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Fragile X Syndrome: Most common form of inherited mental retardation; Site contains a CGG repeated motif, where >200 repeats = full mutation, inactivating the FMR1 gene by hypermethylation of the 5' end
SCIDS: ADA deficiency, can be caused by adenosine deaminiase (ADA) deficiency. ADA catalyzes the irreversible deamination of adenosine to inosine, and deficiency results in cytoxic accumulation of dATP and deoxyadenosine in immature lymphocytes. typically treated with the enzyme imbedded in a PEG tablet; possible bone marrow transplant. experimental gene therapy.
Puromycin: Inhibitor of translation in prok./euk. that acts as an aminoacyl-tRNA analog, and acts as a peptidyl acceptor
Hyperuricemia: excess of uric acid in the circulation and urine
Alkaptonuria: homogentisate oxidase (early in the tyr breakdown pathway) Leads to the accumulation of homogenitisic acid in urine, which turns black on reaction of O2. accumulation of polymerized forms results in arthritis, calcification in the cardiovascular system and urinary tract, and a reddish tint to the skin.
Acanthocytes: RBCs known as spur cells, which typically reflect a change in membrane lipids (e.g., increased sphingomyelin in outer leaflet or increased membrane cholesterol)
Synpolydactyly: HOXD-13 disorder (mutation) of HOX-D13
Glucose 6-Phosphate Dehydrogenase Deficiency: Less active enzyme levels leads to individuals that are more sensitive to oxidative stress, induced by drugs, chemicals , or disease. Can lead to neonatal jaundice, or acute hemolytic anemia
Creutzfeldt-Jakob Disease: Caused by prions (transmissible spongiform encephalopathies), infectious proteins replicating misfolding, producing insoluble aggregates
Emphysema: elastic fiber of lungs the breakdown of the elastic fibers in the alveoli of the lungs leads to a loss of lung elasticity. This means that air in not forced out of the lungs, and the patient becomes barrel-chested and their tidal volume decreases. The elastic fibers are degraded by elastase, which is normally kept in check by alpha1-antitrypsin (which is inhibited by cigarette smoke, among other things).
Erythropoietic Protoporphyria: Deficiency in ferrochelatase in erythrocytes; Proto IX excreted into stool
Fructose Uria: Fructokinase An absence of fructokinase causes the benign condition of fructose uria, where fructose in excreted in the urine due to an impaired ability to metabolize it.
arginosuccinic aciduria: arginosuccinic acid lyase acute ataxia, lethargy, patchy alopecia and skin changes (abnormal collagen), intention tremor. Increased plasma ammonia (underlying problem). Use sodium benzoate and sodium phenylbutyrate for episodes of hyerammonimia. Supplement diet w/arginine, restrict dietary protein. deficiencies in other urea cycle enzymes can cause hyperammonemia
Ehlers-Danlos syndrome (type unknown): collagen fibers a defect in lysyl oxidase results in hyperextensible skin and joints. Lysyl Oxidase covalently links hydroxylysine residues in adjacent tropocollagen molecules, creating insoluble fibrils. It also covalently links tropoelastin molecules to form elastin.
Xanthinuria: catabolism of purines a deficiency in xanthine oxidase (converts xanthine to uric acid) causes increased excretion of xanthine and hypoxanthine, and a decrease in uric acid. May result in xanthine lithiasis (kidney stones).
Zellweger Syndrome: peroxisomes Mutations in the PXR1 gene product, a receptor which imports enzymes into the peroxisomes. Problems in prenatal dev., enlarged liver, high levels of iron and copper in blood, muscle and vision abnormalities. Death by age 6.
Arginase deficiency: Urea cycle Deficiency leads to elevated arginine and ammonia in the plasma, CSF, and urine; arginine, lysine, and ornithine elevated in urine. Treated with a arginine-free, low protein diet.
Methemoglobin Anemia: Defects in either Diaphorase I or II or deficiency in Diaphorse I (cytochrome b5 methemoglobin reductase I) or mutations in the subunits of Hb that make the iron prone to oxidation
Familial Alzheimer's Disease: early-onset three genes responsible: Presenilin 1 (PSEN1): 20-70% of early-onset. PSEN2: rare. Amyloid precursor protein: 10-15%. APP is located on chromosome 21 and is also the cause of alzheimer's-like disease in Down syndrome patients. Apo E (epsilon 4) is also associated with earlier onset. epsilon 2 has a protective effect and is more common in the general population.
Niemann-Pick Disease: sphingomyelinase an autosomal recessive disorder with a deficiency of sphingomyelinase (can't cleave bond between phosphate and backbone) leading to an accumulation of sphingomyelin in neurons and "foamy" reticuloendothelial cells in liver, spleen, bone marrow, and other tissues. onset in early infancy, death before age 3. Symptoms include enlarged liver and spleen, mental retardation, anemia, neurological and physical deterioration.
complete androgen insensitivity syndrome: androgen receptor XY females with testicular tissue that secretes androgents, but there is an androgen receptor defect. Phenotypically normal females - sparse axillary and pubic hair, short vagina, remnants of uterus and fallopian tubes.
Aceruloplasminemia: Absence of ceruloplasmin, leading to damaging accumulation of iron in the spleen, heart, liver, kidney, thyroid, and retina. Results in diabetes mellitus
myocardial infarction: CPK isozymes the CPK isozyme CPK-MB is elevated in MIs
MCAD (medium chain Acyl-CoA Dehydrogenase Deficiency): fatty acid catabolism The catabolism of medium chain fatty acids (6-12 C) is deficient due to a defect in the dehydrogenase. Symptoms (usually in the first two years) are precipitated by fasting or infection, and urine contains MCFA esters of glycine and carnitine. Treat with glucose, high carb diet. Also SCAD (short chain) and LCAD (long chain).
Duchenne Muscular Dystrophy: dystrophin (an actin assoc. ptn. Found in muscle cortical networks) a genetic defect causes dystrophin to be dysfunctional or absent. Dystrophin cross-links the actin filaments into a supportive network and also functions to connect the internal cytoskeleton to the external matrix. As a result, the muscle cell is easily damaged and the disease is ultimately fatal.
Hemolytic jaundice: RBC destruction Seen in conditions with increased destruction of RBCs - too much Hb for the liver to metabolize. Increase in unconjugated bilirubin.
excess beta carotene: > 15 mg: increased lung cancer and mortality in smokers
Potter Sequence: amniotic tear with chronic leakage or bilateral renal agenesis causes oligohydramnios and fetal constraint, causing secondary anomalies s/a fetal growth deficiency, potter facies, limb position defects.
Rifampicin: Inhibitor of transcription that binds to the beta subunit of prokaryotic RNA polymerase and is used to treat tuberculosis
CO poisoning: Hb CO binds reversibly to the O2 site, but with a much greater (200x) affinity. O2 has a higher affinity for CO ligated Hb, but cannot be effieciently released from it in peripheral tissues.
Carnitine Palmityltransferase (acyltransferase) Deficiencies: fatty acid catabolism Autosomal recessive deficiency in CPTI or CPTII - can't transfer long chain fatty acids into mitochondria. Symptoms are triggered by exercise or fasting, and can be treated with a high carb, low-fat diet and short or medium chain triglycerides (don't need a carrier - can diffuse)
Hereditary Spherocytosis: Mutations in spectrin, ankyrin, etc., leads to decreased cell flexibility and subsequent hemolysis by the spleen
Marfan Syndrome: fibrillin-1 gene (15q21.1) Autosomal dominant, variable expressivity. Mutatuion in fibrillin-1 (FBN1) located on chromosome 15q21.1. Fibrillin-1 is an ECM protein found in elastic tissues and so effects connective tissue throughout the body. Dilated aortic root (may rupture). ectopia lentis, long fingers and body. mild joint laxity (look for "thumb sign" or "wrist sign"). beta blockers reduce the force of heart ejection, reducing pressure on the aorta.
Glanzmann's disease: integrin A particular integrin is not produced. Platelets cannot bind fibrinogen, and so they cannot be activated. Patients have excessive bleeding due to lack of clotting.
Cystinosis: cysteine transport results from a defect in cysteine transport, causing a deposition of cysteine crystals in tissues - mortality from renal failure.
Uridine: Treatment for orotic aciduria; creates UMP for UTP, CTP, and TTP; UTP then can down regulate the pathway
Anderson's Disease: Defective brancing enzyme, resulting in abnormally long, unbranched glycogen and subsequent liver failure
Hepatocellular Jaundice: Results from damage to the liver. Elevated unconjugated bilirubin and conjugated bilirubin with elevated liver serum enzymes
Ehlers-Danlos, Type VII: Change in procollagen peptidase, preventing aggregation of tropocollagen. Results in hyperflexible joints and dislocations
Thiamine deficiency: transketolase Thiamine deficiency can be diagnosed by an increase in erythrocyte transketolase activity observed upon addition of thiamine pyrophosphate. previously addressed - see row 55.
excess pyridoxine: > 100-200 mg: peripheral neuropathy leading to ataxia
Myxedema: GAGs caused by an overproductions of GAGs during hypothyroidism. The effected area doesn't indent when you push on it. aka mucous edema
Coombs test: Diagnostic, illustrating IgG coating of RBC, showing auto-immune hemolytic anemia
Aquired Hemolytic Anemia: PIGA enzyme, GPI anchors the PIGA enzyme is essential for GPI anchor synthesis. GPI (glycosylphosphatidylinositiol) is used to anchor proteins to the membrane. When PIGA is mutated, the GPI anchors are not attached. One impacted protein, CD59, normally inhibits C3 convertase in the alternate complement pathway. Without CD59 at the membrane, the cells are more sensitive to complement-mediated lysis, leading to thrombosis. aka Paroxysmal Nocturnal Hemoglobinuria (PNH)
Homocysteinemia: Factor in CHD risk. Low blood folate in associated with high blood homocysteine. Treat with three steps: diet, multivitamin, elevated (prescription) vitamin doses.
