Glucocerebrosidase mutations in 108 neuropathologically confirmed cases of multiple system atrophy.

Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square, UK WC1N 3BG.
Neurology (Impact Factor: 8.3). 04/2009; 72(13):1185-6. DOI: 10.1212/01.wnl.0000345356.40399.eb
Source: PubMed
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Mutations in the lysosomal glucocerebrosidase (GBA) gene increase the risk of Parkinson’s Disease (PD). We determined the frequency and relative risk of major GBA mutations in a large series of Italian patients with primary parkinsonism. Methods We studied 2,766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2,350 PD), and 1,111 controls. The entire cohort was screened for mutations in GBA exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, p.N370S and p.L444P. Results Four known mutations were identified in heterozygous state: 3 missense mutations (p.N370S, p.L444P, and p.D443N), and the splicing mutation IVS10+1G>T, which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. GBA mutations were more frequent in PD (4.5%, RR=7.2, CI=3.3-15.3) and in Dementia with Lewy Bodies (DLB) (13.8%, RR= 21.9, CI=6.8-70.7) than in controls (0.63%). but not in the other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP, 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the PD group, GBA-carriers were younger at onset (52±10 vs. 57±10 years, P<0.0001) and were more likely to have a positive family history of PD (34% vs. 20%, P<0.001). Conclusion GBA dysfunction is relevant for synucleinopathies, such as PD and DLB, except for MSA, in which pathology involves oligodendrocytes, and the tauopathies PSP and CBD. The risk of developing DLB is three-fold higher than PD, suggesting a more aggressive phenotype.
    Parkinsonism & Related Disorders 09/2014; DOI:10.1016/j.parkreldis.2014.09.003 · 4.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in three patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found one patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuropathologically confirmed samples with MSA (n=96), PSP (n=177) and CBD (n=18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS/CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP or CBD in a large series of cases.
    Neurobiology of Aging 08/2014; 36(2). DOI:10.1016/j.neurobiolaging.2014.08.024 · 4.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of α-synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis.
    12/2014; 23(4):277-91. DOI:10.5607/en.2014.23.4.277

Full-text (2 Sources)

Available from
May 21, 2014

Badma Segarane