Lysosomal enzyme deficiency and GBA mutations in Dystonia

Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene causes autosomal-recessive Gaucher`s disease, the most frequent lysosomal storage disorder. Over the past two decades, GBA mutations have been established as the most frequent genetic risk factor to develop Parkinson`s Disease. In dystonia, the underlying aetiology in a relevant proportion of cases remains unknown, hampering the development of causative treatment strategies. Here, we explored the possible role of lysosomal dysfunction in clinical (n=130) and post mortem (n=10) patients with dystonia. As part of extensive diagnostic evaluations (screening for structural, acquired and degenerative causes of dystonia), lysosomal enzyme activity was measured in n=79 retrospectively collected cases of patients with combined dystonia and n=51 prospectively collected cases of patients with cervical dystonia using a clinically validated, fluorescence based assay. Clinical information on all cases was extensively reviewed and an alternative aetiology of dystonia was identified in n=14 cases on followup. Of the remaining n=116 cases of dystonia of unknown origin, complete Sanger Sequencing of GBA exons 1 to 11 was performed using an established protocol in all n=97 of cases with available DNA. Where there was suspicion based on clinical examination or family history, nigrostriatal degeneration was excluded in n=19 (17.2%) cases with dystonia of unknown origin. Furthermore, lysosomal enzyme activity was measured in different brain regions of age, sex and postmortem delay matched cases with dystonia of unknown origin (n=10) and healthy controls (n=10) from the Queen Square brain bank. Among cases with dystonia of unknown origin, decreased white cell Glucocerebrosidase activity was measured in a range typical for homozygous (n=2; 1.7%) or heterozygous (n=23; 19.8%) GBA mutation carriers. The frequency of GBA mutations (5/80=6.25%) was significantly higher in patients than in controls (3/257=1.17%) of a historical control group from the same ethnic background (P=0.02; Odds Ratio=5.64, 95% Confidence Interval=1.44 to 21.58): known pathogenic mutations E326K, T369M and N370S were found. We also identified lower Glucocerebrosidase activity in the cerebellar dentate nucleus (P=0.048) of dystonia patients than healthy controls. This study provides evidence for peripheral and central lysosomal dysfunction in a significant proportion and across the clinical spectrum of dystonia. As in Parkinson`s disease, this was found irrespective of GBA mutation status, indicating a possible role of lysosomal dysfunction as a more general disease mechanism in dystonia.