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.

Keywords: Familial; Genetics; MSA; PD; SNCA; VPS35.

Figure 1

Secondary structure of α-synuclein protein (A). Positions for previously known pathogenic substitutions, p.A30P, p.E46K, and p.A53T (in blue); positions for newly discovered probable pathogenic substitutions, p.H50Q and p. G51D (in red), and positions for newly discovered possible pathogenic substitutions, p.A18T and p.A29S, (in yellow). Pedigrees of the multiple system atrophy family from the Mayo Clinic Florida in Jacksonville, Florida (B). Standard pedigree symbols were used. Round symbols indicate females; squares indicate males; and diagonal lines indicate that the individual is deceased. Diamonds were used to disguise gender. Numbers in diamonds indicate the number of siblings. The solid arrowhead indicates the proband. * indicates autopsy patients.