Final+Exam+Review+2

= =
 * DISEASES FOR FINAL EXAM BLOCK 1**

= = =__Mitochondrial Cytopathy (26)__=
 * UNIT 1 *****


 * Mitochondrion** is the cell component involved. It is a defect of oxidative phosphorylation that increases the size and number of muscle mitochondria. The clinical consequence is high basal metabolism without hyperthyroidism.

=__Kartagener’s Syndrome (26, 121)__=

a.k.a Primary Ciliary Dyskinesia, Immotile Cilia Syndrome

The **microtubule** is the cell component involved. The molecular defect is a lack of dynein in cilia and flagella. This leads to a morphological change that is a lack of arms in the doublet microtubles. The clinical consequence is immotile cilia and flagella with male sterility and chronic respiratory infection.

=//__Mouse (Acomys) diabetes__//=

//The cell component involved is the **microtubule** and the molecular defect is a reduction of tubulin in pancreatic beta cells. The morphological change is a reduction of microtubules in beta cells. This leads to a clinical consequence of high blood sugar content (diabetes).//

//Metachromatic Leukodystrophy//
//The cell component involved is the **lysosome** and the molecular defect is a lack of lysosomal sulfatase. The morphological change is an accumulation of lipid (cerebroside) in tissues. This leads to a clinical consequence of motor and mental impairment.//

=__Tay-Sachs Disease (26) (also studied later in Unit 2 pg. 210)__=

The cell component involved is the **lysosome** and the molecular defect is a deficiency in hexosaminidase A. The enzyme is used to breakdown fatty substances in the brain and nerves. This leads to an accumulation of GM2-ganglioside. The clinical consequence is motor and mental impairment. It is common in Northeast European Jewish (Ashkenazi) Ancestry. = =

=__Hurler’s Disease (26) (also studied later in Unit 4)__=

The cell component involved is the **lysosome** and the molecular defect is a lack of alpha-L-iduronidase. This is a mucopolysaccharide (from proteoglycans, protein-sugar) disorder characterized by the inability to metabolism complex carbohydrates by alpha-L-iduronidase.

This leads to an accumulation of dermatan sulfate in the dermis and heparin sulfate in the basement membrane of connective tissue. This leads to the clinical consequence of growth and mental retardation.

=__Proinsulin Diabetes (26)__=

The cell component involved is the **secretory granule** and the molecular defect is a defect of proinsulin cleaving enzyme. There isn’t a morphological change, but this disease leads to high blood proinsulin content (diabetes).

=__I-cell disease (26)__=

The cell component involved is the **Golgi complex** and the molecular defect is phosphotransferase deficiency. The morphological change is in inclusion-particle storage in fibroblasts and this leads to the clinical consequence of psychomotor retardation and bone abnormalities.


 * __Hereditary Spherocytosis__** **__(73)__**

There is a defect in one ore more cell membrane cytoskeleton proteins. The protein interaction result in decreased stability of the RBC membrane. The cells adopt a more spherical shape. Due to lack of flexibility the cells get stuck in the spleen where they are destroyed.


 * __HIV__** **__(100)__**

T-cell destruction.


 * __Phemphigus Vulgaris__** **__(124)__**

This is an autoimmune disease where antibodies attack and destroy cadheric desmoglein. The result is destruction of desmosomes particularly in the skin. This causes severe blistering due to water loss and increases risk of life threatening infections.


 * __CO Poisoning (144)__**

CO bound Hb has higher affinity for O2. Death may result at 50% desaturation, but 50% loss of Hb in anemia is asymptomatic.


 * __Sickle Cell Disease (145)__**

βGlu6àVal Mutation, causes RBC to alter conformation and allow binding of another Hb Sickle (HbS), forming a polymer that restricts the Hb to the deoxy form. The HbS polymers then, cause the sickling of the RBC.

Reversible Sickling – RBC return to original state as HbS disaggregates and then allows oxygenation. Irreversible Sickling – Leads to RBC Death and occlusion of small blood vessels resulting in organ damage. This results when cells have been in the sickled state for a long time.This disease is prominent in African Americans.


 * __Hypercellular Obesity (I-155)__**

Increased number of fat cells usually due to overfeeding as child. More serious that hypertrophic obesity.


 * __Hypertrophic Obesity (I-155)__**

Increase size of same number of fat cells. This is more common than hypercellular obesity.


 * __Anaphylactic Shock (158)__**

Bronchioles contract, fluid in blood goes to lungs, and you drown.

A severe, often fatal form of shock characterized by smooth muscle contraction and capillary dilation initiated by cytotropic (IgE class) antibodies. (Stedman’s Dictionary)


 * __Scurvy (I-159) (II-85)__**

This disease results from a lack of Vitamin C. Vitamin C is required as a cofactor for hydroxylation of proline in collagen formation. Lack of Vitamin C results in insufficient hydrogen bonding. This weakens the collagen in the bone matrix and a strong osteoid is not formed. The bone is weak due to thinner cortical bone. Also, growth and fracture repaid is retarded. Symptoms: Weak bones, tooth loss, connective tissue issues. Treat with Vitamin C.


 * __Ehlers-Danlos, Type VII (I-159)__**

There is a change in procollagen peptidase that cleaves protein off procollagen to form tropocollagen molecules. Tropocollagen then self-assemble to form collagen fibrils. Symptoms: Hyperflexible joints, dislocations, soft skin.


 * __Ehlers-Danlos, Type IV (I-160)__**

There is a deficiency in Collagen Type III. This results in aneurysms and intestinal rupture.


 * __Marfan’s Syndrome (I-161)__**

There is poor microfibril formation in elastic fiber. This results with a problem in fibrillin. There is a tendency for rupture of aorta and other blood vessels. Patients may be prone to aneurysms.


 * __Edema (I-165)__**

An abnormal build up of interstitial fluid in the ECM. Edema is caused by…

Blocked Lymphatics: surgery, elephantiasis Liver Disease: insufficient Albumin production (lower oncotic pressure at venous end of capillary, resulting in decreased resorption of H2O) Increased vascular permeability from Histamine Hypertension: due to increased hydrostatic pressure at arterial end of capillary bed Starvation: resulting in lack of plasma proteins

“Myxedema” is due to over production of glycosaminoglycans (GAGs) during hypothyroidism.


 * __Emphysema__**

Elastic fibers in lung which force air out are no longer able to re-contract.


 * __Retinoblastoma (I-179)__**

The retinoblastoma protein is involved in G1 to S cell cycle transitioning. The cdk/cyclin B complex phosphorylates the retinoblastoma protein (activating it) and once it is phosphorylated it dissociates from E2F protein thereby allowing the cell to transition from G1 to S.

Retinoblastoma is caused by defects in **both copies** of the Rb gene in C13, whereby the E2F subunit cannot dissociate from the retinoblastoma protein. “Two Hit Hypothesis” as the loss of one allele has no effect—that’s the wild-type genotype. Thus resulting in a tumor.

Symptoms: Right strabismus (crossed eyes), leukocoria, the reflection of a white mass within the eye that makes the pupil look white.


 * __Leukocyte Adhesion Deficiency (I-184)__**

Defect in the integrin protein needed for proper trapping and adhesion of leukocytes to the endothelial cell wall during extravasation. Patients suffer from life threatening infections as leukocytes cannot effectively migrate out of the blood vessel.


 * __Glanzmann’s Disease (I-186)__**

Inactive Integrin on platelets is unable to bind to fibrinogen to participate in clotting. It is first activated by binding to collagen or thrombin. Active integrin can then bind to fibrinogen. Lack of beta-3 integrin results in excessive bleeding because of lack of clotting.


