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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Neurol. Author manuscript; available in PMC 2009 January 21.
Published in final edited form as:
PMCID: PMC2629407

The Spectrum of Parkinsonian Manifestations Associated With Glucocerebrosidase Mutations



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.


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.


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.


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.

In Parkinson disease (PD) and related syndromes, the degeneration of dopaminergic neurons and the formation of Lewy bodies (LBs) manifest clinically as motor dysfunction that includes bradykinesia, resting tremor, and rigidity. Early non-motor signs associated with PD may include olfactory dysfunction, mood and behavioral disturbances, and subtle neurocognitive changes.1 Although genetic alterations have been identified in some with familial PD, in most sporadic cases the cause of neurodegeneration remains unknown. In recent years, multiple loci and mutations have been implicated in the etiology of rare Mendelian forms of PD, with a spectrum of phenotypes encountered.2

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA) (OMIM 606463) result in the autosomal recessive disorder Gaucher disease (GD), which affects the skeletal, hematologic, and nervous systems with varying severity.3 Different lines of evidence suggest that mutant glucocerebrosidase may be a risk factor for parkinsonism. Parkinsonian manifestations have been noted in a subset of patients with GD,4,5 and GBA mutations have been observed with increased frequency in different series of patients with parkinsonism, first in 57 brain bank samples, where 14% had GBA mutations,6 and then in 99 Israeli patients with PD, where 2 GBA mutations were present in 31.3%.7 An increase in GBA mutations subsequently was demonstrated in patients of different ethnicities with PD.810 The carrier frequency for GBA mutations is cited as being less than 1% in the general population and 6% to 7% in Ashkenazi Jews.3 Furthermore, a family history of parkinsonism is often reported in probands with GD.11

Although initial studies noted that patients with GD and parkinsonism had early-onset, levodopa-unresponsive disease, recent studies demonstrated that the pathologic entities associated with GBA mutations include a variety of synucle-inopathies,12 and, hence, the clinical phenotype might also be diverse. The present study details the clinical and neurologic spectrum of the parkinsonian phenotype in 10 patients carrying GBA mutations and is the first documentation, to our knowledge, of olfactory dysfunction in glucocerebrosidase-associated parkinsonism.



Ten consecutive patients with parkinsonism who carried GBA mutations were evaluated at the National Institutes of Health Clinical Center between January 1, 2003, and October 31, 2007 (Table 1 and Table 2). All the patients provided consent and were enrolled under National Institute of Mental Health or National Human Genome Research Institute institutional review board–approved protocols.

Table 1
Demographic and Clinical Characteristics of Patients With Parkinsonism Carrying Glucocerebrosidase Mutations
Table 2
Parkinsonian Manifestations in Patients With Glucocerebrosidase Mutations


Each patient underwent complete physical and neurologic examinations. Motor deficits were quantified using the motor section of the Unified Parkinson Disease Rating Scale (UPDRS III),13 and disease staging was performed according to Hoehn and Yahr criteria.14 Autonomic nervous system function was evaluated using a structured interview to assess postural hypotension, gastrointestinal function, sweating, heat regulation, and bladder and erectile dysfunction, and blood pressure and heart rate were recorded while in the supine position and 5 minutes after standing upright to evaluate orthostatic changes. The Mini-Mental State Examination15 was used to screen for cognitive deficits. Patients 1 through 7 underwent neuropsychometric evaluations using standard methods.16 Mood and behavior were assessed using a semistructured interview, and psychiatric evaluations were completed independently. All neurocognitive and neuropsychiatric assessments were performed while the patient was taking levodopa. Olfaction was evaluated using the University of Pennsylvania Smell Identification Test (UPSIT).17 Normal olfaction corresponded to a raw UPSIT score of 35 or higher, and UPSIT scores were corrected for age and sex. Patients 1 to 6 and 10 had a neuro-ophthalmologic evaluation, with recording of saccadic eye movements. All the patients except patients 8 and 9 had a 21-channel electroencephalogram, and 1 patient with myoclonus was evaluated using multichannel surface electromyography. Patients with GD underwent laboratory and radiologic studies, including echocardiography, pulmonary function testing, and abdominal magnetic resonance imaging to assess disease severity.