Sideroblastic Anemia: Syndrome; Hereditary--ALAS-2 mutation (pyridoxine-responsive) or Acquired--Myelodysplastic syndrome or plumbism (EPO-responsive); both show increased mitochondrial Fe, ineffective erythropoiesis, iron-loading erythroid hyperplasia in marrow
Kernicterus: Serious neurotoxic effects: athetoid cerebral palsy, severe motor delay, dysarthria, sensoneuronal hearing loss, mental retardation
Hypoplastic or Aplastic: Two kinetic classifications of anemia with decreased production of RBCs
beriberi (wet): pyruvate dehydrogenate complex a severe thiamine deficiency leads to neurologic manifestations, cardiovascular symptoms (more apparent) s/a heart enlargement and tachycardia. Cardiac failure is common after stress, and edema and anorexia are characteristic.
Cancer: Ras The mutation of the Ras protein causes it to be unable to hydrolyze bound GTP. The Ras signal is constitutively on and activates downstream protein kinase cascades that promote cell growth.
Factor V Lediden/ Thrombophilia: factor V gene a point mutation at position 1691 in the factor V gene is associated with increased risk of thromboembolism via activated protein C (APC) resistance. mutation swaps arginine for histidine. Predisposed to defeloping blood closts. Homozygous state has greatly increased risk (50-80X). Heterozygous: 4-8X risk
esophageal, breast, and gastric cancers: cyclin D1 an over-expression of cyclin D1 is associated with these cancers
Pitting Edema: ECM an abnormal buildup of interstitial fluid in the ECM. Can be caused by protein imbalance (liver disease, starvation), blocked lymphatics (surgery, elephantiasis), increased vascular permeability, hypertension (too much hydrostatic pressure on arterial end), heart failure (too much hydrostatic pressure on venous end).
Ezetimibe: Drug that inhibits the cholesterol transporter in mucousal intestinal cells; decreases cholesterol absorption by 50%
Type I dyslipidemia: chylomicron A deficit in Lipoprotein Lipase causes elevated TG levels
beriberi: thiamine deficiency - currently a problem with alcoholic malnutrition. Supplemented in flour.
Small Dense LDL: same diet as for lowering TG, weight reduction, exercise, TG-lowering statin, Niacin or Fibrate if TG>1000.
Myasthenia Gravis: Autoimmune response (umbrella) against the nicotinic acetylcholine receptor; results in skeletal muscle weakness
Kearns-Sayre Syndrome: mtDNA deletion multisystem disorder characterized by brain anda muscle dysfunction, progressive external opthalmoplegia, and pigmentary retinopathy. Short stature, hearing losss, mental retardatio nr dementia, and endocrinopathy. Deletions can be >40% of mtDNA.
Allopurinol: Inhibitor of uric acid production by inhibiting xanthine oxidase; therapy of gout
Campomelic dysplase: SOX9 loss-of-function mutation of SOX9 results in underdeveloped throrax, bent limbs, and sex reversal (XY female)
Retinoic Acid Embryopathy: anterolateral displacement of hair whorl, micrognathia, U-shaped palate. Down-slanting palpebral fissures, microtia or anotia. Hydrocephalus possible. Heart and limb defects.
Hemolytic: Kinetic classification of anemia with increased destruction of RBCs
Glanzmann's Disease: Lack of beta-3 integrin; Results in excessive bleeding due to lack of clotting
Pyropoikilocytosis: Classification of anemia, most often due to alpha or beta-spectrin mutation, where red cells are particularly sensitive to heat.
Scurvy: Vitamin C shortage, resulting in weak collagen formation due to lack of post-translation formation of hydroxyproline; few or weak H bonding
Acquired Porphyrias: heme synthetic pathway
Amnion rupture sequence: amniotic rupture leads to exposed chorion then transient oliohydramnios and fetal constraint. Disruption by amniotic bands.
Osteoporosis: Severe bone loss during aging
Steatorrhea: Greasy, malodorous stool indicative of biliary or pancreatic problems
Polycythemia: Results from overproduction of RBCs (caused from continuous signals to produce RBCs through mutations in EPO or in JAK2)
PRPP Synthetase: Mutant enzyme form that is not regulated, causing an increase in purine synthesis and leading to gout
Hereditary Elliptocytosis: Defects that affect the interaction within the spectrin tetramer, affecting horizontal interactions of the cytoskeleton
von Gierke's Disease: G-6-Phosphatase activity is deficient, resulting in enlargement of the liver due to increased glycogen
Neural Tube Defect: Multifactorial genetic syndrome; Diagnosis through amniotic AFP and cholinesterase levels and alpha-fetoprotein. Prevented with folate supplementation
Prader-Willi Syndrome: SNRPN gene (15q11q13 - maternal copy only) hyperphagia and obesity, skin picking and high pain threshold, hypotonia, mild to moderate MR, hypopigmentation, behavioral disturbances. Paternal del(15q11q13) or uniparental disomy (UPD) - maternal. Few imprinting mutations. SNRPN gene product assoc. with snRNPs (pre-RNA processing)
Fusidic Acid: Inhibitor of translation in prok./euk. that inhibits elongation and binds eEF2/GDP
Methemoglobin Anemia: methemoglobin reductase II, cytochrome b5 reductase, alpha or beta subunits A result of any number of mutations that leads to an excessive production of Methemoglobin. Defects in methemoglobin reductase II are relatively mile, but can be induced by oxidant stress. Defects (severe or mild) or deficiency (mild) in cytochrome b5 reductase can cause symptoms. Mutations in the alpha or beta subunits in Hb can make the iron more prone to oxidase (Hb Ms).
Beriberi: Deficiency in thiamine; Results in neuropathy, fatigue, and cardiac failure
Klinefelter Syndrome: Aneuploidy: 47, XXY; tall stature, with breast development, female-pattern pubic hair, testicular atrophy; treated with hormone replacements; diagnosed in fertility clinic; no characteristics as child; produce children with testis biopsy
Iron Deficiency Anemia: Hb Microcytic, hypochromic RBCs (decrease in both MCV and MCHC). Increase in total iron binding capacity (increase in transferrin, transferrin receptor, and DMT-1) - different from anemia of chronic disease. Serum iron, ferritin, and ALA-S (regulatory enzyme for heme formation) decrease. General anemia effects: increase in serum EPO and 2,3-BPG. Bone marrow won't have iron stores (no blue when stained). You will also see an increase in reticulocytes 5 - 7 days after therapeutic iron. also see row 72
Waardenburg Syndrome, type 1: PAX3 (human analog: HuP2) loss-of-function of PAX3 gene mutation. Hearing problems (cochlear deafness), white forelock, iris heterochromia or hypochromia.
Osteoarthritis: Non-inflammatory and progressive deterioration of articular cartilage
Ehlers-Danlos, Type VII: collagen fibers Procollagen Peptidase can no longer cleave procollagen, causing poor aggregation and binding of the procollagen molecules into fibers. This leaves the fibers weak, giving the patient hyperflexible joints, dislocations, and soft skin.
Emphysema: Breakdown of elastic fibers in alveoli, preventing rebound of air. Results in lung dysfunction
Pearson's Syndrome: mtDNA deletion non-neurological childhood loss of blood cells (pancytopenia) and pancreatic dysfunctions. Becomes clinically similar to Kearns-Sayre in those that survive to adulthood.
Gout: Inflammation of joints due to the deposit of sodium urate crystals
Argininosuccinase (lyase) deficiency: Urea cycle deficiency leads to elevated argininosuccinate and ammonia levels in plasma, CSF and urine. Recessive - usually fatal in first two years. Treated with arginine.
Type I diabetes: pancreatic cells Insulin is not produced by the pancreas, impacting glucose utilization and insulin-dependant functions. Increase in adipose lipase, Acetyl-CoA carboxylase falls (not making F.A.s). Untreated diabetics produce excessive ketone bodies and their breath may have acetone. aka Juvenile Diabetes
Essential Fructose Uria: Deficiency in Fructokinase; Results in fructose in urine. Benign
Neurofibromatosis (type I): 17q11 (NF-1 gene - tumor supressor) autosomal dominant with variable expression. Café au lait paatches, freckling in on-sunexposed areas. Peripheral neurofibromata. Scoliosis and neurological problems common. High risk for CNS tumor (benign but problematic).