 * **UNIT 2 *******


 * __FATTY ACID CATABOLISM__**

- Catabolism of medium chain fatty acids (6-12 carbons) deficient due to defect in Medium Chain Acyl-CoA Dehydrogenase (Beta Oxidation) - Precipitated by fasting or infection - Urine contains MCFA esters of glycine and carnitine - Treat with IV glucose (immediate treatment), high carb diet, avoid fasting
 * MCAD** (Medium Chain Acyl-CoA Dehydrogenase Deficiency)


 * SCAD** (Short Chain Acyl-CoA Dehydrogenase Deficiency) [4-6 carbons] [p. 15]
 * LCAD** (Long Chain Acyl-CoA Dehydrogenase Deficiency) [12-18 carbons] [p. 15]

- Fatty Acids unable to be shuttled into mitochondria from cytosom - Autosomal recessive - Triggered by exercise, fasting - Symptoms include muscle pain, stiffness, myoglobinuria (pinkish urine from muscle damage) and may include enlarged liver - Treat with high carb, low fat diet and medium chain triglycerides o Medium and short chain F.A.’s can enter mitochondria without the enzyme.
 * Carnitine Palmityltransferase Deficiencies** (CPT I or II Deficiency) [p. 20]

- Rare hereditary disorder affecting infants - Problems in prenatal development, enlarged liver, high levels of iron and copper in blood, muscle and vision abnormalities. Death by age 6. - Mutations in PXR1 gene product (receptor found on surface of peroxisimes that is vital for import of enzymes, such as those in beta oxidation, detox reactions, and copper and iron byproducts). Peroxisomes are empty.
 * Zellweger Syndrome [p. 29]**


 * __CARTILAGE AND JOINTS__**

- Extrusion of nucleus pulposis, the gelatinous matrix of the intervertebral disc, into the surrounding fibrocartilage (annulus fibrosis) - Impinges on nerve rootlet and spinal cord - Treatment o Usually heal by it self by taking weight off back o Surgery, cortisone, manipulation, bed rest
 * Herniated Disc (aka Slipped Disc) [p. 38]**

- Degenerative arthritis that affects synovial joints - Most common type of arthritis - Non-inflammatory & progressive deterioration of articular cartilage - Characterized by o fibrillation of articular cartilage (loss of ground substance and retention of fibers) § less slippery o proliferation of cartilage at periphery o replacement of cartilage spur with bone tissue to form bone spurs which reduce degree of movement
 * Osteoarthritis [p. 43]**

- //Inflammatory autoimmune// disease (<= difference from osteoarthritis) o Body attacks own joint cartilage and synovial membrane o Synovial membrane thickens and synovial fluid secretion increases § Pressure due to increased amounts of synovial fluid causing pain and tenderness o Pannus of tissue (granulation tissue) forms across cartilage and erodes away cartilage. This exposes bone that eventually fuses across the joint.
 * Rheumatoid Arthritis [p. 43]**


 * __BONE DEVELOPMENT, MODELING, AND REPAIR__**

Stimulate bone formation and accelerate closure of epiphyseal plate
 * Androgens and Estrogens (II-84)**

A.K.A. somatotropin. GH is secreted by the anterior pituitary gland and stimulates bone formation. If there is an excess of GH in a growing child Gigantism may result. Pituitary Dwarfism results from a deficiency in GH. Acromegaly results from excess GH in adults. It is characterized by thickening of the bones, especially facial bones near the eyebrows and enlargement of hands and feet.
 * Growth Hormone (II-85)**

Vitamin A acts to balance bone deposition with bone degradation (remodeling). Excess Vit. A leads to rapid erosion of cartilage resulting in premature closure of epiphyseal plate (dwarfism). A Vitamin A deficiency will lead to a decreased growth rate. This would lead to a lack of bone resorption during normal remodeling. Bone growth would not keep up with the growth rate of the rest of the body. The cranial cavity and spinal column would fail to enlarge fast enough to accommodate the growing brain and spinal cord.
 * Vitamin A (II-85)**

Vitamin D controls the normal absorption of Ca++ from the gut.
 * Vitamin D (II-85)**


 * 1) Rickets: This is a calcium deficiency in children. There is no mineralization of the cartilage in the epiphyseal plate and bone osteiod. Bone lacks structural strength and bend due to an enlarged zone of calcification (“bow legs”)


 * 1) Osteomalacia (adult rickets): This is a calcium deficiency in adults. Newly formed bone (osteons) does not calcify sufficiently during remodeling. This weakens the bones and makes them more prone to breaking. May be seen in pregnancy when mother is supplying calcium to the fetus.

Cholesterol is a precursor for vitamin D which is formed in the skin via photolysis from UV light. The previtamin D is then shipped to the liver to be hydroxylated to vitamin D.

Normally there is a loss of bone from all parts of skeleton with aging. This is due to the rate of bone resorption in remodeling remaining unchanged while the rate of bone deposition decreases. This result is the thinning of cortical bone and loss of trabecula through the bone mass.
 * Age related bone loss (II-86)**

This is severe bone loss of bone mass with aging. The reduction of bone mass of skeleton so great that it is no longer able to maintain mechanical support. It afflicts 25% of all postmenopausal women and is characterized by fractures, backaches, and vertebral deformities.
 * Osteoporosis (II-86)**


 * __LIPIDS (II-95)__**

It’s important to recognize this enzyme in fatty acid synthesis because it is the primary regulatory site. It catalyzes the conversion of Acetyl CoA to Malonyl CoA, and has biotin as its prosthetic group. This enzyme is inhibited by high amounts of FA, activated by citrate and by forming aggregates. In a high carbohydrate diet, Insulin activates Protein Phosphatase to dephosphorylate and activate Acetyl CoA Carboxylase. Glucagon and Epinepherine do the opposite by activating Protein Kinase A, which leaves the enzyme phosphorylated and inactive.
 * Acetyl CoA Carboxylase**

Essential Fatty Acid (EFA) Deficiency typically occurs in infants who are fed EFA deficient formula and is also caused by long term total parenteral nutrition. The symptoms include: decreased growth, skin abnormalities, and impaired immune response. To correct the problem, supplement the diet with essential fatty acids like vegetable oils.
 * Essential Fatty Acid Deficiency**

Myasthenia Gravis is an autoimmune disorder characterized by chronic progressive muscle weakness. The autoimmune antibodies block Acetylcholine receptors in the neuromuscular junction. This causes a decrease in Acetylcholine receptors and a reduction in muscle excitation/contraction which makes muscles appear fatigued. The treatment is to inhibit Acetylcholinesterase with blockers.
 * Myasthenia Gravis** (pg 127)

//Type I (Juvenile Diabetes):// insulin is not produced in the pancreas. Glucose utilization and all other insulin dependent functions are affected (adipose lipase will go up, acetyl-CoA carboxylase will go down).
 * Diabetes** (pg 134)

//Type II (Adult Onset//): Insulin is produced but the effects of insulin on glucose transport/utilization are impaired (mechanism unknown). Glucose accumulates in the blood, which stimulates the pancreas to produce more insulin. (Other insulin dependent functions are preserved, ex. Acetyl CoA carboxylase stimulated- FA increases and adipose lipase decreases). Eventually the pancreas becomes resistant to glucose and stops responding with insulin production.

Glucagon activates hormone sensitive lipase, which releases fatty acids from adipocytes. The fatty acids are converted to acetyl-CoA in the liver, and with low levels of insulin Acetyl-CoA carboxylase is inactive and doesn’t produce malonyl-CoA for fatty acid synthesis. As a result, there is more fatty acid oxidation (normally malonyl-CoA would inhibit carnitine acyl transferase). The excess acetyl-CoA is converted to acetoacetate. The ketone bodies are released into the blood for export to tissues that can use them.
 * Ketogenesis in Diabetes** (pg 148)


 * THE CITRIC ACID CYCLE (II-165)**


 * Thiamine deficiency (vitamin B1)**


 * //“Dry” Beriberi://** This condition is the result of chronic low thiamine levels. Symptoms may include peripheral neuropathy, fatigue, and an impaired capacity to work.


 * //“Wet” Beriberi://** This condition results from severe thiamine deficiency. It may lead to neurological manifestations such as lesions and emotional disturbances, cardiovascular symptoms, heart enlargement and tachycardia, cardiac failure after stress, edema and anorexia.


 * //Wernicke-Korsakoff syndrome://** This condition results from Chronic Thiamine Deficiency. Patients with this disorder have been shown to have defective transketolase that exhibits a reduced affinity for TPP (Thiamine Pyrophosphate). This in a thiamine-deficient condition, transketolase activity in these individuals is reduced. This condition is sometimes seen in patients with chronic alcoholism because of their poor nutrition coupled with impaired absorption of the vitamin. Clinical manifestations of the syndrome include weakness or paralysis and impaired mental function.


