Gaucher Disease and Parkinsonism: Clinical Course and Prognosis - PowerPoint Presentation

1. Gaucher Disease and Parkinsonism: Clinical Course and PrognosisJenny Kim1, Dahima Cintron2,Catherine Groden1, Edythe Wiggs1, Joie Davis1, Pramod Mistry3, Gregory Pastores4, Ari Zimran5, Ozlem Goker-Alpan6, Ellen Sidransky1 and Grisel Lopez1 <your name><your organization>Email:Website:Phone:Contact ReferencesMutations in the glucocerebrosidase (GBA1) gene, which encodes the enzyme glucocerebrosidase, result in Gaucher disease (GD), a disorder characterized by glycolipid accumulation and lysosomal dysfunction. Careful attention to family history and clinical observations among patients with GD led to the discovery of an association between mutations in GBA1 and the development of parkinsonism, a neurodegenerative disorder, in a subgroup of patients. While it has been suggested that the presence of a GBA1 mutation is indicative of a more aggressive parkinsonian phenotype, this has not been closely evaluated in patients with GD and parkinsonism. AbstractOur findings indicate that after the initial onset of symptoms, our patients had a similar clinical course to those with sporadic PD and sporadic dementia with Lewy bodies (DLB) depending on the phenotypic presentation. As previously reported, we found an earlier age at onset of parkinsonism (mean 49.7 years) and motor impairment (average “on” UPDRS-III score 26.9, average L-dopa response 19.1%). There was evidence of significant cognitive dysfunction that was most prominent in memory and processing speed in our cohort. However, when examined as a group, we did not observe a uniformly aggressive form of parkinsonism. Longitudinal evaluation of patients with GD and parkinsonism may help to discern whether GBA1 mutations can indeed be proposed as a predictor of a more aggressive parkinsonian clinical presentation and disease course.IntroductionIn this study, we reviewed clinical data on nineteen patients with GD and parkinsonian manifestations followed longitudinally at the NIH Clinical Center. Neurological evaluations, family history, neurocognitive evaluations, olfactory testing, and validated questionnaires were analyzed to evaluate the severity of parkinsonian symptoms and prevalence of non-motor symptoms. Methods and MaterialsConsistent with other studies in the literature, this study demonstrated an earlier age at onset of parkinsonian symptoms in this cohort when compared to patients with idiopathic Parkinson disease. Aside from motor symptoms, our patients developed a wide range of prodromal nonmotor manifestations including cognitive impairment, olfactory dysfunction, and sleep and neuropsychiatric disturbances.Regarding cognitive dysfunction, the domains most affected in our cohort were memory and processing speed. Those most often affected in Parkinson-associated dementia include decision-making, visuospatial abilities, and attention. This hints at a possible separate mechanism of cognitive impairment in our cohort. There are limitations of this study. Interpretation of clinical data is complicated by the clinical heterogeneity seen in Parkinson disease as well as the clinical overlap between PD, DLB and other synucleinopathies, which make it difficult to make a clinical diagnosis.DiscussionThe age at onset of parkinsonism in our patients is earlier than in sporadic PD, consistent with the current literature. The disease duration in our cohort is slightly shorter than that seen with sporadic PD. However, age at death is earlier due to the younger age at onset.Cognitive impairment is frequent in this cohort, with deficits in performance and non-verbal tasks and preserved verbal abilities.Mood disturbances such as depression and anxiety are frequent in our cohort.Hallucinations are frequent in this cohort either due to drug side effects or as manifestations of dementia with Lewy bodies (DLB).Our patients reported non-motor manifestations including olfactory, urinary, bowel, and cognitive dysfunction as well as sleep disturbances.There is phenotypic heterogeneity in our patients with GD and parkinsonism. We did not see a uniformly aggressive parkinsonian course.Longitudinal follow-up and autopsy studies of this cohort are essential to help elucidate the role of lysosomal dysfunction in PD.ConclusionsGaucher disease (GD) is a rare lysosomal storage disorder caused by a deficiency in glucocerebrosidase with defective glycolipid metabolism. It is characterized by hematological, skeletal and visceral problems. There are 3 types of GD and neurological involvement occurs in GD type 2 and type 3. The treatment is enzyme replacement therapy.Parkinson disease (PD) is a common progressive neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra. It affects approximately 2% of the population by age 70. The clinical diagnosis is given when a patient has bradykinesia and at least one of the following: rest tremor, rigidity, or postural instability. The treatment includes levodopa as well as other medications that target specific symptoms.The current literature on patients with GD and PD suggests that they have a more rapid and aggressive clinical course and a worse prognosis compared to patients with sporadic PD. More specifically, the literature shows an earlier age at onset of parkinsonian signs, more cognitive impairment, and earlier and more frequent complications to levodopa treatment. Although only a minority of patients with GD ultimately develop PD, characterization of these patients may help to elucidate the mechanisms underlying this association and potential prognostic indicators.ResultsEvaluation of Non-Motor Symptoms of Parkinsonism1Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, 2University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico, 3Yale School of Medicine, New Haven, CT, United States, 4Mater Misericordiae University Hospital, Dublin, Ireland, 5Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, Israel, 6Lysosomal Disorders Research & Treatment Unit, O & O Alpan LLC, Fairfax, VA Average and Median Values for Quantitative MeasuresAverageMedianAge at Onset (years)# (n=18)49.22249.0UPSIT Score (out of 40)* (n=10)19.319Disease Duration (years)^ (n=8)10.62510.5Age at Death (years) (n=8)64.12561.5# Mean for PD without GBA1 mutation is 62.4y (Hughes et al.) and for GBA1 carriers is 54.8y (NEJM 2009)* Abnormal score is <35^ Mean PD duration for sPD population is 13.1y (Hughes et al.)