GBA-Associated Parkinson’s Disease and Other Synucleinopathies
Purpose of Review
GBA mutations are the most common known genetic cause of Parkinson’s disease (PD). Its biological pathway may be important in idiopathic PD, since activity of the enzyme encoded by GBA, glucocerebrosidase, is reduced even among PD patients without GBA mutations. This article describes the structure and function of GBA, reviews recent literature on the clinical phenotype of GBA PD, and suggests future directions for research, counseling, and treatment.
Several longitudinal studies have shown that GBA PD has faster motor and cognitive progression than idiopathic PD and that this effect is dose dependent. New evidence suggests that GBA mutations may be important in multiple system atrophy. Further, new interventional studies focusing on GBA PD are described. These studies may increase the interest of PD patients and caregivers in genetic counseling.
GBA mutation status may help clinicians estimate PD progression, though mechanisms underlying GBA and synucleinopathy require further understanding.
KeywordsParkinson’s disease Glucocerebrosidase Genetics Synucleinopathy
Compliance with Ethical Standards
Conflict of Interest
Ziv Gan-Or is supported by research grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canadian Glycomics Network (GlycoNet), and the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program. Dr. Gan-Or is consulting for Sanofi and for Lysosomal Therapeutics Inc. (LTI).
Christopher Liong declares no potential conflicts of interest.
Roy N. Alcalay is supported by the Parkinson’s Disease Foundation, the Michael J. Fox Foundation, and the National Institutes of Health.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
- 2.Van Bogaert L, Froehlich A. Un cas de maladie de Gaucher de l'adulte avec syndrome de Raynaud, pigmentation, et rigidite du type extrapyrajidal aux membres inferieurs. Ann Med. 1939;45:57–70.Google Scholar
- 6.•• Gan-Or Z, Amshalom I, Kilarski LL, Bar-Shira A, Gana-Weisz M, Mirelman A, et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology. 2015;84(9):880–7. This meta-analysis showed differential odds ratios for PD between mild and severe GBA mutation carriers (2.2 and 10.3, respectively), as well as differential age of PD onset, with severe GBA mutation carriers having earlier age of onset than mild GBA mutation carriers (53.1 vs. 58.1, respectively). PubMedPubMedCentralGoogle Scholar
- 7.Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Ross BM, et al. Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. Arch Neurol. 2010;67(9):1116–22.PubMedPubMedCentralGoogle Scholar
- 43.Aerts JM, et al. Glucocerebrosidase, a lysosomal enzyme that does not undergo oligosaccharide phosphorylation. Biochim Biophys Acta Gen Subj. 1988;964(3):303–8.Google Scholar
- 44.Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, von Figura K, Schmidt B. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-pick C1 disease - lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim Biophys Acta. 2009;1793(4):710–25.PubMedGoogle Scholar
- 53.• Alcalay RN, Levy OA, Waters CH, Fahn S, Ford B, Kuo SH, et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015;138(Pt 9):2648–58. The authors show that GCase activity was significantly different between PD patients and controls, even among non-carriers of GBA or LRRK2 mutations, suggesting that the biological pathway of GBA is important to idiopathic PD. Further, higher GCase activity was associated with longer disease duration, suggesting a milder disease course. PubMedPubMedCentralGoogle Scholar
- 70.Zunke F, et al. Reversible Conformational Conversion of a-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 97(1):92–107. e10Google Scholar
- 84.•• Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, Tesei S, et al. Survival and dementia in GBA-associated Parkinson's disease: the mutation matters. Ann Neurol. 2016;80(5):662–73. The authors compared PD patients with and without GBA mutations longitudinally, and showed that mutation carriers had a greater risk for dementia (hazard ratio = 3.16) and death (hazard ratio = 1.85) than noncarriers, and that carriers of severe mutations had greater risk for dementia than carriers of mild mutations but similar mortality risk. PubMedGoogle Scholar
- 86.• Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, et al. GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2015;30(3):407–11. This study examines a cohort of PD patients with and without GBA mutations over 3 years, finding that GBA PD patients had earlier age of onset, faster motor progression, and reduced survival rates compared to non-carriers. PubMedGoogle Scholar
- 90.Li Y, Sekine T, Funayama M, Li L, Yoshino H, Nishioka K, et al. Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease. Neurobiol Aging. 2014;35(4):935.e3–8.Google Scholar
- 91.• Liu G, Boot B, Locascio JJ, Jansen IE, Winder-Rhodes S, Eberly S, et al. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Ann Neurol. 2016;80(5):674–85. A total of 2,304 PD patients from 7 cohorts were followed for up to 12.8 years, showing that GBA mutation carriers were more likely to develop cognitive impairment, as measured by the mini-mental state exam, than non-carriers. Cognitive decline was faster in carriers of severe mutations in GBA compared to mild ones. PubMedPubMedCentralGoogle Scholar
- 107.Barber TR, Lawton M, Rolinski M, Evetts S, Baig F, Ruffmann C, et al. Prodromal parkinsonism and neurodegenerative risk stratification in REM sleep behavior disorder. Sleep. 2017;40(8)Google Scholar
- 125.Sokol LL, Young MJ, Jankovic J. Counseling at-risk Parkinson’s disease cohorts: integrating emerging evidence. Curr Genet Med Rep. 2017;5(2):100–7.Google Scholar