Gaucher disease is a lysosomal glycolipid storage disorder characterized by the accumulation of glucosylceramide (glucocerebroside), a normal intermediate in the catabolism of globoside and gangliosides.

Three types of Gaucher disease have been delineated. Type 1, by far the most common, is distinguished from type 2 and type 3 disease by the lack of primary central nervous system involvement. Type 2, the acute neuronopathic form of the disease, has an early onset with severe central nervous system involvement and death usually within the first 2 years of life. Patients with type 3 (subacute neuronopathic) Gaucher disease have neurologic symptoms with a later onset and a more chronic course than that observed in type 2 disease. Hepatosplenomegaly, bone lesions, and sometimes involvement of lungs and other organs occur in all forms of Gaucher disease.

Gaucher disease is most common in the Ashkenazi Jewish population, where the frequency of Gaucher disease-causing alleles is approximately 0.0343. The 1448C mutation exists at polymorphic levels in northern Sweden, causing type 3 disease among homozygotes.

The gene coding acid β-glucosidase is located on chromosome 1. A pseudogene that has maintained a high degree of homology is approximately 16 kb downstream from the active gene. A number of other active genes have been identified in the flanking regions. These include thrombospondin and metaxin. Liver/red cell pyruvate kinase is located only 71 kb downstream from the glucocerebrosidase gene.

Most of the disease alleles in Gaucher disease are missense mutations that lead to the synthesis of acid β-glucosidases with decreased catalytic function and/or stability. Several nonsense mutations have a moderate frequency, but occur in the heteroallelic state with a missense allele. A variety of other mutations have been found to cause Gaucher disease. Included are missense mutations, frameshift mutations, a splicing mutation, deletions, gene fusions with the pseudogene, examples of gene conversions, and total deletions. The most common mutation in the Ashkenazi Jewish population is at the cDNA nt 1226 where an A → G transition results in an N370S amino acid substitution in acid β-glucosidase. This is associated with nonneuronopathic disease only, and the clinical manifestations can be relatively mild, particularly in 1226G homozygotes. Other mutations, such as T → C at nt 1448 (L444P), are highly associated with neuronopathic disease. However, there is much diversity in phenotypic expression within all genotypes.

The quality of life of patients with Gaucher disease can be improved by a variety of medical and surgical procedures such as joint replacement or splenectomy. The accumulation of glucosylceramide and associated clinical manifestations can be reversed by repeated infusions of modified acid β-glucosidase (alglucerase or imiglucerase). Cure of visceral and probably skeletal manifestations of the disease can be achieved by stem cell transplantation.

Approximately 97 percent of mutations in Ashkenazi Jews can be detected by screening for the five most common mutations. Only about 75 percent of the mutations in non-Jewish populations can be detected in this manner. Population screening in the Ashkenazi Jewish population is feasible, but phenotypic variability makes accurate genetic counseling difficult.