Gaucher's disease: clinical features and natural history

Abstract

Gaucher's disease is an inherited disorder characterized by pathological storage of glycolipid in mononuclear phagocytes: it is a multi-system disease associated with striking variation in its clinical manifestations, severity and course. Although molecular analysis of the glucocerebrosidase gene in patients with Gaucher's disease has permitted broad correlations between genotype and phenotype to be made, with few exceptions genetic variation at this locus does not allow confident prediction of clinical phenotype or prognosis. Partial deficiency of glucocerebrosidase is associated principally with parenchymal disease of the liver, spleen, bone marrow and, in severe cases, the lung, in non-neuronopathic, Type 1, Gaucher's disease: here storage material in macrophages originates from turnover of exogenous glycolipids. Severe deficiency of glucocerebrosidase caused by disabling mutations is additionally associated with neurological manifestations that in part reflect a failure to degrade endogenous neuronal glycosphingolipids, the so-called neuronopathic, Type 2 and Type 3 disease categories. Here we describe the clinical features, complications and natural history principally of Type 1 Gaucher's disease: emphasis is placed on emerging pulmonary, osseous and other manifestations of obscure pathogenesis that respond poorly to enzyme-replacement therapy.