 * Thiamine Testing:** A diagnostic test is based on the measurement of the ratio of lactic to pyruvic acids in the blood after administration of glucose. Blood and urinary pyruvic acid levels are characteristically elevated in thiamine deficiency, as would be expected from the role of thiamine in pyruvic acid metabolism; but abnormal blood lactic acid-pyruvic acid ratios are said to be more specific indicators of vitamin B1 deficiency than the levels of pyruvic acid alone.


 * __MUSCLE (II-194)__**


 * //Endurance Training://** Some examples include jogging, running, cycling, and swimming. This can lead to an increase in the number and the size of mitochondria. There will be an increase in oxidative enzyme activities and also in glycolytic enzymes.


 * //Resistance Training://** This will increase the strength of muscles by the neural factor and by muscle fiber enlargement (hypertrophy).


 * //Limb Extension://** ex. crutches. The greatest percent decrease in size in knee extensor, then knee flexor, and then knee adductors.


 * //Bed Rest://** The greatest percent decrease in strength in the ankle extensor, then knee extensor, then ankle flexor, then knee flexor.


 * //Aging://** With aging there is a decrease in the number of muscle fibers, muscle mass, fiber distribution, and muscle strength.


 * __LIPIDS 4: Phospholipids. Sphingolipids, and Arachidonic Acid (II-199)__**


 * Dipalmitoyl-phosphatidylcholine**: This is a major component of lung surfactant that is essential to keeping alveoli open. Its deficiency is the basis for respiratory distress syndrome, common in premature infants. Treat with synthetic surfactant.

There is a defect in B-N-acetylhexosaminidase (hexosaminidase A). Gangliosides that end with GalNac cannot be degraded. Some symptoms include early neurological deterioration, blindness, deafness, paralysis death by 3. Neuron lysosomes are filled with lipids. There is prenatal testing for Hex A activity, but no treatment.
 * Tay-Sachs**

There is a defect in glucocerebrosidase (B-glucosidase). Types 1-3: early childhood to late adult onset. Symptoms include easy bruising, fatigue due to anemia, large liver and spleen, weakness of skeleton, occasional lung and kidney impairment. Type 2 and 3 more severe extensive brain damage. Type 1 can be treated with enzyme replacement (ceredase). The enzyme is responsible for cleaving glucose off of Ceramide.
 * Gaucher’s Disaease**

There is a deficiency of sphingomyelinase. Sphingomyelin accumulates in neurons and foamy reticuloendothelial cells in liver, spleen, bone marrow and other tissues. There is early onset death before age three. Large liver and spleen, mental retardation, anemia, neurological and physical deterioration. The enzyme is responsible for cleaving the P-Choline off of Ceramide.
 * Niemann-Pick**


 * __NEURONS (II-229)__**

Glial cells are the primary source of **tumors** in the central nervous system.


 * Wallaerian degeneration**- degeneration and phagocytosis of the distal portion of the axon from the site of injury to the tip.


 * Retrograde Axonal Degeneration**- degeneration of the proximal portion of the axon back towards the cell


 * Chromatolysis**- hypertrophy of the cell body, nucleus moves to eccentric location within the soma, nissl substance becomes dispersed and disorganized.


 * Transneuronal Degeneration:** Damage to the major inputs or major targets of a population of neurons may result in the death of neurons one synapse removed from those sustaining direct injury.


 * __LIPIDS (II-272)__**


 * 21- Hydroxylase Deficiency**- Most common inherited disorder of steroid hormone synthesis, enzyme required for synthesis of glucocorticoids and mineral corticoids, Increased secretion of ACTH by anterior pituitary acting as a feedback inhibitor, Enlarged adrenals (Hyperplasia) with accumulation of pregnenolone-progesterone-and androgens, Symptoms present at birth: short stature due to early bone maturation, Los of Na+ in the urine, Hypotension, possible shock or death. Therapy: hormone replacement therapy

Fatty streak >fibrous plaque>occlusive plaque>rupture> thrombus> six feet under
 * Atherosclerosis**-

1) Some risk factor injures the endothelium (Major ones: smoking, hypertension, diabetes, and dyslipidemia)

2) LDL-cholesterol and Monocytes enter the sub endothelial space,

3) LDL is oxidized and macrophages (formerly monocytes) take up oxidized LDL-eat too much because they don’t have a negative feedback mechanism for cholesterol uptake- These foam cells eventually lyse,

4) Smooth muscle cells infiltrate, inflammatory reaction starts,

5) Endothelial Nitrous Oxide (a vaso dilator) decreases because oxidized LDL decreases NOS (nitrous oxide synthetase)- vascular adhesion molecules/cytokines go up,

6) Endothelial ACE (angiotensin converting enzyme) forms Angiotensin 2 leading to vasoconstriction,

7) Eventual proteolysis and endothelial rupture,

8) Platelet aggregation around the ruptured fibrous cap> a big ass thrombus can form and unless you get some heparin and some major clot busters fast you are in big trouble. You can also throw these clots, which will eventually get stuck in your lungs or brain depending where they originated.


 * Atherosclerosis** is generally not a lumen disease. It is intramural in the sub-endothelial space and the tunica media. The artery expands outward (not into the lumen) as the foam cells and cholesterol build up. Expansion is eventually overcome (from forces coming from the elastic fibers in the artery wall) and the lumen narrows. There are **vulnerable plaques** (which have a thin fibrous cap and are lipid rich, T-lymphocyte activated smooth muscle cells are kicking out a lot of inflammatory signals) and **stable plaques** (which have a thick fibrous cap and are lipid poor plaques, the smooth muscle cells tend to have more extra cellular matrix around them).

Unit III: Diseases 19-88

__Inhibitors of Electron Transport__ (29): -Rotenone= extremely toxic insecticide and fish poison, Sodium Amytal (barbiturate) blocks FP1 à CoQ -Antimycin A= blocks flow form Cyt b à C1 -Cyanide and Carbon Monoxide= blocks Cyt a + a3 à O2

__Uncouplers of Electron Transport__ :

__Genetic Defects in Oxidative Phosphorylation (49__): Genetics-
 * 1) Mitochondria are the only organelles outside the nucleus that have their own DNA
 * 2) Some of the proteins that comprise the respiratory chain and ox. phos. system are encoded by mitochondrial DNA, and some by nuclear DNA
 * 3) Several disorders of ox. phos. have been ID’d as a result of nuclear or mitochondrial DNA that’s involved on proper biosynthesis of the ox. phos. system

Defects in Nuclear DNA: Alpers Syndrome Benign infantile myopathy Fatal infantile myopathy Leigh Syndrome MNGIE (mitochondrial neuropathy, GI disorder, encephalopathy) Syndrome

Defects in Mitochondrial DNA: Kearns- Sayre Syndrome LHON (Leber hereditary optic neuropathy) MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) MERRF (myoclonic epilepsy and ragged red fibers) NARP (neuropathy, ataxia, and retinitis pigmentosa) Pearson Syndrome

Clinical Manifestations= muscle cramping and weakness, fatigue, lactic acidosis, CNS dysfunction and vision problems

Treatment= difficult for patients with respiratory chain disorders and often unsuccessful Improvement noted after therapeutic doses of substances that mediate electron transfer- ubiquinone and vit. C

