Comprehensive Pathophysiology: Final exam material

Pathophysiology

Abetalipoproteinemia: (RBC membranopathy) acanthocytosis (spur cells) increased sphingomyelin in outer leaflet. Caused by an absence of beta-lipoprotein (mutation in the MTTP Gene), a protein that normally functions in the absorbtion of dietary fats and fat-soluble vitamins. Can present with diarrhea, steatorrhea, and ataxia. Aceruloplasminemia: absence of ceruloplasmin (copper ferroxidase that facilitates Fe release from cells). Iron accumulation in spleen, heart, liver, kidney, thyroid, retina (tissue damage). Liver iron overload = diabetes due to beta cell destruction. Hemochromatosis secondary. Ex: thalassemia, alcoholism

Acidosis/Alkalosis: Off balance of proton release from kidneys or CO2 release from lungs, relates to the bicarbonate buffer system of the lungs. Generally, acidosis is said to occur when arterial pH falls below 7.35, while its counterpart alkalosis occurs at a pH over 7.45. Arterial blood gas analysis and other tests are required to separate the main causes.

Achondroplasia: Disorder of bone growth that causes the most common type of dwarfism, characterized by normal to large-sized head, shortened arms and legs (especially thighs and upper arms), a normal size trunk, and a waddling gait. - autosomal dominant trait -most adults are heterozygotes (homozygotes dont survive) - gain of function mutation in fibroblast growth factor receptor 3 (FGFR3) arginine substitution (i.e. for glycine) abnormal endochondral ossification - dwarfism with disproportionate arms and legs - abnormal pelvis, neuro and cardiopulmonary problems, hearing loss, spine deform - somatotrophin (synthetic human growth hormone) can treat, in early years Acute intermittent porphyria (AIP): is a rare metabolic disorder in the production of heme, the oxygen-binding prosthetic group of hemoglobin. Specifically, it is characterized by a deficiency of the enzyme porphobilinogen deaminase. Porphyria involved in steps in heme biosynthesis. Hepatic. Abdominal pain, NOT over-producing porphorins therefore do not see skin lesions (cant make the linear tetrapyrole). Excrete ALA, PBG in urine. Normally, heme synthesis begins in the mitochondrion, proceeds into the cytoplasm, and finishes back in the mitochondrion. However, without porphobilinogen deaminase, a necessary cytoplasmic enzyme, heme synthesis cannot finish, and the metabolite porphyrin accumulates in the cytoplasm. Additional factors must also be present such as hormones, drugs and dietary changes that trigger the appearance of symptoms. Symptoms of AIP may include abdominal pain, constipation, and muscle weakness. Acquired Hemolytic Anemia/Paroxysmal Nocturnal Hemoglobinuria (PNH): The PIGA enzyme takes the GPI anchor to its spot in the plasma membrane. However in this disease the PIGA enzyme

is mutated. Therefore the GPI anchor is not getting to its spot and the proteins that usually attach to it are unable to attach. Leads to hemolysis, anemia, and thrombosis A molecule called PIGA (phosphatidylinositol glycan A) is needed to make a cell membrane anchor for proteins called GPI (glycosylphosphatidylinositol). The gene that codes for PIGA is inherited in an X-linked fashion. If a mutation occurs in this gene then PIGA may be defective, which leads to a defect in the GPI anchor. When this mutation occurs in a bone marrow stem cell (which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect. Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system. The complement system is part of the immune system and helps to destroy invading microorganisms. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins which carry out this function are CD16, CD55 and CD59 (CD is an acronym for cluster of differentiation). The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelets. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

Albinism: Defect in Melanin production. - lack of pigmentation - defect is autosomal recessive - defect in tyrosinase gene (catalyzes the reactions necessary to make dark pigment, tyrosine to melanin) - heterozygous has normal phenotype, must be homozygous aa to have condition. -Oculocutaneous- most severe form- the hair skin and iris are all white/pink

Alkaptonuria: (phenylalanine metabolism pathway) defect in homogentisate oxidase. Therefore unoxidized homogentisate accumulates and polymerizes resulting in joint damage, calcification of CVS and urinary tract, ochre to the skin, black urine. Can not metabolize homogentisate to maleyloactoacetic acid. A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black (depending on diet) after several hours because of the accumulation of homogentisic acid. Similarly, urine exposed to air can become dark; this is useful for diagnosising young children using diapers. In adulthood, but usually not before age forty, persons suffering from alkaptonuria develop progressive arthritis (especially of the spine), due to the long-term buildup of homogentisate in bones and cartilage. The urine is malodorous.

Anaphylactic shock: Anaphylaxis is an acute systemic and severe Type I Hypersensitivity allergic reaction in humans and other mammals. The term comes from the Greek words ana (against) and phylaxis (protection). Anaphylaxis occurs when a person or animal is exposed to a trigger substance, 3

called an allergen, to which they have already become sensitized. Minute amounts of allergens may cause a life-threatening anaphylactic reaction. Anaphylaxis may occur after ingestion, skin contact, injection of an allergen or, in rare cases, inhalation. Anaphylactic shock, the most severe type of anaphylaxis, occurs when an allergic response triggers a quick release from mast cells of large quantities of immunological mediators (histamines, prostaglandins, leukotrienes) leading to systemic vasodilation (associated with a sudden drop in blood pressure) and edema of bronchial mucosa (resulting in bronchoconstriction and difficulty breathing). Anaphylactic shock can lead to death in a matter of minutes if left untreated.

Anemia of Chronic Disease: Seen with infections, inflammation, cancer, it is cytokine mediated. -Usually normocytic, but can be microcytic, low serum iron, low serum transferrin, high serum ferritin, low iron absorption from gut, poor response to oral iron, serum EPO is low, RBC lifespan shortened moderately (but marrow does not compensate with increased RBC production bc low EPO signal) -Macrophage releases cytokines which cause increased hepcidin production. Hepcidin binds to ferroportin and decreases export of iron from the enterocytes and the macrophages. This lowers serum iron quickly (but still have high levels of serum ferritin bc they are stored in macrophages). Enterocytes eventually slough off bc packed with iron. Anyone chronically sick will have low iron Andersons Disease: It is also known as Glycogen Storage Disease type IV, and is a result of the absence of the glycogen branching enzyme amylo-1,4-1,6 transglucosidase, which is critical in the production of glycogen. This leads to very long unbranched glucose chains being stored in glycogen. The long unbranched molecules have a low solubility which leads to glycogen precipitation in the liver. These deposits subsequently build up in the body tissue, especially the heart and liver. The end result is liver failure and eventual death occurring before age 2.

Angina

- partial loss of circulation to heart muscle chest pain, chronic condition

Anglemans syndrome (aka Happy Puppet Syndrome) - most patients have deletion in the AS region of maternal chromosome 15 - some have paternal uniparental disomy for chromosome 15 - few (3%) have defect in maternal imprinting - candidate gene: UBE3A - transfers ubiquitin to protein - targets protein for breakdown by proteasome - characterized by mental retardation, speech impairment, excitability, inapprop. laughter - unsteady gait and unsteady limb Anhidrotic extodermal dysplasia - mosaicism, resulting from incomplete X-inactivation in females 4

- mutant X chromosome gene lack sweat glands - use electrochemical resistance test to find areas of skin that are mutant

Aniridia - caused by a PAX6 mutation - absence of the iris

Arginase deficiency: (makes urea and ornithine from arginine in liver) Arg and ammonia elevated in plasma, CSF and urine. Arg. Lys and ornithine in urine. Diet of essential AA minus arginine. Low protein. Hyperargininemia. Cant make urea and ornithine.

Argininosuccinase deficiency: (makes fumarate and arginine from argininosuccinate) Usually fatal. Argininosuccinate and ammonia in plasma, CSF and urine. Treat w/ arginine.

Argininosuccinate synthetase deficiency: (forms argininosuccinate from citrulline, Asp, and ATP) elevated Citrilline and ammonia in plasma, CSF, and urine. Treat w/ arginine (enhances citrulline excretion).

Arteriosclerosis

- hardening of the arteries (general term)

