Parkinson's disease phenotype is influenced by the severity of the mutations in the GBA gene

Thaler, Avner; Bregman, Noa; Gurevich, Tanya; Shiner, Tamara; Dror, Yonatan; Zmira, Ofir; Gan‐Or, Ziv; Bar‐Shira, Anat; Gana‐Weisz, Mali; Orr-Urtreger, Avi; Giladi, Nir; Mirelman, Anat

doi:10.1016/j.parkreldis.2018.05.009

Cited by 96 publications

(90 citation statements)

References 29 publications

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“…In a more recent study, motor and some non-motor features (depression, RBD, and olfactory loss) were significantly worse in GBA-PD patients with severe mutations than in those bearing mild mutations (Thaler et al, 2018a).…”

Section: Genotype-phenotype Correlation In Gba-pd Subjectsmentioning

confidence: 87%

“…A meta-analysis revealed that the risk for dementia in PD patients carrying ''severe'' mutations is 2-to 3-fold higher than in those carrying ''mild'' mutations (Cilia et al, 2016). A more recent study extended this notion demonstrating that psychiatric symptoms, cognitive impairment, and olfactory deficiency are more pronounced in PD patients carrying severe GBA1 mutations (Thaler et al, 2018a).…”

Section: Introductionmentioning

confidence: 99%

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Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Avenali

Blandini

Cerri³

2020

Front. Aging Neurosci.

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Heterozygous mutations of the GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), occur in a considerable percentage of all patients with sporadic Parkinson's disease (PD), varying between 8% and 12% across the world. Genome wide association studies have confirmed the strong correlation between PD and GBA1 mutations, pointing to this element as a major risk factor for PD, possibly the most important one after age. The pathobiological mechanisms underlying the link between a defective function of GCase and the development of PD are still unknown and are currently the focus of intense investigation in the community of pre-clinical and clinical researchers in the PD field. A major controversy regards the fact that, despite the unequivocal correlation between the presence of GBA1 mutations and the risk of developing PD, only a minority of asymptomatic carriers with GBA1 mutations convert to PD in their lifetime. GBA1 mutations reduce the enzymatic function of GCase, impairing lysosomal efficiency and the cellular ability to dispose of pathological alpha-synuclein. Changes in the cellular lipidic content resulting from the accumulation of glycosphingolipids, triggered by lysosomal dysfunction, may contribute to the pathological modification of alpha-synuclein, due to its ability to interact with cell membrane lipids. Mutant GCase can impair mitochondrial function and cause endoplasmic reticulum stress, thereby impacting on cellular energy production and proteostasis. Importantly, reduced GCase activity is associated with clear activation of microglia, a major mediator of neuroinflammatory response within the brain parenchyma, which points to neuroinflammation as a major consequence of GCase dysfunction. In this present review article, we summarize the current knowledge on the role of GBA1 mutations in PD development and their phenotypic correlations. We also discuss the potential role of the GCase pathway in the search for PD biomarkers that may enable the development of disease modifying therapies. Answering these questions will aid clinicians in offering more appropriate counseling to the patients and their caregivers and provide future directions for PD preclinical research.

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Section: Genotype-phenotype Correlation In Gba-pd Subjectsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Avenali

Blandini

Cerri³

2020

Front. Aging Neurosci.

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“…Whereas LRRK2 ‐PD is not considered to affect cognitive capabilities, mGBA‐PD and more so sGBA‐PD have been associated with increased rates of dementia . Recently, the International Parkinson and Movement Disorder Society committee on Rating Scales Development rated the MoCA as recommended for cognitive assessment; we, on the other hand, previously noted that the MoCA might not be a sensitive enough screening tool to identify mild cognitive changes among this population . UPSIT scores were not entered to the multivariate model; however, LRRK2 ‐PD trended for better olfactory scores whereas both mGBA‐PD and sGBA‐PD trended for worse UPSIT scores compared to iPD …”