__Ammonia Toxication (49__): tremor, slurred speech, blurred vision and ultimately death if untreated. Results from increased levels of ammonia in the blood. __Glutamate OAA Transferase and Glutamate Pyruvate Transferase (58__): Elevated serum levels of these enzymes indicates tissue damage. __Urea Cycle Disorders (71-73):__ Inherited genetic defects in any of the 6 enzymes of the Urea Cycle. Most severe when at the first reaction. Once the citrulline level is reached the symptoms are less severe due to some covalent linkage of NH3 to C UCD affect 1/25,000 births and there are 155 new cases per year Symptoms usually arise at birth: convulsions, ataxia, lethargy, vomiting, poor feeding, eventually coma Late onsets and cases in adults: hyperactivity, enlarged liver, avoidance of high protein foods Screening= blood ammonia levels, liver biopsy Prognosis= if undiagnosed results in 100% mortality; diagnosed results in fair prognosis (the earlier the better to prevent mental retardation) Type I Hyperammonemia= Carbamoyl phosphate synthetase; ammonia intoxication, mental retardation; treat w/ arginine which stimulates residual enzyme N-acetylglutamate synthetase= mental retardation; treat w/ carbamoyl glutamate (analogue of N-acetylglutamate synthetase) which activates carbamoyl phosphate synthetase Arginosuccinate synthetase= Citrullinemia; high amts. Citrulline and ammonia in plasma, CSF and urine; recessive inheritance; treat w/ arginine which enhances citrulline excretion and/or Benzoate which diverts ammonium nitrogen to other products Argininosuccinic aciduria= Arginosuccinase; ammonia and argininosuccinate high in plasma, CSF and urine; recessive inheritance; early and late onset (2 yrs.) usually fatal; treat w/ arginine and benzoate to promote nitrogen excretion Hyperargininemia= Arginase; rare; abnormal development and CNS function; ammonia and arginine accumulate in blood and CSF; Arg, Lys and ornithine in urine; treat w/ diet of essential aa’s excluding arg and low protein to lower plasma ammonia levels Correlations w/ all UCDs: Ammonia intoxication and accumulation in the blood Brain damage; coma; death; lack of ATP Neural defectsà in the brain ammonia is made into glutamate which depletes its aketoglutarate causing oaa levels to fall and the TCA cycle to stop and leads to permanent cell damage Increased glutamate leads to glutamine formation- depletes glutamate stores needed for GABA synthesis General Treatment UCDs: Limit protein intake- low protein diet: replace with aketo acids which are transaminated in vivo; frequent small meals Remove xs ammonia- can be reduced w/ levulose (acidifies the colon); kill ammonia producing bacteria w/ antibiotics; sodium benzoate or sodium phenylacetate to bind glycine and glutamine for removal or other byproducts Replace missing intermediates in the urea cycle- supplement w/ arg or citrulline

Cystinuria (83): inherited metabolic disorder; excretion cystine increased 20-30 times; excretion of lys, arg and ornithine also increased; renal defect in absorption; cystine relatively insoluble \it precipitates in kidney tubules of cystine calculi Cystinosis (83): defect in carrier mediated cysteine transfer; deposits of cystine crystals in tissues leads to early mortality due to acute renal failure PKU/ Hyperphenylalanemia I (85): Phenylalanine hydroxylase deficiency; 1/ 10,000 people; recessive gene; xs phe allows for alternative catabolites of phe to form; causes mental retardation in infants; phenylpyruvate (alternative catabolite) reacts w/ ferric chloride yielding a black color; treat by restricting phe until age 10 Neonatal Tyrosinemia (86): defect in tyrosine transaminase Type II Tyrosinemia (86): defect in hydroxyphenol pyruvate hydroxylase Alkaptonuria (86): lack of homogentisate oxidase; homogentistic acid in urine; xs homogentisate in urine when made alkaline and exposed to oxygen will convert to melanin (turn black); vit. C reqd for max efficiency of enzymeà vit. C deficiency leads to high-level excretion of phenylpyruvic acid and homogentisic acid Maple Syrup Disease (87): branched chain amino acid DH defect Hartnup’s Disease (88): defect in intestinal and renal transport of tryptophan and other neutral amino acids


 * Final Exam Review - Unit 3**
 * Pgs. 89-158**


 * Homocystinuria I** (pg 94)


 * Deficiency in //cystathionine-B-synthase//, which catalyzes the reaction of homocysteine to cystathionine, in methionine catabolism


 * Homocystinuria II, III, IV** (pg 94)


 * Deficiency in //tetrahydrofolate// (THF) enzyme in methionine catabolism
 * Results in increased homocysteine and SAM in urine


 * Pernicious anemia** (pg 95)


 * Deficiency in the absorption of Vitamin B12


 * Maple Syrup Disease** (aka branched chain ketoaciduria)(pg. 97)


 * Caused by lack of the //alpha-ketoacid dehydrogenase// enzyme
 * This is the enzyme that oxidatively decarboxylates the keto acids formed in the catabolism of leucine, isoleucine & Valine


 * //(PG. 99 is the table with all the diseases for Amino Acids Catabolism for Quick Review)//**


 * Dyslipidemia Classification (pg. 124)**

__Type Abnormal Lipoprotein Abnormal Lipid__

I Chylomicron TG

IIa LDL (beta) LDL Cholesterol

IIb LDL & VLDL LDL-C & TG

III IDL (dys-beta) LDL-C & TG

IV VLDL (pre-beta) TG

V Chylomicron & VLDL TG


 * Hypertriglyceridemia** (pg. 126)


 * <150 mg/dL – Normal TG level
 * >500 mg/dL – very high TG level


 * __Enhances atherogenesis by enhancing__:
 * low HDL
 * high chylomicron remnants
 * Risk greater for women
 * Small dense LDL
 * Cholesterol-rich VLDL remnants


 * __Diet therapy__ (p 157)
 * Increase fat intake (primarily mono and polyunsaturated fatty acids)
 * Decrease carbohydrate intake


 * Lactic Acidosis** (pg. 145)


 * Blood lactate levels are >5mM (normal is 1.2mM)


 * __Cause__
 * Hypoxia – lack of oxygen- reduces mitochondrial production of ATP with consequent activation of PFK, thus, increasing glycolysis and lactate production in anaerobic conditions
 * Increased formation or decreased utilization of lactate

Unit 3 p.159-228
 * __Results__
 * Lowered blood pH & bicarbonate levels

Dylipidemia
High levels believed to be a trigger for CHD Lack of Cystathionine leads to high levels of Homocysteine High risk- Plasma Levels > 15umole/L
 * Homocysteinemia (p164-165)
 * Treatment: Diet- fortified cereals, leafy green vegetables**
 * Multivitamin which includes Folic Acid, Vit. B6, and Vit. B12**

LDL HDL TG Statins- ¯20-60% ­5-12% ¯10-45%
 * Drugs used in treatment of Dyslipidemia (p.167)

Niacin- ¯15-20% ­15-35% ¯25-30%

Fibrates- **­**20% ­15-25% ¯25-50% (Used for high trigs)

BAS- ¯15-25% ­0-3%

Ezetimibe- ¯15-25%

Restrict intake of trans-fatty acids Niacin and Statin drug treatment
 * Lipoprotein a Treatment (p.169)

30-35% kcal diet Weight reduction (ab fat) Exercise Niacin (or Fibrate depending on how high trigs are) and Statin drug treatment
 * Small Dense LDL Treatment (p.170)

Pentose Pathway
Transketolase contains thiamine pyrophosphate (TPP) as a coenzyme Diagnosed by an increase in RBC transketolase activity upon addition of TPP Deficiency Diseases: **Beri-Beri and Wernicke-Korsakoff Syndrome**
 * Thiamine Deficiency (p.176)

RBC Metabolism
The following defects all lead to an increase in Fe 3+ The oxidized form does not bind O2 Defects in Methemoglobin Reductase I & II Deficiency in cytochrome b5 methemogloblin reductase I Hemoglobin Ms- not an enzyme defect, mutation in subunit
 * Methemoglobin Anemia (p.209-210)

Common X-Linked disorder (11% of African Americans) Affected individuals are more sensitive to oxidative stress May lead to **Neonatal Jaundice or Acute hemolytic anemia**
 * Glucose 6-Phosphate Dehydrogenase Deficiency (p.211)

b-Spectrin, a- Spectrin, Ankrin- lead to defects in interaction with Band 3 Mutated cells are not as resilient as normal cells and are deformed as the pass thru capillaries =Condition known as Hereditary Spherocytosis= If affected RBC are elliptical or oval- aka **Elliptocytes or Ovulocytes** __Unit 3: 229-298__
 * Defect in RBC membrane proteins (p.223-224)

__Interconversion of Hexoses—Manning__

-autosomal recessive disease caused by the absence of galactose-1-phosphate uridyl transferase -afflicted infants fail to thrive; vomiting or diarrhea occurs following the onset of milk consumption; enlargement of liver and jaundice are common; many with this disease are mentally retarded -treated by the exclusion of galactose from the diet -high levels of galactose lead to galactitol, a toxic substance that leads to the formation of cataracts
 * Galactosemia**

__Type 2 Diabetes—Repka__

-Individuals with high visceral fat (gut) show an increase resistance to insulin, leading to an excessive rise in blood glucose(blood sugar). As the amount of visceral fat increases increase in insulin resistance  elevated fasting plasma glucose (prediabetes)  diabetes