Jaundice: Excessive bilirubin in the blood
Excess vitamin A: >8000 IU: increased osteoporosis in elderly women. >10,000 IU: fetal cranio-facial, CNS or heart defects. >50,000 IU: hepatomegaly, bone thickening, blurred vision, headache.
Galactosemia: GALT cataracts, low blood sugar. Autosomal recessive. Usually due to a deficiency in GALT, but can also be due to a deficiency of gactokinase or epimerase.
Genetic Porphyrias: heme synthetic pathway Involve defects in specific steps in heme biosynthesis, leading to accumulation of product form the previous step. Characteristic features often include photosensitivity, hair growth, accumulation of porphyrins in urine (reddish). Acute intermittent porphyria (porphobilinogen deaminase impacted) is the most common.
Phenylketonuria: phenylalanine hydroxylase phenylalanine hydroxylase normally converts phenylalanine to tyrosine. Without this enzyme, phenylalanine and its' breakdown chemicals from other enzyme routes accumulate in the blood and body tissues. Symptoms include hyperactive reflexes, mental retardation, and seizures.
Sideroblastic Anemia: Iron accumulates in the mitochondria because there is a block in the ETC at complex III, which leads to excess O2. This causes Fe2+ to be converted to Fe3+ before it reaches ferrochelatase - protoporphyrin doesn't get converted to heme.
Hyperammonenia Type 2: Elevated blood ammonia, amino acids, orotic acid, and glutamine from deficiency in ornithine transcarbamylase.
Erythromycin: Inhibitor of translation in prok. that binds 50S and inhibits translocation
Schizocytes: Fragmented RBCs
Ehler-Danlos Type IV: Deficiency in Type III collagen. Results in aneurysms and intestinal ruptures
Phenylketonuria (again): phenylalanine hydroxylase phenylalanine hydroxylase normally converts phenylalanine to tyrosine. Without this enzyme, phenylalanine and its' breakdown chemicals from other enzyme routes accumulate in the blood and body tissues. Symptoms include hyperactive reflexes, mental retardation, light pigmentation (phe --> tyr --> melanin), and seizures. Treated with a phenylalanine restricted, tyrosine supplemented diet. also see row 30
ethanol inhibition of gluconeogenesis: gluconeogenesis the metabolism of ethanol requires NAD+ and doesn't regenerate it. This can inhibit gluconeogenesis, leading to hypoglycemia and lactic acidosis.
Gilbert's Syndrome: Results from reduced UDP-glucuronosyl transferase. Mild condition resulting in elevated unconjugated bilirubin due to slower clearance
Multiple Sclerosis: Disruption of myelin, thought to be by autoimmunity to oligodendrocytes
Atherosclerosis: Arteriosclerosis due to formation of plaques
VLCAD Deficiency: Enzyme deficiency, thus no acyl-CoA is produced. Results in accumulation of acyl carnitine and blockage of metabolism
Arteriosclerosis: Hardening of the arteries
Type IV dyslipidemia: VLDL (pre-beta) elevated TG - can go as high as 800 (norm - 160)
Duchenne (becker) muscular dystrophy: Xp21 an X-linked recessive disorder involving mutatuion in the dystrohin gene at Xp21 resulting in progressive myopathy. Worse form involves a frameshift mutation and absent protein. Milder form involves an in-frame mutation and partially functioning protein.
Down Syndrome: meiosis Trisomy 21. Mental retardation. Flat nose, close-set eyes. Slanting eyelids, protruding tongue. Hypotonia; predisposition to leukemia. Amyloid precurser protein (APP) on chromo. 21 - will develop alzheimer's-like disease. 1/800. 85% maternally derived. can also be due to Robertsonian translation. 10 - 15% reccurrance risk.
Anhidrotic ectodermal dysplasia: Caused by a mutation of an X chromosome gene resulting in a lack of sweat glands. Occurs in patches reflecting the mosaicity of X chromosome inactivation.
Colchicine: Anti-inflammatory therapy used for gout; inhibits MT assembly in leukocytes
Paroxysmal Nocturnal Hemoglobinuria: Enzyme required for GPI anchor of CD59 is mutated, leading to complement-mediated lysis of RBC; results in anemia
pseudo-hermaphroditism: SRY gene XX male - SRY gene translocated to X chromosome due to aberrant recombination outside of the pseudoautosomal region.
Lead Poisoning: ALA DH in heme synthesis, ALA DH forms porphobilinogen from two ALAs. This enzyme has an active site zinc that is displaced by lead - enzyme deactivated (ALA appears in urine). Also inhibits protoporphyrinogen oxidase leading to the accumulation of free protoporphyrinogen IX and Zn-protoporphyrinogen IX. Ferrochelatase is also inhibited by lead (protoporphyrin IX can't be converted to heme - final step)
Wernicke-Korsakoff Syndrome: Chronic thiamine deficiency, sometimes seen in chronic alcoholism; Results in paralysis, impaired mental function
Hypercholesterolemia: high LDL-cholesterol treatment for high LDL: diet low in saturated/trans fats (fat = 30% of calories). Reduce total calories. If diet isn't enough, statins reduce LDL. If diet and statins aren't enough, can supplement with a BAS. Exetimibe and phytosterols can also help reduce LDL levels moderately.
Uniparental Disomy: Results from the inheritance of two copies of a chromosome pair from one parent and no copy from the other parent
Galactosemia: galactose-1-phosphate uridyl transferase the absence of galactose-1-phosphate uridyl transferase is a severe autosomal recessive disease that lease to an accumulation of toxic substance. Galactitiol, formed by the reduction of galactose, is one of these and leads to the formation of cataracts (galactitol is osmotically active). Symptoms include failure to thrive, liver enlargement, jaundice. vomiting or diarrhea following milk consumption. mental retardation common.
Excess vitamin A: epiphyseal plate If there is an excess of vitamin A in a growing child, there is rapid erosion of cartilage resulting in premature closure of the epiphyseal plate, causing Dwarfism. Vitamin A coordinate the activity between osteoblasts and osteoclasts.
osteoporosis: bones a severe loss of bone mass with aging - the skeleton is no longer able to maintain mechanical support. Afflicts 25% of postmenopausal women and is characterized by fractures, backaches and vertebral deformities.
Acromegaly: bones If there is an excess of GH in adults, excessive remodeling leads to thickening of bones - especially facial bones by the eyebrows and enlargement of hands and feet.
Type V Dyslipidemia: Extremely elevated chylomicron and triacylglyceride levels due to decreased Apo C-II or increased Apo C-III
Myasthenia Gravis: Ach receptors at the neuromuscular junction An autoimmune disorder characterized by chronic progressive muscle weakness. Antibodies that block the Ach receptors at the neuromuscular junction cause a decline in the secondary synaptic cleft area and consequently the total number of receptors. There is a reduction in the muscle excitation/contraction. Can be treated with ACh esterase (AChE) blockers.
Cystic Fibrosis: ABC-type chloride channel most commonly due to the expression of a mutant protein, deltaF508 CFTR. In this protein, the ABC-type Chloride channel is made (primary active transporter) but has a single AA deletion. Consequently, it doesn't make it to the membrane and chloride builds up in the cell, drawing in water. This dehydration leads to thick mucus and defective function of the respiratory tract cilia, as well as increased infections.
Retinoblastoma: RB gene on chromo. 13 Two Hit Hypothesis: a mutation in one copy of the RB gene is inherited, and the second copy develops a somatic mutation. This allows the cell to proliferate in an uncontrolled manner. [this type of cancer] tumors are typically only found in young children.
Phenylketonuria: MR, Seizure, fairer skin than unaffected sibs; restrict PHE intake; caused by defect in biopterine synthesis or defect in dihydropterine reductase; affected mother can cause by not restricting PHE from diet during pregnancy
Anaphylactic Shock: Mast Cells, basophils An intense generalized response following a second exposure the same allergen. A large number of basophils and mast cells degranulate, leading to widespread vasodilatation and increased permeability. This leads to reduction of blood volume (as well as constriction of the bronchioles - respiratory insufficiency) and sends the person into circulatory shock.
Phemphigus vulgaris: Auto immunity to cadherin desmoglein, destroying desmosomes and breaking down protective barriers. Causes severe blistering due to water loss
Triploidy: meiosis complete extra set of chromosomes. 20% of chromosomally abnormal miscarriages. Early spontaneous abortion, low birth weight, small trunk to head size, syndactyly. Paternal Triploid: underdeveloped embryo with trophoblastic disease. Maternal triploid: developed embryo, underdeveloped placenta.
