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 or by the identification of biallelic pathogenic variants in GBA.
Note: The amino acid numbering for glucocerebrosidase used in this GeneReview follows the HGVS-recommended nomenclature, which includes the first 39 amino acids, and differs from the traditional numbering system, which does not include the first 39 amino acids. Using the HGVS-recommended nomenclature, the pathogenic variant p.Asn370Ser is named p.Asn409Ser and the pathogenic variant p.Leu444Pro is named p.Leu483Pro.
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 anti-bone resorptive agents, calcium, and vitamin D for osteoporosis.
Prevention of primary manifestations – targeted therapies: 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. Miglustat may be indicated in symptomatic individuals with GD type 1 who are not able to receive ERT. Eliglustat has been shown to improve or stabilize key disease features in those naïve to or switched from enzyme replacement therapy. 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 or SRT.
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 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 biallelic pathogenic variants can benefit from early diagnosis and treatment if indicated.
Pregnancy management: Pregnancy can exacerbate preexisting symptoms and trigger new features in affected women. Those with severe thrombocytopenia and/or clotting abnormalities are at increased risk for bleeding around the time of delivery. Evaluation by a hematologist prior to delivery is recommended. The lack of studies on the safety of eliglustat use during pregnancy and lactation has led to the recommendation that this medication be avoided during pregnancy, if possible.
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 analysis for pathogenic variants 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 p.[Asn409Ser;Asn409Ser] phenotype is variable, individuals who undergo carrier testing may be identified as being homozygous. Prenatal testing for a pregnancy at increased risk is possible using molecular genetic testing when both pathogenic variants in a family are known – or assay of glucocerebrosidase enzymatic activity if only one or neither pathogenic variant in the family is known.
Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.