Final+Exam+Review

Tay Sachs Disease: -p22 Unit 1 -p94 Unit 2 -Lysosomal Storage Disease -Hexosamindase A deficiency -GM2 Ganglioside buildup -Autosomal Recessive -Northeast European Jewish ancestry -early neurologic deterioration, blindness, deafness, paralysis, death by 3 -lipid filled lysosomes in neurons (swollen) Defect in B-N-acetylhexosaminadase Gangliosides that end with GalNAc (GM2) cannot be degraded

Kartageners syndrome: -p23 Unit 1 (also p181) -Lack of dyniein in cilia and flagella -Lark of arms of the doubled microtubles -Immotile cilia and flagella with male sterility and chronic respiratory infection

Hurler’s Disease: -p23 Unit 1 -Lack of lysosomal alpha L iduronidase -accumulation of dermatan sulfate in tissues -growth and mental retardation

Proinsulin diabetes: -p23 Unit 1 -defect of proinsulin cleaving enzyme high blood proinsulin content (diabetes)

I cell disease: -p23 Unit 1 -Phosphotransferase deficiency -Inclusion particle storage in fibroblasts -Psychomotor retardation, bone abnormalities -golgi involved

Aquired Hemolytic Anemia -p95 Unit 1 -somatic mutation leading to PIGA defect or protein being unable to anchor (GPI) into the membrane -CD59 for example cant bind to surface so leads to hemolysis anemia and thrombosis

Hereditary Spherocytosis: -p105 Unit 1 -Autosomal Dominant -Affect spectrin (allows RBC to deform), ankyrin or other -weakened interaction of peripheral and integral membrane proteins. Cytoskeletal architecture altered -destruction in spleen

Cardiotonic Steroid Drugs: -p124 Unit 1 -ouabain inhibits action of Na/K Atpase -leads to increased sodium in cardiac myocytes. This leads to increased calcium in cell via the sodium/calcium transporter. -increase contraction strength of heart muscle for more effective action

ABC pumps in Failure of Cancer Chemotherapy -p 126 Unit 1 -Mdr1 gene is frequently amplified in multidrug resistant cells -leads to failure of chemotherapy and decreased survival in liver cancer -they work by pumping the drug out of the cell.

Cystic fibrosis: -p127 Unit 1 -autosomal recessive disease of the bodys mucus glands -affects the respiratory and digestive systems. Patients live average of 30 yrs -most common mutation is 3bp deletion of f508 -the mutated protein fails to reache surface -CFTR pumps chloride out of cell -It is activated by increased intracellular cAMP -Results in thick dehydrated mucus

Phemphigus vulgaris -p184 Unit 1 -Autoimmune disease -antibodies to cadherin desmglein -patient desmosomes are destroyed, particularly in the skin -causes severe blistering due to water loss -infections that are life threatening

CO poisoning: -p232 Unit1 -CO binds to O2 site reversibly -CO affinity/o2 affinity = 200 -CO inhibits O2 delivery -toxicity is a consequence of the higher affinity for O2 of the CO ligated hemoglobin which cannot efficiently release O2 in peripheral tissues.

Sickle Cell: -p235 Unit 1 -Mutation from Glu to Val -Frequent in areas where malaria is common -more prevalent in African Americans -altered conformation causes polymer formation and aggregation of deoxy form -cells assume a contorted shape at low oxygen tension -reversible sickling-cells assume their normal shape as hemoglobin S disaggregates and is oxygenated. -Irreversible sickling-when cells have been in a sickled state for a long time interval their shape remains contorted, even after the hemoglobin polymers disaggregate, due to changes in the cytoskeleton associated with the red cell membrane. This result in part from covalent disulfide cross linking of actin. -the sickle cells occlude small blood vessels resulting in serious organ damage. HbS deoxygenation ---à HbS aggregation --à RBC sickling---àIrreversible Sickling--àDeath Hypercellular obesity P246 Unit 1 -Increased number of fat cells -Usually due to overfeeding as infant -this is most serious of two conditions

Hypertropic obesity -p246 Unit 1 -Increased size (more lipid) of same number of fat cells -most common

Scurvy: -p250 Unit 1 -caused by lack of Vitamin C -Vitamin C is cofator required for hydroxylation of proline (in collagen formation)

Ehlers-Danlos, Type VII -p250 Unit 1 -Due to procollagen peptidase change -hyperflexible joints, dislocations, soft skin -procollagen peptidase cleaves procollagen to form tropocollagen molecules outside of the cell membrane which in turn forms collagen fibril in extracellular matrix

Ehlers-Danlos, Type IV -p251 Unit 1 -due to deficiency in type III collagen -Aneurysms and intestinal rupture common -type III is associated with reticular fibers (delicate support)

Marfans Syndrome -p252 Unit 1 -poor microfibril formation in elastic fiber -tendency to rupture aorta and other blood vessels