Cyanosis: Results from reduced delivery of oxygen to peripheral tissues
Pituitary dwarfism: epiphyseal plate If there is a deficiency of Growth Hormone (somatotropin) in a growing child, dwarfism results
Genetic (Hereditary) hemochromatosis: membrane glycoprotein HFE - normally interacts with transferrin Common genetic disorder in people of western European ancestry. A defect in a membrane glycoprotein (HFE) regulating affinity of the transferrin receptor for transferrin leads to excessive absorption of iron. Cells can't take up iron from transferrin, and so produce more DMT-1. Often manifests in adulthood with symptoms of cardiomyopathy, liver cirrhosis, diabetes and athropathies (due to iron accumulation in tissues). Can also be Hepcidin-assoc (not enough - uncontrolled release of iron) or other mutations - these are rare and juvenile onset. iron loading syndrome
Osteogenesis imperfecta: a heterogeneous group of brittle-bone diseases characterized by an excessive tendency to antenatal or postnatal fractures. 1/15,000. all types due to an abnormality in type I collagen. Genes: COL1A1 (alpha-1 chain) and COL1A2 (alpha-2 chain).
oxidative phosphorylation diseases: ETC chain due to defects in nuclear or mitochondrial DNA. Symptoms include muscle cramping and weakness, fatigue, lactic acidosis, CNS dysfunction , and vision problems. Treatment often unsuccessful. no questions on exam but will need to know details for USMLE.
Velocardiofacial Syndrome: Deletion on the 22 chromosome; Characterized by a cleft palate, congential heart defect, and prominent nose with small nasal wings
Congential Adrenal Hyperplasia: High cortisol levels; Large clitoris in females, dark scrotum in males.
Hexokinase Deficiency: Genetic condition that reduces 2,3 DPG levels by decreasing flux through glycolysis
Methylene Blue: Drug that reduces met-Hb through enhancing the production of NADPH through G6PD
Severe Combined Immunodeficiency: Deficiency in adenosine deaminase; leads to a buildup of dATP in T and B cells, which in turn inhibits ribonucleotide reductase and DNA synthesis
Acromegaly: Excess of growth hormone in adults
Pituitary Dwarfism: Deficiency of growth hormone in a growing child
skeletal dysplasias: FGFR3 mutation of variable severity - achondroplasia, hypochondroplasia, and thanatophoric dysplasia. Different mutations - related/overlapping conditions.
Phenobarbital: Drug that induces UDP-glucuronysl transferase activity; increases bilirubin glucuronide secretion into bile
Gigantism: Excess of growth hormone in a growing child
sarcomas and gliomas: CDK4 has been shown to be amplified in...?
Marfan's Syndrome: elastic fiber Caused by poor microfibril formation in elastic fiber (microfibrils surround the amorphous elastin center). This weakens the elastic fibers and leads to a tendency to rupture the aorta and other blood vessels.
Orotic Aciduria: Deficiency in two enzyme activities due to a defect in gene encoding UMP synthase; leads to lack of pyrimidines for DNA and RNA, leading to an increased intermediate
Biotin Deficiency: biotin Rare - unless antibiotics of the ingestion of v. large amounts of avidin (present in raw egg whites).
osteoarthritis: synovial joints non-inflammatory degenerative arthritis that affects synovial joints. Fibrillation of articular cartilage (loss of GS and retention of fibers), proliferation of cartilage at periphery, eventual replacement of cartilage spur to form bone spurs - reduces degree of movement.
Craniosynostosis: FGFR2 premature fusion of the sutures (some). Can cause Crouzon or Apert syndrome.
Angleman Syndrome: Characterized by severe MR, speech impairment, and an unsteady gait. Individuals present with high laughter and excitability. Caused by paternal UPD, imprinting, and deletions on chromosome 15.
Anisocytosis: Morphological classification of anemia with high RDW
5p Deletion (Cri du chat): Aneuploidy; Characterized by round face, low set ears, receding chin, high pitched cry; significant MR
Blooms Werners and Rothmund-Thomson Syndromes: Three diseases involving defects in different helicases. Genomic instability, increased cancer incidence, and premature aging are characteristic of all three.
Hepatocellular Jaundice: liver seen in liver damage in hepatitis or cirrhosis. Damaged liver can't take up bilirubin quickly enough - increased levels of unconjugated bilirubin (even at normal levels of production). May also have some release of bilirubin glucouronide due to cellular damage - possible increase in direct bilirubin.
Turner Syndrome: Aneuploidy: 45, X; Short stature; treatment with female/growth hormone. pregnancy via donated eggs.
Pyruvate Kinase Deficiency: Genetic condition that increases 2,3 DPG levels by the reduction in the rate of conversion of phosphoenol pyruvate to pyruvate.
McArdle's Disease: Defective glycogen phosphorylase, leading to excessive glycogen deposition in the muscle. Painful muscle cramps with exercise
Xanthinuria: Genetic deficiency of xanthine oxidase, causing increased excretion of xanthine and hypoxanthine and decreased uric acid
Deficiency of vitamin A: a vitamin deficinecy in a growing child, there will be a decrease in the growth rate, leading to a lack of bone resorption during remodeling. Bone growth won
metabolic acidosis: glutaminase results from the production of metabolic acids (ketoacidosis in uncontrolled diabetes is the most common) or the excessive loss of bicarbonate (s/a in diarrhea). Urea production is suppressed and ammonium is excreted directly by the kidney through the action of glutaminase (glutamine + water --> glutamate + NH4+
Cystic Fibrosis: Mutation of CFTR, a ABC-type chloride channel. Results in accumulation of Cl- in cell, causing influx of water. Causes thick, dehydrated mucous and defective respiratory tract.
Streptomycin: Inhibitor of translation in prok. that affects formation of initiation complex
Acute intermittent porphyria: Results from a defect in porphobilinogen deaminase; ALA and PBG excreted into urine
Type IIb dyslipidemia: LDL and VLDL elevated LDL and TG
Lesch-Nyhan Syndrome: nucleotide salvage pathways the lack of HGPRT prevents the slavaging of guanine and hypoxanthine, leadind to increased de novo synthesis of purine nucleotides and increased levels of uric acid. Neurological features include self-mutilation, choreoathetosis, spastciity, and mental retardation.
pellagra: niacin deficiency. Was a problem in the south where maize was a staple. Currently supplemented in flour. Four Ds: Dermatitis, diarrhea, dementia, and death.
disorders of laterality: ZIC3 ZIC3 mutations lead to disorders of laterality - Situs inversus (everything flipped) or Situs ambiguus (no specifice symmetry)
Hyperammonenia Type 2: Urea cycle X-linked ornithine transcarbamylase deficiency, causing elevate blood ammonia, amino acids, orotic acid, glutamine. Treated with a high a high carb, low protein diet as well as benzoic or phenylacetic acid to treat ammonia intoxication.
Uricosuric drugs: Therapy used to increase uric acid clearance by inhibiting reabsorption; treats gout
Collagen disease: elevated levels of glycine in the urine are indicative of?
Gaucher's Disease: Caused by accumulation of glucocerebroside due to a deficiency of glucocerebroside. No neurological effects, and different tissues have different isoforms of the enzyme, leading to other types of this disease if deficient.
rheumatoid arthritis: synovial joints inflammatory autoimmune disease. Attacks synovial membrane and joint cartilage - membrane thickens (inflamed) and synovial fluid production increases. Pannus of tissue forms across cartilage and erodes away cartilage, exposing bone which eventually fuses across joint.
Hemolytic Jaundice: Increased destruction of red cells, with release of hemoglobin. Results in significant increase in unconjugated bilirubin
Platelet Activating Factor: This is a mediator of allergic hypersensitivity and synthesized in response to presentation of antigen-IgE complexes. Causes release of serotonin as well as its primary effects
Hemophilia A: deficiency of blood clotting factor VIII; excessive bleeding from minor traumas; internal bleeding.
Lipoprotein (a): doesn't really normalize with diet therapy. Restrict intake of trans fatty acids. Niacin and Statin (LDL < 80 to mitigate impact of Lp(a)).
Polychromasia: Term for a pale-blue RBC in routine stains, due to RNA content
Sickle Cell Anemia: Hb A hydrophillic glutamine (Glu 6) is substituted for a hydrophobic valine (Val 6), creating a hydrophobic spot on the outside of the HbS molecule. This patch inserts into a hydrophobic pocket created by Ala 70, Phe 85, and Leu 88 on another molecule (deoxy form only) and begins to polymerize. Polymerization in affected by solubility (HbS is less soluable than HB), pO2 (likely at <40 torr), and an elevated body temperature. Disulfide bridges form between actin filaments if any of these factors last too long.
Williams Syndrome: Elastin (ELN) gene at 7q11 autosomal dominant but mostly de novo mutations. Overfriendliness; very verbal but cognitively impaired. 75% with mental retardation. SVAS (supravalvular aortic stenosis). Elastin arteriopathy. Full lips, short nose, broad nasal tip. contiguous gene deletion (size correlates with severity)
Phenylketouria: phenylalanine hydroxylase or DHPR autosomal recessive. Can't convert phenylalanine to tyrosine. High levels of Phe in blood stream. Inadequate synthesis of myelin (low IQ, decreased head size). 1/10,000. Phenylalanine hydroxyase deficiency. Can also be due to deficiency in dihydropteridine reductase (DHPR) or a biosynthetic defect in the synthesis of BH4. Phe restricted diet; L-Dopa and 5-hydroxytryptophan in case of the latter.
