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)

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

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

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 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

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

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

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

11140 Rockville Pike, Suite 350

Rockville, MD 20852-3106

ngf@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)

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.

The information in this outline was last updated in 2002.