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249 Cards in this Set
- Front
- Back
- 3rd side (hint)
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What are the fat soluble vitamins?
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Vitamin A,D,K,and E
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Vitamin A- Vision
Vitamin D- Bone calcification and Ca+2 homeostasis Vitamin K- Clotting Factors Vitamin E- Antioxidant |
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What are the water soluble vitamins?
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Vitamin C
Thiamine-B1 Riboflavin-B2 Niacin-B3 Pantothenic acid-B5 Pyridoxine-B6 Biotin Folate Cobalamin- B12 (Blood and CNS) |
All wash out easily from the body except B12 and folate (stored in the liver)
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Where does the absorption of fat soluble vitamins occur?
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dependent on the gut (ileum) and pancreas
toxicity more common for fat soluble vitamins because they accumulate in fat |
Malabsorption syndrome can cause fat-soluble vitamin deficiencies
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Vitamin A (retinol)
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Deficiency- Night blindness, dry skin
Function- Constituent of visual pigments Excess- Arthralgias, fatigue, headaches, skin changes, sore throat, and alopecia |
Retinol is vitamin A, so think Retin-A (used for wrinkles and acne).
Found in leafy vegetables |
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Arthralgias
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joint pain
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Alopecia
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hair loss
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Vitamin B1 (Thiamine)
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Deficiency- Beriberi and Wernicke-Korsakoff syndrome. Seen in alcoholism and malnutrition
Function- TPP: cofactor for oxidative phosphorylation |
Spell berieri as Ber1Ber1 (B1)
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Vitamin B2 (Riboflavin)
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Deficiency- Angular stomatitis and Cheilosis and Corneal vascularization
Function- Cofactor in oxidative and reduction (FADH2) |
Fad and Fmn are derived from riboFlavin
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Angular Stomatitis
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inflammation of oral mucous linings
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Cheilosis
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inflammation of lips
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Vitamin B3 (niacin)
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Deficiency- Niacin is made in the body by tryptophan - synthesis requires B6, Pellagra can be caused by Hartnup disease, malignant carcinoid syndrome, and INH
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Function- Constituent of NAD+, NADP+ (used in redox reactions)
Derived from tryptophan using B6 |
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Pellagra
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Pellagra symptoms are the three Ds: Diarrhea, Dermatitis, and Dementia
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Alcoholic develops rash, diarrhea, and altered mental status
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Hartnup disease
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decreased tryptophan absorption
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Malignant carcinoid syndrome
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increased tryptophan metabolism
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Vitamin B5 (pantothenate)
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Deficiency- Dermatitis, enteritis, alopecia, adrenal insufficiency
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Function- Constituent of CoA (a cofactor for acyl transfers) and component of fatty acid synthase
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Enteritis
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inflammation of small intestine
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Vitamin B6 (pyridoxine)
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Deficiency- Convulsions, hyperirritability, peripheral neuropathy
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Function- Converted to pyridoxal phosphate, a cofactor used for transaminations, decarboxylations, and also required for the syntesis of niacin from tryptophan
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Vitamin B12 (cobalamin)
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Deficiency- Macrocytic, megaloblastic anemia, neurologic symptoms, and glossitis
Function- cofactor for homocysteine methyltransferase, stored primarily in the liver, very large reserve pool, and synthesized only by microorganisms. |
Deficiency is usually caused by malabsorption (sprue,enteritis) lack of intrinsic factor (pernicious anemia and gastric bypass surgery) or absence of terminal ileum (Crohn's disease)
Abnormal myelin is also seen in B12 deficiency |
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Macrocytic
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large red blood corpuscles
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deficiency of folic acid and vitamin B12
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Megoblastic anemia
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macrocytic changes are evident in RBCs
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What is the difference between folic acid deficiency and B12 deficiency?
