Patients’ Opinions on Genetic Counseling on the Increased Risk of Parkinson Disease among Gaucher Disease Carriers

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.

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Levodopa-induced dyskinesia in dementia with Lewy bodies and Parkinson disease with dementia

Neurology Clinical Practice ◽

10.1212/cpj.0000000000000703 ◽

2019 ◽

Vol 10 (2) ◽

pp. 156-161

Author(s):

Pierpaolo Turcano ◽

Cole D. Stang ◽

James H. Bower ◽

J. Eric Ahlskog ◽

Bradley F. Boeve ◽

...

Keyword(s):

Parkinson Disease ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Population Based ◽

Olmsted County ◽

Levodopa Dosage ◽

Younger Age ◽

Increased Risk ◽

Incident Cohort ◽

Median Interval

ObjectiveTo investigate the frequency of levodopa-induced dyskinesia in dementia with Lewy bodies (DLBs) and Parkinson disease with dementia (PDD) and compare these frequencies with patients with incident Parkinson disease (PD) through a population-based cohort study.MethodsWe identified all patients with DLB, PDD, and PD without dementia in a 1991–2010 population-based parkinsonism-incident cohort, in Olmsted County, Minnesota. We abstracted information about levodopa-induced dyskinesia. We compared patients with DLB and PDD with dyskinesia with patients with PD from the same cohort.ResultsLevodopa use and dyskinesia data were available for 141/143 (98.6%) patients with a diagnosis of either DLB or PDD; 87 (61.7%), treated with levodopa. Dyskinesia was documented in 12.6% (8 DLB and 3 PDD) of levodopa-treated patients. Among these patients, median parkinsonism diagnosis age was 74 years (range: 64–80 years); 63.6%, male. The median interval from levodopa initiation to dyskinesia onset was 2 years (range: 3 months–4 years); the median daily levodopa dosage was 600 mg (range: 50–1,600 mg). Dyskinesia severity led to levodopa adjustments in 5 patients, and all improved. Patients with dyskinesia were diagnosed with parkinsonism at a significantly younger age compared with patients without dyskinesia (p < 0.001). Levodopa dosage was unrelated to increased risk of dyskinesias among DLB and PDD. In contrast, 30.1% of levodopa-treated patients with PD developed dyskinesia. In age-, sex-, and levodopa dosage–adjusted models, Patients with DLB and PDD each had lower odds of developing dyskinesia than patients with PD (odds ratio = 0.42, 95% CI 0.21–0.88; p = 0.02).ConclusionsThe dyskinesia risk for levodopa-treated patients with DLB or PDD was substantially less than for levodopa-treated patients with PD.

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Prodromal Clinical Markers of Parkinson disease in Gaucher Disease Individuals

European Neurology ◽

10.1159/000447510 ◽

2016 ◽

Vol 76 (1-2) ◽

pp. 19-21 ◽

Cited By ~ 10

Author(s):

Emilia M. Gatto ◽

Jose Luis Etcheverry ◽

Ana Sanguinetti ◽

Martin Cesarini ◽

Nicolas Fernandez Escobar ◽

...

Keyword(s):

Parkinson Disease ◽

Gaucher Disease ◽

Clinical Markers

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Occurrence of Amyotrophic Lateral Sclerosis in Type 1 Gaucher Disease

Neurology Genetics ◽

10.1212/nxg.0000000000000600 ◽

2021 ◽

Vol 7 (4) ◽

pp. e600

Author(s):

Lais M. Oliveira ◽

Tara Rastin ◽

Graeme A.M. Nimmo ◽

Jay P. Ross ◽

Patrick A. Dion ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mutation Carrier ◽

