Gaucher Disease

Clinical characteristicsGaucher 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/testingThe 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.ManagementTargeted therapy: Options include enzyme replacement therapy (ERT) or substrate reduction therapy (SRT; e.g., miglustat, eliglustat). Hematopoietic stem cell transplantation may be an option in individuals with severe GD, primarily those with chronic neurologic involvement (type 3 GD). Supportive care: When possible, management by a multidisciplinary team at a GD Comprehensive Treatment Center. Symptomatic treatment includes partial or total splenectomy for those with massive splenomegaly, significant areas of splenic fibrosis, and persistent significant thrombocytopenia (platelets Genetic counselingGD 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.