Atherosclerosis: Arteriosclerosis due to formation of plaques (atheromas). Disease in which cholesterol-rich plaques block off arteries. Cholesterol is carried by LDL in the blood, when LDL is oxidized it is taken up by macrophages which enlarge to become foam cells which get trapped in blood vessels walls leading to the formation of the plaques Progression: 1. Foam cells begin to accumulate under the endothelial cells of the artery forming a fatty streak down the artery (this by itself is not a problem). Within the fatty streak T-cells are activated, and begin to see platelets and leukocytes in the area. 2. As more and more foam cells accumulate a lipid-rich plaque forms with a lipid core and a fibrous cap. Get formation of a necrotic core containing dead cells. The fibrous cap is made from the muscle cells. 3. If gets even larger becomes an occlusive plaque because it is now large enough to partly block the artery (associated with angina). 4. If the fibrous cap ruptures then get a thrombosis as WBCs and platelets occlude the 5

area and form a clot blocking the artery. See hemorrhaging from plaque microvessels and thinning of the fibrous cap Effects: unstable angina, MI, coronary death, stroke, leg ischemia Endothelial Injury Increases risk: Get injury from smoking, diabetes, insulin resistance, ischemia, peripheral artery disesase, inflammation, obesity, dyslipidemia, hyperhomocysteinemia, hypertension, and genetic abnormalities. Inflammatory Disease: Immune cells in plaque release inflammatory cytokines, have similar cellular interactions to other chronic inflammatory diseases, have chronic inflammation at sites of plaque formation Ataxia Telangiectasia - a disease of DNA repair (nothing else mentioned in lecture) thalassemia: imbalanced globin chain synthesis, hemoglobinopathy. People often end up with 2 2 conformation of hemoglobinTreat w/ defroxamine Becker Muscular Dystrophy (see DMD) Beriberi (wet vs. dry): Thiamine (vitamin B) deficiency, causes fatigue, neuropathy, inability to work. In wet there is edema and it is also the more severe form heart enlargement, tachycardia. Its symptoms include weight loss, emotional disturbances, impaired sensory perception (Wernicke's encephalopathy), weakness and pain in the limbs, and periods of irregular heart rate. In advanced cases, the disease may cause heart failure and death. Wet beriberi affects the heart; it is sometimes fatal, as it causes a combination of heart failure and weakening of the capillary walls, which causes the peripheral tissues to become waterlogged. Dry beriberi causes wasting and partial paralysis resulting from damaged peripheral nerves. It is also referred to as endemic neuritis. Blooms syndrome - defect in BLM helicase (but other helicases not affected) helicase works to unwind tetraplex DNA structures - leads to chromosomal and genetic instability Causes: Growth retardation Sunlight sensitivity Decreased fertility Immunodeficiency Cancer (both solid tumors and leukemias) Branched chain keto aciduria (maple syrup disease): deficiency in -keoacid DHD complex (therefore no oxidative decarboxylation of keto acids no CoA derivatives formed-- from Leu, Ile,

and Val). Accumulate: -ketoisocaproate (Leu), -keto-B-methyl Valerate (Ile) and -ketovalerate (Val). Brutons agammaglobulinemia - defective tyrosine kinase defective maturation of B-cells no Ig production bacterial infection susceptibility at 4-8 months (initially ok, b/c antibodies from mothers breastmilk) CPT I or II: Carnitine Palmityltransferase (Acyltransferase) deficiency, long chain Fatty Acids cant enter the mitochondria for B-oxidation, due to lack of this carnitine shuttle system. Medium chain (612 C) can enter mitochondria without shuttle therefore supplement with MCFA. Campomelic dysplasia - mutant SOX9 gene (homologies to SRY, sex determining region of Y chromosome) - underdeveloped thorax, bent limbs - sex reversal (i.e. female with XY karyotype) Cancer (in terms of integrins / cell cycle proteins): Several Cyclins, CDKs as well as p53 and Rb have links to cancer. Cataracts: Side effect of Galactosemia (absence of Gal-1-P-uridyl transferase). Build up of unreacted Galactose-1-P, will be reduced by Aldose Reductase (and NADPH) to D-Galactitol, which is toxic. Changes osmotic pressure of the eye and lens becomes opaque. Chemotherapy drug resistance: MDR1 ABC type active transport pump the planar drugs out of the cells Cholera - caused by a toxin, produced by Vibrio cholera - irreversibly modifies Gs subunit of adenylate cyclase - stuck in GTP bound state (active) cAMP levels, PKA activation PKA regulated Cl- channel disrupted loss of water to intestine diarrhea

Chronic atrophic gastritis see pernicious anemia Collagen disease (diagnostic test?): Glycine in the urine bc 1/3 of the collagen fiber is glycine

Complete Androgen Insensitivity Syndrome (Testicular Feminization) - XY female - has testicular tissue (secretes androgens - but defective androgen receptor androgen insensitive - phenotypically normal female, with some abnormalities Congenital Adrenal Hyperplasia - defect. adrenal cortex overproduction of androgens virilization of female infants - often caused by deficiency 21 hydroxylase Congestive Heart Failure: Digitalis is used as a cardiotonic steroid drug to treat congestive heart failure. It blocks the phosphorylation of the Na/K ATPase so that the sodium release at the NA/Ca pump which then pumps in more Calcium and causes greater contraction of the heart Craniosynostosis - caused by Fibroblast growth factor response genes (cell division/migrat/diff.) - mutant FGFR 2 - irregular shape of skull - i.e. Crouzon syndrome and Apert syndrome Creutzfeldt-Jakob disease (CJD): Prions, human form can be inherited (10-15%), sporadic (85%), or infectious through iatrogenic (<5%) or variant causes. Prion that replicates and transfers protein misfoldings, in the absence of nucleic acid, to form insoluble aggregates. Crigler-Najjar Syndrome rare, recessive disorder resulting in severe (type 1) or moderate (type 2) jaundice due to reduced or absent UDP-glucoronosyl transferase activity. Type II often responds to inducers of the enzyme (phenobarital) wheras type I oftentimes requires a liver transplantType II mild, responds to Phenobarbital. Type I w/ kernicterus and may require liver transplant. Severe jaundice due to reduced or absent UDP-glucuronosyl-transferase. Type I = enzyme absent, bilirubin levels 20-50 mg/dl, bile pale (sm amounts of unconjugated), Kernicterus, d/n respond to Phenobarbital. Type II = enzyme reduced, bilirubin levels <20, bile w/ increased Monoglucuronide, responds to Phenobarbital, Liver enzymes normal in both. Cri du Chat syndrome - caused by deletion of the p region of chromosome 5 - classified as a contiguous gene syndrome (segmental aneusomy syndrome) - characteristic cat cry in newborns, caused by a pharyngeal defect Cystinosis: defect in cysteine transport. Cysteine crystal deposition in tissues. Mortality from renal failure.

Cystinuria: Excretion of cystine (di-sulfide version of cys) elevated as well as Lys, Arg and ornithine. Normal transporter protein allows certain amino acids, including cystine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutation in transporter and AA concentrate in the urine.. Crystals of cystine forms calculi in kidney tubules. Cystic Fibrosis - autosomal recessive disorder (horizontal inheritance, heterozygotes not affected) - single gene mutation, involving a 3 BP deletion (therefore in frame), 508 common - mutant cystic fibrosis transmembrane regulator gene (CFTR) - abnormal regulation of chloride ion passage through endothelial cells - In skin, CFTR normally keeps Cl- ions out of sweat ducts - mutant increased NaCl in sweat salty sweat diagnosis - In endoth. cells lining airways, Cl- not transported out of cells Na rushes in, followed by water highly dehydrated mucus - causes lower airway inflammation and infection, chronic breathing difficulties - GI reabsorption problems, diabetes mellitus, defective pancreatic secretion, cirrhosis - azoospermia, lack of vas deferens in men - also decreased fertility in women - average survival age of 33 yrs. - more common in Caucasians - no good molecular test for CF Diabetes (uncontrolled): increase gluconeogenesis and lipolysis glycogenolysis, decrease glycolysis Type I: Insulin not produced by pancreas, TG lipase will increase, ACC will fall Type II: Insulin produced but effects on glucose transport/utilization impaired. TG lipase decreases, ACC stimulated, Eventually pancreas resistant to glucose and stops producing insulin altogether. Diabetes Type I: Due to destruction of beta cells of pancreas by autoimmune reaction of unknown cause, primary treatment is injection of insulin. ~10% of diabetes is Type 1. Diabetes Type II: Decreased response to insulin in peripheral tissues (insulin resistance). Have initial hyperinsulinemia, eventually leading to beta cell dysfunction and deficiency of insulin. Associated with visceral obesity and often preceded by metabolic syndrome Insulin produced but effects on glucose transport/utilization impaired. TG lipase decreases, ACC stimulated, Eventually pancreas resistant to glucose and stops producing insulin altogether. -Leads to hyperglycemia because insulin secretion eventually decreases this leads liver to continue glucose synthesis bc has no signal to stop, and the rest of the tissues in the body arent using the glucose so it stays in the blood -Hyperglycemia leads to the symptoms of diabetes: polyuria, thirst, glycosuria (BG > 180), protein glycation -Fasting Blood Sugar standards: normal (<99), prediabetes (100-125), diabetes (>126) 9

-Though have higher levels of TGs and lower levels of HDL, see no difference in levels of LDL btwn those with or without diabetes, however though amts of LDL not different, diabetics have the smallest most dangerous LDLs DiGeorge anomaly of brachial arch defects (related to the other DiGeorge stuff below???) - defect in thymus development (site of T-cell differentiation and selection) leads to T-cell deficiency susceptible to yeast and viral infections DiGeorge Velocardiofacial syndrome - actually a combo of 3 sydromes:

DiGeorge Syndrome (DGS) Conotruncal anomalies face (CTAF) Velocardiofacial syndrome (VCFS) - deletion in DiGeorge Syndrome critical region (DSCR) [chromosome 22] - Cardiac problems are the most life threatening - also cognitive impairments and neonatal hypocalcemia

Down syndrome see trisomy 21 Duchene muscular dystrophy (DMD) - x-linked recessive trait - apparent non-carrier mother might produce offspring with germline mosaics - increased risk of child passing on to their progeny - carrier females are normal - mutation in the dystrophin gene at Xp21 - the largest human gene - most common mutation is deletion, though duplication or bad splicing also poss. - frameshift mutation absent protein - dystrophin mainly found in skeletal, heart, smooth muscle tissue - interfaces between cytoskeletal proteins and group transmembrane proteins - protein helps maintain muscle calcium permeability - also acts as shock absorber (prevents damage when fibers contract) - characterized by progressive myopathy (muscle wasting), starting at age 3-5 - death at age 20-25 from respiratory failure * Becker muscular dystrophy (BMD) - less severe progressive myopathy than DMD, less common than DMD - truncating mutations at Xp21 - in-frame mutation partially functioning dystrophin protein - typically later onset than DMD - Molecular Testing: - Immunofluorescence staining for dystrophin protein in muscle sample - PCR amplification of gene Dyslipidemia: Disease in which have elevated levels of one or more types of lipoproteins or

