Of the many known phenotypic variations of Parkinson’s disease (PD), mutations of the glucocerebrosidase (GBA) gene are highly associated with more rapid motor disease progression, according to results of a multicenter study reported in JAMA Neurology.
Progression to mild cognitive impairment (MCI) or to dementia was also higher among GBA carriers compared to noncarriers, although this association was predominantly seen in those with polymorphism changes to E326K. Neither GBA mutations nor E326K polymorphisms were associated with increases in tremor scores.
Based on results from 3 previous studies,1-3 in which GBA mutations (associated with the lysosomal storage disorder, Gaucher disease) corresponded to rapid disease progression in PD patients, investigators from 7 sites conducted longitudinal assessments of 733 patients diagnosed with clinical PD according to criteria from the UK Parkinson’s Disease Society Brain Bank. The patients were genotyped for all possible mutations associated with Gaucher disease as well as the nonsynonymous polymorphism E326K.
Eleven mutations to GBA were found in the study population, plus 5 variants of unknown significance and 3 types of nonsynonymous single-nucleotide polymorphisms. The investigators were able to adjust for differences in levodopa doses among the cohort.
The pathogenesis of GBA on PD is largely unclear, although several types of studies have pointed to disruptions of several different molecular pathways that contribute to the onset of the disease. Blood assays previously demonstrated that normal GBA activity appears to be significantly reduced in carriers of polymorphisms as well as GBA mutations compared to noncarriers4 and other nonclinical studies (using cell cultures and animals) have pointed to mechanisms of misfolded proteins resulting in accumulations of alpha-synuclean, now widely associated with PD.5-8
The current study used a special version of the Unified Parkinson’s Disease Rating Scale (UPDRS) Part –III assessment standards sponsored by the Movement Disorders Society, to provide a more sensitive measure of disease progression (and particularly of motor signs) than previous studies that relied on Hoehn and Yahr disease staging. By focusing on the presence of GBA mutations in the cohort of patients with probable PD, the investigators were also able to show that the weight of this single genetic factor is at least as great as all other contributing mutations to both cognitive and motor function decline in PD.
The implications of this study clearly indicate that GBA mutations and E326K polymorphism are both predictive of a more rapid progression of motor signs in PD, and that E326K alone is predictive of cognitive decline and further, that these genetic markers are indicative of a more severe clinical course of disease.
The authors contend that based on their results, GBA genotyping can provide a strong biomarker for disease progression in future therapeutic trials, in both patient selection and in stratification of therapy groups.
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- Poewe W. The need for neuroprotective therapies in Parkinson’s disease: a clinical perspective. Neurology. 2006;66(10)(suppl 4):S2-S9.
- Goetz CG, Stebbins GT, Blasucci LM. Differential progression of motor impairment in levodopa-treated Parkinson’s disease. Mov Disord. 2000;15(3):479-484.
- Alcalay RN, Levy OA,Waters CC, et al. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain. 2015;138:2648-2658.
- Keatinge M, Bui H, Menke A, et al. Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein–independent neuronal cell death. Hum Mol Genet. 2015;24:6640-6652.
- Du TT, Wang L, Duan CL, et al. GBA deficiency promotes CA/α-synSNuclein accumulation through autophagic inhibition by inactivated PPP2A. Autophagy. 2015;11:1803-1820.
- Uemura N, KoikeM, Ansai S, et al. Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. PLoS Genet. 2015;11:e1005065.
- Awad O, Sarkar C, Panicker LM, et al. Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells. Hum Mol Genet. 2015;24:5775-5788.