Variants associated with Gaucher disease in multiple system atrophy

Abstract

ObjectiveGlucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series.MethodsWe sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.ResultsIn the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel–Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14–5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15–5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10−3).InterpretationThe findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Prodromal Clinical Markers of Parkinson disease in Gaucher Disease Individuals

“…GBA mutations have been associated with different alpha-synucleinopathies, PD, Lewy Body Dementia and, recently, multiple system atrophy type C [3,4] .…”

“…PD patients with GBA1 mutations cannot be discriminated from idiopathic PD (iPD) [4] . Moreover, fluorodopa PET or SPECT with dopamine demonstrates the same asymmetric pattern in both conditions [4] .…”

“…PD patients with GBA1 mutations cannot be discriminated from idiopathic PD (iPD) [4] . Moreover, fluorodopa PET or SPECT with dopamine demonstrates the same asymmetric pattern in both conditions [4] . Probably, a younger age at onset and a greater risk for earlier and more prevalent cognitive impairment could represent a clinical red flag for differentiating PD-GBA1 from iPD [4] .…”

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

“…21 They found a significantly increased odds ratio for GBA variants in MSA patients compared to controls. In fact, two patients with MSA had homozygous mutations in the GBA gene without a known clinical diagnosis of GD, while none of the controls had homozygous or compound heterozygous mutations.…”

“…The prevalence of GBA mutations among patients with MSA has been studied by a few groups in recent years, and has yielded varied results. [19][20][21][22][23][24][25] Six studies have found no association between GBA mutations and MSA.…”