-Obesity- BMI over 30

Pick 3: Abdominal Obesity (over 40 inch waist in men, 35 in women) TG’s (over 150) HDL (less than 40 in men, 50 in women) BP (over 130/over 85) Fasting glucose (over 110)
 * Metabolic Syndrome**

__Iron Metabolism—Dignam__

-Early Indicators -Total iron binding capacity -Serum ferritin -Late Indicators -Hb levels -Mean corpuscular volume -Signs and Consequences of Iron Deficiency -Person complains of fatigue, weakness, and anorexia; fingernails have a thin and flat spoon-shaped appearance -There is increased susceptibility to infection as a result of impaired cellular immunity
 * Iron Deficiency**

-most common genetic disorder in people of western European descent; 1/10 are carriers and 5/1000 are affected -excessive absorption of iron due to faulty regulation of iron transport -regulates affinity of the transferrin receptor for transferring -cardiomyopathy, liver cirrhosis, diabetes, and arthropathies resulting from accumulation of iron in tissues; half of the individuals are homozygous for the mutation are asymptomatic -because iron accumulation takes many years, it is often manifest in adulthood -treatable by phlebotomy
 * Genetic Hemochromatosis**

-Absence of ceruloplasmin, a copper ferroxidase that facilitates iron release from cells -accumulation of iron in spleen, heart, liver, kidney, thyroid, and retina with accompanying tissue damage -liver iron overload, diabetes due to destruction of the beta cells of the pancreas and nerve damage -Hemochromatosis secondary to other conditions like thalasemia and alcoholism
 * Aceruloplasminemia**

__Protein Nutrition—Repka__

__Stomach__ -Dietary protein is denatured into smaller protein fragments (not aa’s) by HCL -HCL activates pepsinogen and parapepsinogen into their active forms, pepsin and parapepsin

__Intestine__ (some enzymes from pancreas) -Enteropeptidase activates **Trypsinogen**, which activates many enzymes, including carboxypeptidase that cleaves protein segment at terminal COOH; aminopeptidases (from intestine) cleave the NH2 end and dipeptidase (also from intestine) cleaves segments into free AA’s and peptides -AA’s enter the intestinal epithelial cell and the AA pool, where some undergo transamination and protein synthesis (these aa’s are lost); remainder enter into the portal blood

Dietary AA’s enter the liver through portal blood. The liver lacks Branched Chain Amino Acid Transaminases, so some of the portal aa’s (only 25%) are put directly back into the blood. 70% of these AA’s are bcaas, which are then stored in insulin-stimulated muscle for future use. 33% of the aa’s from portal blood become bound to albumin in the liver (another form of storage), which can then return to circulation. Therefore, albumin and other proteins serve as reserve sources protein, making up for the lack of protein storage.
 * Roles of the liver and skeletal muscle in between-meal storage of amino acids**

Nitrogen (gm) X 6.25 = Protein (gm)

High carb intake à large insulin output à increased uptake of BCAA’s by muscle à Decreased competition with Tryptophan for uptake into brain à Tryptophan à Serotonin à Drowsiness
 * Drowsiness induced by high-carb meal**

__Gluconeogenesis—Manning__

In conditions of prolonged fasting, low carb diet, or diabetes, nerves and blood cells, which utilize primarily glucose as a source of energy, cannot survive w/o a continuous supply of glucose produced by gluconeogenesis in the liver and kidney

-coenzyme in carboxylation rxn’s, synthesized by intestinal microorganisms -Deficiency -rarely caused from deficiency in diet because of body’s own production -accompanied by factors such as: -antibiotics that inhibit the growth of intestinal bacteria -ingestion of large amounts of avidin, a protein found in raw egg whites; this protein prevents biotin absorption
 * Biotin**

-results from biotin deficiency or defect in biotin holocarboxylase synthetase, which prevents the attachment of biotin to biotin-dependent enzymes -symptoms include seborrheic dermatitis, anorexia, nausea, and muscular pain Unit 3 -- pgs 288-351
 * Multiple Carboxylase Deficiency**


 * __Gluconeogenesis –__**

Biotin deficiency due to inadequate dietary intake is very rare unless accompanied by other factors such as: i. Antibiotics that inhibit the growth of intestinal bacteria eliminate this source of biotin. ii. Ingestion of large amounts of **avidin**, a protein present in raw egg whites, prevents biotin absorption.

Diabetes increases gluconeogenesis.


 * __Porphyrins and Heme__**

Involve defects in specific steps in heme biosynthesis Product from the previous step accumulates Hepatic porphyrias involve heme synthesis in the liver Erythroid porphorias involve heme synthesis in RBCs Characteristic features include – photosensitivity and excessive hair growth
 * Genetic Porphryias-**
 * Acquired Porphyrias –** result from exposure to various agents – alcoholism, pesticides, herbicides, tumors and iron overload.

α and β globin synthesis is sensitive to iron and heme.

Under conditions of low iron, the iron regulatory protein (IRP) is activated and suppresses the translation of erythroid ALA mRNA; reduced heme synthesis  results in the depletion of heme pools.

Depletion of heme activates a protein kinase (Heme-regulated translational inhibitor – HRI) that phosphorylates a translation initiation factor (eIF-2)  inhibiting translation of globin and α and β chains of mRNAs.

__Porphyria Enzyme Defect Primary Symptom__

Congenital erythropoetic porphyria(CEM) Uroprohyrinogen III cosynthase photosensitivity Erythropoietic protophyria (EPP) Ferrochelatase photosensitivity
 * Erythropoeitic Class**

ALA dehydratate deficiency porphyria(ADP) ALA dehydratase neurovisceral Acute intermittent porphyria AIP PBG deaminase neurovisceral Hereditary coprophyria HCP coprophyrinogen oxidase neurovisceral some  photosensitivity Varigate porphyria VP protoporphyrinogen neurovisceral, some photosensitivity Porphyria cutanea tarda PCT uroprophyrinogen decarboxylase photosensitivity Hepatoerythropoeitic porphyria HEP uroprophyrinogen decarboxylase photosensitivity
 * Hepatic Class**

don’t know if that meant the final too.****
 * Dignam said thre would be no specific question from this “chart” on the exam, but I included it b/c

-Jaundice is excessive bilirubin in the blood, manifest through yellow tint in the skin and in the sclera; indirect bilirubin rises in hemolytic jaundice because the liver cannot metabolize the bilirubin rapidly enough; both indirect and direct bilirubin can rise in hepatocellular jaundice, and total bilirubin increases in obstructive jaundice
 * __Bile Pigments – Dignam__**


 * Kernicterus** – athetoid cerebral palsy, severe motor delay, dysarthria, sensoneuronal hearing loss, mental retardation.

Treatment à photo therapy light 425-275 nm, exchange transfusion in extreme cases, Tin- protoporphyrin IX – inhibition of heme oxigenase
 * Neonatal Jaundice**- low UDP glucuronosyl transferase activity, blood group incompatibility—mother typically O, child A or B. Rh incompatibility is rare as a result of the use of Rho(D) immune globin. Glucose-6-phosphate dehydrogenase deficiency


 * Hemolytic Juandice-** Seen in conditions with increased destruction of red cells with the release of hemoglobin. Increase in unconjugated bilirubin (indirect reacting). The indirect measurement can be 10-20 times the direct value.


 * Hepatocellulare Juandice –** Seen in liver damage in hepatitis or cirrhosis. Unconjugated bilirubin (indirect reacting) is elevated due to reduced uptake of bilirubin. Some bilirubin glucuronide is released from the liver due to cellular damage, so that direct bilirubin may also be elevated.


 * Obstructive Juandice –** Results from interference with the delivery of bilirubin glucuronide to the intestine. Total bilirubin, mostly bilirubin glucuronide (direct) increases. Bilirubin glucuronide appears in the urine (dark brown).


 * Gilbert’s Syndrome -** common disorder (5-10 % of Caucasian population) that is usually mild. Results from reduced levels of UDP-glucuronosyl transferase, the rate limiting enzyme for bilirubin glucuronide productions. It results from a number of different mutations in the promoter of the gene that decrease expression of the protein.