Maple Syrup Disease: Deficiency in the branched chain alpha-ketoacid dehydrogenase complex. Results in severe mental retardation through accumulation of intermediates of Val, Ile, and Leu metabolism.
Alkaptonuria: Defect in homogentisate oxidase, resulting in accumulation of homogentisic acid in urine. Polymerized forms results in damage to joints, calfications in CV and UT, red skin
Tay Sachs Disease: lysosome a lysosomal storage disease where a deficiency in hexosaminidase A leads to an accumulation of GM2-ganglioside in the lysosomes. This causes motor and mental impairment, and is most common in those of northeast european Jewish ancestry.
Hurler Syndrome: alpha-L-iduronidase gene (4p16.3) Autosomal recessive. unsteady gait, lost speech. Coarse facial features, spade hands, enlarged liver. urine metabolic screen positive for mucopolysaccharides (Dermatan and Heparan sulfate). Buildup of dermatan and heparn sulfate in NS (urine spillover). alpha-L-Iduronidase usually breaks them down. Low leukocyte iduonidase. fatal.
Cystic Fibrosis: chloride channel gene (7q31) Mutations in CFTR (cystic fibrosis transmembrane regulator gene), located on 7q31, cause reduced or absent activity of the chloride channel. 3 bp deletion at codon 508 accounts for 70% of mutations. Autosomal recessive. 1/25 carrier frequency. Causes pulmonary disease, meconium ileus (10-20% of newborns), pancreatic insufficiency, and male infertility.
Zellweger Syndrome: Rare hereditary disorder affecting the PXR1 gene product, vital for the import of enzymes into the peroxisomes.
Alzheimer's: late onset (75% of affected) deposition of two fibrillary proteins: beta-amyloid (amyloid plaques) and Tau protein (neurofibrillary tangles). susceptibility gene (Apo E) at 19q13 and a different susceptibility gene locus on chromo. 12q. Multifactorial.
Multiple Sulfatase Deficiency: Posttranslational enzyme defect in at least seven enzymes in the body
Lead Poisoning: Results from this metal inactivating ALAD. This metal also inhibits ferrochelatase and interferes with iron transport into the mitochondria.ALA, URO III, COPRO III excreted in the urine
congenital adrenal hyperplasia: 21-hydroxylase 21-hydroxylase deficiency (others possible but this is most common) results in overproduction of androgens and virilizaiton female infants. Internal structures normal.
Herpes Simplex Virus: Treated with Acyclovir (acycloguanosine), which the HSV-tyrosine kinase phosphorylates. The phosphorylated acycloguanosine functions as a DNA chain terminator.
Dipalmitoyl-phosphatidylcholine: This is a major component of lung surfacant, the lack of which is the basis for respiratory distress syndrome
Hereditary Fructose Intolerance: Phosphofructoaldolase B An absence of phosphofructoaldolase B leads to the inability to metabolize glucose. A severe disorder can cause hepatic failure. Treatment is to avoid fructose in the diet.
Aplastic: Classification of anemia with significantly decreased RBC and WBC precursors in bone marrow.
CDKIs (esp. p16): [?] such as p16 mutations, are involved in the development of multiple tumor types, including: head and neck, pancreatic, non-small-cell lung carcinoma.
excess folic acid: >1 mg: can mask anemia due to vitamin B12 deficiency
Leber's Hereditary Optic Neuropathy (LHON): mtDNA point mutation (protein-encoding gene) rare neurodegenerative disease of young adults that results in blindness due to optic nerve degeneration (G11778A mutation in ND4, NADH DH subunit 4)
Maple Syrup Disease: BCKAD (branched chain keto acid DH) a deficiency in the alpha-keotacid dehydrogenase complex leads to the accumulation of intermediates of the breakdown of branched chain amino acids. Causes severe mental retardation. Rare, recessive disorder in isolated asian and caucasion (Amish) communities.
Mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms: MELAS is due to a mutation in tRNA (leu)
Levulose: Drug that is metabolized by bacteria in the gut to produce a more acidic environment, resulting in increased amonia excretion as ammonium and less absorption
Type IIa dyslipidemia: LDL (beta) elevated LDL
Homocystinuria: Cysathionine beta-synthase (formation of cysteine from methionine) a deficiency in this vitamin B6-dependant enzyme in recessive and manifests with eye ectopia lenitis, osteoporosis, mental retardation, and vascular thrombotic events. There are two types - vitamin responsive can be treated with supplements and vitamin unresponsive must follow a methionine restricted diet supplemented with cystine and betaine (can serve as a methyl donor) to promote remethylation of homocysteine.
Diabetes and deafness: occasionally associated with mtDNA deletions or duplication sin certain pedigrees showing a maternal pattern of inheritance.
Microcytic: Morphological classification of anemia with small MCV
Huntington's Disease: 4p16.3 (huntingtin gene) expansion of a repeat CAG (>36) in the protein coding reigon results in a polyglutaminyl tract in the protein Huntingtin. Protein is insoluable and toxic to specific neurons. Autosomal dominant. Location: 4p16.3. repeat expansion disorder
Channelopathies: Alteration of Ion Channel Structure/Function
Gout: purine metabolism an extreme case of hyperuricemia. Inflammation of joints due to deposits of sodium urate crystals. Often found in the big toe and other joints. defects in purine matabolism (PRPP Synthetase, G6PD, or a partial HGPRTase defeciency). Treatment: anit-inflammatory (colchicine), inhibition of uric acid production (allopuinol - inhibits xanthine oxidase), or increase uric acid clearance (urcosuric drugs inhibit reabsorbtion).
Niemann-Pick Disease: Caused by accumulation of sphingomyelin in neurons and foamy reticuloendothelial cells due to a deficiency of sphingomyelinase
Tetracycline: Inhibitor of translation in prok. that affects aminoacyl tRNA binding at A-site
Cystic Fibrosis: Pulmonary infections with Pseudomonas aeruginosa; many organs affected by >1000 mutations; diagnosis by trypsinogen in blood filter paper, sweat test, mutation analysis
Glucose 6-Phosphate DH deficiency: G6P DH A deficiency/defect in this enzyme reflects a less active form or one with a shorter half-life. A common X-linked disorder found in 11% of African Americans. G6P Dh is an enzyme that produces NADPH which is necessary for glutathione reduction. A deficiency leaves the patient susceptible to oxidative stress, which can trigger an attack of hemolytic anemia.
Excess vitamin A: Causes rapid erosion of cartilage, resulting in premature closure of epiphyseal plate
Acquired Iron Overload: can be caused by conditions (s/a thalassemia or sideroblastic anemia) that require transfusions. These conditions themselves contribute minimally to the iron-loading, but the transfusion is the major factor. Can also be caused by chronic liver disease (alcoholism), Porphyria Cutanea Tarda (responds to phlebotomy - patients are commonly heterozygotes for the HFE mutation), dietary ingestion (bantu beer), etc. EPO production is down regulated, decreasing formation of RBC from bone marrow.
Genetic Hemochromatosis: Faulty regulation of iron transport resulting in excessive iron absorption, through a defect in a glycoprotein that regulates transferrin receptor's affinity for transferrin. Results in cardiomyopathy, cirrhosis, diabetes. Treatable by phlebotomy
Alph-amanitin: Inhibitor of transcription that inhibits both eukaryotic RNA polymerases II and III
21-Hydroxylase deficiency: steroid hormone synthesis 21-hydroxylase deficiency (required for synthesis of glucocorticoids and mineralcorticoids) leads to increased secretion of ACTH by anterior pituitary (lack of feedback inhibition). This causes enlarged adrenals (hyperplasia) w/ accumulation of pregnenolone, progesterone, and androgens. symptoms include early virilization, short stature (early bone maturation). loss of Na in urine. Hypotension, possible shock or sudden death. Can be treated by hormone replacement.
Argininosuccinate Synthetase Deficiency: Deficiency that results in elevated citrulline and ammonia in plasma, CSF, and urine.
Crigler-Najjar syndrome: UDP-glucuronosyl transferase rare recessive disorder that results in moderate (type II) to severe (type I) jaundice due to reduced or absent UDP-glucuronosyl transferase activity (rate limiting enzyme). Type II often responds to inducers (Phenobarbital) of the enzyme while type I may require liver transplantation. caused by a number of different mutations. Kernicterus seen in type I.
Phocomelia (Thalidomide embryopathy): thalidomide prenatal exposure to thalidomide is a phenocopy of the inherited disease. Causes limb shortening.
Maternal myopathy and cardiomyopathy: MMC is due to a mutation in tRNA (leu)
Deficient vitamin A: Causes lack of bone resorption, resulting in the cranial cavity and spinal column failing to enlarge fast enough to accommodate growing brain and spinal cord
Macrocytic: Morphological classification of anemia with high MCV
Rickets: calcium absorption from gut a lack of vitamin D in growing children leads to a calcium deficiency (vit. D controls absorption of calcium from gut), and there is no mineralization of cartilage in the epiphyseal plate and bone osteoid. This leads to weak bones and is characterized by "bow legs".
