmental factors.