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Biochemistry 4463G
P Ferguson

Topic 3: Gaucher Disease - A lysosomal storage disease and a model for future therapies of some genetic disorders - Main characteristics: - Defective glucocerebrosidase gene - Autosomal-recessive transmission - Lysosomal storage disease – glucocerebrosidase substrate accumulates ~10 000 affected individuals worldwide - Multi-systemic symptoms - Progressive course - Lysosome: small, sub-cellular organelle in most cells, contains 60-80 enzymes that break down proteins - Lysosomes are very acidic (pH 4–5), degradive enzymes that do NOT float around the body - The substrate for this enzyme is ONLY found in certain tissues Non-neuropathic Neuropathic Type 1 Type 2 Type 3 - Panethnic (1/50,000) - Panethnic (1/100,000) - Panethnic (1/100,000) - Prevalent in Ashenazi Jews - Onset in infancy - Onset in infancy/childhood - Onset at any age; can be - Life expectancy is 2-3 years mild Non-neuropathic (Type 1) Acute Neuropathic (Type 2) - Symptoms: - Symptoms: - Splenomegaly (major site for enzyme) - Strabismus (poor eyes) - Hepatomegaly - Retroflexion of neck (backward arch) - Bone disease (due to marrow) - Cortical thumbs (twisted) - Thrombocytopenia (low platelets) - Visceromegaly - Anemia (spleen holds blood) - Failure to thrive (ex. inability to swallow) - Growth Retardation - Cachexia - Brusing/bleeding - Individuals tend to have an enlarged spleen - Fatigue and liver - Bone pain/crisis - Abdominal pain - Gaucher cells look “full” (glucocerebrosidase substrate) - Two phenomena tend to happen to the cell: apoptosis & inflammatory response (from material storage) - There is an accumulation of undergraded substrate = glucocerebroside Functions of Glucocerebroside - Role in neuronal growth and differentiation - The penultimate step in the catabolism of more complex glycolipids that are present in many tissues Clinical Manifestations Reflect Cellular Sites of Substrate Storage - Macrophages phagocytes formed elements of blood which have accumulated glucosylceramide - Most prominent in spleen, bone marrow, Kupffer cells and alveolar macrophages - We measure glucocerebrosidase level in leukocytes (that lack the enzyme in the diseased state) - Tissues that become the disease target are those which accumulate the substrate - β -glucocerebrosidase is constitutively expressed in most tissues - Target tissues determined by substrate distribution Manifestations of Gaucher Disease Characteristic Type 1 Type 2 Type 3 Age at onset Any Infancy Childhood Life span 6 – 80 y ~2 y 2 – 60 y Primary CNS disease - +++ +  +++ Hepatosplenomegaly +  +++ ++ +  +++ Hematologic abnormalities +  +++ +++ +  +++ Skeletal abnormalities -  +++ - -  +++ Genetic Counseling - ¼ recurrence risk at each conception for a couple who has a previous child with Gaucher disease - Prenatal diagnosis is available using either chorionic villi or amniocytes - Prenatal diagnosis by assaying β-glucocerebrosidase or DNA analysis if parental mutations are known Diagnosis Enzyme Assay - Biochemical assay of glucocerebrosidase activity in leukocytes (peripheral blood) & fibroblasts (skin biopsy) - Typical adult Gaucher patient has enzyme activity between 10%-30% of normal - Children with more severe form of Gaucher disease have >10% activity - Residual activity is NOT always a good predictor of clinical severity DNA Analysis - Mutation analysis of alleles (sequence the gene) - Reliable means of carrier testing among relatives at risk (as opposed to enzymology, which was unreliable) - Particularly important for families with neuropathic subtypes DNA Testing - Over 100 mutations have been identified in the GBA gene – only a few are prominent - In the Ashkenazi Jewish population, 5 mutations account for ~95% of mutations in that population - In non-Jewish patients there is a greater variety of mutations Mutation Frequency Percent N370S 721 57 ? (uncharacterized allele) 184 15 L4444P 173 14 84GG 96 8 IVS2 23 2 Rare allele 65 5 - There are some of the most common mutations (we’re focusing on N370S & L4444P) Genotype-Phenoty
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