Kartagener's Syndrome: Axoneme (dynein or radial spokes) The lack of dynein or cross arms in cilia and flagella causes immotile cilia and flagella with sterility, chronic respiratory infection and malrotation of the heart (unclear why malrotation of the heart is a symptom). aka primary ciliary dyskinesia or immotile cilia syndrome
Infant of diabetic mother: high BW (macrosomia), brain anomalies, heart defects
(Primary Ciliary Dyskinesia/ Immotile cilia syndrome) Kartagener: Structurally lacking dynein arms; results in uncleared respiratory tract, numerous lung infections, malrotation of heart
Hyperammonenia Type I: Reduced carbamoyl synthesis from either by deficiency in carbamoyl phosphate synthetase I or N-acetylglutamate synthase.
Actinomycin D: Inhibitor of transcription that inhibits prokaryotic and eukaryotic transcription by intercalating in DNA and blocking RNA polymerase progression
Iron deficiency Anemia: Syndrome; ; pica, pallor, koilonychia, glossitis; Decreased serum Fe, ferriton, %sat, MCV, MCHC; Increased TIBC
Trisomy 16: most commonly identified trisomy in abortuses (30% of all autosomal aneuploidy in abortuses).
Leukocyte Adhesion Deficiency: integrin Integrin is not produced properly and so leukocytes can not effectively migrate out of the blood vessel. Patients suffer fro life-threatening infections.
CPT Deficiency: Inability to transport long fatty acid chains into the mitochondria. Treatments includes low fat diet consisting of medium-chain triglycerides
Biotinidase Deficiency: Body cannot properly use biotin; skin rashes, seizures, hearing loss, MR; prevented by adding extra biotin to diet
Klinefelter Syndrome: 47,XXY 1/1000 newborn males. Normal face, tendency towards lond arms and legs. Small genitalia; gynecomastia. Infertility. IQ usually normal.
Multiple Carboxylase deficiency: biotin results from a biotin deficiency or a defect in biotin holocarboxylase synthetase. Prevents the attachment of biotin to biotin-dependent enzymes. Symptoms include seborrheic dermatitis, anorexia, nausea, and muscular pain.
Type I Dyslipidemia: Extremely elevated chylomicron and triacylglyceride levels due to decreased lipoprotein lipase synthesis
Tay Sachs Disease (again): hexosaminidase (beta-N-acetylhexosaminidase) An autosomal recessive lysosomal storage disease where a defect in hexosaminidase (gangliosides that end with GalNAc (GM2) cannot be degraded) leads to an accumulation of GM2-ganglioside in the lysosomes. This causes motor and mental impairment, and is most common in those of northeast european Jewish ancestry. Death by age 2
Fragile X Syndrome: FMR1 gene at Xq27.3 most common form of inherited mental retardation. Fragile site contains a CGG repeated motif in the 5' untranslated region of the FMR1 gene. 6 - 50 repeats is normal, >200: full mutation - prevents transcription of gene (hypermethylation) and so the RNA binding protein (FMR1 gene product) is absent. Repeats are generated by aberrant recombination. Penetrance increases with each succeeding generation (amplification of region). 1/4000 males. folate-sensitive fragile site at Xq27.3 repeat expansion disorder
Porphyria Cutanea Tarda: Results from a deficiency in URO decarboxylase; URO III excreted in urine; oxidative damage to skin from light absorption of URO III and facial "monkey hair"
Smith-Magenis Syndrome: 17p11.2 deletion at 17p11.2. psychological disturbances: hyperactivity, behavioral problems (most). Self-injurious behavior (2/3). Insertion of foreign bodies (2/3). Head banging (2/3). Ocular abnormalities: myopia, retinal deachments, strabismus, iris anomalies. Neurological abnormalites: self-hugging, periperal neuropathy, and sleep disturbances.
Werner's Syndrome: WRN helicase Recessive mutation in WRN helicase- accelerated aging. Cardiovascular disease, arthritis, cancer. Chromosomal and genomic instability.
Myoclonic epilepsy with ragged red fiber: MERRF disease is due to a mutation in tRNA (lys)
Diphtheria Toxin: Inhibitor of translation in Euk. that inactivates eEF2 by polyribosylation
Contiguous Gene Syndromes: common features: microduplications or microdeletions - require FISH to visualize. Phenotype tends to be variable due to different breakpoints. Occurrence is usually sporadic, but may cluster in families. aka segmental aneusomy syndromes
hypoxia/ischemia: heart the heart has a very small margin for hypoxia. Ischemia (reduced blood flow) leads to decreased contractions for in 10 - 20 seconds, stops in 10 min., and dies in 20.
Osteomalacia: Caused by deficiency of vitamin D in adults; results in insufficient calcification during remodeling, causing brittle bones
Galactosemia: Absence of Galactose-1-Phospate Uridy Transferase; Caused by toxic buildup of galactitols; Treated by avoiding exclusion of galactose in diet
colorectal cancer: cyclin D2 Cyclin D2 has been shown to be amplified in what cancers?
Crigler-Najjar Syndrome: Results from reduced or absent UDP-glucuronosyl transferase. Rare and moderate to severe condition
Pyruvate Kinase deficiency: 2,3-DPG Pyruvate Kinase is at the end of the glycolysis pathway. A deficiency leads to higher concentration of 2,3-DPG due to a slower conversion of PEP to pyruvate, causing a right shift in the O2 binding isotherm.
G6Phosphatase Deficiency: This enzyme deficiency leads to an increased reactant, which increases ribose-5-phosphate via PPP, causing an increase in purine synthesis and leading to gout
Leber's Hereditary Optic Neuropathy (LHON): Rare neurodegenerative disease of young adults that results in blindness due to optic nerve degeneration caused by multiple mtDNA point mutations encoding proteins
Microcytosis: Caused by iron deficiency, thalassemia, and anemia of chronic disease
atherosclerosis: cholesterol Cholesterol is carried by LDL in the blood. Oxidized LDL is taken up by macrophages, which enlarge to become "foam cells". Foam cells are trapped in BV walls, leading to the formation of cholesterol-rich plaque. As lumen is narrowed by plaque, blood flow is restricted.
Waardenburg Syndrome: Caused by mutations that cause pigmentation disturbances (frontal white patch of hair), cochlear deafness, and wide nose bridge
Pellegra: Deficiency in niacin; Results in dermatitis, diarrhea, and dementia
Trisomy 13: Aneuploidy: Characterized by cleft lip/palate
Congenital Hypothyroidism: Low T4, high TSH; not genetic
Type II Diabetes: glucose transport/utilization Insulin is produces but the effects of insulin on glucose transport/utilization are impaired (mech. unknown). Other insulin-dependent functions are preserved - Acetyl-CoA carboxylase is stimulated to make fatty acids. Eventually, pancreas becomes resistant to glucose and stops responding with insulin, and can no longer be reversed with diet. Obesity is a major risk factor. Untreated diabetics produce excessive ketone bodies and their breath may have acetone. aka Adult-Onset Diabetes
pernicious anemia: Vitamin B12 deficiency. A result of the loss of intrinsic factor or unsupplemented vegan diet.
Ehlers-Danlos, Type IV: Collagen type III Deficiency in type III collagen makes aneurysms and intestinal rupture common.
Type V dyslipidemia: chylomicron and VLDL elevated TG due to a deficit of production of Apo CII - defective removal of TGs from chylomicrons and VLDL. TGs very high - 1500+. Fibrate drugs induce the synthesis of Apo CII, reduce the synthesis of ApoCIII, and increase Lipoprotein Lipase activity and so are a good choice for treatment.
Phemphigus Vulgaris: desmoglein (a cadherin) an autoimmune disease where antibodies to the cadherin desmoglein (found in desmosomes - extends across gap) are created, destroying the patient's desmosomes (especially in skin). This leads to severe blistering and infection.
Cri du Chat Syndrome: chromosome 5 chromosome 5p deletion. Infant's cry sounds like a cat.
Type III dyslipidemia: IDL (dys-beta) elevated LDL and TG - problem with the conversion of IDL. Causes yellowish eruptions (cholesterol) on elbow, ankles.
Cystinuria: kidney transporter a defect in the kidney transporter involved in the reabsorption of some amino acids leads to the excretion of cystine, lysine, arginine, and ornithine. Cystine (least soluable) forms calculi in kidney tubules.
Pernicious Anemia: B12 deficiency Due to a deficiency in intrinsic factor (caused by a deterioration of the stomach lining due to the autor-immune disease, chronic atrophic gastritis), B12 absorption is reduced. Methylmalonyl CoA Mutase and Methionine synthase both require B12. Increased methylmalonic acid in urine.
Pure gonadal dysgenesis: XY female with nearly normal phenotype. Can't undergo puberty.
macrocytic anemia: folic acid deficiency. Associated with a diet low in leafy vegetables. Macrocytic RBCs (MCV >90). Can cause neural tube defects and homocysteinemia. Currently supplemented in flour.
Wernicke-Korsakoff syndrome: transketolase defect, thiamine deficiency This results from chronic thiamine deficiency coupled with defective transketolase (reduced affinity for TPP). Symptoms include weakness or paralysis and impaired mental function.
