title: Update on novel familial forms of Parkinson's disease and multiple system atrophy.
abstract: Parkinson's disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Fujioka
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogaki
authors.forename: Pawel M
authors.initials: PM
authors.lastname: Tacik
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D019578:Multiple System Atrophy / Q000235:genetics* / Q000266:history / Q000503:physiopathology*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000266:history / Q000503:physiopathology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D019883:Alkyl and Aryl Transferases; C021386:4-hydroxybenzoate polyprenyltransferase
keywords: Familial; Genetics; MSA; PD; SNCA; VPS35