10

lipids. Can be caused by inherited defects or by metabolic disturbances and obesity. Can see which lipoproteins are elevated by running gel electrophoresis. In many of these if build-up gets too bad can get deposition in other parts of body, such as in skin. Can lead to photosensitivity due to oxidation of the fats in the skin. Type 1: Elevated levels of chylomicrons and TGs, due to decreased lipoprotein lipase synthesis (therefore FA not hydrolyzed from TG of chylomicrons and FA not transported to adipose cells). Type 2a: Elevated levels of LDL and LDL cholesterol Type 2b: Elevated levels of LDL, VLDL, LDL cholesterol, and TGs Type 3: Elevated levels of IDL, LDL cholesterol and TGs Type 4: Elevated levels of VLDL and TGs Type 5: Elevated levels of chylomicrons, VLDL, and TGs. Due to decreased apo C-II (needed for docking on adipose, stimulates LPL activity). Or increased apo C-III (inhibitor of LPL). Hypercholesterolemia: Elevated LDL-C Hypertriglyceridemia: Elevated TGs Edema: Abnormal build-up of interstitial fluid in extra cellular matrix due to many things (blocked lymphatics, blocked venous return, liver disease, increased vascular permeability, hypertension, starvation) -Myxedema: due to overproduction of GAGs during hypothyroidism (dont get pit like it pitting edema Edwards syndrome see trisomy 18 Ehlers-Danlos, Type IV: Due to deficiency in Type III collagen causes aneurysms and intestinal rupture Ehlers-Danlos, Type VII: The procollagen peptidase is changed and thus does not perform the cleavage on the procollagen molecule. Therefore have weak collagen that leads to hyperflexible joints, dislocations and soft skin. Emphysema: Lung dysfunction caused by break down of elastic fibers. Emphysema is caused by loss of elasticity of the lung tissue, from destruction of structures supporting the alveoli, and destruction of capillaries feeding the alveoli. The result is that the small airways collapse during exhalation (although alveolar collapsability has increased), leading to an obstructive form of lung disease (airflow is impeded and air is generally "trapped" in the lungs in obstructive lung diseases). Symptoms include shortness of breath on exertion (typically when climbing stairs or inclines, and later at rest), hyperventilation, and an expanded chest. Environmental factors can influence genes - 1-anti-trypsin, coded by the Serpina genes (multiple alleles) -blocks degradation of proteins (inhibits trypsin and elastase) - smoking introduces superoxide anion inhibits this enzyme cant protect breakdown of structural proteins emphysema 11

End-stage kidney disorder (and RBC production) - kidney damage leads to decreased erythropoietin synthesis - therefore dec in RBC production. Enzymopathies: Types of inherited destructive disorders that impair synthesis of heme, reduction of MetHb, protection of oxidants (G6PD), modulation of Hb/oxygen affinity (BPG mutase deficiency, leads to very little 2,3BPG and thus less likely to release O2, moves curve to left), and ATP production (pyruvate kinase deficiency) Erythropoietic Protoporphyria (EPP): enzyme deficiency in ferrochelatase during heme synthesis. Cant insert FE in last step of heme synthesis. Excrete PROTO IX in feces. Fabrys: defect in -galatosidase, can not remove galactose from lactosylcerebroside, Kidney failure, skin rash. Faconi Anemia - bone marrow failure, growth retardation - skin, G.I., and kidney abnormalities - increased cancer occurrences, particularly myolegnous leukemia - increased chromosome damage (more susceptible) - defect in a Faconi complementation group possibly knocks out important signal or repair pathway Factor V Leiden Trhombophilia - single point mutation in factor V gene at nucleotide 1691 - G A base substitution leads to Arginine to histidine - occurs at an APC cleavage site (therefore Activated Protein C resistance) - causes slower inactivation of Factor V by APC increases thrombin production - increased risk of clotting (thrombosis) - heterozygotes have slightly elevated risk - detect mutation by MnI 1 enzyme digestion (mutants have one less cleavage site, so produces 2 DNA fragments instead of 3) Fetal Alcohol syndrome - teratogen = ethanol - causes low birthweight, growth delay, heart defects Fetal Dilantin syndrome - teratogen dilantin (anti-epileptic drug) - causes hypertelorism, short nose and low nasal bridge 12

Favism - example of ecogenetics - decreased activity in glucose-6-phosphate dehydrogenase less reduced glutathione oxid. damage to RBCs - oxidant drugs can accelerate loss of glutathione - or ingestion of fava beans Folate deficiency - see homocysteinemia, neural tube defects, megaloblastic anemia

Fragile X syndrome - classified as a DNA repeat expansion disorder, loss of function - most common inherited form of mental retardation (remember, trisomy 21 is common, yet it is not caused by the inheritance of a specific gene, but rather by having an extra whole chromosome) - some have mild facial dysmorphic features, while others have no symptoms at all - self-injurious, hyperactive, and impulsive behaviors most common - fragile site contains a CGG sequence, repeated in the 5 region of FMR1 gene - repeat occurs upstream of the start codon - FMR1 encodes an RNA binding protein that interacts with polyribosomes - with disease, characteristic low expression in brain and testes - more repeats greater inactivation (b/c highly unstable during mitosis) (6-50 repeats is normal, 50-200 is permutation, 200+ is full mutation) - repeats due to uneven crossing over or amplification b/c of defect replication - repeats accumulate over generations - to test for fragile X, run PCR of FMR gene, then separate using electrophoresis look for large DNA sequence (wont move far in the gel) Fructose Uria: lack of fructokinase, cant make F-1-P, excreting fructose in urine. G6PD deficiency: Regeneration of GSH from its oxidized (GSSH) form requires the NADPH produced from the G6PD (Glucose-6-phosphate dehydrogenase) reaction, therefore this deficiency subjects cells to oxidative injury and hemolytic anemia (Heinz bodies). G6PD deficiency confers some resistance to malaria. Often a common problem, and can be offset by a simple infection, ingestion of fava beans, or reaction with medicines, AAA, antibiotics, antipyretics, and antimalarials. Galactosemia: absence of galactose-1-P-uridyl transferase, must exclude galactose from diet. Accumulation of galactitol (reduction of galactose) which can result in hepatomegaly renal failure, cataracts, and brain damage. Without treatment, mortality in infants with galactosemia is about 75%. autosomal recessive, equal gender and race ratios Gauchers: Tissues accumulate glucocerebroside (lack -glucosidase, glucocerebrosidase). Cannot remove the final glucose from cerebroside. Tissue-specific isoforms. Type I: (RBCs) The most common form of the disease, characterized by build-up of glucocerebrosides which causes easy bruising, fatigue due to anemia, enlargement of liver and 13

spleen, weakness of skeleton, and lung and kidney impairment. Onset can be in early childhood to late adulthood. Some success in IV enzyme replacement therapy Type II: cell membranes of neurons, extensive brain damage. Most severe but rare, glucocerebrosidase isozyme found in membrane of neurons, has early onset with extensive brain damage. There is no treatment. Gestational (Maternal) Diabetes - teratogenic - causes large birthweight, brain anomalies, heart defects Gilberts syndrome: common, mild, reduced UDP-glucuronosyl transferase (rate-limiting enzyme of bilirubin glucuronide synthesis) therefore elevated unconjugated bilirubin. Bile with increased production of monoglucuronide, serum bilirubin conc. <3 mg/dl. Glanzmanns disease: Beta 3 integrin is not produced and thus clotting cannot occur, thus causing excessive bleeding Gout - defective purine metabolism excess uric acid - Sodium urate crystal deposits in joints painful attacks, often in toes - multiple possible causes: - defective PRPP synthase cant be regulated oversynth of purines therefore many broken down) - defective glucose-6-phosphatase increased G6P inc Ribose 5-P via PPP therefore oversynthesis of purines - partial HGPRTase deficiency cant salvage purines properly inc uric acid Hand-foot-genital syndrome - caused by HOX-A13 mutation - just like it sounds, defects in the hands, feet, and genitals Hartnups Disease lack of niacin (vitamin B3) Dermatitis, Dementia, Diarrhea (the 3 Ds) genetic inability of the body to produce niacin from tryptophan

Hemochromatosis: excessive iron absorption due to faulty regulation of iron transport. Tissues accumulate iron. Defect in 343-residue membrane glycoprotein (regulates transferrin receptor affinity for transferrin). Cardiomyopathy, liver cirrhosis, diabetes, arthropathies. Treatment = phlebotomy.