Argininosuccinase Deficiency: Deficiency that results in argininosuccinate and ammonia in plasma, CSF, and urine. Usually fatal in the first two years
acute M.I.: Troponin isozymes TnT and TnI are elevated in...
Luft's Syndrome: Uncoupling in the mitochondria, leading to inefficient ATP production and heat generation.
Hereditary Fructose Intolerance: Absence of Phosphofructoaldolase B; Results in hepatic failure and hypoglycemia. Avoid fructose in diet.
Iron Deficiency: Hb At the early states, total iron binding capacity (increases) and serum ferritin (decreases) are impacted. Late indicators are Hb levels and MCV (low). Fatigue, weakness, anorexia, koilonychia are symptoms. There is also in increases susceptibility to infections (impaired cellular immunity). beta thallasemia major and hemochromatosis mentioned - both have an increase in the iron bound
maternal PKU effects: simialar to FAS - mental retardation a problem due to high phenylalanine/phe byproducts levels interfering with NS development.
warfarin/cumadin: drugs used for anticoagulate therapy (interferes with the carboxylation of glutamic acid) but interferes with the production of osteocalcin, which prevents calcium deposition and can lead to severe bone disorders.
SGPT and SGOT: Two enzymes whose activity is elevated in liver disease and after a myocardial infarction
excess vitamin D: > 25,000 IU: growth retardation, calcification of kidney and heart
Anemia of Chronic Disease: A cytokine-mediated anemia seen with infections, inflammation, cancer. Cytokines act on the liver, increasing hepsidin production causing the iron to be trapped in cells (enterocytes, hepatocytes, macrophages) and less to be absorbed from the diet. Decreased iron-transferrin in serum. unlike iron deficiency, the transferrin levels either remain the same of decrease (no increase in iron binding capacity). marrow doesn't compensate with increased RBC production.
Deferoxamine: Drug that binds free plasma iron and enhances its urine excretion
excess niacin: >500 mg: monitor for liver toxicity. Can lead to fulminant hepatitis and liver failure.
Gigantism: epiphyseal plate If there is an excess of Growth Hormone (somatotropin) in a growing child
Achondroplasia: Caused by mutations in the FGFR3 gene; disturbance in bone growth
Fetal dilantin syndrome: low BW, coarse face, heart defects. Hepertelorism, short nose, low nasal bridge.
Diphtheria Toxin: eEF-2 eEF-2 normally mediates the traslocation of a developing polypeptide with the hydrolysis of GTP. Diphtheria toxin catalyzes the ADP-ribosylation of eEF-2, which inactivates it.
Obstructive Jaundice: delivery of bilirubin glucouronide results from interference with delivery of bilirubin glucouronide to the intestine. Total bilirubin (esp. direct) increases. Bilirubin glucouronide appears in the urine - dark brown.
Gaucher's Disease Types 2 & 3: glucocerebrosidase rare. Similar to type one but a different isozyme is impacted. Type 2 is most severe - early onset with extensive brain damage
Prader-Willi Syndrome: Characterized by severe hypotonia and insatiable appetite in children, and MR, stubborn-ness, and manipulative behavior in adults; caused by genomic imprinting, maternal UPD, and deletions of chromosome 15.
Noonan Syndrome: 12q autosomal dominant with variable expression. 35% with mild mental retardation. Clinical overlap with Turner Syndrome - neck webbing or redundancy of skin. Cardiac anomalies. Age dependant facial features.
Koilonychia: Thin and flat spoon-shaped fingernails
Muscular Dystrophy (again): dystrophin (an actin assoc. ptn. Found in muscle cortical networks) an X-linked defect causes dystrophin to be dysfunctional or absent. Dystrophin cross-links the actin filaments into a supportive network and also functions to connect the internal cytoskeleton to the external matrix. As a result, the muscle cell membrane (sarcolemma) is easily damaged (ruptures) and the disease is ultimately fatal, due to cummulative damage to cardiac and repiratory muscle cells.
Aceruloplasminemia: ceruloplasmin The absence of ceruloplasmin (a copper feroxidase the facilitates iron release from cells) leads to accumulation of iron in the spleen, heart, liver, kidney, thyroid and retina (damage). Diabetes mellitus due to destruction of the beta cells of the pancreas.
Hereditary Spherocytosis: band 3 loss of interactions between spectrin, ankyrin or band 3 leads to defects in the vertical interactions in the cytoskeleton. see above - row 6
vitamin D resistant rickets.: X (PHEX gene) low blood and high urinary phosphate levels, short stature, and bone defects. Defects in the PHEX gene on the distal portion of the short arm of the X chromosome. 1/20,000 males. aka X-linked dominant hypophosphatemia.
Arginase Deficiency: Deficiency that results in elevated arginine and ammonia in plasma, CSF, and urine. Arginine, lysine, and ornthine present in urine.
Leukocyte Adhesion Deficiency: Improperly produced integrin and leukocytes cannot effectively migrate out of blood vessels; Result is life-threatening infection
Homocysteinemia: An overabundance of homocysteine in the blood. For a Cysthathionine Synthase deficiency, give B6/restrict methionine. For a methionine synthase or methylene THF reductase deficiency, give folate. For a cobalamin interconversion defect or a cobalamin absorption or transport abnormality, give B12. early death due to cardiovascular problems.
Hereditary Elliptocytosis (pyropoikilocytosis): spectrin defects in spectrin that affect interaction within the spectrin tetramer lead to defects in the horizontal interaction.
Edwards Syndrome: meiosis Trisomy 18. flaccid, clenched fists (overlapping fingers). Rocker-bottom feet. Renal malformations, congenital heart defects. 1/8000
aniridia: PAX6 mutation of PAX6 (no iris or very rudimentary iris). Blindness, glaucoma.
Huntingtons Disease: Expansion of CAG repeat element in the protein coding region resulting in a polyglutaminyl tract, which aggregates in brain cell nuclei; results in mental and physical degeneration and death
Carboxyhemoglobinemia: Results from CO poisoning
Marfan's Syndrome: Poor microfibril formation in elastic fibers. Results in tendency to rupture aorta and other blood vessels
Multiple Sclerosis: myelin multiple sclerosis is thought to be an autoimmune disorder in which the oligodendrocytes are marked for destruction by macrophages in the CNS. It is a "demyelinating disease" and results in disruption of neuronal function.
Mixed Dyslipidemia: Diet - exclude alcohol - and TG lowering stating (atorvastatin).
hereditary hemochromatosis: 6p21.3 (HFE gene) autosomal recessive. 1/400 caucasions. 1/10 carrier frequency. Innapropriately high iron absorption due to mutations in the HFE gene (facilitates uptake of Tf bound Fe). Common mutations are C282Y and H63D. 87% have at least one copy of C282Y. Location: 6p21.3
Porphyria: Defects in specific step in heme biosynthesis; Results in photosensitivity, hair growth, etc
Hexokinase deficiency: 2,3-DPG Hexokinase is the first enzyme in glycolysis. A deficiency leads to less flux through the pathway, leading to a decrease in 2,3-DPG, causing a left-shift in the O2 binding isotherm.
Argininosuccinate synthetase deficiency: Urea cycle Deficiency leads to elevated citrulline and ammonia levels in the plasma, CSF and urine. Recessive. Treated with arginine - enhances citrulline excretion.
Hypertriglyceridemia: high TG, low HDL slight higher in fat (35% of calories). Emphasis on monounsaturated fats. Low carbohydrates. If diet isn't enough, a TG lowering statin (s/a Atorvastatin) can be used. Niacin helps to raise HDL levels and also reduces the formation of small LDL and HDL - doesn't impact the total level of LDL.
Megaloblastic Anemia: methionine synthase (both)/ methylmalonyl mutase (B12) Megaloblasts are found in the bone marrow, and large RBCs in circulation. Caused by a disturbance in DNA synthesis. Can be caused by deficits in either B12 (Pernicious anemia) or folate. Excess methylmalonic acid is found in urine in pernicious anemia only.
HGPRT: This enzyme deficiency in the purine salvage pathway causes inefficient salvaging of purine, and leads to gout
Turner's Syndrome: meiosis single X chromosome (45,X). 95-98% abort spontaneously due to vascular abnormalities or fluid imbalance. Lymphedema biggest problem in liveborns. Webbing of neck, short stature, broad chest and widely spaced nipple. Streak ovaries, infertility, amenorrhea.
essential fatty acid deficiency: fatty acid synthesis infants do not get essential fatty acids (s/a linoleic and linolenic acids that can not be manufactured by the body), causing decreased growth, skin abnormalities, impaired immune response. Remedy - supplement EFA
Anemia of chronic disease: Syndrome; decreased Fe, TIBC, ALAS; Increased ferritin, DMT, transferrin receptor
Holoprosencephaly: SHH (sonic hedgehog) loss-of-function of SHH gene mutation.
Achondroplasia: FGFR3 (4p) Autosomal dominant, but most cases are de novo. Homozygous dominant is lethal. Rhizomelic limb shortening, macroencephaly, broad prominent forehead. Trident hand. Can treat youths with growth hormone.
Neural tube defects: can be caused by folate or deficiency, leading to insufficient nucleotide synthesis in rapidly dividing cells.
