Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers

Anheim, Mathieu; Elbaz, Alexis; Lesage, Suzanne; Dürr, Alexandra; Condroyer, Christel; Viallet, François; Pollak, Pierre; Bonaı̈ti, B.; Bonaïti‐Pellié, Catherine; Brice, Alexis

doi:10.1212/wnl.0b013e318245f476

Cited by 218 publications

(204 citation statements)

References 11 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…Penetrance of PD at 65 years, % 1.5 7.7 (Chetrit et al, 2013) 2.2 (Rana et al, 2013) Penetrance of PD at 70 years, % 1.5 15.2 (Chetrit et al, 2013) 21.4 (Anheim et al, 2012) 5.0 7.0 (Rosenbloom et al, 2011) Penetrance of PD at 75 years, % --6.8 (Rana et al, 2013) Penetrance of PD at 80 years, % 9.0 12.0 (Rosenbloom et al, 2011) 29.7 (Anheim et al, 2012) Penetrance of PD at 85 years, % --10.9 (Rana et al, 2013) Overall lifetime RR of PD compared to that in the general population 21.4 (Bultron et al, 2010) 30.0 (McNeill et al, 2012a) 1.4 GBA-associated PD GBA-related parkinsonism largely resembles sporadic PD, but it has been characterized by some subtle differences, for instance a younger age of onset ), a higher frequency of cognitive decline (Goker-Alpan et al, 2008;), bradykinesia (Gan-Or et al, 2009, olfactory dysfunction (Goker-Alpan et al, 2008), and a lower frequency of rigidity (Clark et al, 2007).…”

Section: The Link Between Gba Mutations and Parkinson's Diseasementioning

confidence: 99%

“…It is presently estimated that homozygous or heterozygous GBA mutations confer an increased risk for PD of 20-30 fold (Bultron et al, 2010;; McNeill et al, 2012a) and at least 7% of PD patients have GBA mutations (McNeill et al, 2012a) , (Sidransky et al, 2009a), and this is higher in the Ashkenazi Jewish population (Zimran et al, 1991). The penetrance of GBA mutation carriers to develop PD has been estimated as 13·7% at age 60 years and 29·7% at age 80 years (Anheim et al, 2012), and so a method to determine individual risk for PD expression in this population would be very valuable.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan

Schapira

2013

Annals of Medicine

View full text Add to dashboard Cite

Section: The Link Between Gba Mutations and Parkinson's Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan

Schapira

2013

Annals of Medicine

View full text Add to dashboard Cite

“…Heterozygotes have a 10-30% chance of developing PD by age 80, which constitutes a 20-fold increase compared to non-carriers [7][8][9][10], and approximately 5-25% of "idiopathic" PD patients carry GBA mutations, making GBA mutations the greatest risk factor for PD discovered to date [11,12].…”

Section: G O'regan Et Al / Gba In Parkinson Diseasementioning

confidence: 99%

Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

105

View full text Add to dashboard Cite

Abstract.Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

show abstract

“…Although heterozygous GBA mutations have been considered a risk factor rather than causal for PD, a reported penetrance as high as 30% by age 80 (Anheim et al 2012;Kumar et al 2012) suggests autosomal dominant inheritance with reduced penetrance.…”

Section: Introductionmentioning

confidence: 99%

Cognitive and Antipsychotic Medication Use in Monoallelic GBA-Related Parkinson Disease

et al. 2014

View full text Add to dashboard Cite

Mutations in glucosidase, beta, acid (GBA) are associated with cognitive impairment in Parkinson disease (PD) as well as dementia with Lewy bodies. For both of these diseases, dementia and hallucinations are typically treated with cholinesterase inhibitors and antipsychotics. However, in some lysosomal storage disorders certain antipsychotic medications are poorly tolerated. This study examined cholinesterase inhibitor and antipsychotic use in monoallelic GBA-related PD to explore potential pharmacogenetic relationships. Monoallelic GBA mutation carriers with PD (GBA-PD) with at least two clinic visits (n ¼ 34) were matched for age-of-onset and gender to GBA and leucine-rich repeat kinase 2 (LRRK2) mutation negative idiopathic PD subjects (IPD) (n ¼ 60). Information regarding cholinesterase inhibitor and antipsychotic use as well as impaired cognition (UPDRS Mentation >1) and hallucinations (UPDRS Thought Disorder >1) were obtained. GBA-PD more frequently reported hallucinations (HR ¼ 5.0; p ¼ 0.01) and they were more likely to have cognitive impairment but this was not statistically significant (HR 2.2, p ¼ 0.07). Antipsychotic use was not significantly different between GBA-PD and IPD (HR ¼ 1.9; p ¼ 0.28), but GBA-PD were more likely to have sustained cholinesterase inhibitor use (HR ¼ 3.1; p ¼ 0.008), even after adjustment for cognition and hallucinations. Consistent with reports of worse cognition, GBA-PD patients are more likely to use cholinesterase inhibitors compared to IPD. While there was no difference in antipsychotic use between IPD and GBA-PD, persistent use of quetiapine in GBA-PD suggests that it is tolerated and that a significant interaction is unlikely. Further prospective study in larger samples with more extensive cognitive assessment is warranted to better understand pharmacogenetic relationships in GBA-PD.

show abstract

Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers

Abstract: The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD.

Cited by 218 publications

References 11 publications

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Glucocerebrosidase Mutations in Parkinson Disease

Cognitive and Antipsychotic Medication Use in Monoallelic GBA-Related Parkinson Disease

Contact Info

Product

Resources

About