14

Hemoglobin C Disease: Hemoglobin C (abbreviated as Hb C or HbC) is an abnormal hemoglobin with substitution of a lysine residue for glutamic acid. This mutated form reduces the normal plasticity of host erythrocytes. In those who are heterozygous for the mutation, about 2844% of total hemoglobin (Hb) is HbC, and no anemia develops. In homozygotes, nearly all Hb is in the HbC form, resulting in moderate normocytic hemolytic anemia. Target cells, microspherocytes and HbC crystals are found in a blood smear from a homozygous patient. Individuals heterozygous for both HbC and Hb S (Hb SC disease) or for HbC and thalassemia are known, and have atypical hemolytic anemias; sickling is enhanced in Hb SC disease. Those heterozygous (HbS/HbC) are affected with sickle cell, but a less serious form than the HbS/HbS individuals. Hemoglobin C is found predominantly in West Africa and has been shown to protect against severe malaria. Hemoglobinopathies: Types of inherited destructive disorders, involve decreased solubity of hemoglobin (HbS), unstable hemoglobin (Zurich, have denatured Hb aggregates), increased O2 affinity (Hb Chesapeake), decreased O2 affinity (Hb Kansas), imbalanced globin chain synthesis (thalassemia), methemoglobinemia, and carboxyhemoglobinemia Hemophilia A - X-linked recessive - higher incidence in males (since hemizygous) - deficient in factor VIII (clotting factor) - traced in royal families of Europe Hemosideriurinuria : brown urine, chronic intravascular hemolysis. Hb released from RBCs in excess of haptoglobin bind capacity. Excess Hb filtered by kidney. Reabsorbed by proximal tubule (Fe stored) Tubule cells slough off w/ hemosiderin Hereditary Elliptocytosis (pyropoikilocytosis): Result from different defects in spectrin that affect interaction within the spectrin tetramer (80% HE = alpha spectrin) (affects horizontal interactions) protein 4.1, or glycophorin C. Elliptical or oval cell shape. Mutation either A or B spectrin subunits. Band 3 mutation = ovalcytosis. Hereditary Fructose Intolerance (HFI): absence of phosphofructoaldolase B, buildup of F-1-P, glycolysis stimulated, lactic acid, hypoglycemia, and depletion of ATP.

Hereditary Hemochromatosis - iron overload disorder (transferrin saturation, increased serum ferritin) - autosomal recessive trait, but phenotype is sex-influenced - less common in females (possibly b/c of less dietary iron uptake and losses via menstruation) 15

- molecular testing on HFE gene (common: C282Y and H63D mutations) - HFE facilitates transferrin-bound iron uptake from gut - if mutant, cell fails to sense circulating T.F.-bound iron increased absorption of dietary iron high expression of iron transporters, but low ferritin expression - heterozygotes have elevated serum iron, but no major iron overload complications - takes long time to develop pathology - especially toxic to liver and kidneys Hereditary Melanoma: Linked to disruption of p16 (20-40% of cases linked to the p16 gene mutation). Familial melanoma is genetically heterogeneous. Multiple genetic events have been related to the pathogenesis of melanoma. The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a - a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs). Hereditary nonpolyposis colorectal cancer - a disease of DNA repair (nothing else mentioned in lecture Hereditary Orotic Anemia: Symptoms: Megaloblastic anemia, growth retardation, excess orotic acid in the urin - caused by two deficiencies: cant make pyrimidines - orotidine-5-P phosphorylase - orotidine-5-P decarboxylase - leads to decreased UTP (inhibitor of the pathway) high flux through increased orotic acid -Treatment: uridine (+ kinase) UMP UDP UTP synthesis can downregulate pathway Hereditary spherocytosis: Mutations in genes for spectrin, ankyrin, and others lead to weakened interaction of peripheral and integral membrane proteins. Cytoskeletal architecture is altered. Leads to lysis of the RBC. Hermaphroditism (2 classifications) PSUEDO: - XX male w/ gonadal dysgenesis (cant undergo puberty) - SRY factor was transferred to X chromosome TRUE: - 46, XX - has both testicular and ovarian tissue, both sex organs, or ambiguous Herniated disk: tear or break in laminae of the annulus fibrosus, extrusion of nucleus pulposis. Typically ruptures posterior = intense pain as pushes on lower spinal nerves.

16

Hexokinase deficiency: decrease flux through glycolysis, decrease 2,3 DPG, binding isotherm shifts left (rare) HIV infection: (Human Immunodeficiency Virus) - binds to CD4 on helper T cells, deactivating them - great variety among viruses b/c lacks reverse transcriptase 3-5 exonuclease activity - polycistronic nuclear material, RNA spliced after transcription target for protease inhibitors! Homocystinuria Another CHD risk factor. Elevated homocysteine levels. Defect in cysathionine Bsynthase enzyme requires B6. (homocysteine + serine to cysathioninealong the pathway of Met to propprionyl-CoA). Ectopia lentis, osteoporosis, mental retardation, vascular thrombotic. Treat w/ B12, B6 and folate supplementation or Met-restricted diet. - autosomal recessive - homocysteine is produced from methionine. - Classical Homocystinuria - defect serine cystathione synthase (chromosome 21) - cant covert homocysteine cystathione - also disease with B12 deficiency - cant re-methylate homocyteine to form methionine - Methionine synthase deficiency - converta homocysteine to methionine (requires methyl-THF cofactor) - blocks the reconversion of methyl-THF THF - Characterized by developmental delay, childhood osteoporosis, myopia & ectopia lentis - increased CHD (increased thrombus risk) - TREAT with folic acid, pyroxidine - restrict methionine in diet, and supplement cysteine. Homocysteine Toxicity: Elevated levels associated with increased risk of cardiovascular disease. Homocysteine makes homocysteine thiolactone by methionyl-tRNA synthetase and makes Snitrosohomocysteine when reacted with nitric oxide. Homocysteine thiolactone and Snitrosohomocysteine are cytotoxic and react with protein amino groups rendering the modified protein immunogenic Human Heavy Chain Diseases (HCDs) - disorder of B cells, producing Igs without light chains - result of improper gene rearrangments

Huntingtons Disease - single gene mutation - classified as a DNA repeat expansion disorder 17

- autosomal dominant (vertical inheritance, heterozygotes are affected) - expansion of CAG repeat in the coding region for the protein Huntingtin causes a polyglutaminyl chain to be added (gain of function) - extra glutamines causes Huntingtin aggregation in brain cell nuclei - binds to Huntingtin associated protein (HAP) in brain - later onset, usually well into reproductive age (30-50 years old) - all heterozygotes will eventually express phenotype - 50% express it by age 50 - chorea (abnormal voluntary movement) - dementia (basal ganglia atrophy and dilation of lateral ventricle) (degredation in cerebral cortex and basal ganglia) 21-Hydroxylase Deficiency: inherited steroid hormone disorder. 21-hydroxylase for glucocordicoids (cortisol) and mineralcorticoids (aldosterone) defective. Increased ACTH, pregnenolone, progesterone, androgens accumulate. Early virilization, short stature, loss of Na in urine, hypotension. (no cortisol or aldosterone) Hyperammonemia - autosomal recessive, equal gender ratios - disorder of urea cycle, many enzyme deficiencies possible - most common deficient ornithine transcarbamylase - cant convert carbamoyl phosphate citrilline, for shuttle out of mitochondria - anorexia, hypothermia, edema, respiratory problems, tremors, poor coordination - TREAT: - stop protein uptake - supplement non-protein calories - dialysis Hyperammonenia Type I: 1. Carbamoyl Phosphate Synthetase I (CPI) deficiency: (forms carbamoyl PO4 from NH3, bicarb and 2 ATP). treatment w/ arginine stimulates CPI (via activation of N-acetylglutamate synthase). 2. N-acetylgultamate synthase deficiency: (forms N-acetylglutamate and CoA from acetyl-CoA and glutamateargninine activates!!). (N-acetyl allosterically activates CPI). treatment w/ carbamoyl glutamate, which activates CPI by binding where N-actyl would bind. Hyperammonenia Type II: Orthine transcarbamylase deficiency: (makes citrulline from orthinine inside mito) Elevated blood ammonia, AA, orotic acid, glutamine. Treat w/ high CHO low protein diet and benzoic acid or phenylacetic acid. Hypercholeterolemia: autosomal dominant, High serum cholesterol levels, early onset Coronary Artery Disease Hypercellular obesity: AKA Hyperplastic Obesity. Increased number of fat cells, usually due to overfeeding of infant, this is more serious of 2 conditions. Overfeeding stimulates the overproduction

18

of white fat cells. Cant reduce the number of fat cells only their size. Hyperphenylalaninemia - autosomal recessive (equal gender ratios, but racial differences exist) - generally classified with serum phenylalanine higher than 2mg/dl - Classical Phenylketonuria Hyperphenylalaninemia (most common) - caused by lack of phenyalanine-4-hydroxylase [PAH] (cant catabolize) - allelic heterogeneity allows for different levels of enzyme (different severities) - Non-classical PKU (BH4 deficiency hyperphenylalaninemia) - deficiency in tetrahydrobiopterin (BH4) - this is a necessary cofactor for PAH Hyperphenylalaninemia characterized by: - increased serum phenylalanine - decreased tyrosine, melanin, fumarate, and catecholamines - irritability, eczema-like rash, musty urine odor - microcephaly, mental retardation - TREAT: - supplement BH4 and tyrosine - avoid high protein foods - high carbs and fats instead for energy Hypertrophic obesity: Increased size of the white adipocyte of same number of fat cells, most common. Hyperuricemia - defective purine metabolism - leads to increased uric acid in blood and urine Hypoxia: lack of oxygen, common cause of high blood lactate levels; reduces mitochondrial production of ATP (increase. PFK, increase glycolysis and lactate production). Idiopathic Thrombo purpura (ITP): Very low platelet count. See mucocutaneous bleeding (heavy periods, nose bleeds, mouth bleeding) and petichia. Found through CBC Iron-Loading Syndromes: Hereditary hemochromatosis (assoc. w/ HFE, Hepcidin, hemojuvelin, ferroportin, etc), (Aquired: Thalassemia, Sideroblastic anemia, Multiple transfusions) Liver disease, Porphyria Cutanea Tarda. Jaundice Neonatal: excessive bilirubin in the blood, yellow tint, neurotoxic effects in infants if not treated. Infants have depressed levels of enzymes (UDP-glucuronosyl-transferase) for forming glucuronides, treat w/ phototherapy. (sometimes tin-protoporphyrin IX to inhibit heme oxygenase). Sometimes cause is blood group incompatability, or G6PD deficiency.

