Substrate reduction therapy with miglustat for type 1 Gaucher disease: A retrospective analysis from a single institution

Abstract

Introduction. Gaucher disease (GD) is an infrequent progressive multisystem lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme, glucocerebrosidase. A retrospective, single-center analysis of the clinical experience concerning the use of miglustat (N-butyldeoxynojirimycin), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease (GD1) was conducted to evaluate the efficacy, adverse events (AE), and outcome of miglustat therapy.Patients and methods. Six adult Caucasian patients with GD1 (two women and four men), aged 21–81 years (median age 59 years), were treated with miglustat between October 2005 and April 2011. All but one patient (83%) carried at least one allele with c.1226A>G (N370S) mutation in the GBA1 gene.Results. Weight loss, diarrhea, poor appetite, and tremor were frequently reported AE by the patients. All of them experienced at least 2 AE, and three patients (50%) experienced at least 4 AE. Only two out of six patients (33%) have used miglustat longer than 12 months, of which only one used it longer than 15 months.Conclusions. The major obstacle to successful miglustat therapy in GD1 was the high proportion of patients discontinuing their treatment due to the AE and the worsened quality of life. Further efforts are needed to improve tolerability of miglustat and, in consequence, compliance of patients treated with this orphan drug.

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

“…Since it slows down the production of glycosphingolipids, it should be effective in reducing storage of these compounds. Although positive effects of such treatment in clinical trials were reported (Elstein et al 2004;Pastores et al 2005), its efficacy in Gaucher disease has recently been questioned (Tylki-Szymanska et al 2011;Machaczka et al 2012).…”

Zarys objawów klinicznych, leczenia oraz trudności w rozpoznawaniu choroby Gauchera

“…W Szwecji, liczącej niespełna 10 milionów mieszkańców, częstość występowania choroby Gauchera wynosi ok. 1:170 000 mieszkańców, lecz w pozostałych krajach nordyckich (Dania, Norwegia, Finlandia) jest ona niższa (ok. 1:420 000 mieszkańców) [26]. Co ciekawe, jak dotąd nie stwierdzono przypadku choroby Gauchera na Islandii.…”

Atypical cytomorphology of Gaucher cells is frequently seen in bone marrow smears from untreated patients with Gaucher disease type 1

“…All patients also demonstrated increased plasma chitotriosidase activity. Both enzymes were assessed by a reference laboratory according to standard practice [6,19]. Further, direct DNA sequencing performed at the Academic Medical Centre in Amsterdam, Netherlands, revealed mutations in the GBA1 gene in all cases.…”

“…GD1 is a slowly progressive illness, and clinical picture can vary from severe, lethal cases diagnosed in early childhood to completely asymptomatic patients [13][14][15][16]. Currently, GD is treatable and in the European Union there are two treatment options available for patients: (1) enzyme replacement therapy (ERT) with macrophage-targeted recombinant glucocerebrosidase (Cerezyme ® , Genzyme Corporation, Cambridge, MA, USA; VPRIV ® , Shire HGT, Lexington, MA, USA), and (2) substrate reduction therapy (SRT) with miglustat/N-butyldeoxynojirimycin (Zavesca ® , Actelion Pharmaceuticals, Allschwil, Switzerland) [17][18][19][20].…”