comprehensive pathophysiology

7/31/2019 Comprehensive Pathophysiology

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ComprehensivePathophysiology:

Final exam material

Pathophysiology


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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 withdiarrhea, steatorrhea, and ataxia.

Aceruloplasminemia: absence of ceruloplasmin (copper ferroxidase that facilitates Fe release fromcells). 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 tothe 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 thelinear 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 necessarycytoplasmic 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, andmuscle 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

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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 membraneanchor 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 willalso 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 theimmune 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 un-

oxidized homogentisate accumulates and polymerizes resulting in joint damage, calcification of CVS

and urinary tract, ochre to the skin, black urine. Can not metabolize homogentisate tomaleyloactoacetic 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,

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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 themacrophages. This lowers serum iron quickly (but still have high levels of serumferritin 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

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- 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 inplasma, 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 inblood 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 fattystreak 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 coreand 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 topartly block the artery (associated with angina).

4. If the fibrous cap ruptures then get a thrombosis as WBCs and platelets occlude the

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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 ischemiaEndothelial 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, havesimilar 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 22conformation 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'sencephalopathy), 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 andweakening 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 alsoreferred 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 sensitivityDecreased 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,

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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 (6-12 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 unreactedGalactose-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

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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 (


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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 reabsorbedinto 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 glucoseand 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, Eventuallypancreas resistant to glucose and stops producing insulin altogether.

-Leads to hyperglycemia because insulin secretion eventually decreases this leads liver tocontinue 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 (126)

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-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

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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

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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

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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 normalplasticity 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 andHb 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 affectinteraction 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)

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- 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.

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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 B-

synthase enzyme requires B6. (homocysteine + serine to cysathioninealong the pathway of Met topropprionyl-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 S-nitrosohomocysteine when reacted with nitric oxide. Homocysteine thiolactone and S-

nitrosohomocysteine 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

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- 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 CoronaryArtery Disease

Hypercellular obesity: AKA Hyperplastic Obesity. Increased number of fat cells, usually due tooverfeeding of infant, this is more serious of 2 conditions. Overfeeding stimulates the overproduction

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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 mitochondrialproduction 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 nottreated. 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.

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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 enzymeselevated.

Jaundice Post Hepatic: Obstructive --Results from interference with delivery of bilirubin

glucuronide to intestine, therefore increased conjugated (direct). Total bilirubin, mostly bilirubinglucuronide 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 newcartilage.

-Joint Cartilage Repair: torn cartilage doesnt undergo mitosis to regrow articular hyaline

cartilagemust punch through subchondral bone to allow chondroprogenitor cells to arise frommarrow 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.

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Lead poisoning: inactivates ALA dehydratase. Inhibits protoporphyrinogen oxidase (Zn-

protoporphrin 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 ofguanine 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 weightloss, 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 anenergy 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

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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, rhabdomyolysisthebreakdown 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, urinewith 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 tooi.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 if3 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.

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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 chronicdisease, 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 holocarboxylasesynthetase (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 cellmembrane during repeated contraction, profound muscle cell loss.

Myasthenia Gravis: Autoimmune disorder that destroys or inhibits the nicotinic acetylcholine

receptorFrom the Greekmyastheneia, lit. 'condition of no strength in the muscle', and Latin gravis,

'serious'. The hallmark of myasthenia gravis is muscle weakness that increases during periods ofactivity and improves after periods of rest.

Myotonic dystrophy

- a DNA repeat disorder, CTG repeat occurs after the stop codon

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- 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 inwomens >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

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- 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 bonespurs which reduce degree of movement.

Osteomalacia (adult rickets): deficiency of Vit. D, can cause problems with bodys ability to absorbCa++ .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 todeath. (See: Hartnups disease)

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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 ofhydroxyl). 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, marrowdisorder

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

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- 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 complexthat 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 hemosiderinwhich 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 andinstitionalized 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 byenterohepatic 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 (notjust 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 doesnot appear malnourished with no visible weight loss, have large negative nitrogen

balance and accelerated catabolism of proteins which have a high turnover rated (thusnot 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 ofmuscle is only marginally increased and thus no muscle wasting is evident.

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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 life-

threatening 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 Dipamitoyl-phosphatidylcholine 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.

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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 andepiphyseal 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 intopolymers 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 causesGet 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 bedue to alcohol, lead poisoning, copper defiency, zinc toxicity. Most involve shuttingdown 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 themitochondria bc it is in ferrous form. Once in the mitochondria it seems that it gets

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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 thereby 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 mitochondriaSitus 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 theMalay 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 inGalNAc. 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

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- 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 headTrisomy 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

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(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 importantperoxide 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 fromgluconeogenesis. Since these are the two principal metabolic mechanisms by which the liver supplies

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- 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 canceroccurrence

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 ofperoxisomes (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

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Self Study Part 1 (2007)

Hereditary Fructose Intolerance1.) 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. Fructosewill 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.

Cystanosis1. 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

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o 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

2. What is the molecular defect in this disease?o All forms of the disease have detected CTNS mutations (the gene which codes for cystinosin)

o Most common mutuation is a deletion

o 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

o 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 SyndromeThe 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 themolecular level between insulin resistance and metabolic risk factors arent fully understood and

appear to be complex.

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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 proliferator-activated 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 theproduction 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

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- 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

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comprehensive pathophysiology

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