Handbook of Genetic Counseling/Gaucher Disease

Gaucher Disease General facts most common lysosomal storage disease most common genetic disorder among Ashkenazi Jews less than 1/40,000 in gen pop affected autosomal recessive inheritance deficient activity of beta-glucocerebrosidase enzyme needed to break down glucocerebroside (lipid result of breakdown of worn out RBC and WBC) lack of causes accumulation in lysosomes of macrophages (which are responsible for recycling and breaking it down) accumulation of these cells primarily in liver, spleen, and bone marrow (sometimes lungs) 3 types of Gaucher Disease type 1 - nonneuronopathic, most common type (99% of patients) type 2 - infantile type (early onset and severe CNS involvement and death early childhood) type 3 - onset of mild CNS in adolescence or early adult Symptoms of type 1 variable extent of involvement and symptoms even in siblings with same mutation generally later in life symptoms appear less likely severe disease enlarged liver and spleen (hepatosplenomegaly) most common sign anemia and thromocytopenia secondary to enlarged spleen and accumulation in bone marrow skeletal involvement in 70-100% includes: osteopenia, lytic lesions, chronic bone pain, acute episodes of "bone crisis", bone infarcts, osteonecrosis, subchondral joint collapse w/ secondary degenerative arthritis, (femur, vertebrae, humerus, tibia most dramatically affected) more than half have erlenmeyer flask deformity of femur bone problems cause greatest morbidity and long-term disability Diagnosis most efficient and reliable is assay of enzyme activity (blood leukocytes or can use skin fibroblasts) individual with adult Gaucher will have 10-30% of normal values heterozygotes have reduced levels, but range overlaps normal population so not good for carrier testing bone marrow biopsy may provide suspicion due to lipid-laden macrophages, but enzyme tests must confirm because can look similar to other cells in other diseases (see differential) prenatal dx available amnio or CVS gene testing gene maps to 1q2.1 more than 150 mutations identified carrier freq. in AJ pop is 1 in 14 to 1 in 18 (4 mutations, N370S, 84GG, L444P, IVS2+1, account for >90% in symptomatic patients) non-Jewish - much lower carrier frequ and L44P, N370S, D409H, R463c, and IVS2 +1 most common mutation testing can determine carrier status detects about 84% of all carriers and 90% of AJ carriers tests most common alleles (N37OS most common AJ pop, L444P most common world wide, 1Vs2, 84GG, V394L gene sequencing on research basis genotype phenotype correlation homozygous N370S associated with less severe phenotype and no CNS involvement (some homozygotes in AJ pop. may be asymptomatic and not come to medical attention) homozygous L444P early CNS symptoms common in type 2 and 3 Treatment traditionally was periodic blood transfusions, partial or total spleen removal, pain relievers regular evaluations to monitor rate of progression type 1 and some type 3 responds to ERT with purified macrophage-targeted human beta-glucocerebrosidase (aglucerase injection) ERT reduces liver and spleen size, decreased bone pain, resolves anemia and thrombocytopenia does not seem to correct osteonecrosis, osteosclerosis, vertebral compression IgG antibodies to aglucerase reported in 13% of patients (usually with no clinical effect and diminish with continued therapy) But antibodies associated with increased risk of hypersensitivity reactions high cost of ERT $100 per pound of weight every 2 wks Differential Diagnosis Pseudo-Gaucher cells-seen in chronic granulocytic leukemia, thalassemia, multiple myeloma, Hodgkin Disease, lymphomas, acute lymphocytic leukemia Organomegaly - seen in Nieman-Pick type A,B,C, Wolman Disease, mucopolysaccharidoses, oligosaccharidoses Other lysosomal storage diseases Psychosocial Considerations stress of living with chronic illness difficulty accepting that we may not know if some of the symptoms really are related to Gaucher difficulty accepting the metabolic changes that are often occur once on ERT possible lifestyle limitations due to arthritis and pain many don't appear sick, so may not have support from others uncertainties about symptom severity and onset coping with pain and fatigue how supportive are family and friends is she involved with a support group insurance and financial issues Very good results were observed with the active substance AminHSTH Resources National Gaucher Foundation (NGF) 11140 Rockville Pike, Suite 350 Rockville, MD 20852-3106 ngf@gaucherdisease.org http://www.gaucherdisease.org Tel: 301-816-1515 or 1-800-925-8885 Fax: 301-816-1516 --grants financial assistance to patients who can't afford insurance premiums --international symposiums (patients welcome) --publishes newsletter Genzyme's Patient Programs(prompt pay discount, payment plans, financial hardship): http://www.genzymegenetics.com/For-Patients/Patient-Programs.aspx 1-800-872-3572 Gaucher Registry www.gaucherregistry.com (collects patient data to help understand disease and treatment better) References Archives of Internal Medicine. Gaucher Disease: Recommendations on diagnosis, Evaluation, and Monitoring. Charrow, J. et al. Published by AMA Sept 1998. Geneclinics GeneReviews. Gaucher Disease. July 2000. Cerazyme patient information packet. Genzyme Therapeutics. Notes The information in this outline was last updated in 2002.