19

Jaundice Hemolytic (prehapatic): increased RBC destruction. Increase in unconjugated bilirubin (therefore indirect increases). Increased urobilinogen in urine. Serum liver enzymes normal (no liver damage). Dark feces. Jaundice Hepatocellular: Seen as direct damage to liver, therefore reduced uptake of bilirubin. Increased mostly unconjugated (indirect) and maybe conjugated (direct). Serum liver enzymes elevated. Jaundice Post Hepatic: Obstructive --Results from interference with delivery of bilirubin glucuronide to intestine, therefore increased conjugated (direct). Total bilirubin, mostly bilirubin glucuronide increases, appears in urine and putty stool. Serum liver enzymes slightly elevated. Increase urine bilirubin, pale feces. Joint Pain: Chondrocytes hypertrophy and die hyaline cartilage degenerates. Cartilage regeneration is poor except in children. Chondrogenic cells from perichondrium enter the defect and form new cartilage. -Joint Cartilage Repair: torn cartilage doesnt undergo mitosis to regrow articular hyaline cartilagemust punch through subchondral bone to allow chondroprogenitor cells to arise from marrow and migrate into gap, continuous passive motion. Kearns-Sayre syndrome - caused by deletions in mitochondrial DNA (mtDNA) - multisystem disorder, mainly brain and muscle dysfunction (cant do OXPHOS) - also short stature, hearing loss, mental retardation Kernicterus: Issues relating to jaundice including athetoid cerebral palsy, severe motor delay, dysarthria, sensoneuronal hearing loss, and mental retardation. Klinefelter syndrome - 47, XXY (aneuploidy) - longer arms and legs - imbalanced sexual development - underdeveloped genetials - infertility - abnormal breast development (gynecomastia) - fat distribution in body similar to females Krabbes disease: defect in B-galactosidase, can not degrade galactosylceramide (remove galactose from ceramide). Mental retardation, myelin almost absent. 20

Lead poisoning: inactivates ALA dehydratase. Inhibits protoporphyrinogen oxidase (Znprotoporphrin IX replaces iron). Ferrochelatase inhibited by Pb. Interferes w/ Fe transport into mitochondria. Lesch-Nyhan Syndrome - absence of HGPRT (hypoxanthine-guanine phosphoribosyl transferase) Which is part of the salvage pathway for purines, therefore purines are not recycled well, leading directly to a depletion of guanine and hypoxanthine, which reduces levels of GMP and IMP - hyperuricemia (2 ways) increased PRPP increased purine synthesis increased uric acid decreased GMP increased purine synthesis - since brain is reliant on salvage pathway neurological effects - self-mutilation, mental retardation, etc - No effective treatment. Leukocyte adhesion deficiency: Integrin is not produced properly and so leukocytes can not effectively migrate out of the blood vessel. Patients get life-threatening infections. Li Fraumeni Syndrome: rare inherited cancer due to p53 mutation. Individuals display cancers in a variety of tissues at an early age. Marasmus: Chronic starvation, onset is gradual, due to weeks or months of starvation, get involuntary weight loss (5-10% loss is significant). See muscle wasting only after months of weight loss, decrease in blood proteins does not occur until fat and muscle mass have been extensively depleted (can take up to 5 years to show up on tests). Marfans syndrome: Caused by poor microfibril formation in elastic fiber, tendency to rupture aorta and other blood vessels. -autosomal dominant (vertical inheritance, heterozygotes are affected) - mutant glycoprotein fibrillin-1 gene (FBN1) cant properly synthesize elastic connective tissue ruptured aorta, skeletal manifestations, dislocated lenses - variable expression in humans (different phenotypes in everybody) McArdles disease: Also known as Glycogen Storage Disorder V. Glycogen phosphorylase defective in muscle. Limited ability to perform strenuous exercise, otherwise normal & well-developed. Moderate excess accumulation of glycogen in muscle. People with this disease experience difficulty when their muscles are called upon to perform relatively brief yet intense activity. The inability to break down glycogen into glucose results in an energy shortage within the muscle, resulting in muscle pain and cramping, and sometimes causing serious injury to the muscles. The typical features of McArdle disease include exercise intolerance with myalgia (muscle pain), early fatigue, and stiffness of exercising muscles, which are sometimes 21

relieved by rest. Following a short period of rest, most patients experience a second wind and can resume exercise with less difficulty. The prevailing levels of fatty acids as potential energy sources for muscle may account for the second wind phenomenon. In addition, rhabdomyolysisthe breakdown of muscle tissuecan cause myoglobinuria, a red-to-brown-colored urine. The myoglobinuria can cause kidney damage. Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD): catabolism of 6-12C (medium) chain fatty acids deficient due to defect in the MC acyl-CoA DHD. Hypoglycemia, urine with MCFA esters of gly and carnitine. Treat with high CHO diet, avoid fasting, IV glucose. Megaloblastic Anemia - abnormally large RBC precursors (megaloblasts) abnormally large RBCs (macrocytic) - insufficient nucleotide synthesis in rapidly dividing cells - either folate or B12 deficiency (pernicious anemia) - important to find out though, b/c B12 deficiencies have other effects too i.e. demylenation of neurons (Folate defic. can mask B12 defic.) - find out using serum folate, B12, and methylmalonic acid levels Melanoma - has been targeted with gene therapy (experiemental) - removed T cells from body (therefore ex vivo) - insert gene for specific T-cell receptor (TCR), inject cells into patient t-cells can recognize and trigger immune response against melanoma Metabolic Acidosis - results from production of metabolic acids - increases NH4+, which is excreted as glutamate urea production suppressed

Metabolic syndrome - diagnosed if 3 of the following are present: - Abdominal obesity (men have waist measure >40 in) (females >35 in) - High triglycerides - Low HDL - High blood pressure - High fasting blood glucose Metachromatic Leukodystrophy: defect is arylsulfatase A, can not degrade sulfogalactosylceramide (remove sulfo grp.) Mental retardation, demyelination, psych. Disturbance.

22

Methemoglobin Anemia: accumulation of metHb (c/n bind O2). -defects in methb reductase II (mild, inducible by some drugs) -defects in cytochrom b5 reductase of methb reductase I (severe or mild, but 67% of methb reduction is this path) -deficiency (reduced enzyme concentration) of cytochrome b5 methb reductase (mild) -Hemoglobin Ms: mutations in A or B subunits. That make Fe prone to oxidation!!! (i.e. NOT a defect in enzymes that reduce methb). Microcytosis: decreased MCV could be due to: Fe deficiency, thalassemias, Anemia of chronic disease, Hb E, ALAS-2 mutation (siderroblastic anemia), plumbism, Erythropoietic protoporphyria (ferrochelatase). Mucopolysaccharidoses - autosomal recessive lysosomal storage disease - cant degrade mucopolysaccharides - Sanfilippo syndrome most common, 4 subtypes - hydrocephalus, angina, obstructive airway disease, ophthalmologic, musc/skel disease - many die early in life - TREAT: bone marrow transplant can help with some of the effects, prolong life Multiple Carboxylase Deficiency: biotin deficiency or a defect in the biotin holocarboxylase synthetase (thereby preventing the attachment of biotin to enzymes). Multiple Sclerosis: (thought to be) autoimmune disorder, oligodendrocytes are marked for destruction in CNS. Myelin disruption multiple scars of myelin sheath. Muscular Dystrophy: genetic, recessive mutation in dystrophin protein gene, (bundles of myofibrils attached to cytoplasmic aspect of sarcolemma via dystrophin binds actin). Loss = rupture of cell membrane during repeated contraction, profound muscle cell loss. Myasthenia Gravis: Autoimmune disorder that destroys or inhibits the nicotinic acetylcholine receptor From the Greek myastheneia, lit. 'condition of no strength in the muscle', and Latin gravis, 'serious'. The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. Myotonic dystrophy - a DNA repeat disorder, CTG repeat occurs after the stop codon 23

- Multisystem disorder. Prolonged muscle contraction (myotonia); variable muscle weakening and wasting (atrophy); cataracts, defective impulse conduction by the heart; inadequate gonadal function (Hypogonadism) Neurofibromatosis Type I - autosomal dominant - mutant NF1 gene decrease in neurofibromin (a tumor suppressor protein) - nuerofibromas on the head, neck and body - abnormally dilated blood vessels, stenosis, hypertension, aneurisms, optic nerve gliomas - Pigmented (caf-au-lait) spots Neural tube defects - arise in early fetal development, either from folate of B12 deficiency - possible insufficient nucleotide synthesis in rapidly dividing cells - reduced in number since folate supplementation began (i.e. bread) Niemann-Pick (type A): Sphingomyelin accumulates in neurons and foamy reticuloendotheilal cells. Deficiency of sphingomyelinase (cant remove the phosphocholine from the ceramide). Neurological and physical deterioration, death by 3y. Non-Syndromic Deafness - example of locus heterogeneity - mutations on different loci (therefore different genetic causes) all can lead to deafness (different genotype same phenotype) Noonan Syndrome - similar to Turner syndrome, but has a normal karyotype - both sporatic and autosomal dominant cases have been observed - mutant protein tyrosine phosphatase non-receptor type II (PTPN11) gain of function? (pathophys not completely understood) - facial irregularities, most dangerous is the congenital heart disease