Section: Discussionmentioning

confidence: 99%

“…Two mutations are considered “mild” (mGBA‐PD); p.N370S and p.R496H based on the non‐neuropathic Gaucher's disease (GD) phenotype, whereas the other five mutations—p.L444P, c.84dupG, IVS2 + 1G‐>A, p.V394L, and RecTL/370Rec (p.N409S;p.D448H;p.L483P)—are considered severe (sGBA‐PD). Studies reporting on the GBA ‐PD phenotype point to higher rates of cognitive decline and earlier, more frequent appearance of neuropsychiatric features, compared to idiopathic PD (iPD) . sGBA‐PD was associated with significantly higher risk of death regardless of presence of dementia …”

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confidence: 97%

Survival rates among Parkinson's disease patients who carry mutations in the LRRK2 and GBA genes

et al. 2018

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Background: The G2019S mutation in the LRRK2 gene generates a milder PD phenotype compared with GBA‐PD; however, genetic based survival studies are lacking. Objectives: To compare mortality rates between LRRK2‐PD, GBA‐PD, and idiopathic PD patients (iPD). Methods: Patients were screened for the G2019S mutation in the LRRK2 gene and the seven common GBA mutations among Ashkenazi Jews, classified as mild and severe (mGBA, sGBA). Motor symptoms onset and date of death were ascertained, with mortality rates calculated for each group of patients. Results: Overall, 380 of 1,086 idiopathic PD patients, 49 of 159 LRRK2‐PD, 56 of 148 mGBA‐PD, and 13 of 49 sGBA‐PD participants died by the time of analysis. LRRK2‐PD tended to have longer survival compared to idiopathic PD whereas GBA status did not affect mortality. Genetic status did not predict mortality in a multivariate analysis. Conclusion: Survival of patients with PD does not seem to be related to GBA status, whereas LRRK2 might confer higher survival rates.

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“…For instance, in Gaucher disease, one of the earliest LSDs for which enzyme replacement therapy (ERT) became available, it has emerged affected individuals and their carrier relatives have an increased risk for Parkinson disease (compared with the general population), and that amongst affected patients this risk does not appear to be mitigated by ERT. 38 Perhaps a more relevant situation is the experience relating to follow-up of patients with infantile Pompe disease (including only those with survival to age ≥5 years) on ERT (age ≤6 months at treatment initiation with alglucosidase alfa). Long-term survivors (n-11, median age of 8.0 years; range: 5.4-12.0 years) exhibited sustained improvements in cardiac structure and function, and in gross motor function.…”

Section: Current Perspectivesmentioning

confidence: 99%

<p>Lysosomal Acid Lipase Deficiency: Therapeutic Options</p>

Pastores¹,

Hughes²

2020

DDDT

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Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease) subtype; both inherited as autosomal recessive traits. Cardinal clinical features include the combination of hepatic dysfunction and dyslipidemia, as a consequence of cholesteryl esters and triglyceride accumulation, predominately in the liver and vascular and reticuloendothelial system. Significant morbidity can arise, due to liver failure and/or atherosclerosis; in part related to the severity of the underlying gene defect and corresponding enzyme deficiency. Diagnosis is based on demonstration of decreased LAL enzyme activity, complemented by analysis of the cognate gene defects. Therapeutic options include dietary manipulation and the use of lipid-lowering drugs. Sebelipase alfa, a recombinant enzyme replacement therapy, has garnered regulatory approval, following demonstration of improvements in diseaserelevant markers and clinical benefit in clinical trials, which included increased survival in the most severe cases.

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Parkinson's disease phenotype is influenced by the severity of the mutations in the GBA gene

Cited by 96 publications

References 29 publications

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Survival rates among Parkinson's disease patients who carry mutations in the LRRK2 and GBA genes

<p>Lysosomal Acid Lipase Deficiency: Therapeutic Options</p>

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