Edema -p256 Unit 1 -is abnormal build up of interstitial fluid in ECM -causes pitting edema -causes of: -blocked lymphatics –surgery, elephantiasis -liver disease – insufficient albumin (produced by liver) to pull H20 back in vessel

Myxedema -p257 Unit 1 -due to over production of GAGs during hypothyroidism

Retinoblastoma -p286 Unit 1 -RB gene located on chromosome 13 and is caused by defects in both copies of the gene -a mutation in RB may be inherited, and the second copy may be lost by a somatic muation -RB is need for the cycle to go from G1 to S phase. RB is bound to E2F, a transcription factor. When RB is phosphorylated it releases the transcription factor allowing it to bind and allowing the cell to proceed with gene transcription -The mutation causes the RB protein product to be hyperphosphorylated which leaves the transcription factor on and without regulation so there is no stop to the cell cycle.

Glanzmann’s Disease -p293 Unit 1 -lack of Beta3 integrin causing excessive bleeding due to lack of clotting -Integrin on platelets once activated can bind to fibrinogen and participate in clotting

Troponins as a marker for acute MI and heart disease -p340 Unit 1 -troponin are components of contractile appartatus of muscle that regulate contraction TnT and TnI are isoforms specific for cardiac, skeletal and smooth muscle -TnC same isoform in all tissues -TnT and TnI cardiac isoforms are used as markers for damage to cardiac muscle (by measurement of enzyme level and activity)

Muscular Dystrophy: -p127 Unit2 -genetic disorder characterized by chronic progressive muscle loss -x linked recessive mutation in the gene coding for protein dystrophin -leads to rupture of cell membrane during repeated contraction and profound muscle cell loss -death results from cumulative damage to cardiac and respiratory muscle cells

Myasthenia Gravis: -p127 Unit 2 -autoimmune disorder characterized by chronic progressive muscle weakness -results from the production of antibodies that block acetylcholine receptors at the neuromuscular junction -total Ach receptors decline and muscle excitation/contraction is reduced. Muscle appear weak and fatigue easily -treated with AchE Blockers

Osteoarthritis: -p39 Unit 2 -Degenerative arthritis- affects synovial joints -most common type of arthritis -non inflammatory and progressive deterioration of articular cartilage -Characterized by: -fibrillation of articular cartilage -loss of ground substance and retention of fibers -proliferation of cartilage at periphery -replacement of cartilage spur with bone tissue to form bone spurs which reduce degree of movement

Rheumatoid Arthritis: P39 Unit 2 -inflammatory autoimmune disease -body attacks own join cartilage and synovial membrane -synovial membrane thickens and synovial fluid secretion increases -pressure due to increased amounts of synovial fluid causes pain and tenderness -pannus of tissue forms across cartilage and erodes away cartilage -bone exposed and eventually fuses across joint

Cumadin: P48 Unit 2 -a drug used for anticoagulation therapy -it prevents clotting by interfering with carboxylation of glutamic acid -this has the side effect of interfering with the synthesis of osteocalcin -that prevents Ca+ deposition ( involved in calcification or mineralization process of bone) -in long term warfin therapy the patient can get severe bone disorders

=THINGS THAT EFFECT THE EPIPHYSEAL PLATE=

Sex hormones P77 Unit 2 -androgens and estrogen stimulate bone formation -this accelerates the closure of epiphyseal plate

Growth hormone (somatotropin) P78 Unit 2 -this is secreted by anterior pituitary gland and stimulates bone formation at epi plate -gigantism results if there is an excess of GH in a growing child -Pituitary dwarfism results if thereis a deficiency of GH in a child -Acromegaly results if there is an excess of GH in adults -this is characterized by thickening of bones, especially facial bones by the eyebrows and enlargement of hands and feet.

Vitamin A P78 Unit 2 -this normally acts to balance bone deposition with bone degradation, i.e. remodeling -it coordinates the activity between osteoblasts and osteoclasts -If there is excess vitamin A, there is rapid erosion of cartilage resulting in premature closure of the epiphyseal plate -again this would result in dwarfism -If there is a deficiency, there would be a decrease in the growth rate. -this would lead to a lack of bone resorption during normal remodeling. Bone growth would not keep up with growth rate of rest of body and the cranial cavity and spinal column would fail to enlarge fast enough to accommodate the growing brain and spinal cord.