 * Crigler – Najjar Syndrome –** Rare recessive disorder results in moderate (type II) to severe (type I) jaundice due to reduced or absent UDP glucuronsyl-transferase activity. Type II often responds to inducers (Phenobarbital) of the enzyme, while type I may require liver transplantation.. the two types are caused by a number of different mutations. Kernicterus is seen in type I disease.


 * __Protein Energy Malnutrition – Repka__**

No specific diseases here, just remember the 2 cases, starvations induced PEM and acute PEM.


 * __Glycogen Metabolism - Manning__**

3 diseases covered in class.


 * Von Gierke’s Disease** – Deficiency in glucose-6-phosphate enzyme. Leads to increased glycogen and massive enlargement of the liver. Can lead to hypoglycemia.


 * Anderson****’s Disease** – Branching enzyme is defective, the glycogen molecule is extremely long and unbranched. This leads to progressive cirrhosis, liver failure, and death by the age of 2.


 * McArdle’s Disease –** Decfective enzyme is the phosphorylase, which affects the muscle. This leads to excessive glycogen deposition of glycogen in the muscle. This leads to painful cramps during strenuous activity.

Vitamins – Repka

Pantothenic acid
 * Thiamin (B1**)–beriberi, high carb diet; alcoholic malnutrition; flour enriched
 * Riboflavin (B2)**–oral lesions; marasmus; flour enriched
 * Niacin (B3)–**Pellagra; maize diet, decreased protein; flour enriched
 * Pyridoxine (B6**)–neuritis, malaise; decrease in whole grains and vegetables; decrease in B6 with some oral contraceptive users
 * Biotin**–excessive egg whites, not enough yolks
 * Folic acid**–macorcytic anemia; decrease in leafy green vegetables; neural tube defects, homocysteinemia; flour enriched
 * Cyanocobalamin (B12)–**pernicious anemia; vegan diet; loss of intrinsic factor in unsupplemented vegans, mostly children; Krohn’s Disease; require IM injections

Vitamin A–essential for growth, vision, cell differentiation, bone remodeling, proliferation of mucous epithelium, reproduction, and immunity; found in liver and fish liver oils and fortified milk and eggs; 2/3 comes from retinol (high digestibility even at high intakes), 1/3 comes from carotenoid precursors (low digestibility, worse at high intakes); all trans B-carotene is most active and most important, found in dark green, yellow, and orange foods; NIGHT BLINDNESS is earliest manifestation of Vitamin A defiiciency, followed by keratinization of mucous epithelium, and stunting of growth in children; trans retinol from diet becomes oxidized to cis retinal—>rhodopsin—> vision + bleached rhodopsin—>all trans retinol (lack of this recovery is cause of night blindness)
 * Vitamin C -** shortage leads to decreased H bonds, resulting in fragility of bv’s, bone joints, and scar tissue, SCURVY


 * Vitamin D**–fish liver oils, fortified milk, synthesis of cholecalciferol by light irradiation of dehydrocholesterol in skin; RICKETS–breastfed children who aren’t exposed to sunlight, leads to bowed legs and weak joints; osteomalacia


 * Vitamin E**–found in 8 tocopherols in oil fraction of plant foods; RRR-a-tocopherol (formerly d-a-tocopherol) is most active; widely distributed in veg oils and margarines; acts to prevent preoxidation of unsaturated fatty acids; requirement increases with fa intake; requires fat and bile for absorption; incorporated into chylomicrons, then vldl and ldl which is how it gets into cells; Vit C can regenerate a-tocopherol by itself being oxidized (in other words, vitamin C spares vitamin E


 * Vitamin K**–phylloquinione from green plants, manaquinone from bacteria, and synthetic menadione; half from diet, half from bacterial synthesis in intestine; absorption requires fat and bile; turnover is rapid and little is stored; function is to serve as a cofactor for the carboxylation of glutamate residues in inactive precursor proteins such as clotting factors; Vitamin K antagonists (i.e. warfarin and coumadin) inhibit the reduction of Vitamin K via competitive inhibition of reductase enzyme and thus inhibit clotting of blood; newborn infants are given IM injections because they don’t have much at birth; patients on blood thinners may need to stay away from foods high in vitamin K

TOXICITY due to vitamins –


 * Niacin**–monitor for liver toxicity and failure
 * B6**–peripheral neuropathy, ataxia
 * Folic Acid**–undetected anemia due to B12 deficiency
 * Vitamin A**–fetal cranio-facial, CNS, or heart defects; increased osteoporosis, bone thickening, blurred vision, headache
 * B-carotene–**lung cancer and mortality in smokers
 * Vitamin D–**Growth retardation, calcification of kidney and heart


 * __Diseases for pages 1-155 of Unit 4__**

__Xanthinuria__ – deficiency of xanthine oxidase Increase in hypoxanthine and xanthine Decrease in uric acid Kidney stones

__Gout and Hyperuricemia__ – excess of uric acid in circulation and urine Gout – inflammation of joints due to deposit of crystals Deficiency in: PRPP synthetase (not regulated) Glucose-6-phosphatase (increased ribose 5 phosphate) Partial HGPRTase deficiency (enzyme in salvage pathway) Clearance of Uric acid by kidneys Treatment: Anti Inflammatory (colchicine or NSAIDs) Inhibit Uric acid production (Allopurinol) Increase Uric acid clearance (Uricosuric)

__Severe Combined Immunodeficiency Syndrome__ – deficiency in adenosine deaminase Deficit in both T and B cells of immune system Inhibited DNA synthesis by increase dATP

__Purine nucleoside phosphorylase__ – deficiency in T-cells Increase dGTP which inhibits DNA synthesis

__Hereditary Orotic Aciduria__ – Lack of pyrimidines for DNA and RNA Deficiency in: Orotate phosphoribosyl transferase Orotidine-5’-P decarboxylase Deficiency in UTP (inhibitor of pathway) which leads to increased flow through the pathway leading to accumulation of orotic acid Treatment: Uridine will form UTP which will inhibit carbamoyl phosphate synthetase II to down regulate the pathway

Leads to megablastic anemia, growth retardation and excess orotic acid

__Lesch-Nyhan Syndrome__ – Absence of Hypoxanthine-Guanine phosphoribosyl transferase Symptoms: excessive uric acid and certain neurological features (self mutilation, spacisity and mental retardation)

__Trisomy 13 – Patau Syndrome__ – 3 copies of chromosome 13 Symptoms: Bilateral cleft palate Low set malformed ear Polydactyly Survival is only a few days Due to nondisjunction

__Pernicious Anemia__ – deficiency in intrinsic factor IF enables uptake of B12 Treatment: intramuscular B12 __Homocysteinemia__ – increased homocysteine Caused by defect in methionine synthase due to decreased B12 or Folate Recognized as a major risk factor in cardiovascular disease

__Neural Tube Defects__ – arising in early development Caused by deficiency in folate or B12 leading to insufficient nucleotide synthesis in rapidly dividing cells Folate is now added to fortified foods to reduce the incidence

__Megaloblastic anemia__ – Abnormally large red cell precursors (megablasts) are found in bone marrow Abnormally large erythrocytes are found in the circulation Probably caused by a disturbance in DNA synthesis in the rapidly developing cell Can be caused by deficits in either B12 or Folate deficiency It is important to determine the cause because B12 deficiency can also lead to neurological problems (demyelination) not found in folate deficiency

__Bloom’s Syndrome__ – Pre and post natal growth retardation Sunlight sensitivity Impaired fertility Immunodeficiency High incidence of cancer (solid tumors and leukemias) Genomic instability (chromatid breaks, elevated sister chromatid exchange) Defect: Helicase that unwinds G4 DNA structure Leads to defect in replication and recombination

__Werner’s Syndrome__ – Rare recessive mutation Accelerated aging (cardiovascular disease, arthritis, cancers) Chromosomal and genetic instability Defect: mutations in helicase associated with the disease that may be involved in recombination

__Rothmund-Thomson Syndrome__ – genomic instability Increased cancer incidence Premature aging Defect in helicase

__Fragile X Syndrome__ – Most common form of inherited mental retardation Fragile site contains a CGG repeated motif in 5’ untranslated region of FMR 1 6-50 repeats – normal 50-200 repeats – premutation >200 – mutation FMR 1 is infected by too many CGG repeats FMR 1 encodes a RNA binding protein thought to regulate translation Wide tissue distribution but high concentrations in neurons

__Xeroderma pigmentosum__ – hypersensitivity to UV light Results in multiple skin cancers Autosomal recessive defect in excision repair Eight different complementation groups Carriers are ~1% of population

__Heterogeneous Nonpolyposis Colon Cancer__ – Autosomal dominant Early age of onset Defective mismatch repair 3-15% of sporadic colon cancers due to HNPCC

__Ataxia telangiectasia__ – autosomal recessive Increased sensitivity to damage by X-Ray DNA repair defect

__Faconi’s Anemia__ – autosomal recessive Chromosomal instability defective repair of cross-linking damage repair Pathology – bone marrow failure GI and kidney abnormalities Growth retardation Skin abnormalities Increased incidence of cancer (leukemia) 5 complementary groups


 * II. Intro to Molecular Medicine and Medical Genetics:** This is a Micale lecture, and as we have all seen, there is a lot of clinical relevance to just about all of his material. I’m not going to go page for page, note for note on any of his stuff because then I might die. I’ll do my best to hit all major diseases and concepts. Again, this stuff is fresh in your minds anyway...right? Right?