Genomic DNA was sequenced to identify GBA mutations by selectively amplifying all exonic sequences and most intronic portions in 3 fragments ranging from 1.7 to 3.0 kilobases (kb) long.18 Southern blot analyses were performed to detect recombinant alleles in each patient with an L444P mutation.19 Screening for 3 mutations in the LRRK2 gene (OMIM 609007) was performed as previously described.20


The demographics, genotypes, and clinical features of the 7 patients with GD and the 3 carriers (7 men and 3 women) are summarized in Table 1. N370S was the most common allele identified; 4 patients were homozygotes and 3 were compound heterozygotes for mutation N370S and either L444P, c.84dupG, or a recombinant allele. Mutation c.84dupG was detected in 2 of the carriers, and a recombinant allele was found in the third. The LRRK2 gene was evaluated in all but patient 8, and no mutations were detected.

The mean age at diagnosis of GD was 32.1 years (range, 12–61 years). The diagnosis of GD was incidental in patients 2 and 6. Five patients had skeletal involvement of moderate severity, with episodes of recurrent bone pain, avascular necrosis, or fractures. Patients 1, 3, and 7 underwent splenectomy and subsequently received enzyme replacement therapy (ERT) for a mean of 14 years; each developed parkinsonism during ERT.

The primary parkinsonian features in the 10 patients, including clinical history, motor and olfactory functions, and Hoehn and Yahr staging, are reported in Table 2. Age at onset ranged from 39 to 65 years (mean, 49 years). Half of the patients presented before age 50 years, and the mean disease duration at the time of evaluation was 7.8 years (range, 1.2–16.0 years). Hoehn and Yahr stage and UPDRS III scores also varied considerably. The mean UPDRS III score was 26.3 (range, 13–38), and motor fluctuations were frequent. Tremor and bradykinesia were the most common symptoms at onset, and presentation was asymmetrical in 9 patients. All the patients received either levodopa or dopamine agonists during the study, with a favorable response in 9. Only patient 3 developed “on-state” dyskinesias.

Although cognition was normal at presentation, progressive decline was reported in 6 patients, with a mean duration of 6.3 years(range,2–10years). Of these patients,2 had overt dementia. Patient 1 presented with early cognitive changes, hallucinations, and delirium that partly remitted after adjusting therapy. Neurocognitive testing demonstrated impaired executive functions, including abstract reasoning, initiation and maintenance of goal-directed behavior, and sustained attention. Although word knowledge, recognition, and reading were spared, there were also deficiencies invisual perceptual areas with impaired verbal memory. Patient 4, who complained of memory problems early in his course, had moderate memory loss with disorientation and difficulty handling complex problems. Eight patients described mood and behavioral disorders, including depression and anxiety requiring therapy, and in 5, these symptoms began at or just before disease onset.

Seizures with electroencephalographic abnormalities, seen in 2 patients, were among the atypical features. Patient 1 was diagnosed as having myoclonus, and a multichannel surface electromyogram demonstrated frequent but asynchronous jerks of the proximal and distal muscles, suggestive of a subcortical origin. Patient 8 reported tonic seizures associated with falls. During the interview, 5 patients reported symptoms of dysautonomia, including constipation and bladder or erectile dysfunction. Patient 4 demonstrated orthostatic changes. Each of the 6 patients who had olfactory testing failed the UPSIT, and 3 had complete loss of smell. The mean UPSIT score was 17.6 (range, 10–33).


An earlier description of 17 patients with GD and parkinsonism demonstrated different genotypes,5 and screening patients with PD for GBA mutations has also identified multiple alleles, including the common N370S, L444P, and c.84dupG and other rare or novel mutations.610 In this cohort, 6 different genotypes were encountered in 10 patients, and N370S was the most common allele. Although patients carrying N370S had slightly lower UPDRS III scores, the GBA genotype did not correlate with cognitive function or disease progression. Although the presence of an N370S allele is assumed to preclude central nervous system involvement in GD, the number of patients with parkinsonism carrying the mutation N370S in this study and others further complicates genotype-phenotype generalizations.

In contrast to earlier publications4,5 in which patients with GD had early-onset, treatment-refractory PD, this study demonstrates that there is a range of age at onset, disease progression, levodopa responsiveness, and cognitive changes in GBA-associated parkinsonism. Herein, the mean age at onset was 49 years, and only 1 patient was considered to have early-onset PD. This differs from other genetic forms of PD, which often have an earlier age at onset. The clinical diagnoses also ranged from PD to a phenotype characteristic of LB dementia (LBD). Although previous publications5 suggested that patients with GBA mutations have a limited response to levodopa or dopamine agonists, herein, the response was mostly favorable.

