# 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.