Obesity

- classified if BMI is over 30 (overweight if BMI in 25-30 range) - mens girth (waist) >40 in womens >35 in - can predispose to chronic heart disease - can lead to type II diabetes - increased fat insulin resistance elevated insulin required elevated fasting blood glucose diabetes - increases inter-organ cycling of fat increased free fatty acids in blood 24

- increased caloric intake increased fat storage - diet and exercise, therapy, meds, and even surgery can help Osteoarthritis: progressive deterioration of articular cartilage, loss of proteoglycan aggregates and ground substance w/ fiber retention. Lose Teflon. Replace cartilage spur w/ bone tissueform bone spurs which reduce degree of movement. Osteomalacia (adult rickets): deficiency of Vit. D, can cause problems with bodys ability to absorb Ca++ .During remodeling, new osteons do not sufficiently calcify, bones break easily Osteoporosis: severe loss of bone mass with aging. No longer able to maintain mechanical support of body weight, characterized by fractures, backaches, vertebral deformities. 25% postmenopausal women -age-related bone loss: rate of resorption in remodeling remains unchanged, while rate of deposition decreases, thinning of cortical bone and trabecula loss Osteogenesis Imperfecta - dominant negative mutation - defective type I collagen (made of 2 -1 chains and 1 -2 chain) - -1 (COL1A1 gene) - -2 (COL1A2 gene) - T1 collagen is major struct. component of bone/fibrous tissue - mild type (I) decreased production of collagen, but normal chains - more severe types (II, III, IV) missense mutation = amino acid change abnormal collagen - brittle bone disease, also shortened and bowed femur - presents as multiple current/healed fractures - Molecular Testing: - analysis of collagen - mutation analysis Patau syndrome see trisomy 13 Pearsons Syndrome - caused by mitochondrial DNA (mtDNA) deletion - non-neurological childhood pancytopenia (low RBCs and WBCs) and pancreatic dys. - if survival to childhood, becomes Kearns-Sayre syndrome

Pellagra: Due to deficiency of Niacin. Causes dermatitis, diarrhea, and dementia, sometimes leads to death. (See: Hartnups disease)

25

Pernicious anemia - caused by decreased intrinsic factor cant absorb B12 - causes deterioration of stomach lining Chronic atrophic gastritis (an autoimmune disorder) - can be cured with monthly B12 injections Phenylketonuria (PKU) Defective phenylalanine hydroxylase gene (Phe to Tyr via addition of hydroxyl). Occasionally the problem is w/ the dihydrobiopterin cofactor. Phy restricted, Tyr enriched diet, maintained until brain develops. Phenylpyruvate accumulates in high concentration in urine. see hyperphenylalaninemia Phocomelia - rare genetic disorder - causes severe shortening of the arms and legs - the toxic effects of thalidomide prenatally are considered a phenocopy of phocomelia Polycystic Kidney Disease: Autosomal Dominant. Generally heterogeneous, variable age of onset, see kidney cysts; decreased kidney concentration ability; enlarged kidneys, hypertension. Polycythemia: Increase in total number of RBCs. Primary: Polycythemia vera Neoplasm, overproduction of RBCs, myeloproliferative, marrow disorder Secondary: Polycthemia due to secondary condition caused by either natural or artificial increase in EPO (hypoxia, smoking, MetHb, dec 2,3BPG, ectopic/aberrant EPO prod.) Spurious = decreased plasma volume, normal RBC mass (burns, dehydration). -von Hippel-Lindau: get mutation in this gene which prevents ubiquitation complex which leads to EPO production -Mutated EPO receptor causing continuous signal to produce RBCs Porphyria Cutanea Tarda (PCT): enzyme deficiency in URO decarboxylase during heme synthesis (i.e. c/n make copro III). URO III in urine. (Phlebotomy) Prader-Willi Syndrome (PWS) - most patients have deletion of PWS/AS region of paternal chromosome 15 - some have maternal uniparental disomy for chromosome 15 - few (5%) have mutation in the gene that controls paternal imprinting (still biparental) - candidate gene: SNRPN - encodes SmN protein associated w/ snRNPs 26

- involved in pre-mRNA processing - characterized by severe hypotonia, obesity (insatiable appetite) - short stature, small hands and feet, hypogonadism - mental retardation, stubbornness, controlling/manipulative behavior (bring in Dr. Phil!) Prosthetic Valve Hemolysis: A mechanical lysis, will see low levels of serum haptoglobin, have serum negative for hemoglobin but positive for hemosiderin, can get iron deficiency from long-term loss of hemoglobin and hemosiderin. See many schizocytes in blood smear. Disposal of free plasma Hb: If get RBC lysis in the serum, the free hemoglobin will dissociate into alphabeta dimers. When haptoglobin is available, the dimers bind to haptoglobin to form a complex that can then be recepted by the CD163 receptor on macrophages, liver, and spleen to be destroyed and release bilirubin, CO, and iron. However with large amounts of lysis, haptoglobin becomes unavailable so the dimers go straight to the kidney where the reabsorbed dimers make hemosiderin which is then lost in urine (hemosiderinuria and hemoglobinuria). The dimers can also lose its iron (MetHb) and these free hemes can bind to hemopexin or abumin to go to macrophages, liver ect. The free hemes also are involved in the oxidative damage of lipoproteins and endothelium Protein Energy Malnutrion is very rare in the US, most commonly seen in home care and institionalized patients, and especially in the hospitalized children or elderly -Consequences: increased morbidity (infections, delayed recovery from disease and surgery, diminished mental status), increased mortality, longer hospital stay, increased medical costs, impaired quality of life -Treatment: Provide protein to replace nitrogen loss (~1.2-2g/kgbodywt.) taking note of nitrogen balance and infuse amino acids when feeding IV. Provide energy through carbohydrates and lipids (20-30kcal/kgbodywt) but do not overfeed bc it inhibits the recovery by leading to edema and other rebound effects. -Feeding modalities: oral intake is preferred (supplement with nutritionally complete liquid supplements), enteral tube feedings if necessary (can be naso if temporary, but should be gastrostomy if longterm, has advantages that influx is regulated by enterohepatic system), parenteral feedings (nutrients are infused directly into bloodstream so lack first pass through liver, can use peripheral veins for short term but need to use central veins for long term) Acute Catabolic Insult-Induced PEM: caused by physical injury, severe infection, ect. The catabolic phase lasts 3-10days then goes into an adaptation set. It is a systemic response (not just related to the injury site) and the response is directly proportional to the extent of the injury. It is an acute hormonal response seeing increases in cortical glucagon, and decreased sensitivity to insulin -Alterations of metabolism: accelerated gluconeogenesis, increased glucose utilization by injured tissue, decreased glucose utilization by other tissues, and the patient does not appear malnourished with no visible weight loss, have large negative nitrogen balance and accelerated catabolism of proteins which have a high turnover rated (thus not breaking down skeletal muscle, but visceral tissue protein, blood proteins, and immune proteins). See decreases in blood albumin within 4-10days (indicator of catabolic PEM bc can take up to 5 years in starvation induced PEM), catabolism of muscle is only marginally increased and thus no muscle wasting is evident.

27

Phemphigus Vulgaris: autoimmune disease, antibodies to cadherin desmoglein which destroys patients desmosomes, particulary in skin. Severe blistering due to water loss that can lead to lifethreatening infections. Primary ciliary dyskinesia (immotile cilia syndrome, or Kartageners Syndrome): Immotile cilia, they structurally lack dynein cross arms or radial spokes. Patients cant clear respiratory tract, infertile, malrotation of heart, many lung infections. Pseudothrombocytopenia - false low platelet count - EDTA used in running CBC can cause platelets to clump clumps not picked up by machine patient appears to have low platelet count

Purine Nucleoside Phosphorylase Deficiency - leads to a buildup of dGTP inhibits ribonucleotide reductase dec. DNA synthesis - deficiency of T cells, but B cells are fine Pyruvate Kinase deficiency: - inherited RBC disorder, enzymopathy - enzyme from glycolysis, PEP pyruvate rxn. - leads to buildup of intermediates - therefore increased 2,3 BPG synthesis - isotherm shift to the right (favors HbO2 release Respiratory Distress Syndrome: Found in premature infants that lack Dipamitoylphosphatidylcholine which normally develops in the 3rd trimester of fetal development and is the major component of lung surfactant. Supportive therapy now includes synthetic surfactant and partial liquid ventilation which decreases the mortality rate Retinitis Pigmentosa: Autosomal Dominant, genetically heterogeneous. Progressive loss of night vision and acuity. Retinoblastoma: Cancer of the eye Retinoic Acid Embryopathy - teratogenic - causes cranialfacial defects, heart/limb defects, severe developmental delay Rheumatoid Arthritis: autoimmune; body attacks own joint cartilage and synovial membrane. Synovial membrane thickens and increases fluid secretion, pressure, pannus tissue erodes cartilage, bone exposed and fuses across joint.