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B12 deficiency - you have neurological symptoms
Folate deficiency- there are often NO neurological symptoms |
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Folic Acid
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Deficiency- Macrocytic, Megoblastic anemia, often no neurological symptoms
Function: Coenzyme for 1-carbon transfer; involved in methylation reactions, important in the synthesis of nitrogenous bases for DNA and RNA |
FOLate from FOLiage
eat green leaves because folic acid isn't stored very long *Important in pregnancy to protect against neural tube defects |
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Biotin
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Deficiency- Dermatitis, enteritis
Caused by antibiotic use and excessive ingestion of raw eggs Function - Cofactor for carboxylations (pyruvate-oxaloacetete) (acetyl-CoA- malonyl-CoA) (Propionyl-CoA- methylmalonyl-CoA) |
AVIDin in egg whites AVIDly binds biotin
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Vitamin C (ascorbic acid)
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Deficiency- Scurvy- swollen gums, bruising, anemia, and poor wound healing
Function- Hydroxylation of proline and lysine in collagen synthesis, keeps iron in Fe+2 reduced state to be better absorbed, and cofactor to convert dopamine to NE |
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Vitamin D
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D2= consumed in milk
D3=formed in sun exposure Deficiency- Rickets in children, osteomalacia in adults, and hypocalcemic tetany Function- increased absorption of calcium and phosphate |
Excess- Hypercalcemia, loss of appetite, stupor. Seen in sarcoidosis, a disease where the epithelioid macrophages covert vitamin D into its active form
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Rickets
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bending of bones in children
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osteomalacia
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soft bones in adults
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hypocalcemic tetany
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disease of abnormally low level of calcium in the blood
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Vitamin E
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Deficiency- increased fragility of erythrocytes and neurodysfunction
Function- Antioxidant (protects erythrocytes from hemolysis) |
Vitamin E is for erythrocytes
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Vitamin K
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Deficiency- Neonatal hemorrhage with increase in PT and aPTT but normal bleeding time- because neonates have sterile intestines they are unable to synthesize Vitamin K
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Neonates are given vitamin K injection at birth to prevent hemorrhage
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Vitamin K Function
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Catalyze gamma carboxylation of glutamic acid residues on various proteins concerned with blood clotting
synthesized in intestinal flora. Therefore, vitamin K deficiency can occur afte the prolonged use of broad spectrum antibiotics |
K for Koagulation. Note that the vitamin K -dependent clotting factors are 2,7,9,10 and protein C and S. Warfarin is a vitamin K antagonist
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Zinc Deficiency
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delayed wound healing, hypogonadism, decreased adult hair (axillary, facial, and pubic) may predispose to alcoholic cirrhosis
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Ethanol Metabolism
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Ethanol-Acetaldehyde-Acetate
NAD+ is a limiting reagent and NADH is produced |
Fomepizole inhibits alcohol dehydrogenase
Disulfiram (antabuse) inhibits acetaldehyde dehydrogenase (acetaldehyde accumulates and contributes to hangovers) |
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Ethanol hypoglycemia
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Ethanol Metabolism increases the NADH/NAD+ ratio in the liver, which then causes diversion of pyruvate to lactate and OAA to malate. thereby inhibiting gluconeogenesis leading to hypoglycemia
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Kwashiorkor vs. marasmus
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Kwashiorkor- protein malnutrition, lesions, edema, liver malfunction. (small child with swollen belly)
Marasmus- energy malnutrtion resulting in tissue and muscle wasting, loss of subcutaneous fat, and variable edema |
Kwashiorkor results from a protein deficient MEAL:
M:malnutrition E:edema A:anemia L: liver (fatty) |
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Edema
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fluid accumulation beneath the skin or in one or more body cavities
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rin
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厘
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If you chuck a computer off a cliff, its value would equal a rin. (Rin is a Japanese currency equivalent to 1/1000th of a yen. Current meaning is something very tiny)
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Nucleotide vs. Nucleoside
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Nucleotide - base + ribose + phosphate
Nucleoside- base +ribose |
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Amino Acids that are necessary for purine synthesis
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GAG
G-Glycine A-Aspartate G-Glutamine |
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Nucleotide synthesis
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Purines are made from IMP
Pyrimidines are made from orotate an PRPP (added later) Ribonucleotides are made first and then converted to deoxyribonucleotides |
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Transition vs. Transversion
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Transition - purine for purine
Transversion- conversion between purine for pyrimidine or visa versa |
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Genetic Code Features
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Unambiguous
Redundant non-overlapping universal |
each codon for only 1 aa
more than 1 codon may code for the same aa read from a fixed starting point as a continuous sequence of bases genetic code is conserved |
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eukaryotes vs. prokaryote replication
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eukaryotes genome has multiple origins of replication
prokaryotes have a single origin |
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Helicase
