ß-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters.
Neurology
; 95(6): e685-e696, 2020 08 11.
Article
en En
| MEDLINE
| ID: mdl-32540937
ABSTRACT
OBJECTIVE:
To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and ß-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies.METHODS:
A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years).RESULTS:
ß-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual ß-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean ß-glucocerebrosidase activity by 0.85 µmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in ß-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02).CONCLUSIONS:
Residual activity of the ß-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. ß-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Glucosilceramidasa
/
Mutación
Tipo de estudio:
Etiology_studies
/
Observational_studies
/
Prevalence_studies
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Prognostic_studies
/
Risk_factors_studies
Límite:
Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Neurology
Año:
2020
Tipo del documento:
Article