title: Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1.
abstract: Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism, associated with multisystemic manifestations resulting from the lysosomal accumulation of an incompletely degraded material (glucosylceramide) within cells of monocyte/macrophage lineage. In the majority of GD patients with non-neurological involvement (type 1), the clinical features are dominated by haematological, visceral (hepatic and splenic) and skeletal complications. Infrequently, cardiopulmonary involvement may develop and lead to major morbidity. Investigations of substrate turnover within cellular compartments, such as the lysosome, indicate that progressive tissue storage occurs when the activity of the responsible hydrolytic enzyme declines. Thus, the provision of functional enzyme to deficient cells is a straightforward means of achieving metabolic correction. Conversely, the concentration of stored substrate within cells bearing particular affected enzymes (i.e., expressing residual activity) may be controlled by a reduction of the 'load'. This means that metabolic homeostasis can also be restored by restricting the amount of substrate presented to disease cells to a level that can be hydrolysed by the existing enzyme activity. Proof-of-concept for both approaches has been demonstrated through enzyme replacement therapy using alglucerase/imiglucerase and more recently, substrate reduction therapy by miglustat. Enzyme replacement therapy is proven to be safe and effective in the treatment of GD type 1, establishing imiglucerase as the current standard of care. The experience with substrate reduction therapy, specifically miglustat, is limited but encouraging. This review is an attempt to examine the potential role of this latter approach in light of current patient management. The consideration of miglustat as a therapeutic option requires the appropriate selection of patients (amongst those unwilling or unsuitable to receive enzyme replacement therapy), a definition of the therapeutic objectives and monitoring not only for response but potential adverse effects.
authors.affiliation: Neurogenetics Unit, Department of Neurology and Pediatrics, New York University School of Medicine, New York, USA. gregory.pastores@med.nyu.edu
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Barnett
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology*; D005962:Glucosylceramidase / Q000627:therapeutic use*; D006801:Humans; D013379:Substrate Specificity
chemical_list: D005962:Glucosylceramidase; C090568:imiglucerase