The profile of the motor symptoms at onset may be a determinant of clinical and cognitive outcome in PD. Patients presenting with tremor tend to show less functional impairments and fewer mental status changes, whereas pronounced bradykinesia or rigidity may correlate with progressive cognitive impairment. The finding of motor symptoms consistent with the akinetic-rigid PD in this patient series suggests that early use of rehabilitative services and rigorous treatment of GD skeletal manifestations should be emphasized, as these patients may become significantly disabled because of the comorbidity of both diseases.

Patients with PD exhibit cognitive deficits that may correlate with the neuropathologic stage or the “spread” of the LB abnormalities from brainstem neurons to cortical areas, and, thus, may occur later in the disease course.21 However, in a series of patients with PD and cognitive impairment, postmortem analysis showed limbic and neocortical LB involvement compatible with LBD. Although the present patients reported cognitive changes with a later onset, their progression resembled that of patients with LBD, correlating with the increased frequency of GBA mutations in LBD.12

Although differing olfactory deficits occur in parkinsonian syndromes, a markedly decreased sense of smell remains highly characteristic of PD.22,23 Olfactory dysfunction is a less prominent finding in other genetic conditions, and patients with α-synuclein and LRRK2 mutations mostly have normal olfaction.24,25 Further studies are indicated to determine the predictive value of olfactory testing as a bio-marker in patients carrying GBA mutations.

Although the association between parkinsonism and GD has been described for almost a decade, there has not been a descriptive study of such patients evaluated in a uniform manner. Although the cohort assembled was evaluated prospectively, a significant amount of data, especially related to cognition and disease progression, had to be collected retrospectively, which could have introduced a bias related to patient recall. Owing to the small cohort size, raters were not blinded, which is another limitation. However, the study is ongoing, and future assessments will better establish the natural history and symptom progression in these patients.

Genes implicated in mendelian forms of PD have provided new insights into the disease pathogenesis, and the molecular pathways identified in monogenic cases may also play a role in sporadic forms of PD. Different molecular mechanisms that contribute to PD and related disorders lead to a common pathologic condition characterized by the death of dopaminergic neurons in vulnerable brain regions. The clinical heterogeneity seen in parkinsonism is likely to be the cumulative result of different gene-environment and gene-gene interactions. Although not all genetic causes of parkinsonism were explored in this cohort, no mutations in LRRK2, a gene also associated with varied neuropathologic features, were identified. In monogenic forms of parkinsonism, the mutated gene or the gene product likely contributes to the observed phenotypic spectrum. Several inherited parkinsonian syndromes are postulated to result from loss-of-function mutations,2,26 yet, in some dominant forms, a gain-of-function mechanism has been suggested.2 Although the association with mutant GBA could be due to a loss of enzymatic activity, the identification of Gaucher carriers with parkinsonism renders a gain-of-function disease mechanism related to the aberrant protein more likely. We postulate that GBA mutations may be directly involved in the parkinsonian pathologic abnormality, playing a pivotal role in pathways involved in neurodegeneration.

Sporadic PD is a multifactorial condition, and contributory risk factors are likely to operate early in the causative chain of events. Mutations identified in Parkinson genes may also behave as susceptibility factors for idiopathic PD. Heterozygous mutations in PARKIN are believed to confer an increased risk of late-onset PD.27 Similarly, LRRK2 mutations can be considered a cause of and a susceptibility factor for PD.28 The parkinsonian spectrum associated with GBA mutations likewise suggests that they may be causative in some and a risk factor in others. However, the range of parkinsonian phenotypes observed in Gaucher carriers and the diversity of genotypes encountered renders widespread screening for a single or a small number of GBA mutations inappropriate. Furthermore, the penetrance of GBA mutations leading to a parkinsonian phenotype is currently unknown. Before considering diagnostic or pre-symptomatic screening of “at-risk” individuals, detailed natural history studies and a meta-analysis of association data are necessary to determine the statistical significance and implications of GBA mutations as a risk factor for parkinsonism.


Funding/Support: This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke, National Institutes of Health.


Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Goker-Alpan, Lopez, and Sidransky. Acquisition of data: Goker-Alpan, Lopez, Vithayathil, Davis, and Sidransky. Analysis and interpretation of data: Goker-Alpan, Hallett, and Sidransky. Drafting of the manuscript: Goker-Alpan and Sidransky. Critical revision of the manuscript for important intellectual content: Lopez, Vithayathil, Davis, Hallett, and Sidransky. Obtained funding: Sidransky. Administrative, technical, and material support: Lopez, Davis, and Sidransky. Study supervision: Sidransky.

Financial Disclosure: None reported.

Additional Contribution: Mary E. LaMarca, BA, provided critical reading and editing of the manuscript.


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