Vitamin D: P78 Unit 2 -controls the normal absorption of Ca from the gut -Rickets is cuased by a deficiency in children -Due to lack of Ca there is no mineralization of the cartilate in the epiphyseal plate and bone osteoid -Bone lacks structural strength and bend due to an enlarged zone of calcification -this is characterized by bow legs -Osteomalacia (adult rickets) -is due to deficiency of Ca in adults -during remodeling, the newly formed bone (osteons) does not calcify sufficiently -as a result the bones are greatly weakened and easily break -this may also be seen during pregnancy when the mother is supplying calcium to the growing fetus

Vitamin C: P78 Unit 2 -Scurvy is a deficiency of vitamin C in adults -cofactor for hydroxylation of proline -the lack of hydrogen bonding between the hydroxyproline of adjacent alpha chains result in weak tropocollagen -as a result the collagen in the bone matrix is weak and strong osteoid is not formed -the bone is weak due to thinner cortical bone -growth and repair of fractures are also retarded

Age related bone loss: P79 unit 2 -normally there is a loss of bone from all parts of skeleton with aging -this is due to the rate of bone resorption in remodeling remaining unchanged while the rate of bone deposition decreases. -the result is the thinning of cortical bone and loss of trabecula throughout the bone mass

Osteoporosis: P79 unit 2 -is severe bone loss of bone mass with aging -the reduction of bone mass of the skeleton is so great that it is no longer able to maintain mechanical support -it afflicts 25% of all postmenopausal women -this disease is characterized by fractures, backaches, and vertebral deformities

MCAD: P12 unit 2 -catabolism (beta oxidation) of medium chain fatty acids (6-12) is deficient due to a defect in the medium chain acyl CoA dehydrogenase -characterized by: -1/23000 births -onset of symptoms usually within the first two years -precipitated by fasting >>12 hour or infection -may include vomiting, lethargy, coma, hypoglycemia -urine contains MCFA esters and glycine and carnitine -can cause long term disability or fatality if not treated -treatment with iv glucose, high carb diet, avoid fasting

Zellweger Syndrome: P26 Unit 2 -rare hereditary disorder affecting infants -problems in prenatal development, enlarged liver, high levels of iron and copper in the blood, muscle and vision abnormalities. Death by 6. -Mutation in PXR1 gene product – a receptor found on the surface of peroxisomes -The PXPR1 receptor is vital for the import of enzymes into the peroxisomes

Diabetes: P134 Unit 2 Type I (juvenile) -Insulin is not produced by the pancreas -glucose utilization and all other insulin dependent functions are affected

Type II (adult onset) -Insulin is produced but effects of insulin on glucose transport/utilization are impaired -glucose accumulates in blood, stimulating pancreas to produce more insulin. (other insulin dependent functions preserved) -eventually, pancreas becomes resistant to glucose and stops responding to insulin.

· New concept: fat loaded adipocytes release unique proteins that cause insulin resistance

Ketogenesis during fasting or diabetes: P148 Unit 2 -fatty acids released from adipocytes -hormone sensitive lipase is activated (increase in glucagons) -fatty acids converted to acetyl coA in liver -low insulin results in low malonyl CoA, more FA oxidation (malonyl CoA inhibits carnitine acyl transferase) -excess acetyl-CoA diverted to acetoacetate because low oxalacetate (OAA) limits TCA cycle in liver -Ketone bodies are released into the blood for export to tissues that can use them

Deficiency of Vitamin B1: P168 Unit 2 -lead to disturbances in carbohydrate metabolism and to decreased transketolase activity, particularly in erythrocytes and leukocytes. Clinically, deficiency can lead to cardiovascular and neurologic lesions, as well as to emotional disturbances.

a) Dry Beriberi develops when the diet chronically contains slightly less thiamine than required. Symptoms include peripheral neuropathy, fatigue, and impaired capacity to work. b) Wet Beriberi develops with a sever deficiency. In addition to neurologic manifestations, cardiovascular symptoms are more apparent, including heart enlargement and tachycardia. Cardiac failure is common after stress, and edema and anorexia are characteristic, as well c) Wernike-Korsakoff syndrome a. Results from chronic thiamine deficiency b. Patients with this disorder have been shown to have defective transketolase that exhibits a reduced affinity for TPP. Thus in a thiamine deficient condition, transketolase activity in these individuals is reduced c. This condition is sometimes seen in patients with chronic alcoholism because of their poor nutrition coupled with impaired absorption of the vitamin d. Clinical manifestations of the syndrome include weakness or paralysis and impaired mental function

Gaucher’s Disease: -p194 Unit 2 -Three types. Type 1 is the most common -Easy bruising, fatigue due to anemia, enlargement of liver and spleen, weakness of skeleton, occasionally lung and kidney impairment. -onset may be early childhood to late adulthood -tissues accomadate glucocerbroside, due to deficiency of glucocerebrosidase (B-glucosidase) -types 2 and 3 are rare. Type 2 is most severe –early onset with extensive brain damage -some success with IV enzyme replacement therapy in type 1 (ceredase; cerzyme)

Niemann Pick Disease: P195 Unit 2 -enlarged liver and spleen, mental retardation, anemia, neurological and physical deterioration -onset during early infancy, death before age 3 autosomal recessive -sphingomyelin accumulates in neurons and foamy reticuloendothelial cells in liver, spleen, bone marrow and other tissues. -due to a deficiency of sphinomyelinase -Cer-P-Choline

