[page 24] [Cardiogenetics 2013; 3(s1):e4] Molecular basis and clinicalmanagement of Gaucher disease

Gaucher disease (GD) type I is an autoso-mal recessive disease caused by a genetic deficiency of lysosomal b-glucocerebrosidase that leads to accumulation of undergraded substrate glucocerebroside and other glycol-ipids, thus causing damage in different organs. GBA is the only gene in which muta-tions are known to cause GD. Nearly 300 mutations have been identified in GD patients, including frame-shift mutations, point mutations, deletions, insertions, splice site mutations and recombinants. The variety of phenotypes associated to GD shows imper-fect correlation with mutations. GD encom-passes a spectrum of clinical findings from a perinatal lethal form to an asymptomatic form. However the classification of GD by clinical subtype is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clini-cal types are delineated: type I (chronic non-neuropathic), type II (acute neuropathic), and type III (chronic neuropathic). Patients with type I GD present with vis-ceromegaly, hematological complications, and bone disease. Cardiac and pulmonary complica-tions are rare. Type I GD adult patients have ele-vated risk of malignancies, Parkinson’s disease or Parkinsonism. Neuropathic forms of GD are rare and clinically ranging from lethal perinatal form to very mild form limited to abnormalities of horizontal ocular saccades. Diagnosis of acid b-glucosylceramidase relies on enzyme activity in peripheral blood leukocytes or skin fibrob-lasts and/or identification of GBA mutations. Enzyme replacement therapy is an effective treatment for non-neuropathic GD. Substrate inhibitor is the alternative therapy for some patients with GD is miglustat, iminosugar inhibitor of glucocerebroside synthase