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Cited by 696Lysosomal Storage Disorders ResearchParkinson's Disease Mechanisms and TreatmentsGlycogen Storage Diseases and Myoclonus

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease

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Neumann, Juliane, Bras, Jose, Deas, Emma, O'Sullivan, Sean S., Parkkinen, Laura, Lachmann, Robin H., Li, Abi, Holton, Janice +9 more·2009·Brain
DOI 10.1093/brain/awp044PMC PMC2702833
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Abstract

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.

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  • Biallelic loss-of-function mutations in GRN cause juvenile-onset neuronal ceroid lipofuscinosis (NCL).

    “Subsequently, rare families with biallelic loss of function mutations in GRN were identified, and affected individuals were found to have a juvenile-onset neuronal ceroid lipofuscinosis (NCL).114–116”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [116]

    The Introduction discusses GBA mutations and Gaucher disease, while the Mutations in GBA section reports GBA variants; neither addresses GRN. Searches for biallelic GRN loss of function and juvenile-onset neuronal ceroid lipofuscinosis found no relevant passage in our copy. Page numbers were not available. (LLM, conf=0.78)

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Authors
Neumann, J., Bras, J., Deas, E., O'Sullivan, S. S., Parkkinen, L., Lachmann, R. H., Li, A., Holton, J., Guerreiro, R., Paudel, R., Segarane, B., Singleton, A., Lees, A., Hardy, J., Houlden, H., Revesz, T., & Wood, N. W.
Affiliations
  • UCL Queen Square Institute of Neurology (GB)
  • National Institutes of Health (US)
Corresponding author
Neumann, Juliane
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2009-03-13
Volume
132
Issue
7
Pages
1783-1794
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awp044
PMC
PMC2702833
OpenAlex
W2165400844
Cited by
696
References
1
Citations by year
2026: 21 · 2025: 32 · 2024: 38 · 2023: 43 · 2022: 49 · 2021: 51 · 2020: 48 · 2019: 38 · 2018: 41 · 2017: 48 · 2016: 37 · 2015: 46 · 2014: 34 · 2013: 44 · 2012: 38
FWCI
27.26
Type
journal article
Language
en
Open access
Locations
  • Brain (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • U.S. Department of Health and Human Services
  • Parkinson's UK (G-0907, G0909, 948776, G-0612)
  • Brain Research Trust
  • Imperial College London
  • Studienstiftung des Deutschen Volkes
  • National Institutes of Health
  • Medical Research Council (G0400074)
  • Fundação para a Ciência e a Tecnologia (SFRH/BD/27442/2006, SFRH/BD/29647/2006)
  • National Institute on Aging
  • Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology,University College London
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
Keywords
Parkinson's disease, glucocerebrosidase, GBA mutations, Gaucher disease, alpha-synuclein pathology, Lewy bodies, Braak staging, genotype-phenotype correlation, mutation frequency, British patients, novel mutations, dementia, hallucinations, genetic risk factors
MeSH terms
Adult, Aged, Brain, DNA Mutational Analysis, Female, Gaucher Disease, Genotype, Glucosylceramidase, Humans, Male, Middle Aged, Mutation, Parkinson Disease, Phenotype, Risk Factors, Cohort Studies

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