Aspirin -p200 Unit 2 -permanently modifies and inactivates cyclooxygenase by acetylation of Ser -Inhibits formation of prostaglandins that mediate inflammation and fever -Inhibits formation of TXA2, a stimulator of platelet aggregation

Ibuprofen P201 Unit2 -blocks the hydrophobic channel where arachidonate enters the active site of cyclooxygenase -inhibits formation of prostaglandins that mediate inflammation and fever -inhibits formation of TXA2, a stimulator of platelet aggregation

Acetaminophen P201 Unit2 -also inhibits prostaglandin H2 synthase (cyclooxygenase), but does so reversibly -exact mechanism unknown -acts mainly centrally – not in peripheral tissues. Can reduce fever and raise pain threshold, but lacks peripheral anti inflammatory and anti clotting effects of aspirin and ibuprofen


 * Begin Part 2:**

Electron Transport Inhibitor Rotenone- electron transport from Site I to CoQ Actinomycin- cytochrom b --à c blocker (0.5 ATP) Cyanide- cytochrome oxidase blocker -p29 Unit 3

Oxidative Phoshorylation Uncoupler: -2,4 Dinitrophenol –weight loss drug -Dicumarol- used as anticoagulant -Fatty acids in brown adipose tissue -Uncoupling Protein (B33)

Clinical Manifestations of Mitochondrial Diseases: P49 Unit3 -Kearns, Pearsons, Leber -muscle cramping, weakness, fatigue, lactic acidosis, CNS dysfunction, and vision problems -Treatment for patients with electron transport disorders are difficult but there has been improvement with substances that may mediate electron transfer, such as ubiquinone and Vit. C

Diabetes test using hemoglobin Aic: P112 Unit 3 -glucose reacts non enzymatically with hemoglobin to yield Aic. The concentration HbAic depends on the glucose levels in the blood. This is a useful measurement for diabetic patients as it indicates how well blood glucose levels can be controlled over time.

Lactic Acidosis: -p145 Unit 3 -blood lactate levels can rise substantially over normal -high concentration of lactate leads to decreased pH and bicarbonate levels -can result from increased formation or decreased utilization of lactate -Lack of ATP -hypoxia or lack of oxygen is a common cause of high blood lactate levels -shortage of oxygen reduces mitochondrial production of ATP with consequent activation of PFK, which increases glycolysis and lacate production -tissue hypoxia may occur in conditions that impair blood flow (eg shock) in respiratory disorders, and severe anemia

Excess Alcohol: P152 Unit 3 -takes place in liver and converts ethanol into fatty acids. In the process, it depletes the NAD+ levels needed for fatty acid oxidation, TCA cycle, and oxidation of pyruvate to acetyl CoA -inhibits gluconeogenesis after vigorous exercise and after prolonged fast via depletion of NAD+ -can lead to hypoglycemia and lactic acidosis

-antabuse used for treatment of alcohol abusers. Inhibits acetaldeyhyde dehydrogenase (an enzyme involved in conversion of acetaldehyde to acetic acid. Leads to build up of acetaldehyde (toxic) making patients very ill.

Fructose Metabolism: (mainly in liver by fructokinase) P240 Unit 3 -Hereditary Fructose intolerance -absence of phosphofructoaldolase B -can cause hepatic failure (avoid fructose in diet) -the enzyme is used for conversion of fructose-1-P to D-glyceraldehyde -Fructose Uria -lack of fructokinase leading to buildup of fructose (benign) Galactosemia: -p243 Unit3 -absense of galactose-1-phosphate uridyl transferase -autosomal recessive -vomiting, diarrhea following milk intake -Inlarged liver and jaundice are common -mental retardation -remove galactose from diet -damage caused by accumulation of toxic substance galacitol which is formed by reduction of galactose. Leads to cataracts. -this enzyme converts Gal-1-P to UDP-gal. Without it; there is a build up of galactose and gal-1-p

Uronic Acid Pathway: P246 Unit 3 -production for glucoronides are important for use as a detoxifying agent -ex: UDP-glucornic acid + ROH (foreign alcohol) = R-O-glucuronide + UDP

Biotin Deficiency: P296 Unit 3 -biotin acts as coenzyme for carboxylation reactions where it is a carrier of carbon dioxide. -found in liver and eggs. Also synthesized by intestinal microorganisms -multiple carboxylase deficiency -either by biotin deficiency or defect in biotin holocarboxylase synthetase -seborrheic dermatitis, anorexia, nausea, and muscular pain

Diabetes: (regulation of gluconeogenesis and glycolysis) P298 Unit 3 -increased gluconeogeneis, lipolysis, glycogenlysis -glycolysis is decreased