28

Rickets: Absence of Vit. D, results in deficiency in absorption of Calcium and Phosphorous, chondrocyte proliferation normal but matrix not calcified, therefore no mineralization in cartilage and epiphyseal plate and bone osteoid. Epiphyseal plate large and wide (no CA to kill) bones bend bow legs due to enlarged zone Sanfilippo syndrome see mucopolysaccharidoses Scurvy: Caused by lack of Vitamin C, Vitamin C is a cofactor required for hydroxylation of proline. Thus without hydroxylation of proline the 3 alpha polypeptide chains of the triple helix of the tropocollagen molecule are not held together by the H-bonds. Therefore collagen is weaker. Leads to piticieye in the feet, teeth falling out etc. Severe Combined Immunodeficiency Syndrome (SCIDS) - deficient adenosine deaminase [ADA] (catalyzes deamination of adenosine to inosine) buildup of dATP inhibits ribonucleotide reductase therefore inhibits DNA synthesis - disease has deficiency in both B and T cells NO immune system - could also be caused by defect in Ig or TCR (no effective immune system) - like defective RAG genes (improper recombination) - X-linked form = mutation in IL-2 receptor gene subunit - bubble boy - possible treatment involves ingestion of ADA enzyme in a polyethylene glycol tablet (PEG-ADA), or gene therapy w/ retrovirus Sickle Cell Disease: Hemoglobin S, Mutation of a glutamate to a valine in the hemoglobin AA chain. More frequent in areas of malaria. Altered conformation in the deoxy form leads to aggregation into polymers that cause sickling of the cells which occludes the small blood vessels leading to organ damage Sideroblastic Anemia: Hereditary: 1. ALAS-2 mutation, 2. Erythropoeitic porphyria (ferrochetalase) Acquired: Myelodysplastic (preleukemic), several other causes Get high mitochondrial iron, ineffective erythropoiesis, iron loading, erythroid hyperplasia in marrow leading to apoptosis (high turnover of Hb), low retic count, increased iron absorption from diet, transfusions also increase iron load, -Very rarily hereditary (ALAS-2 mutation, erythropoietic protoporphyria) -Acquired: Myelodysplastic anemia syndrome (clonal/preleukemic, elderly), also can be due to alcohol, lead poisoning, copper defiency, zinc toxicity. Most involve shutting down of ALAS-2 thus inhibiting heme production -Possibility 1: Iron travels via transferrin, is recepted and is then released in the acidic enviro of the endosome, it is then reduced to ferrous iron by ferric reductase and pumped out of the endosome by DMT1, here it is able to pass the membrane of the mitochondria bc it is in ferrous form. Once in the mitochondria it seems that it gets

29

oxidized (possibly by the electron transport chain) before it has a chance to condense with protoporphyrin XI via ferricholatase (which only works with Fe2+). -Possiblity 2: Iron again comes to mitochondria to make heme, but gets sequestered there by ferritin -Possibility 3: Iron-Sulfur clusters form and they are unable to be exported from the mitochondria -Sideroblasts: RBC precursors with heavy iron deposits within the mitochondria Situs Inversus - caused by mutant ZIC3 gene (zinc-finger gene) - abnormal left/right organ alignment in body Skeletal dysplasia - caused by Fibroblast growth factor response genes (cell division/migrat/diff.) - mutant FGFR 3 - i.e. Achondroplasia (see for more info) Southeast Asian Ovalocytosis: Result of K56E mutation, a mutation of Band 3, found in the Malay archipelago and Philippines. Benign in heterozygotes but appears to be embryonic lethal in homozygotes, confers resistance to a type of malaria. Form oval shape of RBC Steatorrhea: greasy, malodorous stool; indicative of biliary or pancreatic problems. MCT oil used as hyperalimentation b/c the Med. Chain FA d/n require the bile and pancreatic lipase (just require the gastric lipase) Synpolydactyly - caused by a HOX-D13 mutation - bony fusions and accessory bones in hands and feet Tay-Sachs disease: (One of the Sphingolipidoses) Lipid filled lysosomes due to ineffective ganglioside breakdown, defect in hexosaminidase A. Cannot breakdown gangliosides that end in GalNAc. Early neurologic deterioration, paralysis, blindness, deafness, death by 3y. A frameshift mutation (4 BP insertion). Increased prevalence in the Eastern European Jewish (Ashkenazi) populations. Telomerase (in aging and cancer) AGING: - activity of telomerase decreases with aging (serves a counting mechanism) chromosome ends degrade cell division stops CANCER: - increased activity in 85% - 90% of human tumors turns off counting cells divide more than they should cancer 30

therefore, telomerases would be good targets for antineoplastic drugs

Tetraploidy - 4N chromosome number (92) - either XXXX or XXYY - caused by failure to complete cleavage in early zygote cell division (genetic material duplicates, but cell doesnt actually divide) Thalassemia - group of hereditary anemias, caused by defective globin chain synthesis (/) - possible genetic causes: - defect mRNA processing (intron mutations) i.e. sickle cell - nonsense mutations (termination codon added) - termination code mutations - -thalassemia is an example of modifying loci (gene modifies other gene) - leads to decreased severity of sickle cell disorder (less Hb decreased amount to polymerize and change cell shape) Thalidomide embryopathy - phocomelia and heart/ear anomalies Thrombocytopenia - low platelet count, can be detected with a CBC (but watch out see pseudothrombocytopenia) - causes abnormal bleeding time Triploidy - 3N, having an extra sex chromosome (XXX or XXY) - lethal, early spontaneous abortion - trunk:head disproportion and syndactyly (fused fingers) - Causes: - 2nd polar body doesnt eject from egg [diagyny] - fertilization by two sperm (improper polyspermy block) [diandry] - nondisjunction in meiosis I/II - nondisjunction in mitosis (cleavage furrow before complete separation) Diandry: - extra paternal set (contributes more to membranes and placenta) - huge placenta, larger than fetus (partial hydatidiform mole) Diagyny: - [think gyn = woman] - extra maternal set (contributes more to embryo proper) - small placenta, normal fetus development with enlarged head Trisomy 13 (Patau syndrome) - if babies come term, often die within the first year - polydactyl (extra fingers) - cleft lip and palate - lower set ears (dont fully shift up to normal position during development) - microencephaly and mental retardation - Holoprosencephaly incomplete midline differentiation in head 31

(combined single eye or eyes too close, defects in nose and mouth) Trisomy 18 (Edwards syndrome) - if babies come term, often die within the first year - mental retardation - short neck, lower set ears - characteristic clenched fist (can be visualized with ultrasound) Trisomy 21 (Down Syndrome) - 3 copies of chromosome 21 (therefore 47, XY (or XX) +21) - mental retardation, flat nose, close-set eyes w/ slanting eyelids, protruding tongue - likelihood related to maternal age - 85% of cases maternal derived - An estimated 1.5 fold increase in expression of genes on chromosome 21, including an important
peroxide mutase enzyme. This has been implicated in both having enhanced protective effects on individuals with down syndrome (cardioprotective, anti-cancer), but could disrupt the free O2 balance, possibly leading to Alzheimers.

Turner syndrome - 45, X (aneuploidy) - often spontaneously aborted due to fluid imbalance - severe lymphedema (lymphatic blockage) - cystic hygroma (fluid filled sac in the back of the head) UV Light Damage - causes pryimidine dimer (thymine) - thymines can be reversed with photolyase (breaking cyclobutane ring of the dimer) - enzyme activated by UV light exposure (smart ) Vitamin A deficiency - common in developing countries - causes night blindness (eventually leading to total blindness) keratinization of the skin and mucosal membranes

Von Gierkes: G-6-phosphatase is defective. (therefore glucose-6-P is unable to go to free glucose in last step of gluconeogenesis). Severe hypoglycemia!! Enlarged liver. Glycogen storage disease type I or von Gierke's disease, is the most common of the glycogen storage diseases. This genetic disease results from deficiency of the enzyme glucose-6-phosphatase. This deficiency impairs the ability of the liver to produce free glucose from glycogen and from gluconeogenesis. Since these are the two principal metabolic mechanisms by which the liver supplies 32

glucose to the rest of the body during periods of fasting, it causes severe hypoglycemia. Reduced glycogen breakdown results in increased glycogen storage in liver and kidneys, causing enlargement of both. Both organs function normally in childhood but are susceptible to a variety of problems in the adult years. Other metabolic derangements include lactic acidosis and hyperlipidemia. Frequent or continuous feedings of cornstarch or other carbohydrates are the principal treatment.

