Autosomal dominant Parkinson's disease caused by SNCA duplications

Abstract

The discovery in 1997 that mutations in the SNCA gene cause Parkinson’s disease (PD) greatly advanced our understanding of this illness. There are pathogenic missense mutations and multiplication mutations in SNCA. Thus, not only a mutant protein, but also an increased dose of wild-type protein can produce autosomal dominant parkinsonism. We review the literature on SNCA duplications and focus on pathologically-confirmed cases. We also report a newly-identified American family with SNCA duplication whose proband was autopsied. We found that over half of the reported cases with SNCA duplication had early-onset parkinsonism and non-motor features, such as dysautonomia, rapid eye movement sleep behavior disorder (RBD), hallucinations (usually visual) and cognitive deficits leading to dementia. Only a few cases have presented with typical features of PD. Our case presented with depression and RBD that preceded parkinsonism, and dysautonomia that led to an initial diagnosis of multiple system atrophy. Dementia and visual hallucinations followed. Our patient and the other reported cases with SNCA duplications had widespread cortical Lewy pathology. Neuronal loss in the hippocampal cornu ammonis 2/3 regions were seen in about half of the autopsied SNCA duplication cases. Similar pathology was also observed in SNCA missense mutation and triplication carriers.

Visual dysfunction in Parkinson’s disease

“… a Marras et al , 2011; b Alcalay et al , 2013; c Somme et al , 2015; d Ehrminger et al , 2015; e Kertelge et al , 2010; f Alcalay et al , 2014; g Sixel-Doring et al , 2015; h Simon-Tov et al , 2015; i Alcalay et al , 2012; j Neumann et al , 2009; k Gan-Or et al , 2015; l Konno et al , 2016; m Petrucci et al , 2016; n Nishioka et al , 2009.…”

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

“…Most PD cases are sporadic and of unknown etiology, although during the last years the identification of gene mutations responsible for familial forms of PD and the mapping of risk variants for the disease [4] have improved our understanding of the disease. One of the first mutated gene that was found to be associated with familial PD was α-synuclein [5,6] and additional missense mutations and duplications have been found to be rare causes of hereditary PD or PD-like syndromes [7][8][9][10]. Moreover, genome-wide association studies have demonstrated an association between non-coding variants in and around the α-synuclein gene and sporadic disease [11].…”

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

“…PD families with members carrying four copies of SNCA gene have been detected in South Africa, Iran, Japan, Pakistan and Italy [35][36][37][38][39][40]: in general, triplication generates very high expression of mRNA and protein and influences the clinical manifestations of PD, causing severe forms of Parkinsonism similar to dementia with Lewy body. Duplications have been reported in more numerous families than triplications [33,38,[41][42][43][44][45][46][47][48][49][50][51]. In some of the patients with the same ethnic background (Japan), haplotype analysis revealed their derivation from common founders [43,44].…”