Glycogen Storage Disease: P339 Unit 3 -von Gierkes -glucose 6 phosphatase is defective -glucose 1 P which is result of breakdown of glucose is then converted to Glucose 6 P and then to glucose using the enzyme above. Without it; glycogen cannot be broken down effectively to make glucose. -Andersons -branching enzyme is defective and the glycogen is abnormally long and unbranched

-McArdles Disease -muscle glycogen phosphorylase is defective, leading to excessive glycogen deposition in muscle

Urea Cycle Disorders: P71 Unit 3 -any of the 6 enzymes in the urea cycle -most severe at first reaction -once get to citrulline level some covalent linkage of NH3 to carbon as occurred-symptoms lesson -1/25,000 births - (birth) convulsions, ataxia, lethargic, vomiting, poor feeding, eventually coma -(late onset) hyperactivity, enlarged liver, avoidence of high protein foods -Characteristics -ammonia accumulates in blood (intoxication) -brain damage, coma, death, lack of ATP -Neural defects: in the brain ammonia is made into glutamate which depletes the brain of alpha ketoglutarate causing OAA levels to fall and TCA cycle to stop resulting in permanent cell damage -Increased glutamate leads to glutamine formation which depletes glutamate stores needed for GABA production

Type 1 Hyperammoniemia CPS 1 Deficiency -ammonia intoxication, high NH4 in blood, mental retardation -treatment is arginine which stimulates residual CPS

N-acetylglutamate synthetase deficiency -mental retardation -treat with carbamoyl glutamate (analog of Nacetylglutamate) -activates carbamoyl phosphate synthetase

Type 2 Hyperammonemia OTC deficiency -most common -ammonia and aa in blood and increased orotic acid glutamin high in glood, CSF and urine -X linked -Treatment is high carbs, low protein diet-administer benzoic acid or phenyacetate for ammonia detoxification

Argininosuccinate synthease deficiency -Cintrullinemia: citrullin and ammonia high in plasma, CSF and urine -Recessive inheritance -treatment with arginine-enhances citrulline excretion, benzoate diverts ammonium nitrogen to other products.

Arginosuccinic aciduria -Arginosuccinase deficiency -ammonia and arginosuccinate high in plasma, CSF and urine -recessive inheritance -early and late onset (2yrs)-usually fatal -treat with arginine and benzoate promotes nitrogin excretion

Hyperargininemia -Arginase deficiency -rare abnormal development and CNS function, ammonia and arginine accumulate in blood and CSF. Arg, Lys and Orn in urine. -treat with diet of essential aa without arginine, and low protein diets

Cystinuria P83 Unit3 -excretion of cystine is increased 20-30X normal -excretion of Lys, Arg and Ornithine is also increased -renal defect in absorption of these four aa rather than enzyme deficiency -cystine is relatively insoluble and thus patients develop precipitates in kidney tubules of cystine calculi Cystinosis P83 Unit 3 -results from a defect in carrier mediated cysteine transfer. -deposition of cystein crystals in tissues results in early mortality from acute renal failure

PKU P85 Unit 3 -enzyme that converts phenylalanine into tyrosine (phen. Hydroxylase) -also called hyperphenylalanemia I -recessive disorder -excess Phe allows for alternate catabolites of Phe to form, these causing mental retardation in children -one of these, phenylpyruvate reacts with ferric chloride giving a black color

Type II tyrosinemia or neonatal tyrosinemia P86 Unit 3 -defective tyrosine transaminase or hydroxyphenylpyruvate hydroxylase -enzymes involved in the eventual conversion of tyrosine into acetoacetate and fumarate

Alkaptonuria P86 Unit 3 -also in step of tyrosine breakdown -homogentisate oxidase is defective -excess homogentisate in urine (turn black if made alkaline and exposed to O2) -Vitamin C needed for maximum efficiency of this enzyme so Vit C deficiency can lead to this as well

Maple Syrup Disease P87 Unit 3 -Valine, leucine, isoleucine -branched chain amino acid dehydrogenase is defective (decarboxylation) -leads to buildup of branched chain ketoacids -side note: leucine metabolism leads to production of HMG-CoA (cholesterol biosyn)

Hartnups Disease -p88 Unit 3 -defect in intestinal and renal transport of trp and other neutral amino acids

Cancer in Signal Transduction: P194 Unit 3 -protooncogenes conversion to oncogenes (deregulated proteins) -in about 30% of human cancers, Ras is mutated so that it is permanently on and cells grow without proper signal -chronic myeloid leukemia is a cancer of blood cells, characterized by invasion of bone marrow with malignant leukemic cells. Lesion is consititutively activated tyr kinase -about 90% of human pancreatic carcinomas show loss of part of chromosome 18. DPC4 (smad4) is deleted. No TGF-B signaling which is potent regulator of cell cycle

-treatments -receptor antagonist: tamoxifen (estrogen) -receptor inhibitor: beta blockers -Ras inhibitor (block binding)

