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)