The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations

Arch Neurol. 2008 Oct;65(10):1353-7. doi: 10.1001/archneur.65.10.1353.


Background: Mutations in the glucocerebrosidase gene (GBA) result in Gaucher disease and can be associated with a phenotype characterized by adult-onset progressive neurologic deterioration and parkinsonism.

Objective: To define the clinical and neurologic spectrum of parkinsonian manifestations associated with GBA mutations. Design, Setting, and Patients A prospective case series of 10 patients (7 men and 3 women) with parkinsonism and GBA mutations evaluated at the National Institutes of Health Clinical Center.

Main outcome measures: The GBA genotypes were identified by means of DNA sequencing. Tests evaluating neurologic, motor, cognitive, ocular, and olfactory functions were performed and the results were analyzed by a single team.

Results: Genotyping identified GBA mutations N370S, L444P, and c.84dupG and recombinant alleles. The mean age at onset of parkinsonian manifestations was 49 years (range, 39-65 years), disease duration was 7.8 years (range, 1.2-16.0 years), and Unified Parkinson Disease Rating Scale part III score was 26.3 (range, 13-38). Half of the patients reported cognitive changes later in the disease course. Six patients were diagnosed as having Parkinson disease, 3 as having Lewy body dementia, and 1 as having a "Parkinson plus" syndrome. The most frequent nonmotor finding was olfactory dysfunction. Atypical manifestations included myoclonus, electroencephalographic abnormalities, and seizures.

Conclusions: In the homozygous and heterozygous states, GBA mutations are associated with a spectrum of parkinsonian phenotypes ranging from Parkinson disease, mostly of the akinetic type, to a less common phenotype characteristic of Lewy body dementia.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Cognition Disorders / diagnosis
  • Cognition Disorders / genetics
  • Cognition Disorders / physiopathology
  • DNA Mutational Analysis
  • Disability Evaluation
  • Female
  • Gaucher Disease / complications*
  • Gaucher Disease / enzymology*
  • Gaucher Disease / genetics
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genotype
  • Glucosylceramidase / deficiency*
  • Glucosylceramidase / genetics
  • Humans
  • Lewy Body Disease / diagnosis
  • Lewy Body Disease / genetics
  • Lewy Body Disease / physiopathology
  • Male
  • Middle Aged
  • Mutation / genetics
  • Olfaction Disorders / diagnosis
  • Olfaction Disorders / genetics
  • Olfaction Disorders / physiopathology
  • Parkinsonian Disorders / enzymology*
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / physiopathology
  • Phenotype
  • Prospective Studies


  • Glucosylceramidase