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Pathology Lecture 11 Hereditary Disorders 1) Know the major types of mutations and be able to give an example of each. Point Mutation (missense, nonsense) – replacement of one base pair with another creating a codon for a different amino acid (missense) or a stop codon (nonsense). Ex: Sickle cell anemia. Frameshift (deletion or insertion) – addition or removal of a number of base pairs causing the reading frame to shift and thus resulting in faulty transcoding downstream from the mutation. Ex: Tay Sachs disease. Trinucleotide repeats – excessive reproduction of the same three base pairs in sequence causing increased susceptibility to genetic disease. Ex: Fragile X syndrome (CGG) and Huntington’s Disease (CAG). 2) Know the mode of inheritance, pathological features and clinical presentation of the disorders discussed in lecture. Disorder Mode of Inheritance Familial Autosomal Hypercholesterolemia Dominant Adult Polycystic Kidney Disease Autosomal Dominant Gaucher’s disease Autosomal Recessive Tay-Sachs (GM2 gangliosidosis) Autosomal Recessive Niemann-Pick disease (Type A) Autosomal Recessive Fragile X syndrome X-linked Down Syndrome (Trisomy 21) Cytogenic Klinefelter’s Syndrome Cytogenic Turner’s Syndrome Cytogenic Pathological Features Clinical Presentation Mutations in chromosome 19 (35 identified) for the cell surface receptor for LDL removal. Hundreds of cysts form all over the nephron. Three different mutations exist. Increased plasma LDL accumulating to form arterial plaques and lipid laden macrophages (xanthomas). Chronic pain, hypertension, and bilateral enlargement of the kidneys. Other organs may be involved. Splenomegaly (anemia, leucopenia, thrombocytopenia), Bone involvement (pain and fractures) Motor and mental deterioration. “Cherry red spot” on macula, vision impairment and blindness. Death occurs at 2-3 years. Mutation of gene encoding β-glucosidase. Phagocytic cells accumulate large sums of glucocerebrosides. Mutation of α-subunit of hexosaminidase A gene. GM2 ganglioside accumulates in all organs (mostly neurons and retina) Mutation of gene for Loss of motor and mental sphingomyelinase. Foam function. Progressive wasting cell formation in spleen, and death by age 3. (Type B is lymph nodes, bone marrow, less severe with no CNS GI tract and lungs. involvement – live to adulthood) Long repeating sequence of Leading cause of familial mental trinucleotides (CGG) on the retardation. Constriction in the X chromosome. long arm of X chromosome. Progressive MR, flat face and occiput, reduced interpupillary distance, epicanthal folds, brushfield spots, small stature, “Simian crease”, increased risk of Leukemia, heart defects, heart disease, and Alzheimer’s disease. 47, XXY – Tall stature thin build, no masculinization at puberty, feminine characteristics predominate (high voice, gynecomastia), and Azoospermia (infertility). 45, X – Primary amenorrhea and sterility, short stature, neck webbing, wide carrying angle of arms, broad chest, cardiovascular abnormalities, oocyte degredation (none by 2yr), and ovaries are converted to fibrous streaks (uterus+ normal) 3) Be able to identify the major chromosome abnormalities secondary to alterations in chromosome structure and/or number. Alterations in Chromosome structure include: Deletions, Duplications, Inversions, and Translocations, which result from chromosome breakage followed by loss or rearrangement of material. Alterations in Chromosome number include: Polyploidy – more than two complete chromosome sets, usually resulting in spontaneous abortion. Trisomy – three repeats of a chromosome. Most result in spontaneous abortions but trisomies of chromosomes 13, 18, 21, X, and Y do occur with appreciable frequency. Monosomies – most are nonviable, except Turner’s syndrome (45, X).