The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations.
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.


METHODS
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.
Section on Molecular Neurogenetics, National Human Genome Research Institute, National Institutes of Health, 35 Convent Dr, MSC 3708, Bldg 35, Room 1A213, Bethesda, MD 20892-3708, USA.
Ozlem
O
Goker-Alpan
Grisel
G
Lopez
Joseph
J
Vithayathil
Joie
J
Davis
Mark
M
Hallett
Ellen
E
Sidransky
D000328:Adult; D017668:Age of Onset; D000368:Aged; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D004252:DNA Mutational Analysis; D004185:Disability Evaluation; D005260:Female; D005776:Gaucher Disease / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D005962:Glucosylceramidase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D020961:Lewy Body Disease / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000857:Olfaction Disorders / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D011446:Prospective Studies
D005962:Glucosylceramidase