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enzyme that unwinds DNA at the replication fork
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Single stranded binding (SSB) protein prevents strands from re-annealing
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DNA topoisomerase
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create a nick int he helix to reliece supercoils
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DNA gyrase is a specific prokaryotic topoisomerase
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Primase
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makes the RNA primer on which DNA polymerase III can initiate replication
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DNA polymerase III
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elongates the chain by adding deoxynucleotides to the 3' end and elongates lagging strand until it reaches next primer
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Has proofreading activity
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DNA Polymerase I
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Degrades RNA primer and fills in the gap with DNA
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excise the DNA with a 5' to 3' exonuclease
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Nucleotide excision repair
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specific endonucleases release the oligonucleotide-containing damaged bases; DNA polymerase and ligase fill and reseal the gap respectively
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mutated in xeroderma pigmentosum (dry skin with melanoma and other cancers) - prevent the repair of thymidine dimers
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Base excision repair
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specific glycosylases recognize and remove damaged bases, AP endonuclease cuts DNA at apyrimidimic site, empty sugar is removed, and the gap is filled and resealed
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mismatch repair
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unmethylated, newly synthesized string is recognized and mismatched nucleotides are removed and the gap is filled and resealed
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Mutated in HEREDITARY NONPOLYPOSIS COLORECTAL CANCER (HNPCC)
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Non-homologous end joining
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brings together two ends of DNA fragments
no requirement for homology |
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RNA Pol I
RNA Pol II RNA Pol III |
I- rRNA
II- mRNA III- tRNA |
prokaryotic RNA polymerase makes all 3
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RNA processing
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1. Capping the 5' end
2. Poly-A tail at 3' end 3. Splicing of introns |
intial transcript called heterogenous nuclear RNA (hnRNA)
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Aminoacyl-tRNA synthase
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scrutinizes aa before and after it binds to tRNA. if incorrect bond is hydrolyzed by synthase. The aa-tRNA bond has energy for formation of the peptide bond
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Protein Synthesis (Initiation)
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Initiation- Activated by GTP hydrolysis, eIFs help assemble the 40S subunit wit the initiator tRNA- then are released when the mRNA and 60S subunit assemble
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Protein synthesis (elongation)
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1. Aminoacyl-tRNA binds to A site (except for methionine)
2. Peptidyltransferase catalyzes peptide bond formation, transfers growing polypeptide to amino acid in A site 3.Ribosome advances 3 nucleotides toward 3' end of RNA, moving peptidyl RNA to site |
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Protein synthesis (termination)
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Completed protein is released from the ribosome through simple hydrolysis and then dissociates
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Posttranslational modifications
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Trimming - removal of N or C terminal
Covalent modifications- phosphorylation, glycosylation, and hydroxylation Proteasomal degradation - attachment of ubiquitin to defective proteins to tag them for breakdown |
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Checkpoints in the cell cycle are regulated by?
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cyclin and CDKs and tumor suppressors
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Cyclins- activate CDKs
tumor suppressors- p53 and pRb normally inhibit G1 to S progression |
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Permanent cells
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remain in G0
regenrage from stem cells |
Neurons, skeletal, cardiac muscle cells and RBCs remain in G0
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Labile cells
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never go into G0
divide rapidly with a short G1 |
Bone marrow, gut epithelium, skin, and hair follicles
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Nissel Bodies
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in neurons
synthesize enzymes and peptide neurotransmitters RER |
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Free Ribosomes
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unattached to any membrane
site of synthesis of cytoslic and organellar proteins |
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What type of cells are rich with RER?
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mucus secreting goblet cells of the small intestine and antibody secreting plasma cells
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Smooth ER
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site of steroid synthesis and detoxification of drugs and poisons
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Liver hepatocytes and steroid hormone producing cells of the adrenal gland are rich in SER
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Function of Golgi Apparatus
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1. Distribution center of proteins and lipids from ER to (plasma membrane, lysosomes, and secretory vesicles)
2. Modifies N-oligosacchardies on asparagine residues 3. Adds O-oligosaccharides to serine and theronine residues 4. Addition of Mannose-6-Phosphate - targets to lysosome 5. Proteoglycan assembly 6. Sulfation of sugars in proteoglycans |
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I-Cell Disease
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failure of addition of mannose-6-phosphate to lysosome proteins, enzymes are secreted outside the cell instead of being targeted to the lysosome.