Erythropoietin (EPO) (drive RBC production) P201 Unit 3 Important for patients with blood disorders with decreased RBC production -end stage kidney disease -HIV patients using RT inhibitors -Cancer patients on some chemotherapy -Following surgery

Glucose 6 Phosphate Dehydrogenase Deficiency P211 Unit 3 -for PPP pathway and production of NADPH for RBC and dealing with Oxidative damage -x linked disorder -patients are more sensitive to oxidative stress -neonatal jaundice (neurological damage can result); acute hemolytic anemia

Hereditary Spherocytosis: P223 Unit 3 -protein interaction with Band 3 -causes vertical release of cytoskeleton giving the RBC a spherical shape

Hereditary elliptocytosis, pyrophoikilocytosis: P225 Unit 3 -defects in spectrin that affect interaction within the spectrin tetramer(alpha and beta sub) -causes lateral release or change in shape giving an elliptical shape

Indicators of Iron Deficiency: -p264 Unit 3

-hemoglobin -mean corpuscular volume -both are late indicators

-total iron binding capacity -serum ferritin (small amount released from tissue) -more sensitive to early stage

shaped appearance
 * person complains of fatigue, weakness and anorexia; fingernails have a thin and flat spoon
 * Increased susceptibility to infection as result of impaired cellular immunity

Genetic Hemochromatosis: P277 Unit3 -excessive absorption of iron due to faulty regulation of iron transport -defect in (cys260Tyr) in a 343 residue membrane glycoprotein (HFE) -regulates affinity of transferring receptor for transferring -cardiomyopathy, liver cirrhosis, diabetes, and arthropathies -half of individuals who are homozygous are asymptomatic -treatable by phlembotomy

Aceruloplasminemia P278 Unit3 -Absense of ceruloplasmin-is a copper ferroxidase that facilitates iron release from cells -accumulation of iron in spleen, heart, liver, kidney, thyroid, and retina with accompanying tissue damage -liver iron overload, diabetes mellitus due to destruction of beta cells of the pancreas and nerve damage

Lead Poisoning (hemoglobin production): P312 Unit 3 -lead inactivates ALA dehydratase; ALA appears in urine -lead inhibits protoporphyrinogen oxidase leading to accumulation of free protoporphyrinogen IX and Zn protophorphyrin IX (Zn in place of iron) -ferrochetalase is inhibited by lead -interferes with iron transport into mitochondria -other heavy metals (Hg, As) are also offenders.

Porphyrias: P312 Unit 3

Aquired: -alcholism, pesticides, herbicides, tumor, iron overload

Genetic: -involved defects in specific steps in heme synthesis and build up of product of previous step -photosensitivity due to accumulation of byproducst in skin -hair growth -accumulation of porphyrins in rune (red) -acute intermitten porphyria (AIP) is most common -porphobilinogen deaminase

Jaundice: P10 Unit 3 (extra handout from dignam) -juandice is excessive bilrubin in blood – yellow tinit in skin and can lead to neurotoxic effects -kernicterus: -athetoid cerebral palsy -severe motor delay -dysarthria -sensoneuronal hearing loss -mental retardation

Hemolytic Jaundice -excessive destruction of RBC and release of HB whose heme is converted to bilirubin -liver is overloaded

Neonatal Jaundice -low UDP-glucuronosyl transferase activity -blood group incompatibility -glucose 6 phosphate dehydrogenase deficiency

treatment: phototherapy, transfusion, tin-protoporphyrin IX –inhibit heme oxygenase

Hepatocellular Jaundice -seen in liver damage in hepatitis or cirrhosis -unconjugated bilirubin is elevated due to reduced uptake of bilirubin -some bilirubin glucuronide released from liver due to cellular damage

Obstructive Juandice -interference with delivery of bilirubin glucuronide to intestine -total bilirubin, mostly bilirubin glucuronide increases and seen in urine

Bilirubin Metabolism Disorder: P12 Unit 3 (dignam handout)

Gilberts syndrome -reduced levels of UDP glucuronosyl transferase, the rate limiting enzyme for bilirubin glucuronide production. -mild

Crigler Najjar Syndrome -rare recessive -moderate (type II) or severe (type 1) jaundice due to reduced or absent glucuronosyl transferase activity -Type one may require liver transplantation. Kernicterus is seen in type one

P341 Unit 3

Vitamin Deficiency Related Diet Current Problem Enriched/Fortified Thiamine (B1) Beriberi Refined grain Alcoholic malnutri In flour Riboflavin (B2) (rare) oral lesions Maramus No In flour Niacin Pellagra Maize No In flour Pyridoxine (B6) (rare) neuritis, malaise Low whole grain Low vegetables Low blood B6 in 20% of oral contra No Biotin Virtually nonsexist Excessive egg whites No No Pantothenic acid No None No No Folic acid Macrocytic anemia Low leafy vege Neural tube defect Homocysteinuria In flour