-**Types of genetic diseases**: single gene (Mendelian), multifactorial, chromosomal, and somatic mutations. Chromosomal are most rare and multifactorial most common. Remember, virtually all diseases have a genetic component. Also remember to distinguish between genetic determinism and susceptibility. -**Single gene mutations/rare diseases:** cystic fibrosis and Huntington’s. Examples of susceptibility loci related diseases: Alzheimer’s, migraines, non-insulin diabetes mellitus, and psoriasis. -**Human genome project:** while we probably won’t know the cure for all diseases, we will likely know all the genes. The benefits here are primarily for testing/diagnosis. -**Gene mutations and disease:** 1. cystic fibrosis: an in-frame mutation (3 base pair deletion) at F508 2. Tay-Sachs: frameshift insertion (4 base pairs), alters reading frame -**Pathogenetic Classification of Mutations:** gain of function, loss of function dominant negative effect-->mutant loses fxn AND interferes w/ product of normal  allele; observed in multimeric proteins (e.g. collagen I). We see this in the PAX3 gene and PMP22 gene. -**Molecular genetic testing:** unambiguous determination of presence/absence of mutation, early diagnosis (presymptomatic), distinguishing between orders of similar phenotypes, prenatal testing. Limited by allelic heterogeneity (e.g. cystic fibrosis).
 * Loss of fxn and gain of fxn in same gene can lead to **different** diseases*


 * III. Complicating Factors and Multifactorial Inheritance:** Another Cicila lecture... lots of terminology here. I’m not going to define these terms but remember to distinguish between these: epistasis, penetrance, variable expression, genetic heterogeneity, pleiotropy, phenocopy, and mosaicism.

-only males affected, only father-to-son transmission -**Genetic heterogeneity:** remember that we saw this for cystic fibrosis. Cicila also raises Phenylketonuria (PKU) as an example. Defects can result in either reduced phenylalanine hydroxylase activity, or complete absence. -**Pleiotropy:** Again, PKU is an example. We see multiple manifestions in different tissues as a result of a mutation in a single gene (one gene>multiple phenotypes) ­-**Mosaicism:** Cicila’s example, germline mosaicism in Duchene Muscular Dystrophy. Mothers are apparently non-carriers but an ovary may contain a cluster of calles carrying the mutant allele.
 * -Y-linked inheritance:**

-**Down Syndrome (trisomy 21... karyotype example: 47, XX, +21)** -Signs/Symptoms: mental retardation, nuchal thickening, “double bubble,” hyoptonia, epicanthic folds, flat facial profile, simian crease, congenital  heart defects, etc. -incidence closely related to maternal age (older mom, higher risk). -**Patau Syndrome (trisomy 13)** -Signs/Symptoms: microcephaly, mental retardation, polydactyly, rocker- bottom feet, umbilical hernia, renal defects, holoprosencephaly. -**Edward’s Syndrome (trisomy 18)** -Signs/Symptoms: mental retardation, low set ears, short neck, overlapping fingers, congenital heart defects, rocker-bottom feet -**Autosomal monosomies:** just remember, these guys almost never live to term -**Disorders of sex chromosomes:** -FMR1 gene (spans about 40kb, composed of 17 exons). --disorder exhibits over production of gene product in brain/testes --FMRP (protein product of the gene) associated w/ polyribosomes -**CGG** repeat. 40-45 normal, 60-200 premutation, >230 affected. -In affected state, FMR1 is hypermethylated and transcription is turned off. -Mom carries premutation: high risk of expansion in offspring -Dad carries premutation: low risk of expansion in offspring -**Huntington’s Disease:** -**CAG** repeat. <24-28 normal, 36-39 reduced penetrance, >40 affected
 * IV. Principles of Clinical Cytogenetics:** Micale lecture. Things to remember from the test: mosaicism, trisomy rescue, monosomy rescue, chromosomal rearrangements, etc. There are a number of specific conditions discussed in this lecture so I’ll focus solely on those.
 * Klinefelter syndrome (47, XXY):** 1/1000 newborn males. Observed: normal face, long arms/legs, small genitalia, abnormal breast development,  infertility, sometimes lower IQ.
 * Turner syndrome (45, X):** One of the most common chromosome abnormalities in miscarriages (abort due to vascular abnormalities or fluid  imbalance). Observed: webbing of neck, short stature, infertility, widely  spaced nipples, coarction of aorta.
 * <>disorders of sexual differentiation<>**
 * Pseudohermaphroditism:** SRY (+) XX male; translocation of SRY gene to X chromosome, gonadal dysgenesis
 * Pure gonadal dysgenesis:** XY female, nearly normal phenotype, does not undergo puberty. 50% develop gonadoblastoma (malignant tumor in  lower ab).
 * -Triplet repeat expansion mutations: Fragile X and Huntington’s**
 * -Fragile X syndrome:**
 * -**mental retardation, narrow face, hyperactivity
 * -**late onset; choreiform movements, grimacing, mental deterioration -neuropathology: atrophy of basal ganglia, dilatation of lateral ventricle

Disease List from Unit 4 (pages 309-465)


 * __Prader-Willi Syndrome-__** (pp. 309-316)

§ 15q11-q13 § Clinical Features: Mild to moderate mental retardation; Hypotonia; Neonatal failure to thrive (w/ poor feeding); skin picking and high pain threshold; hyperphagia and obesity; hypopigmentation of eyes, skin, and hair; short stature; small hands and feet; almond shaped eyes; behavioral disturbances; microbrachycephaly; hypogonadism § has a __deletion in paternal__ chromosome and maternal has been imprinted § SNRPN gene-expressed in heart and brain and encode SmN protein associated with pre-mRNA procession § There is a loss of gene function because the allele from one parent is imprinted (inactivated) and the other allele has been deleted § Also caused by __maternal__ uniparental disomy


 * __Angelman Syndrome-__** (pp. 309-316)

§ 15q11-q13 § Clinical Features: Severe mental retardation; hypotonia of trunk and hypertonia of extremities; absent speech; movement or balance disorder – stiff ataxic movements; “happy puppet” disposition; seizures; protruding tongue and drooling; hypopigmentation of eyes, skin, and hair § has a __deletion in maternal__ chromosome and paternal has been imprinted § UBE3A gene transfers ubiquintin to protein substrates in the ubiquintin-protesome proteolytic pathway § There is a loss of gene function because the allele from one parent is imprinted (inactivated) and the other allele has been deleted. § NOTE: imprinting is restricted to the brain § Also caused by __paternal__ uniparental disomy

= = =__Phenylketonuria (PKU)__- (p. 320)= =(locus heterogeneity- different genes can cause same clinical manifestation)= Clinical Presentation: § Severe Mental Retardation § Musty Odor § High Phenylalanine in plasma and urine

Metabolic Defect (different causes)- § Phenylalanine Hydroxylase deficiency (90%) § Deficiency in Dihydropteridine Reductase § Defect in Synthesis of BH4 Consequences in Body- § Phenylalanine Hydroxylase- cleaves Phenyalanine into Tyrosine § build up of Phenylalanine in body § Dihydropteridine Reductase-required for the conversion of an essential cofactor for Phenyalanine Hydroxlylase, BH4 § BH4- also needed for Tyrosine HydroxylaseàL-dopa, Tryptophan Hydroxylase

Pattern of Inheritance- autosomal recessive Treatment- § Phenylalanine Restricted Diet- not totally taken out, need some for growth § Addition of L-dopa and 5-OH Tryptophan in case of DHRP or BH4 deficiency § See variation as to how some people can tolerate the Phenylalanine who have this problem- for some its ok to take in.