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Characterized by coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes. Often fatal in childhood
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Vesicular trafficking proteins
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COPI: retrograde (Golgi to ER)
COPII: anterograde Clathrin: trans- golgi to lysosome to plasma memb. to endosomes |
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Microtubules
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Cylindrical structures composed of a helical array of polymerized dimers of alpha and beta tubulin.
Each dimer has 2 bound GTP Grows slowly and disassembles quickly |
involved in flagella, cilia, and mitotic spindle
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Chediak-Higashi syndrome
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defect in microtubule polymerization so that the phagosome doesn't fuse with the lysosome
1) recurrent pyogenic infections 2) albinism 3) peripheral neuropathy |
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Cilia Structure
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9+2 arrangement of microtubules
Dynein is an ATPase that links to the 9 doublets and causes bending of cilium by differential sliding of doublets |
Dynein = retrograde
Kinesin= anterograde |
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Kartagener's Syndrome
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Immotile cilia due to a dynein arm defect. Results in male and female infertility, bronchiectasis, and recurrent sinusitis
Associated with sinus inversus |
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Plasma Membrane
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Asymmetric fluid bilayer
50% cholesterol and 50% phospholipids (sphingolipids, glycolipids) and proteins |
High cholesterol or long saturated fatty acid content- increases the melting temperature and decrease fluidity
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Phosphatidylcholine (lecithin) function
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Major component of RBC membranes of mylein, bile, and surfactant
Used in esterification of cholesterol |
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Sodium/Potassium Pump
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For every 3 Na+ that go out: 2 K+ come in
the ATP on the cytosolic side P the pump and allows it to open |
Ouabain - inhibits by binding to K+ site
Cardiac glycosides- inhibit the Na+-K+ATPase causing increased cardia contractility |
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Collagen Types
Most abundant protein in the body |
Type I- Bone, Skin, Tendon, late wound repair, cornea, fascia, and dentin
Type II- Cartilage (hyaline) Type III-Reticulin - skin, blood vessels, uterus, and fetal tissue Type IV- Basement membrane |
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Collagen synthesis
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1. Synthesis on RER- preprocollagen
2. Hydroxylation- of proline and lysine residues (requires Vit. C) 3. Glycosylation- of pro-alpha-chain forms procollagen 4. procollagen moves to extracellular space 5. cleavage of procollagen to tropocollagen 6. Cross linking to make collagen fibrils |
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Ehlers- Danlos syndrome
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Faulty collagen synthesis causing:
1. Hyperextensible skin 2.Tendency to bleed and easily bruise 3. Hypermobile joints |
Type III collagen is most frequently affected
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Osteogenesis imperfecta
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Variety of gene defects; all result in abnormal collagen synthesis (usually dominant inheritance with mutated Type I)
1.brittle bone disease 2. blue sclerae due to the translucency of the connective tissue over the choroid 3. Hearing loss (abnormal middle ear bones) 4. Dental imperfections due to lack of dentin |
May be confused with childhood abuse
Type II is fatal in utero or in neonate period 1:10,000 |
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Elastin
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Stretchy protein within lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava
Rich in proline and glycine |
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Marfan Syndrome
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caused by a defect in fibrillin
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tropoelastin and fibrillin make a scaffolding together
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What processes occur in the mitochondria?
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fatty acid oxidation (beta), acetyl-CoA production, Krebs cycle, and oxidative phosphorylation
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What processes occur in the cytosol?
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Glycolysis, fatty acid synthesis, protein synthesis, steroid synthesis
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What processes occur in both mitochondria and the cytosol?
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HUG
H:Heme synthesis U: Urea cycle G: Gluconeogenesis |
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Rate determining step for glycolysis
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PFK-1
and can be affected by insulin through PFK-2 |
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Rate determining for gluconeogenesis?
