*Any chromosomal disorder not on the sex genes.
*Single phenotype caused by any number of genetic variations
^Why are enzymatic mutations more impacted by recessive genes?
*Both chromosomes are affected. The other chromosome cannot compensate for loss of enzyme function.
^Why are regulatory systems more prone to dominant genes?
*The dominant gene usually presents with a negative effect. Mixing 1 part toxin with 1 part water. The toxin will dominate your response as you die.
*Many genes contribute to the overall condition of disease.
^Clinical presentations of Turner's Syndrome
*No development of secondary sex characteristics, amenorrhea (menopause before menarche), and webbed neck. Distended lymph vessels also causes edema and congenital heart failure.
*Autosomal recessive genetic mutation in the noncoding region that affects alpha/beta subunit synthesis. Consequently gamma subunit is produced, builds up in RBCs and kills them.
^Thallacemia Clinical Symptoms
*Anemia due to decreased Hgb function.
*Hydrops fetalis. Severe anemia results in hypoxia. Hypoxia damages the liver. The liver doesn't produce albumin and presents edema.
*Anemia induces release of erythropoetiin in thalassemia. Erythropoietin causes bone marrow to expand to compensate for decreased RBC function.
^Why is Autosomal Polycystic Kidney Disease dominant?
*The mutation is in PKD1 and PKD2 for genes that produce polycystin 1 and 2 proteins. This protein is a signaling protein in the tubules that signals pressure levels. Mutations result in fluid accumulation and development of fluid filled cysts later in life.
^What condition is related to development of berry aneurisms?
*Autosomal Polycystic Kidney Disease. 10-30% of patients get this in the cerebral Circle of Willis.
*Autosomal Polycystic Kidney Disease.
^Hurler's Syndrome Enzyme Deficiency
*alpha-1-iduronidase. Deficiency results in mucopolysaccharide accumulation in cells because it cannot be metabolized.
^How is accumulation of mucopolysaccharides pleiotropic?
*Its accumulation leads to widespread problems in all organ systems. Skeletal and gross morphologic deformities are prominent.
^Why is a cherry red spot prominent in lysosomal disorders?
*Lysosomes fill up with indigestible substance and turn pale. Vessels around them look more red.
^What are the mucopolysaccharidosis metabolites and where do they accumulate?
*Heparin sulfate and dermatan sulfate. They accumulate in the subendothelial cell lysosomes of arteries in the CNS or heart.
^Clinical features of mucopolysaccharidosis.
*Hepatosplenomegaly, coarse facial features, skeletal deformities, lesions in the brain and valvular lesions.
^Tay-Sachs enzyme deficiency, metabolite accumulate and target tissue
*Enzyme = alpha-hexosaminidase, Accumulate = gangliosides, Target tissue = neurons
^Tay-Sachs clinical manifestations
*Motor and mental deterioration = flaccidity, blindness, dementia and death by age 2-3.
^Niemann-Pick A and B enzyme deficiency, metabolite accumulate and target tissue
*Enzyme = sphingomyelinase, Accumulate = sphingomyelin, Type A = CNS, Type B = All other organs
^Niemann-Pick A & B clinical manifestations
*Infant with hepatosplenomegaly, lymphadenopathy, bone marrow infiltrate, psychomotor deterioration, failure to thrive, vomiting and fever. Cherry red spot and death by 3 years old.
^Niemann-Pick C mutation, accumulate and symptoms
*Mutation = NPC1 and NPC 2 receptors, Accumulate = cholesterol inside lysosomes, Symptoms = ataxia, dystonia and psychomotor regression
^Gaucher enzyme deficiency, accumulate and target tissue
*Enzyme = glucocerebrosidase, Accumulate = glucocerebrosides, Target tissue = spleen and bone marrow
^Gaucher clinical manifestations
*Bones that break easily due to bone erosion by macrophage activity. Hypersplenism. Pancytopenia. Thrombocytopenia.
*Alcian blue stain of mucopolysaccharides.
*Cytoplasmic clearing typical of lysosomal storage disorders.
*Alder-Reilly anomaly. Mucopolysaccharides stain a deep granular purple in blood leukocytes.
^How is hypercholesterolemia developed genetically?
*Mutations in LDL receptors in hepatocytes increase the amount of LDL circulating in the plasma. When both genes are defective, disease manifestation worsens.
*Cholesterol-filled macrophages accumulating under the skin in xanthoma.
Xanthoma. Cholesterol accumulation under the skin.
^Down's Syndrome Clinical Manifestations
*Clinodactyly of 5th finger, Simeon creases, Epicanthal folds, Slanted palpebral fissures, intestinal atresia
^Why do patients with down syndrome have higher incidence of Alzheimer's and leukemia?
*Genes coding for amyloid precursor protein and leukemia are on chromosome 21. This is due to over expression of these genes.
^How does intracellular cholesterol affect the cell?
*Inhibits HMG CoA Reductase = inhibition of cellular cholesterol production, Activates acyl CoA = activates cholesterol storage, Decreases LDL receptor production
^Glycogen storage disease categories. What enzyme is deficient? What accumulates where? What clinical manifestations are present?
*Hepatic: deficient in glucose-6-phosphatase. Glycogen accumulates in hepatic cells and in kidney. Hypoglycemia, gout, high cholesterol. Myopathic: deficient in muscle phosphatase. No lactate ever accumulates in muscles. Intense pain when exercising. High CPK. Miscellaneous: deficient in alpha-glucosidase. Glycogen accumulates under sarcolemma membrane. Cardiac disease & cardiomegaly.
^LDL receptor mutations
^How does the liver play a central role in cholesterol metabolism?
^Trisomy 21 Clinical Presentations
^Trisomy 18 Clinical Presentations
^Trisomy 13 Clinical Presentations
^Why do Klinefelter patients exhibit decreased masculinity?
*They have two X chromosomes. The X chromosome codes for the androgen receptor. Androgen response is amplified with shorter CAG repeats, but in Klinefelter's the X chromosome with shorter CAG repeats is inactivated.
*FSH is elevated, atrophied testis, gynecomastia, infertility and female hair distribution. These patients have 20x greater risk of breast cancer.
*Deficiency in homgenistic oxidase. Inability to metabolize Phe or Tyr. Ochronosis (black pigmenting) in collagen from excess homogenistic acid.
^Fragile X Syndrome
*Excessive trinucleotide repeats of G and C in the FMR gene coding for the FMR protein. Results in male retardation and huge balls. Gets worse with generations due to extension of trinucleotide repeats.
^How can mother and father genetic imprinting contribute to different diseases on chromosome 15?
*A paternal deletion of the gene results in Angelman Syndrome. A maternal deletion of the gene results in Prader-Willi Syndrome. Both syndromes result in slight variations in mental retardation.