Differential effects of severe vs mild
 GBA
 mutations on Parkinson disease

Gan‐Or, Ziv; Amshalom, Idan; Kilarski, Laura L.; Bar‐Shira, Anat; Gana‐Weisz, Mali; Mirelman, Anat; Marder, Karen; Bressman, Susan; Giladi, Nir; Orr-Urtreger, Avi

doi:10.1212/wnl.0000000000001315

Cited by 305 publications

(360 citation statements)

References 40 publications

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“…Among these, 5 (1.8%) carried one of the two founder mutations in SMPD1 - 4 had the c.996delC (fsP330) and 1 carried the L302P mutation. One patient harbored the SMPD1 R496L mutation, which was previously shown not to increase the risk for PD [23], and therefore was excluded from the analyses. Of the 54 (20%) PD patients who harbored 1 of the 6 founder mutations in GBA , 45 carried mild mutations (N370S, n = 42 and R496H, n = 3) and 9 carried severe mutations (84GG, n = 8 and V394L, n = 1).…”

Section: Resultsmentioning

confidence: 99%

“…GBA mutations can be classified as mild (N370S and R496H) and severe (84GG, IVS2 + 1, V394L, D409H, L444P, and RecTL). It has been shown that carriers of severe GBA mutations present with a 4- to 5-year earlier age of PD onset compared to mild GBA mutation carriers [23]. Recently, Ashkenazi founder mutations in the SMPD1 gene [p.L302P, c.996delC (fsP330), but not p.R496L], which cause Niemann-Pick disease type A, were reported in excess in PD patients [14,15,24].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

LRRK2, GBA and SMPD1 Founder Mutations and Parkinson's Disease in Ashkenazi Jews

Dagan

Schlesinger

Kurolap

et al. 2016

Dement Geriatr Cogn Disord

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Background/Aim: Parkinson's disease (PD) is associated with mutations in LRRK2, GBA, and SMPD1 genes. We describe the clinical characteristics of PD patients related to their carrier status of the Ashkenazi founder mutations in the aforementioned genes. Methods: Ashkenazi PD patients (n = 270) were recruited following informed consent, and tested for the founder Ashkenazi mutations in the above genes. Clinical characteristics were compared between carriers and noncarriers. Homozygotes for mutations in GBA or LRRK2, and those who carried mutations in two causative genes were excluded from the analysis. Results: Five (1.85%), 54 (20%), and 22 (8.1%) PD patients carried mutations in SMPD1, GBA or LRRK2, respectively. By post hoc Bonferroni analysis, GBA carriers were singled at a significantly earlier age at diagnosis compared to noncarriers (58.06 ± 10.84 and 62.65 ± 10.86 years, respectively; p = 0.036), and due to bilateral manifestation at diagnosis compared to all other PD groups (n = 8, 15.7% compared to n = 2, 1.1%, respectively; p < 0.001). Other clinical manifestations were comparable between groups. Conclusion: Although only GBA mutation carriers, compared to noncarriers, reached statistical significance regarding age at diagnosis, it appears that LRRK2 and SMPD1 mutation carriers may reach significance with larger group numbers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LRRK2, GBA and SMPD1 Founder Mutations and Parkinson's Disease in Ashkenazi Jews

Dagan

Schlesinger

Kurolap

et al. 2016

Dement Geriatr Cogn Disord

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show abstract

“…46,65 The classification of GBA mutations as "severe" or "mild" according to the type of GD that they lead to (severe mutations lead to the neuropathic GD types and mild mutations lead to the non-neuropathic type), 66 is also valid for PD, as carriers of severe GBA mutations have higher risk and earlier onset compared to mild GBA mutation carriers. 67 It is still unclear how GBA mutations lead to PD, and several hypotheses have been raised, including mechanisms involving lossof-function or gain-of-function mutations. 68 First, it was demonstrated that chemical inhibition of GBA can lead to accumulation of SNCA, 69 a finding that was later replicated in other models with GBA mutations.…”

Section: Gba-gaucher Diseasementioning

confidence: 99%

“…This can be explained by the fact that null GBA mutations, which result in lack of expression of GBA, also cause PD. 67 Hence, if no protein is produced, it cannot cause a toxic effect, and loss of function is more likely to be the cause of increased susceptibility for PD.…”

Section: Gba-gaucher Diseasementioning

confidence: 99%

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

2015

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“…No difference was observed in tremor and dyskinesia between GBA and idiopathic cases in one series [49], although a large European series reported that levodopa induced dyskinesia was more severe in PD with GBA mutations than with controls [48]. Severity of the GBA mutation in terms of its effect on enzyme activity, is associated with earlier age of onset [48,50].…”

Section: Motor Featuresmentioning

confidence: 93%

Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

105

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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.

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Differential effects of severe vs mild GBA mutations on Parkinson disease

Abstract: These data demonstrate that mild and severe heterozygous GBA mutations differentially affect the risk and the AAO of PD. Our results have important implications for genetic counseling and clinical follow-up.

Cited by 305 publications

References 40 publications

<b><i>LRRK2, GBA </i></b>and<b><i> SMPD1 </i></b>Founder Mutations and Parkinson's Disease in Ashkenazi Jews

<b><i>LRRK2, GBA </i></b>and<b><i> SMPD1 </i></b>Founder Mutations and Parkinson's Disease in Ashkenazi Jews

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

Glucocerebrosidase Mutations in Parkinson Disease

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