 * __Galactosemia__-**(p. 322) **(**allelic and locus heterogeneity)

Clinical Presentation-

§ jaundice, lethargic, seizures, cataracts, liver & renal dysfunction, hypoglycemia § Urine- positive for reducing sugar but negative for glucose § Plasma- Galactose and Galactose-1-Phosphate is increased § Erythrocyte GALT activity is absent § Can lead to mental retardation and learning disabilities if not treated.

Metabolic Defect- § Galactose Kinase Deficiency § Galactose-1-Phosphate Uridyl Transferase Deficiency § UDP- Galactose Epimerase

Consequences in Body of Defect: § Cannot convert galactose to UDP glucose- build up of galactose § Galactose Kinase- converts galactose to galactose-1-phosphate § G-1-P Uridyl Transferase- converts UDP gal to UDP glucose. § Can have a build up of Gacitol- cause cataracts by sucking out the water in the eyes

NOTE: Eperimerase Def- asymptotic, not serious problem, see mild elevation of gal-1-p in RBC

Pattern of Inheritance- autosomal recessive Treatment- elimination of Galactose in Diet- it is toxic à breast milk and lactose

=Homocystinuria – see genetic polymorphisms for people- (see different clinical symptoms for same prob)= Clinical Presentation: § Attention deficit hyperactivity disorder, tall, slender, elongated limbs, pectus excavatum, scoliosis, bilateral ectopia lentis

§ Plasma and Urine: high methionine, high homocystine § Skin Fibroblasts- deficiency in cystathionine synthase

Metabolic Defects: Cysthathione Synthase Deficiency- high homo and met § Methionine Synthase Deficiency (will see no increase in met here) high homo § Methylene HF4 Reductase Deficiency-high homo § Cobalamin Absorption or Transport Abnormality § Dietary Deficiency

Consequences in Body of Defect- elevation of homocystene and methionine (test for high met)

§ Cysthathione Synthase-converts homocytiene to cystathione § Methionine Synthase- converts methyl tetrahydrofolate back to tetrahydrfolate- this form of folate needed for many other metabolic reactions in body § Methylene HF4 Reductase- converts tetrahydrfolate back to methyl tetrahydrofolate – needed for in conversion of Homocysteine back to Methionine

§ Cobalamin Absorption or Transport Abnormality- Pernicious Anemia – could be prob with intrinsic factor

Pattern of Inheritance- autosomal recessive disorder Treatment: § Cysthathione Synthase Deficiency- B6 or restricted Methionine Diet § Methionine Synthase Deficiency- Folic Acid § Methylene HF4 Reductase Deficiency- Folic Acid § Cobalamin Absorption Problem- B12

autosomal recessive disorder Clinical Presentation: can have acute or chronic manifestations URI, hypoglycemia, metabolic acidosis, enlarged liver Coma, life threatening, severe mental retardation Plasma: High hexoanolycarnitine High octanoylcarnitine
 * Medium Chain Dehydrogenase Deficiency (MCAD) and Carnitine Deficiency**

Metabolic Defect- Medium Chain Dehydrogenase Deficiency- stops 1st step in beta oxidation- cannot breakdown medium fatty acid chains (6-12 C long)

Carnitine Deficiency- transport of FA to mitochondria is stoppedà beta oxidation cannot proceed Necessary for removal of toxic Acyl compound at high concentration can interfere with energy production

Consequences in Body of Defect- MCAD- Cannot breakdown fatty acid chain in body

Carnitine Def- Decreased lipid concentration with accumulation of lipid in Heart and Muscle Hyperammonia Metabolic Acidosis Hypoglycemia because of affect on gluconeogenesis Stimulation of glycolysis with glycogen depletion Inhibition of Pyruvate Deghydrogenase

Pattern of Inheritance- autosomal recessive disorder Treatment- avoid fasting, IV glucose


 * Arginosuccinic Aciduria-** genetic heterogeneity

Clinical Presentation: Mild mental retardation, ataxia, lethargy, patchy alopecia, dry scaly fissured skin over legs and arms, gait ataxia, tremor, and inability to walk.

Plasma-Ammonia levels are high Citrulline and Arginosuccinc acid and low arginine Low Arginosuccinic Acid lysase

Metabolic Defect- Arginosuccinic Acid Lysase Deficiency

Consequences in Body of Defect- Cannot cleave arringosuccinic into fumarate and arginine and because of that cannot make urea See increased levels of enzymes proceeding that deficiency and product build up also.

Build up of Ammonia

Pattern of Inheritance-autosomal recessive

Treatment- Dietary protein restriction Supplemental arginine- able to excrete ammonia Sodium benzoate and sodium phenylbutyrate for acute episodes of hyperammonemia

Hemodiaylsis for extreme ammonia levels

=Hurler Syndrome=

Clinical Presentation: Developmental regression Unsteady gait, limited speech to single words Coarse Facial Feature- kyphosis Gibbous Deformity Thickened spade like hands Enlarged liver

Urine: positive for mucopolysaccarides Chromatography- large amounts of Heparan and Dermatan sulfate

Leukocyte: low Iduronidase

Metabolic Defect- Iduronidase Deficiency

Consequences in Body of Defect- Cannot cleave mucopolysaccarides, cannot metabolize them, and have a build up of them High concentrations of Dermatan and Heparan Sulfate in Urine (should have very low concentrations) Can also be assessed in a blood sample to distinguish between different types of enzyme deficiency

Pattern of Inheritance- autosomal recessive

Treatment- Bone marrow transplant to treat deficient enzyme activity Iduronidase Injections or by IV, but cannot cross the blood brain barrier

Hedgehog Sonic- ventral neural tuba and midline differentiation Loss of fxn-àHoloprosencephaly- Cyclopes Patched gene mutà basal nervous syndrome or basal cell carcinoma – skin cancer
 * Segmental Genes**- Interact with one another to subdivide embryo into linear series of progressively smaller but similar segments

Transcription factors bind to the DNA ZIC 3 gene – disorders of laterality Left /right symmetry Anything can be reversed- no rhyme or reason
 * Zinc Finger**- four amino acid loop structure ( very long tube like proteins)

Have a 79 amino acid motif known as HMG box Regulate transcription and are expressed in specific tissues during embryogeneisis Los of function- Campomelic Dysplasia (SOX 9 mutation) Underdeveloped thorax Bent limbs Sex Reversal (46 X,Y but is female)
 * SOX genes-** shows homology with SRY gene

Most products are located on inner side of cell membrane where they receive signals from outside the cellà send to nucleus Mutations = Malignancy and developmental disorders
 * Signal Transdcution Genes**

Ras- many tumors Abl – cytoplasmic cytosine kinase Ret- membrane tyrosine kinase loss of fxn-Hischprung disease- congenital mega colon gain of fxn- Medullary Thyroid Cancer

=Fibroblast growth receptors= Key role in cell division, migration, and differentiation Mutations FGFR2- Craniosynostenosis à Crouzon and Apert Syndrome FGFR3- skeletal dysplasias à achodroplasia, hypocondroplasia, and thanatophoric - Autosomal Dominant - Fresh mutations - Homozygous increases severity - Clinical o Rhizomelic limp shortening o Macrocephaly o Broad and prominent forehead o Finger and hand abnormalities
 * ACHONDROPLASIA**

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

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

- Autosomal Dominant - Mutation on C17 - Defect in gene for neurofibronin - Lifetime risk of CNS tumors - Small percent with mild retardation - Clinical o Cafe au lait macules o Optic glioma o Freckline o Lesions o Neurofibromas (benign skin tumors) - Automsomal Dominant - Mutation in C12 - Some with mild retardation - Clinical o Short o Short neck with webbing or redundancy of skin o Cardiac Problems o Age dependent facial features
 * NEUROFIBROMATOSIS**
 * NOONAN SYNDROME**

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

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

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

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

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

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

DMD vs. BMD

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

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

Severity determined by type not extent of deletion.

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

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