Faculty Bibliography

OBJECTIVE: To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. METHODS: We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category. RESULTS: 13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO < or = 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO < or = 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P. CONCLUSIONS: This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset.

Clinical literature suggests an association between essential tremor (ET) and Parkinson's disease (PD), and recent pathological studies describe Lewy bodies in some ET patients. If some ET were an expression of Lewy body disease, one could hypothesize that ET patients who develop parkinsonism would more likely develop PD (a Lewy body disease) than non-Lewy body forms of parkinsonism. The objective was to compare the proportions of patients with PD vs. Parkinson-plus syndromes who had diagnoses of ET. Retrospective chart review at the Neurological Institute (NI) of New York. A larger proportion of the 210 PD than 210 Parkinson-plus syndrome patients had kinetic tremor on examination (119 [56.7%] vs. 70 [33.3%], P < 0.001). Patients with PD were more likely to have a prior diagnosis of ET than were patients with Parkinson-plus syndromes (7.1% vs. 2.4%, OR 3.16, 95% CI 1.13-8.85, P = 0.02) and more likely to have a diagnosis of ET assigned by an NI neurologist (5.3% vs. 0.0%, OR 12.85, 95% CI 1.66-99.8, P = 0.001). Patients with PD were three to thirteen times more likely to have diagnoses of ET than were patients with Parkinson-plus syndromes. These data further confirm the link between ET and PD, and possibly, between ET and Lewy body disease.

Geste antagonistes, or sensory tricks, are well described in focal dystonia affecting the neck, hand, and face. Improvement in dystonic movements is typically maintained while the trick is performed, but disappears when the geste ends. We investigated the phenomenological features of geste antagoniste maneuvers in 19 patients with idiopathic lower cranial dystonia who were prospectively evaluated over a period of 6 years. Of the 19, 10 were men, mean age of onset was 49.8 years, and the most commonly involved lower cranial area was the jaw (10 patients). In most patients, dystonia was task-specific. Taking advantage of the improvement with a sensory geste, we manufactured oral appliances that mimicked the geste in 8 patients, and 3 continue to use it.

Focal task-specific dystonia (FTSD) of the hand and face have been well described; however, FTSD of the leg is exceedingly rare. We describe and demonstrate by videotape 2 patients with FTSD affecting the leg, in both cases triggered specifically by walking down steps. Walking on a level surface, up steps, and down steps backward, and sideways were normal. An interoceptive sensory trick (imagining walking in a different modality) led to temporary improvement. Our patients appear to demonstrated that task-specificity in focal dystonia may not be limited to skilled, rehearsed actions and that FTSD may occur in an activity that is relatively autonomic.

Parkin mutations account for the majority of familial and sporadic early onset Parkinson's disease (EOPD) cases with a known genetic association. More than 100 mutations have been described in the Parkin gene that includes homozygous, compound heterozygous, and single heterozygous mutations. We have designed a Parkin mutation genotyping array (gene chip) that includes published Parkin sequence variants and allows their simultaneous detection. The chip was validated by screening 85 PD cases and 47 controls previously tested for Parkin mutations. Similar genotyping microarrays have been developed for other genetically heterogeneous diseases including age-related macular degeneration. Here, we show the utility of a genotyping array for Parkinson's disease by analysis of 60 subjects from the Genetic Epidemiology of Parkinson Disease (GEPD) study that includes 15 early-onset PD case probands and 45 relatives.

Movement disorder emergencies occur in both hypokinetic and hyperkinetic patients. Prompt recognition of these emergencies is crucial, and diagnosis is based on history and phenomenology. Supportive and temporizing measures must be implemented immediately before disease-specific therapy is begun. For neuroleptic malignant syndrome and related conditions, we recommend a three-tier approach depending on severity, starting with benzodiazepines, dopamine agonists or levodopa, and dantrolene or electroconvulsive therapy. Methylprednisolone pulse therapy also is beneficial for neuroleptic malignant syndrome due to abrupt medication withdrawal in patients with Parkinson's disease. In treatment of other acute antidopaminergic-induced emergencies, anticholinergics usually suffice. To manage airway obstruction related to movement disorders, we rely on laryngoscopic evaluation to determine whether noninvasive or invasive interventions are needed. Hyperkinetic emergencies are treated individually based on the type of abnormal movements. If an antidopaminergic is needed, we prefer a dopamine depletor to a dopamine receptor blocker because of the risk of tardive syndromes with the latter. When focal hyperkinetic movements dominate the picture, botulinum toxin injection is a useful adjunct to medications.

Although myoclonus and dystonia are the hallmarks of myoclonus-dystonia (M-D), psychiatric features, particularly obsessive-compulsive disorder and alcohol dependence, have been reported in three families linked to chromosome 7q21. As the epsilon sarcoglycan (SGCE) gene for M-D was subsequently identified, we evaluated the relationship between psychiatric features and SGCE mutations in these original and two additional families and confirm that OCD and alcohol dependence are associated with manifesting mutated SGCE.

Dopaminergic imaging has been found to be normal in approximately 15% of parkinsonian patients enrolled in neuroprotective trials. We used (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) to determine the metabolic basis for this finding. We reviewed scans from 185 patients with clinical signs of Parkinson's disease (PD) who underwent (18)F-fluorodopa PET imaging for diagnostic confirmation. Of this group, 27 patients (14.6%) had quantitatively normal scans; 8 of these patients were additionally scanned with FDG PET. Pattern analysis was performed on an individual scan basis to determine whether the metabolic changes were consistent with classic PD. Computer-assisted single-case assessments of the FDG PET scans of these 8 patients did not disclose patterns of regional metabolic change compatible with classical PD or an atypical parkinsonian variant. Similarly, network quantification revealed that PD-related pattern expression was not elevated in these patients as it was in an age- and duration-matched cohort with classical PD (P < 0.0001). None of these patients developed clinical signs of classical PD or of an atypical parkinsonian syndrome at a follow-up visit conducted 3 years after imaging. The results suggest that parkinsonian subjects with normal dopaminergic imaging do not have evidence of classical PD or an atypical parkinsonian syndrome