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Pyruvate carboxylase
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Rate limiting step for Kreb's cycle?
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Isocitrate dehydrogenase
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Rate determining step for Glycogen synthesis
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Glycogen synthase
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Rate determining step for Glycogenolysis
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Glycogen phosphorylase
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Rate determining step fro HMP shunt
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Glucose- 6- Phosphate dehydrogenase
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Rate Determining step for fatty acid synthesis
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Acetyl-CoA carboxylase (ACC)
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Rate determining step for fatty acid oxidation
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Carnitine acyltransferase I
Adds the carnitine where CoA use to be to shuttle into mitochondria |
First enzyme in carnitine transport system
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Rate determining for Ketogenesis
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HMG-CoA synthase
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Rate determining for Heme synthesis
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ALA synthase
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8 succinyl-CoA + 8 glycine = 8 ALA
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Rate determining for Urea cycle
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carbamoyl phosphate synthase I
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ATP
(Aerobic vs. Anaerobic) |
Aerobic Metabolism of glucose by malate-aspartate shuttle =32 ATP -liver and heart
Anaerobic- glycolysis only 2 net ATP |
ATP hydrolysis can be coupled to energetically unfavorable reactions
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universal electron acceptors
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NAD+ and NADP+ and FAD+
NAD+ used in catabolic reactions - NADH NADPH is used in anabolic reactions, respiratory bursts, and P-450 |
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Hexokinase
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High affinity and low capacity uninduced by insulin
in all other tissues expect liver (where glucokinase is located) |
Feedback inhibited by glucose-6-phosphate
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Glucokinase
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low affinity but high capacity (opposite of hexokinase)
induced by insulin |
No direct feedback inhibition
Phosphorylates excess glucose (after a meal) to sequester it in the liver |
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Fructose 2,6 Bisphosphate
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Most potent activator of phosphofructokinase (overrides inhibition of ATP and citrate) and is a potent regulator of glycolysis and gluconeogenesis
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Increase in F 2,6 BP then activate glycolysis
Decrease in F 2,6 BP then activate gluconeogenesis |
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Glycolytic enzyme deficiency
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Associated with hemolytic anemia by decreasing activity of Na/K ATPase -leads to RBC swelling and lysis
Due to deficiencies in pyruvate kinase and other glycolytic enzymes |
RBCs metabolize glucose anaerobically (no mitochondria) and thus depend solely on glycolysis.
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The 5 cofactors for the Pyruvate Dehydrogenase Complex
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1. B1 (thiamine; TPP)
2.FAD (B2, riboflavin) 3. NAD (B3, niacin) 4. CoA (B5, pantothenate) 5. Lipoic Acid |
PDH Complex activated by exercise : Increase in NAD+, ADP, and Ca+2
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How does arsenic affect PDH complex
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it inhibits lipoic acid
Vomiting, Rice water stools, and Garlic breath |
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Pyruvate dehydrogenase deficiency
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causes backup of substrate (pyruvate and alanine) resulting in lactic acidosis
FIndings: neurological defects |
Treatment: intake of ketogenic nutrients (high fat content or increased lysine and leucine)
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Fates of Pyruvate
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1. Alanine
2. Oxaloacetate 3. Acetyl-CoA 4. Lactate |
1. alanine carries amino group from muscle to liver
2. replenish TCA cycle or gluconeogenesis 3. glycolysis to TCA 4. anaerobic glycolysis end |
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Function of the Cori cycle
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allows lactate generated during anaerobic metabolism to undergo hepatic gluconeogenesis and become a source of glucose for RBCs and muscle
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Shifts the metabolic burden from the muscles to the liver
and uses 4 ATP every cycle |
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TCA Cycle
Krebs Cycle |
Produces 3 NADH, 1 FADH2, 2 CO2, 1 GTP= 12 ATP/aceytl-CoA
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alpha-ketogluterate dehydrogenase requires all the same cofactors as pyruvate dehydrogenase
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Electron transport chain
oxidative phosphorylation |
electrons from NADH from glycolysis enter the mitochondria via the malate-aspartate shuttle or the glycerol-3 phosphate shuttle
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1 NADH- 3 ATP
1 FADH2- 2 ATP |
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Pyruvate carboxylase (irreversible)
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mitochondria- pyruvate to oxaloacetate
this step can also be utilized in gluconeogenesis |
Requires biotin, ATP
Activated by acetyl-CoA |
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PEP carboxykinase
(irreversible) |
in cytosol- oxaloacetate to PEP
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Require GTP
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Fructose 1,6 Bisphosphatase
(irreversible) |
In cytosol- Fructose 1,6 bisphoshphate to fructose 6-P
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Glucose 6-Phosphatase
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In ER - G6P to Glucose
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Can muscle participate in gluconeogenesis?
