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Gaucher Disease.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
2000 Jul 27 [updated 2015 Feb 26].

Excerpt

CLINICAL CHARACTERISTICS:

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.

DIAGNOSIS/TESTING:

The diagnosis of GD relies on demonstration of deficient glucocerebrosidase (glucosylceramidase) enzyme activity in peripheral blood leukocytes or other nucleated cells. Carrier testing by assay of enzyme activity is unreliable because of overlap in enzyme activity between carriers and non-carriers. Identification of two disease-causing alleles in GBA, the only gene in which mutations are known to cause GD, provides additional confirmation of the diagnosis. However, given the broad heterogeneity in causative mutations, biochemical testing should be considered in individuals in whom genetic testing identifies a novel GBA mutation.

MANAGEMENT:

Treatment of manifestations: When possible, management by a multidisciplinary team at a Comprehensive Gaucher Center. For persons not receiving enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), symptomatic treatment includes partial or total splenectomy for massive splenomegaly and thrombocytopenia. Supportive care for all affected individuals may include: transfusion of blood products for severe anemia and bleeding, analgesics for bone pain, joint replacement surgery for relief from chronic pain and restoration of function, and oral bisphosphonates and calcium for osteoporosis. Prevention of primary manifestations: ERT is usually well tolerated and provides sufficient exogenous enzyme to overcome the block in the catabolic pathway, clearing the stored substrate, GL1, and thus reversing hematologic and liver/spleen involvement. Although bone marrow transplantation (BMT) had been undertaken in individuals with severe GD, primarily those with chronic neurologic involvement (GD type 3), this procedure has been largely superseded by ERT. Miglustat may be indicated in symptomatic individuals with GD type 1 who are not able to receive ERT. Prevention of secondary complications: The use of anticoagulants in individuals with severe thrombocytopenia and/or coagulopathy should be discussed with a hematologist to avoid the possibility of excessive bleeding. Surveillance: Recommendations for comprehensive serial monitoring have been published by the International Collaborative Gaucher Group Registry (ICGG) and other groups. Agents/circumstances to avoid: Nonsteroidal anti-inflammatory drugs (NSAIDs) in individuals with moderate to severe thrombocytopenia. Evaluation of relatives at risk: It is appropriate to offer testing to asymptomatic at-risk relatives so that those with glucocerebrosidase enzyme deficiency, or two disease-causing alleles, can benefit from early diagnosis and treatment if indicated.

GENETIC COUNSELING:

Gaucher disease (GD) is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Targeted mutation analysis can be used to detect carriers in high-risk populations (e.g., Ashkenazi Jewish persons). Because the carrier frequency for GD in certain populations is high (e.g., 1:18 in individuals of Ashkenazi Jewish heritage) and the N370S/N370S phenotype is variable, individuals who undergo carrier testing may be identified as being homozygous. Prenatal testing for pregnancies at increased risk is possible using assay of glucocerebrosidase enzymatic activity and molecular genetic testing when both disease-causing mutations in a family are known.

Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.

PMID:
20301446
[PubMed]
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