MCAD: Catabolism of medium chain fatty acids is deficient due to a defect in the medium chain acyl-CoA dehydrogenase
beriberi (dry): pyruvate dehydrogenate complex a chronic minor deficiency in thiamine, leading to disturbances in carbohydrate metabolism and decreased transketolase activity. Symptoms include peripheral neuropathy, fatigue, and impaired capacity to work. also impacts the alpha-KGDC (and other thiamine dependant enzymes), but PDC is gatekeeper.
Scurvy: collagen Vitamin C (ascorbate) is a necessary cofactor for prolyl hydroxylase. This enzyme hydroxylates proline so that it may form hydrogen bonds in the collagen fibrils.
Hyperammonenia Type 1: Urea cycle Carbamoyl phosphate synthetase I (CPI) or N-acetylglutamate synthetase deficiency. Treat the former with arginine (positive modulator for the formation of N-acetylglutamate) and the latter with carbamoyl glutamate (activates CPI).
(Severe Combined Immunodeficiency Syndrome) SCID: purine metabolism a deficiency in adenosine deaminase can cause a deficit of both T and B cells, possibly due to a buildup of dATP which inhibits ribonucleotid reductase (and hence DNA synthesis). A deficiency of purine nucleoside phosphorylase can induce a deficiency of T-cells only. possibly due to an accumulation of dGTP, inhibiting the reduction of pyrimidines by ribonucleotide reductase.
Beta-thalassemia: Kinetic classification of anemia with increased apoptosis of RBC precursors in marrow and decreased beta-globin chains. This leads to excess alpha-chains and ineffective erythropoiesis
Angelman Syndrome: UBE3A gene (15q11q13 - paternal copy only) Severe MR, hypotonia of trunk and hypertonia of extremities. Absent speech. Movement or balance disorder. Seizures. Protruding tongue, hypopigmentation. Maternal del(15q11q13) or imprinting center mutation. Few uniparental disomy (UPD) - paternal. UBE3A gene product transfers ubiquitin; imprinting restricted to brain.
Hereditary Orotic Aciduria: pyrimidine nucleotide biosynthesis caused by a deficiency in UMP Synthase (composed of two enzymes, orotate phosphoribosyl transferase and orotidine decarboxylase), which leads to a deficiency of UTP, a lack of pyrimidines, and increased flux through the first steps of the pathway, giving an accumulation of orotic acid. Symptoms include magaloblastic anemia, growth retardation. treated with oral uridine.
Hereditary Spherocytosis: Spectrin (or Ankryn, etc) mutations in the genes for Spectrin or Ankryn lead to a weakened interaction between the integral and peripheral proteins of the RBC membrane. This results in the loss of deformability in the RBC and they are subject to destruction in the spleen.
Hereditary Spherocytosis: Defects in the interactions of spectrin or ankyrin with Band 3 in RBCs, disrupting vertical interactions and leading to membrane loss
Gaucher's Disease Type 1: glucocerebrosidase Tissues accumulate glucocerebroside due to a deficiency of glucocerebrosidase - can't cleave the cerebroside-glucose linkage. Symptoms include easy bruising, fatigue due to anemia, enlargement of liver and spleen, weakness of skeleton; occasional lung and kidney impairment. early childhood to late adult onset. some success with IV enzyme replacement therapy (ceradase or cerezyme).
Blooms Syndrome: BLM helicase Recessive mutation in BLM helicase- accelerated aging. Cardiovascular disease, arthritis, cancer. Chromosomal and genomic instability.
Pernicious Anemia: Methylmalonyl CoA mutase caused by a deficiency in methylmalonylCoA mutase (converts methylmalonyl Coal to Succinyl CoA) or a lack of vitamin B12 due to inadequate intrinsic factor (a glycoprotein secreted by the stomach required for the absorption of vitamin B12) or a strictly vegan diet
Rickets: Caused by deficiency of vitamin D in children; results in no mineralization of cartilage in the epiphyseal plate and bone osteod. Causes bow legs
HIV: Viral RNA integrates into T-helper cell DNA, destroying cell. Results in low immune system
Fetal Alcohol Syndrome: short palpebral fissure, short now, long philturm, thin upper lip. Low BW, growth delay, heart defects.
Ineffective erythropoiesis: RBC You will see lots of hemosiderin in the bone marrow, a hypochromatic peripheral smear, and a low reticulocyte count.
Insulin resistance/ Type II diabetes: GLUT 4 can be caused by a defect in the GLUT 4 receptor. GLUT 4 functions in the facilitated diffusion of glucose and is insulin-responsive and is found in muscle and adipose tissue. (Insulin triggers the release of GLUT 4 protein to the membrane).
HIV: helper T-cells the HIV virus binds the CD4 protein on the helper t-cells and enters them. The virus then kills the cells, leading to a breakdown of the immune system.
Homocystinuria: Deficiency in cysathionine beta-synthase, resulting in elevated serum homocysteine. Causes osteoporosis, mental retardation, vascular thrombosis.
Patau Syndrome: meiosis Trisomy 13. 1/15,000-25,000 live births. Bilateral cleft palate. Low-set malformed ear. Renal and cardiac defects. Polydactyly.
Phenylketonuria: Defective phenylalanine hydroxylase. Results in mental retardation, epilepsy, brain calcification, mousy smelling urine, etc. if untreated. Treated with phenylalanine restricted, tyrosine supplemented diet.
DiGeorge Syndrome/Velocardiofacial Syndrome: 22q11.2 a developmental field defect caused by a chromosome 22q11.2 microdeletion. Cleft palate. parathyroid hypoplasia, thymus hypoplasia, immunodeficiency, cardiac defects, renal and urinary tract defects, mental retardation. deletion syndrome
Sickle Cell Anemia: Measured by hemoglobin electrophoresis; substitution of valine for glutamic acid in beta-globmin autosomal recessive; infection with streptococcus pneumoniae; multiple effects over all organ systems
Tay-Sachs Disease: Caused by a defect in beta-N-acetylhexosaminidase, in which gangliosides ending in GalNAc cannot be degraded. Prenatal testing
Galactosemia: Body cannot break down galactose; diet without milk sugar, lactose free diet may prevent brain and liver damage; can cause E. coli sepsis, jaundice, liver failure by toxicity. later MR, cataract, ovarian insufficiency; enzyme decay in summertime
Atherosclerosis: initiation: endothelial injury due to: smoking, diabetes, hypertension, genetic abnormalities, insulin resistance ischemia, peripheral artery disease, inflammation, obesity, dyslipidemia, hyperhomocysteinemia. Once the endothelium in injured, LDL-C can enter (smaller LDLs are worse) and they become oxidized. Once oxidized, they attract monocytes and promote the production of CAMs, allowing more LDLs and macrophages to be present. oxLDL is picked up by macrophages by attaching to the scavenger receptor (no feedback inhibition). hypertrophy and form foam cells. activated smooth muscle cells move in (pro-inflammatory). endothelial cap stability is an important factor in plaque stability. entire lectures devoted to this - see Dr. Repka's lectures
Kearns-Sayre Syndrome: Multisystem disorder characterized by brain and muscle dysfunction in which patients often have short stature, hearing loss, mental retardation, etc. mtDNA deletion sizes range up to >7kb or >40% of genome
Kernicterus: excessive bilirubin in the blood caused by untreated jaundice - severe neurotoxic effects: athetoid cerebral palsy, severe motor delay, dysarthria, sensoneuronal hearing loss, mental retardation
Gilbert's syndrome: UDP-glucuronosyl transferase a deficiency in UDP-glucuronosyl transferase (due to defects in the promoter), the rate limiting step in bilirubin glucouronide production, causes mild symptoms. Affects 5-10% of the Caucasian population. Slower clearance of unconjugated bilirubin.
True hermaphroditism: most commonly 46,XX with testicular and ovarian tissue.
Rheumatoid Arthritis: Inflammatory autoimmune disease, affecting joint cartilage and synovial membranes
Rothmund-Thomson: RecQ5 helicase Recessive mutation in RecQ5 helicase- accelerated aging. Cardiovascular disease, arthritis, cancer. Chromosomal and genomic instability.
MCAD: Medium chain acyl CoA DH autosomal recessive. Urine has high acylglycine levels and plasma has high acylcarnitine levels. After fast, hypoglycemia, metabolic acidosis, enlarged liver.
Cholera: G protein Cholera toxin causes the irreversible covalent modification of the alpha-subunit of Gs (attaches an ADP-ribose group to an arg residue), locking it in the GTP-bound state. The causes the constitutive activation of adenylate cyclase giving high levels on cAMP. This causes persistent activation of PKA, which phosphorylates a chloride channel - leads to excessive loss of NaCl and water in the intestine.
Osteomalacia (adult rickets): calcium absorption from gut A calcium deficiency in adults (can be caused by vit. D deficiency) means that newly formed osteons do not calcify sufficiently, weakening bones. Common in pregnancy.
Scurvy: Caused by deficiency of vitamin C in adults; results in weak collagen in the bone matrix and weakly formed osteod

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Number of cards 359