Clinical Information

Gaucher disease is a relatively rare lysosomal storage disorder resulting from a deficiency of acid beta-glucocerebrosidase. Reduced or absent activity of this enzyme results in accumulation of its substrate in lysosomes, interfering with cell function. There are 3 major types of Gaucher disease: nonneuropathic (type 1), acute neuropathic (type 2), and subacute neuropathic (type 3). In addition, there are 2 rare presentations of Gaucher disease: a perinatal lethal form associated with skin abnormalities and nonimmune hydrops fetalis, and a cardiovascular form presenting with calcification of the aortic and mitral valves, mild splenomegaly, and corneal opacities. Gaucher disease demonstrates large clinical variability, even within families.

Type 1 accounts for over 95% of all cases of Gaucher disease and is the presentation commonly found among Ashkenazi Jewish patients. The carrier rate of Gaucher disease in the Ashkenazi Jewish population is 1:18. There is a broad spectrum of disease in type 1 Gaucher disease, with some patients exhibiting severe symptoms and others very mild disease. Type 1 disease does not involve nervous system dysfunction; patients may display anemia, low blood platelet levels, massively enlarged livers and spleens, lung infiltration, and extensive skeletal disease. Type 2 is characterized by early-onset neurologic disease with rapid progression to death by 2 to 4 years of age. Type 3 may have early onset of symptoms, but generally a slower disease progression than type 2.

Mutations in the GBA gene cause the clinical manifestations of Gaucher disease. Over 250 mutations have been reported to date. The N370S and L444P mutations have the highest prevalence in most populations. N370S is associated with type 1 Gaucher disease, and individuals with at least 1 copy of this mutation do not develop the primary neurologic disease seen in types 2 and 3. Conversely, L444P is associated with neurologic disease.

For carrier screening of the general population, the recommended test is GAUP / Gaucher Disease, Mutation Analysis, GBA, which tests for the 8 most common GBA mutations. For diagnostic testing (ie, potentially affected individuals), enzyme testing (BGL / Beta-Glucosidase, Leukocytes) should be performed prior to mutation analysis. In individuals with abnormal enzyme activity and 1 or no mutations detected by a panel of common mutations, sequence analysis of the GBA gene should be utilized to detect private mutations.