Clinical characteristics: Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The characterization of three major clinical types (1, 2, and 3) and two clinical forms (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. Cardiopulmonary complications have been described with all the clinical phenotypes, although varying in frequency and severity.
Type 1 GD is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia, thrombocytopenia, lung disease, and the absence of primary central nervous system disease.
Type 2 GD is characterized by primary central nervous system disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years.
Type 3 GD is characterized by primary central nervous system disease with childhood onset, a more slowly progressive course, and 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.
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 GBA1 on molecular genetic testing.
Management: Targeted Therapy. Options include enzyme replacement therapy (ERT) or substrate reduction therapy (SRT; e.g., miglustat, eliglustat). Hematopoietic stem cell transplantation (HSCT) may be an option in individuals with severe GD, primarily those with chronic neurologic involvement (type 3 GD).
Treatment of manifestations: When possible, management by a multidisciplinary team at a Comprehensive Gaucher Center. Symptomatic treatment includes partial or total splenectomy for those with massive splenomegaly, significant areas of splenic fibrosis, and persistent significant thrombocytopenia (platelets <30,000/mm3) with a risk of bleeding; splenectomy may be needed even in those on targeted therapy. Supportive care for all affected individuals may include: Orthopedic management of bone disease; 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; transfusion of blood products for severe anemia and bleeding; 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 treatment of cholelithiasis, pulmonary disease, pulmonary hypertension, multiple myeloma, psychological manifestations, parkinsonism, and seizures according to the relevant specialist; social work support and care coordination as needed.
Surveillance: Clinical assessment of disease progression at least every six months to include hematologic, orthopedic, pulmonary, cardiac, psychiatric, and neurologic assessment; clinical assessment for abdominal pain, early satiety, evidence of bleeding diathesis, growth and weight gain, clinical disease markers, and liver enzymes; imaging for spleen and liver volumes at least every one to two years. Additional evaluations to be done as needed include X-rays, MRI, and dual-energy x-ray absorptiometry (DXA), bone age in children with growth and pubertal delay, ultrasound for gallstones, serum iron, ferritin, and vitamin B12 in those with anemia, and EKG and echocardiography with Doppler in individuals after splenectomy and those with elevated pulmonary artery pressure.
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: GD is inherited in an autosomal recessive manner. The parents of an affected individual are typically heterozygous for a GBA1 pathogenic variant; in some families, an asymptomatic parent may be found to be homozygous rather than heterozygous. If both parents are known to be heterozygous for a GBA1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial GBA1 pathogenic variants. Once the GBA1 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk family members, preimplantation genetic testing, and prenatal testing for GD are possible. The identification of 0%-15% of normal glucocerebrosidase enzyme activity in fetal samples obtained by chorionic villus sampling (CVS) or amniocentesis – ideally complemented by molecular genetic testing – can also be used to establish affected status in a fetus.
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