Search

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder of unknown etiology that presents with variable combinations of progressive ataxia, parkinsonism and autonomic instability. Pathologic expansion of a hexanucleotide repeat in the gene C9orf72 gene has been demonstrated to cause neurodegeneration with diverse neurological presentations. To test the hypothesis whether pathologic expansions in C9orf72 are a cause of MSA, we undertook genetic screening in 100 neuropathologically confirmed cases. No pathologic repeat expansions were detected suggesting that MSA is not a C9orf72-related neurodegenerative disease.

We recently reported that mutations in the valosin-containing protein (VCP) gene are a cause of 1%–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three U.S. cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS but account for

Multiple system atrophy (MSA) is a fatal oligodendrogliopathy characterized by prominent α-synuclein inclusions resulting in a neuronal multisystem degeneration. Until recently MSA was widely conceived as a nongenetic disorder. However, during the last years a few postmortem verified Mendelian pedigrees have been reported consistent with monogenic disease in rare cases of MSA. Further, within the last 2 decades several genes have been associated with an increased risk of MSA, first and foremost the SNCA gene coding for α-synuclein. Moreover, genes involved in oxidative stress, mitochondrial dysfunction, inflammatory processes, as well as parkinsonism- and ataxia-related genes have been implicated as susceptibility factors. In this review, we discuss the emerging evidence in favor of genetic players in MSA.

Multiple system atrophy (MSA) and Parkinson’s disease (PD) are progressive neurodegenerative disorders with overlapping clinical, biochemical and genetic features. To test the hypothesis that the Parkinson’s disease genes parkin and PINK1 also play a role in the pathogenesis of MSA, we performed a mutational screening study involving 87 pathology-proven MSA cases. In parkin we identified eight sequence variants and four heterozygous deletions, and in PINK1 we identified nine variants of which two silent mutations have not been previously reported (p.Gly189Gly and p.Arg337Arg). The frequencies of the observed variants were not significantly different from previously published control data and none of the possibly pathogenic variants were found in a homozygous state. Our results indicate that genetic variants at the parkin and PINK1 loci do not play a critical role in the pathogenesis of MSA.