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
- 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.