Cyanocobalbumin (b12) Perniciouse anemia Vegan diet Loss of Intrinsic factor no


 * CLINICAL GENETICS AND DYSMORPHOLOGY**
 * //Dr. Kurczynski//**

ACHONDROPLASIA - Autosomal Dominant - Fresh mutations - Homozygous increases severity - Clinical o Rhizomelic limp shortening o Macrocephaly o Broad and prominent forehead o Finger and hand abnormalities

HURLER’S SYNDROME - Autosomal Recessive - Mucopolysaccharide disorder - Deficiency in alpha-L-iduronidase - Urine o high heparin and dematan sulfate and o low leukocyte iduronidase - Clinical o Unsteady gait o Limited speech o Kyphosis (anteriorly concave back) o Microcephaly

MARFAN SYNDROME - Autosomal Dominant - Mutation on C15 - Poor fibrillin in elastic tissue - Life expectancy halved - Death results mainly from cardiovascular problems - Connective Tissue problems - Clinical o Aorta dilation and rupture o Scoliosis (lateral curvature of spine)

NEUROFIBROMATOSIS - Autosomal Dominant - Mutation on C17 - Defect in gene for neurofibronin - Lifetime risk of CNS tumors - Small percent with mild retardation - Clinical o Cafe au lait macules o Optic glioma o Freckline o Lesions o Affected 1st degree relative o Neurofibromas (benign skin tumors)

NOONAN SYNDROME - Automsomal Dominant - Mutation in C12 - Some with mild retardation - Clinical o Short o Short neck with webbing or redundancy of skin o Cardiac Problems o Age dependent facial features

DiGEORGE – VELOCARDIOFACIAL SYNDOME - Autosomal Dominant - Deletion on C22 - Detected mainly by FISH (99%), then Chromosomal Analysis - Cognitive impairment - Heart lesions - Unique facial features - Palatal Abnormalities - Hypocalcemia - Immune deficiency - Clinical o Nasal speech from cleft palate o Short o Long face o Prominent nose o Slender

WILLIAMS SYNDROME - Autosomal Dominant - Mostly new mutations - Deletion on C7 - Clinical o Cognitive impairment § Sine strengths in particular areas o Unique facial features § Full lips o Connective tissue problems § Hoarse voice o Cardiovascular problems § Elastin Arteriopathy - stenosis o Some have hypocalcemia § Short o Unique personality characteristics § Overly nice and friendly § Anxiety


 * CONGENITAL ANOMALIES AND TERTOGENESIS**
 * //By Dr. Micale//**


 * Malformation**

Myelomeningocele (Meningomyelocele) - failure of neural tube to close during development - clinically noticeable protrusion in back - Spina bifida

Holoprosencephaly - problem with midline differentiation - ex. cyclops, one front tooth, nose between eyes

Micrognathia - small mandible or jaw

Potter Sequence - Sirenomelia (union of legs and feet, mermaid like) - Defect in BV in lower extremities - Curled legs - Oligohydramnios (def. amniotic fluid) à fetal constraint and deform/malform

Robin Sequence - failure of tongue to descend - cleft palate

Occipital Encephalocele - spinal tube remains open during development - large protrusion in back of head

Anencephaly - failure of most of anterior part of tube to close during development - top of head is flat, not a clearly defined cranium


 * Deformation**


 * Includes:** cleft foot, plagiocephaly (head deformed), mandibular asymmetry, cleft palate

Craniosynostosis - fusion of cranial suture - skull expands at right angles to suture in order to accommodate brain

Compressed Faced - during prolonged delivery - most recover


 * Disruption**

Disruptive forces lead to limb reduction.

Amnion Rupture - amniotic bands become entangled with the fetus - loose anything related to loss of blood supply in a vessel - facial cleft - limb loss - Encephalocele: gap in head and fluid buildup leads to protrusion


 * Sequences**

Multiple defects leading from a single anomaly or mechanical factor.

Potter Sequence: defined above


 * Syndrome**

A serious of multiple, nonsequential, pathogenetically related anomalies

DiGeorge/Velocardiofacial Syndrome - microdeletion on chromosome 22 - absence of thymus gland leading to lack of T cells - more with Dr. Kurczynski


 * Association**

A nonrandom occurrence of multiple anomalies not yet known to represent a developmental field defect, syndrome, or sequence.


