Gaucher's Disease Flashcards
What is Gaucher’s disease?
Lysosomal storage disease
What are some functions of the lysosome?
Exocytosis: secretion of proteins from the ER and golgi
Exocytosis: discharge of undegraded residual material from a secondary lysosome
Endocytosis: fusion with endosome carrying contents from the extracellular environment
Phagocytosis: fusion with phagosome carrying contents from extracellular environment. Phagosomes are larger than endosomes and carry larger structures like microbes
Autophagy: degradation of cellular debris
What enzyme is defective in Gaucher’s disease and what reaction does it catalyze?
Acid B-glucosidase (glucocerebrosidase) is a lysosomal enzyme that catalyzes hydrolysis of the sphingolipid glucocerebroside (aka glucosylceramide) into glucose and ceramide.
Where does glucocerebroside come from?
Component of the plasma membrane; comes from damaged or aged cells that have been taken up by macrophages
How can an enzyme deficiency shift metabolism?
- Depletion of downstream metabolites
- Upregulation of minor pathways to consume metabolite
Describe the appearance of a Gaucher’s lysosome.
Buildup of glucosylceramide in macrophages gives macrophage containing lysosomes a “crepe paper” appearance
What cells and tissues are effected by Gaucher’s?
Abnormal macrophages accumulate in various organs:
- Bone marrow: monocytes are macrophage precursors
- Liver: Kupffer cells
- Bone: osteoclasts and osteoblasts
- Lung: alveolar macrophages (less significant)
- Spleen: tissue macrophages
What are the symptoms of Gaucher’s disease?
- Hepatomegaly
- Splenomegaly = enlarged spleen becomes overactive and begins removing healthy RBCs, platelets, etc.
- Thrombocytopenia = low platelet count causing easy bruising and excess bleeding
- Anemia = low RBCs
- Leukopenia = low WBCs
- Bone disease = Erlenmeyer flask deformity (convex instead of concave bones), avascular necrosis (bone death)
- Bone pain = chronic aching + acute excruciating pain lasting days to weeks and requiring opioid analgesics
What is the prevalence of Type I Gaucher’s disease?
- Most common type of types I-III Gaucher’s
- 1 in 40,000-60,000 in general populaiton
- 1 in 500 Ashkenazi Jews
What is the genetic pattern of transmission of Gaucher’s disease?
Autosomal recessive
When is Gaucher’s usually diagnosed?
~ 50% of cases by age 10 with ~2/3 by age 20
Varied severity of disease can lead to delayed recognition
What are the childhood symptoms of Gaucher’s and how does the disease progress?
- Growth retardation after first 1-2 years of life
- Delayed puberty
- Progressive disease: glucocerebroside continues to accumulate
What is the treatment for Gaucher’s and how effective is it?
- Enzyme replacement therapy was introduced in 1991; prior there were only symptomatic treatments
- Recombinant human enzyme (imiglucerase) is given every other week by IV
- $400,000+ annual price tag
- Dramatic improvement of hemoglobin, platelets, liver/spleen volume, bone pain, and bone crisis in first 6-12 mo followed by plateau/slight improvement
What is the purpose of the Orphan Drug Act?
- Provide an incentive for pharma to invest in drug development for rare diseases as it can cost $500mil-$1bil to bring a drug to market but rare diseases have a small market.
- Incentives include marketing exclusivity, grants and tax credits for clinical trials, and FDA fee exemptions.
What is the definition of a rare disease?
Affecting < 200,000 in the US
