Objective: To report on the observation of decreased levels of GCase in peripheral blood in patients presenting with dystonia without signs of parkinsonism.

Background: Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene causes autosomal-recessive Gaucher`s disease. GBA mutations are associated with an increased risk to develop Parkinson`s Disease, while an association with dystonia has not been reported so far. We here report the observation of decreased GCase levels and GBA mutations in dystonia patients.

Methods: Patients with isolated dystonia and clinical red flags indicating a secondary cause to their presentation were screened for structural, acquired and degenerative causes of dystonia as part of their diagnostic workup. This included neuroimaging, blood tests for copper, caeruloplasmin, genetic analysis and lysosomal enzyme activity using a fluorescence-based essay. Sequencing of GBA exons 8-11 was performed using standard Sanger Sequencing.

Results: After exclusion of possible alternative aetiologies, n=27 patients (m/f=13/14) with dystonia without parkinsonism and abnormal GCase activity were identified retrospectively. Cases showed GCase activity within the range typical for heterozygous (normal range: 2.5-8.9μmol/l/h, n=24) and homozygous (0.29-2.5; n=3) GBA mutations, while Chitotriosidase was found elevated in n=2. No other lysosomal enzyme activity was found abnormal. Age at onset differed between cases with enzyme levels typical for heterozygous (28.1yrs) and homozygous (50.3yrs) GBA mutations. Alternative mutations in DYT1, Parkin, SCA1, 2, 3, 6, 7, mitochondrial genes and GCH-1 were excluded dependent on presentation in n=22. A significant proportion of cases displayed a positive family history for PD (n=6), dystonia (n=3) and other neurological conditions (n=15). On Sanger sequencing (n=22), known GBA mutations (het. N370S & het. E326K) were found in one male and female patient with late-onset isolated foot dystonia and (serial) normal DaT scans. In a prospective sample of consecutive patients with dystonia without parkinsonism, GCase enzyme activity was found to be abnormally low in 67% of n=39.

Conclusions: The observation of decreased GCase activity levels and GBA mutations in this series of dystonia patients provides evidence that lysosomal dysfunction may be associated with dystonia in the absence of parkinsonism. Epidemiology and mechanism of this remain to be established.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/decreased-blood-beta-glucosidase-activity-and-gba-mutations-in-dystonia/