 * Teratogenesis**

Thaladomide Embryopathy - result from overdose on the drug Thaladomide - Phocomelia: lack of upper or lower limbs, hands and feet attached close to body

Retinoic Embryopathy - hair whorl displacement - craniofacial defects Macrosomia - abnormally large body - result of diabetic mother

Fetal Alcohol Syndrome - palpebral (eyelid) fissures - short nose - thin upper lip

Fetal Dilantin Syndrome - caused by dilantin - short nose - low nasal bridge


 * GENETIC BASIS OF COMMON DISEASES**
 * //By Dr. Micale//**

- Autosomal Recessive - 1:25 carrier frequency - High number of mutations - predominately affects Caucasians, and Ashkenazi Jews, North European Descent - Majority of causes from F508 deletion on C7q, classic form is Homo for F508 (del Phe) - Problems o Pulmonary o GI including pancreatic o Genitourinary o Cl- concentration - CFTR: CF Transmembrane Conductance Regulator o Functions § Cl- ion channel § Regulated opening and lcosing of ion pore § Regulates activity of other ion channels o Types § I – Absent protein § II – defective processing, includes deltaF508 § III – defective regulation § IV – defective conduction due to alteration of Cl- channel o Locations § Sweat duct: remove Cl- à Na+ removal from lumen § Respiratory: pump out Cl- - No simple test. Test for most common mutations. - Can test using electropharogram: measures peaks of different genes. If have high peak, computer marks it. - Compound heterozygote: two alleles for the same trait with different mutations. The mutations then determine the severity of the disorder. - Severity based on mutation
 * Cystic Fibrosis**

- Iron overload à High absorption and storage - Autosomal Recessive - High in Caucasians - 1:10 Carrier frequency - Can be prevented: best case for a disease - Testing o Biochemical Testing for elevated transferring-iron and serum ferritin o Liver biopsy for iron storage o HFE gene testing (C6p) § C282Y and H63D Mutations § Most C282Y Homo or Hetero C282Y/H63D · If either case is lacking, the group may still have liver disease or other metabolic sundromes. § electrophoresis - Heterozygotes tend to have elevated serum iron, but not overload
 * Hereditary Hemochromatosis**

- Autosomal Dominant - Point mutation in Factor V gene increases APC resistance à clotting o G à A substitution: arginine replaced by histidine at one of three APC cleavage sites in the gene à slower inactivation of Factor V by APC o Increased risk of thrombosis in heterozygotes and even more in homozygotes o Also increased risk in pregnancy, placenta - APC resistance is most common form - Risk Factors o Antithrombin III def. o Protein C def. o Protein S def. o Activated Protein C def. - Normally: Thrombin activates Protein C à anticoagulant
 * Factor V Leiden Thrombophilia**

- X linked recessive on Xp21 - Affects mainly males - Dystrophin à mainly in all muscles, acts as a shock absorber and maintaining membrane calcium permeability - Cells are replaced by fibrous CT and loose ability to do some things - Becker is less severe than Duchenne à truncating mutation in Xp21 o Onset age is later and retain ambulatory ability - DMD is autosomal translocation of Xp21 o Largest known gene o High mutation rate because of large size o Size of deletion does not correspond with severity of presence of MR o Deletion, duplication, or normal size (missense, splicing, or promoter problems)
 * Duchenne/Becker Muscular Dystrophy**

DMD vs. BMD

DMD: frameshift mutation resulting in termination codon in middle of mRNA à absence of dystrophin protein

BMD: in-frame mutation, intact mRNA reading frame downstream of mutation à production of modified, partially functioning dystrophin protein

Severity determined by type not extent of deletion.

- brittle-bone disease o abnormality in Type I Collagen à two alpha-1 chains and one alpha-2 chains o bone is not mineralized properly - dominant negative mutation o normal and mutant collagen mixed together where process cannot tell them apart o randomly put together forms weak collagen - Four types with Type II the most lethat - Shortened and bowed bones - Treatment o Medical and surgical methods o Bisphosphonates: reduce bone resorption à increase bone density and mineral content
 * Osteogenesis Imperfecta**

- most common form of dementia - increased risk if have first degree relatives with it - common in Down Syndrome - progressive deterioration of memory, higher cognitive functions, etc… - Deposition of two fibrillary proteins o Beta-amyloid peptide (Abeta) à amyloid or senile plaques in the cerebral ECM o Tau protein: nuerofibrillary tangles in the cytoplasm of neuron, encircle and displace nucleus, tangles remain after neuron degeneration - Cortical brain atrophy - Types o Sporadic § Negative family history § Multiple factors leading to it o With Down Syndrome § Amyloid precursor protein (APP) gene is on C21 § Overproduction of APP à deposition o Family § Three common alleles: epsilon 2, epsilon 3, epsilon 4 · Epsilon 4: (4/4 genotype early age of onset (<70), (2/4 or ¾ late onset) · Epsilon 2: has protective effect and is more common in general population · ApoE polymorphisms may influence accumulation of Abeta peptides in the brain, ApoE is not specific for AD, absence of epsilon 4 does not rule out AD § Three Genes Responsible · Presenilin 1: most common, family history · Presenilin 2: rare mutations · Amyloid precursor protein: family history, test not available · PSEN1 and PSEN2 are early onset with familial AD with increased Abeta production
 * Alzheimer Disease**