Waardenburg Syndrome - autosomal dominant, loss of function mutation - vertical inheritance, heterozygotes are affected - defect in HuP2 (PAX3) homeobox gene ( TF) - causes white forelock, premature graying, different colored eyes, deafness Werners syndrome - defective WRN helicase - this helicase may be involved with recombination - chromosomal and genetic instability - causes excessive aging cardiovascular disease, arthritis, cancer Wernicke-Korsakoff syndrome: Alcohol induced beriberi (chronic thiamine deficiency). The syndrome is a combined manifestation of two eponymous disorders, Korsakoff's Psychosis and Wernicke's encephalopathy. Korsakoff's psychosis is characterized by confusion, Anterograde and retrograde amnesia, and confabulation. Wernicke's encephalopathy is characterized by nystagmus, ophthalmoplegia, anisocoria, ataxia, sluggish pupillary reflexes, coma and death if untreated. Williams Syndrome - rare, deletion involving elastin gene (ELN) - cardiovascular problems (i.e. supravalvular arotic stenosis) - connective tissue problems, hypercalcemia, distinct facial features Xanthinuria - Deficiency is xanthine oxidase (converts xanthine uric acid) - increased excretion of xanthine and hypoxanthine - decreased uric acid production - causes kidney stones (xanthine lithiasis) X-linked dominant hypophosphatemia (aka Vitamin D deficient Rickets) 33

- in pedigrees, more evident in females than males - heterozygotes are affected - defect PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) - low blood phosphate levels, high urinary phosphate levels - short stature, bone defects as seen in classic rickets

Xeroderma Pigmentosum - autosomal recessive - growth and neurological defects -extreme sensitivity to light - defect in excision repair - protein XPA binds to damaged site complex unwinds DNA 30 nucleotide sequence removed and repaired - since such a large chunk removed for repair, higher likelihood of error - increased cancer occurrence Zellweger Syndrome: Congenital mutation in the PXR1 gene product affecting a receptor on surface of peroxisomes, vital for import of all enzymes into peroxisomes. Death by 6y. High Fe and Cu in blood, muscle and vision abnormalities. It is recognized by the reduction or absence of peroxisomes (cell structures that rid the body of toxic substances) in the cells of the liver, kidneys, and brain. It is characterized by an individual's inability to beta-oxidize very-long chain fatty acids in the peroxisomes of the cell, due to a genetic disorder in one of the several genes involved with peroxisome biogenesis

34

35

36

Self Study Part 1 (2007) Hereditary Fructose Intolerance

1.) Basic biochemical defect in HFI results from genetic defects in coding for Aldolase B. Aldolase B consists of
a tetramer of eight-membered /-barrel subunits with an active site in the middle of the structure. The coding defects result in alteration of the active site or tetrameric structure. 2.) Fructose is unable to be metabolized in the diet due to the enzyme Aldolase B being dysfunctional. Fructose will still be phosphorlyated, but will not be able to continue in glycolytic pathways without functional Aldolase B. 3.) Fructose ingestion is toxic in two ways. First, fructose phosphorylation is unregulated, resulting in the buildup of fructose-1-phosphate which is toxic when accumulated. Second, due to the unregulation, ATP stores are used up for the phosphorylation and thus gluconeogenesis and glycogenolysis are slowed down significantly resulting in hypoglycemia and associated problems from it.

The X-Linked Neurodegenerative Disease, Adrenoleukodystrophy (ALD)

1.) Symptoms include dementia, loss of sight, hearing, speech, and ambulation (ability to walk). These symptoms are believed to due to the build up of very long chain saturated fatty acids (VLCSFAs) which actually solubilize the myelin sheath of neurons, disabling their function. 2.) VLCSFAs tend to accumulate in ALD patients due to a dysfunction in -oxidation of these fats. VLCSFA synthesis occurs in the ER, from where it is transported to the peroxisomes for -oxidation. A key enzyme in oxidation (VLCFA-CoA synthase) produced in the cytoplasm is not properly transported into the peroxisomes, thus VLCSFAs are not broken down. 3.) Lorenzos Oil contains unsaturated fatty acids and is used to competitively inhibit the production of VLCSFAs. Instead of adding more carbons to the saturated chains, they are added using the unsaturated fatty acids as substrates. Lorenzos Oil is Oleic acid and Erucic acid.

Cystanosis
1. What are the clinical manifestations and pathological features of cystinosis?
Clinical Features - most common familial form of the renal Fancomi syndrome due to the failure of renal tubules to reabsorb small molecules o Based on age at onset and severity of the symptoms o Infantile cystinosis - most severe form Fluid and electrolyte loss, aminoaciduria, glycosuria, phosphaturia, renal tubular acidosis, rickets, and growth retardation generally between 6 and 12 months of age Subsequent glomerular impairment leads to end-stage renal disease (ESRD) o Juvenile Cystinosis Individuals with juvenile cystinosis present with a glomerular impairment between 12 and 15 years of age but do not suffer from severe tubulopathy or growth retardation Progression to ESRD is slow and occurs at variable ages o Ocular Cystinosis - no renal abnormalities Cystinosis o autosomal recessive disorder

37

Nephropathic Cystinosis - free cystine accumulates continuously in lysosomes, eventually resulting in intracellular crystal formation throughout the body o Defect in one of the lysosomal hydrolases results in the accumulation of undegraded cystine lysosomal storage disorder Cystinosin - protein that is mis-translated due to defect in CTNS o Lysosomal cystine transporter - cotransports cystine and H+ (cystine/H+ symporter) its cystine activity is H+ driven o

2. What is the molecular defect in this disease?

o o

All forms of the disease have detected CTNS mutations (the gene which codes for cystinosin) Most common mutuation is a deletion Many of the mutations associated with the infantile form are deletions, insertions, splice site mutations, and nonsense mutations that cause premature termination of cystinosin (however missense mutations and in-frame deletions or insertions have also been detected) o *G339R - recurrent missense mutation - noteworthy because a simple screening tool could be carried out for G339R in high risk populations providing a rapid identification of heterozygous carriers Juvenile and Ocular forms - point mutations that do not disrupt the open reading frame of cystinosin are more common with these forms

Metabolic Syndrome
1. Clinical Manifestations of Metabolic Syndrome
The metabolic syndrome is characterized by a group of metabolic risk factors in one person. They include: Abdominal obesity (excessive fat tissue in and around the abdomen) Atherogenic dyslipidemia (blood fat disorders high triglycerides, low HDL cholesterol and high LDL cholesterol that foster plaque buildups in artery walls) Elevated blood pressure Insulin resistance or glucose intolerance (the body cant properly use insulin or blood sugar) Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor1 in the blood) Proinflammatory state (e.g., elevated C-reactive protein in the blood) People with the metabolic syndrome are at increased risk of coronary heart disease and other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease) and type 2 diabetes. The metabolic syndrome has become increasingly common in the United States. Its estimated that over 50 million Americans have it. The dominant underlying risk factors for this syndrome appear to be abdominal obesity and insulin resistance. Insulin resistance is a generalized metabolic disorder, in which the body cant use insulin efficiently. This is why the metabolic syndrome is also called the insulin resistance syndrome. Other conditions associated with the syndrome include physical inactivity, aging, hormonal imbalance and genetic predisposition. a. Some people are genetically predisposed to insulin resistance. Acquired factors, such as excess body fat and physical inactivity, can elicit insulin resistance and the metabolic syndrome in these people. Most people with insulin resistance have abdominal obesity. The biologic mechanisms at the molecular level between insulin resistance and metabolic risk factors arent fully understood and appear to be complex.

38

2.) What is the cellular receptor(s) for these drugs and what is mechanism of action of this receptor as it relates to the treatment of type II diabetes?
The potent insulin-sensitising effect of the TZDs is mediated through activation of the peroxisome proliferatoractivated receptor gamma (PPAR), a nuclear receptor that regulates the production of proteins involved in glucose and lipid homeostasis.[26] The TZDs appear to improve insulin sensitivity via several mechanisms mediated by PPAR, primarily in adipose tissue.[26] While the pre-dominant insulin-sensitising effects occur in skeletal muscle, these appear to be mediated indirectly via altered free fatty acid (FFA) supply.[27] For example, PPAR acts as a central regulator of adipocyte differentiation.[26] First, stimulation of PPAR by TZDs promotes fat cell differentiation, leading to the production of smaller, more insulin-sensitive adipocytes, which in turn promotes insulin-dependent glucose uptake into adipose tissue.[26] Second, PPAR activation by TZDs affects the secretion of several substances from adipocytes that are involved in the regulation of insulin sensitivity and glucose metabolism, such as FFA and tumour necrosis factor alpha, which may lead to improvements in insulin signalling in insulin-sensitive tissues.[28] Importantly, the TZDs have been shown to increase levels of adiponectin, [19,29,30] a protein secreted by adipocytes that has anti-inflammatory properties,[31] is thought to enhance insulin sensitivity,[32] and is down-regulated in obesity and in type 2 diabetes. [33,34] All of these mechanisms decrease blood glucose levels.

Alzheimers Disease and Spongiform Encelphalopathies

1. Protein misfoldng and aggregation leading to amyloid fibril formation and human disease
Many human diseases are caused by failure of specific proteins to adopt or remain in their native functional conformational states: - called protein misfolding diseases - misfoldings cause reduction of the protein amounts The largest group of diseases is when the proteins are changed from their soluble foldings to highly organized fibrillar aggregates - called amyloid fibrils or plaques

39

- large table in article showing the diseases with amyloid fibrils - can be both sporadic and hereditary - spongiform encephalopathies, a prion protein disease, are transmissible in mammals, and cause accelerated fibrillation in mice when they ingested amyloid fibrils Fibrils all have the following associated with them - major protein component forming the core - metal ions - GAGs - serum amyloid P component - apolipoprotein E - collagen Amyloidal structures can serve as nonchromosomal genetic elements (prions!)

2. What are mechanisms of the aggregation process; such as protein conformational changes, methods of transition, the role of oligomers or structured protofibrils.
Amyloid formation occurs via a Nucleated Growth Mechanism - includes a lag phase followed by rapid exponential growth - lag phase assumed to form nucleus Oligomers - present right before fibril formation, thought to help form fibrils and are implicated in toxicity of neurodegenerative disorders - also known as protofibrils, they help to form different fibrils by starting the pathway Aggregation - proteins have a tendency to aggregate under conditions that promote their partial unfolding, such as high temp, high pressure, low pH or organic solvent conc. - can occur via partial unfolding of protein or via native-like oligomers Aggregation Process - oligomers and/or protein unfolding start to create the protofibrils in the system which then aggregate together

40

41

42

43

44