Gaucher Disease ◽

Family Members ◽

Carrier Mother ◽

Increased Risk ◽

Type 1 Gaucher Disease ◽

Population Controls ◽

Lateral Sclerosis

ObjectiveTo report the association between type 1 Gaucher disease (GD1) and amyotrophic lateral sclerosis (ALS) in 3 unrelated families and to explore whether GBA variants influence the risk of ALS.MethodsWe conducted retrospective chart reviews of patients with GD1 or their family members diagnosed with ALS. To further investigate whether there is an association between ALS and GD, we performed exploratory analyses for the presence of GBA variants in 3 ALS cohorts from Toronto (Canada), Montreal (Canada), and Project MinE (international), totaling 4,653 patients with ALS and 1,832 controls.ResultsWe describe 2 patients with GD1 and 1 obligate GBA mutation carrier (mother of GD1 patient) with ALS. We identified 0 and 8 GBA carriers in the Toronto and Montreal cohorts, respectively. The frequencies of GBA variants in patients with ALS in the Montreal and Project MinE cohorts were similar to those of Project MinE controls or Genome Aggregation Database population controls.ConclusionsThe occurrence of ALS in biallelic or monoallelic GBA mutation carriers described here, in addition to common pathogenic pathways shared by GD1 and ALS, suggests that GBA variants could influence ALS risk. However, analyses of GBA variants in ALS cohorts did not reveal a meaningful association. Examination of larger cohorts and neuropathologic studies will be required to elucidate whether patients with GD1 are indeed at increased risk for ALS.

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Association of SHANK3 Gene Polymorphism and Parkinson Disease in the North of Iran

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.12.1.255.4 ◽

2021 ◽

Vol 12 (1) ◽

pp. 57-62

Author(s):

Nahid Mizban ◽

◽

Nasim Vousooghi ◽

Nasrin Mizban ◽

◽

...

Keyword(s):

Parkinson Disease ◽

Neurodegenerative Disorder ◽

Genotype Distribution ◽

Scaffolding Proteins ◽

Allele Distribution ◽

The North ◽

Increased Risk ◽

Significant Difference ◽

North Of Iran ◽

Domain 3

Introduction: Parkinson Disease (PD), the second most common chronic neurodegenerative disorder, is characterized by tremor, bradykinesia, rigidity, and postural instability. SHANK3 (SH3 and multiple ankyrin repeat domain 3) belongs to the extremely conserved ProSAP/ Shank family of synaptic scaffolding proteins. Meanwhile, rs9616915 is a non-synonymous SNP (T>C) located in the exon 6 of the SHANK3 gene, which induces substitution of isoleucine to threonine and affects the function of the resulted protein. The present study aimed to evaluate whether rs9616915 polymorphism of SHANK3 is involved in the susceptibility to PD. Methods: The study subjects were 100 patients diagnosed with PD and 100 control volunteers. The obtained samples were evaluated by the polymerase chain reaction-restriction fragment length polymorphism method. Results: A significant association was found in genotype distribution between cases and controls. Individuals with TC genotype had increased risk of PD (P=0.035, OR=1.98, 95% CI=1.04 - 3.74). No significant difference was found in allele distribution (P=0.7). Conclusion: The findings suggest that the SHANK3 rs9616915 polymorphism is associated with an increased risk of PD in the population. Further studies are needed to confirm the role of the SHANK3 gene in PD.

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Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

Frontiers in Neurology ◽

10.3389/fneur.2021.694764 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elisa Menozzi ◽

Anthony H. V. Schapira

Keyword(s):

Parkinson Disease ◽

Progressive Disease ◽

Clinical Aspects ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Risk Variants ◽

Increased Risk ◽

Severe Motor ◽

Heterozygous Carriers

Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.

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Somatic Mosaicism in a Patient with Gaucher Disease Type 2: Implication for Genetic Counseling and Therapeutic Decision-Making

Blood Cells Molecules and Diseases ◽

10.1006/bcmd.2000.0341 ◽

2000 ◽

Vol 26 (6) ◽

pp. 611-612 ◽

Cited By ~ 9

Author(s):

Mirella Filocamo ◽

Gloria Bonuccelli ◽

Raffaella Mazzotti ◽

Fabio Corsolini ◽

Marina Stroppiano ◽

...

Keyword(s):

Decision Making ◽

Genetic Counseling ◽

Gaucher Disease ◽

Somatic Mosaicism ◽

Disease Type ◽

Therapeutic Decision ◽

Therapeutic Decision Making

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Risk Factors for Periprosthetic Femoral Fracture in Non-cemented Total Hip Arthroplasty Through the Direct Anterior Approach

HSS Journal ® ◽

10.1177/15563316211050884 ◽

2021 ◽

pp. 155633162110508

Author(s):

Zachary Berliner ◽

Cameron Yau ◽

Kenneth Jahng ◽

Marcel A. Bas ◽

H. John Cooper ◽

...

Keyword(s):

Risk Factors ◽

Total Hip Arthroplasty ◽

Parkinson Disease ◽

Hip Arthroplasty ◽

Femoral Fracture ◽

Categorical Variables ◽

Patient Specific ◽

Periprosthetic Femoral Fracture ◽

Total Hip ◽

Increased Risk

Background: Although total hip arthroplasty (THA) performed through the direct anterior (DA) approach is frequently marketed as superior to other approaches, there are concerns about increased risks of intraoperative and early postoperative femoral fracture. Purpose: We sought to assess patient-specific and radiographic risk factors for intraoperative and early postoperative (90-day) periprosthetic femoral fracture (PPFx) following DA approach THA. Methods: We retrospectively reviewed 1107 consecutive, primary, non-cemented DA THAs, performed between April 2009 and January 2015, for intraoperative and early postoperative PPFx. Patients lost to follow-up before 90 days (63), cemented or hybrid THA (52), or early femoral failure for another indication (3) were excluded, yielding 989 hips for analysis. Demographic variables and patient comorbidities were analyzed as risk factors for PPFx. Continuous variables were initially compared with 1-way analysis of variance (ANOVA) and categorical variables with chi-square test. A demographic matched-paired radiographic analysis was performed for femoral stem canal fill and compared using univariate logistic regression. Results: The incidence of perioperative PPFx was 2.02%, including 10 intraoperative and 10 early postoperative fractures. Sustaining a postoperative PPFx was associated with being 70 years old or older with a body mass index (BMI) of less than 25, or with having either osteoporosis or Parkinson disease. Radiographs demonstrated that intraoperative PPFx was associated with stems that filled greater proximally rather than distally. Conclusion: Our cohort study found older age, age over 70 with BMI of less than 25, osteoporosis, and Parkinson disease were associated with increased risk for early postoperative PPFx following DA approach THA. Intraoperative fractures may occur with disproportionate proximal femoral canal fill. Further study can evaluate whether cemented femoral components may mitigate risk in these patient populations.

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Palliative Management of Parkinson Disease: Focus on Nonmotor, Distressing Symptoms

Journal of Pharmacy Practice ◽

10.1177/0897190008318370 ◽

2008 ◽

Vol 21 (4) ◽

pp. 262-272 ◽

Cited By ~ 2

Author(s):

Jack J. Chen ◽

Dominick P. Trombetta ◽

Hubert H. Fernandez

Keyword(s):

Parkinson Disease ◽

Long Term Care ◽

Functional Dependence ◽

Care Facility ◽

The United States ◽

Elderly Persons ◽

Motor Complications ◽

Term Care ◽

Increased Risk

Parkinson disease is a progressive neurodegenerative disease that commonly affects elderly persons. In the absence of neuroprotective or curative therapies, currently available therapies only provide symptomatic benefit. Progression to advanced Parkinson disease is often accompanied by functional dependence with increased risk of admission to a long-term care facility. The prevalence of Parkinson disease in long-term care facilities, within the United States, has been estimated to be between 5.2% and 10%. Patients with advanced Parkinson disease also experience other distressing motor and nonmotor conditions, such as motor complications, dementia, depression, gastrointestinal distress, orthostatic hypotension, pain, and psychosis, which can be a challenge for clinicians to manage. The presence of distressing symptoms along with the fact that Parkinson disease remains incurable necessitate discussion on a palliative care approach to this disorder. This article discusses the symptomatic management of distressing symptoms encountered in the long-term care resident with Parkinson disease, including motor complications and nonmotor features.

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