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NO!
Only in liver, kidney, intestinal epithelium |
Deficiency in gluconeogenic enzymes causes hypoglycemia
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Pentose Phosphate Pathway (HMP Shunt)
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Produces NADPH - required for fatty acid and steroid biosynthesis and for the glutathione reduction inside RBCs
Occurs in Cytoplasm and no ATP is used |
Key Enzymes:
Oxidative- Glucose 6 phosphate dehydrogenase - produces NADPH NON-oxidative - transketolases |
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Glucose 6 phosphate dehydrogenase deficiency
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G6PD is the rate limiting step in PPP. NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides. Decreased NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents
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increase to malaria resistance
but can't metabolize the malaria drugs |
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Fructose intolerance
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hereditary deficiency of aldolase B (recessive). F 1 P accumulates causing a decrease in available phosphate resulting in inhibition of glycogenolysis and gluconeogenesis
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Symptoms: hypoglycemia, jaundice, cirrhosis, and vomiting
Treatment: must decrease intake of both fructose and sucrose |
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Essential fructosuria
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Involves a defect in fructokinase and is a benign, asymptomtic condition, since fructose does not enter cells
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Symptoms: fructose appears in blood and urine
Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose metabolism |
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Galactosemia
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Absense of galactose 1 phosphate uridyltrnasferase. Autosomal recessive. Damage is caused by accumulation of toxic substances rather than absence of essential compound
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Symptoms: cataracts, hepatosplenomegaly, MR
Treatment: exclude galactose and lactose from diet |
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Galactokinase deficiency
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Caused by galactosemia and galactosuria, galactitol accumulation if galactose is present in diet
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Lactase deficiency
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Age-dependent and or hereditary lactose intolerance (blacks and asians) due to loss of brush-border enzyme
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Symtoms: bloating, cramps, osmotic diarrhea
Treatment: avoid milk or add lactase pills to diet |
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Transport of Ammonium
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Done by Alanine and glutamine between the muscle and liver
Glucose from liver to muscle Alanine from muscle to liver Glutamate contributes the NH3 |
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Hyperammonemia
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Can be acquired or hereditary
excess NH4 depletes alpha-ketoglutarate, leading to inhibition of TCA cycle |
Treatment: benzoate or phenylbutyrate to lower serum ammonia levels
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Ammonia intoxication
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tremor, slurring of speech, somnolence, vomiting, cerebral edema, and blurring of vision
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Somnolence
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Drowsiness
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Urea Cycle
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DOESN'T degrade amino acids into amino groups. Instead it DOES function to excrete excess nitrogen (NH4) generated by amino acid catabolism
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CO2 + NH4 = Carbamoyl Phosphate + Ornithine = Citrulline + Aspartate = Arginosuccinate - Arginine - Ornithine
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What does Phenylalanine make?
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Tyrosine - Thyroxine and Dopa
Dopa- Melanin and Dopamine Dopamine- NE and Epi |
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What does Tryptophan make?
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Niacin and Serotonin
Serotonin- Melatonin Niacin- NAD+ and NADP+ |
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What does Histidine make?
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Histamine
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What does Glycine make?
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Porphyrin - Heme
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What does Arginine make?
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Creatine and Urea and Nitric Oxide
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What does Glutamate make?
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GABA and Glutathione
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GABA (requires B6)
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Phenylketonuria
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Normally, phenylalanine is converted to tyrosine (nonessential). In PKU, there is defective phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor. Tyrosine becomes essential and phenylalanine build up- leading to phenylketones in urine.
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Findings: MR, growth retardation, fair skin, eczema, and musty body odor.
Treatment: decrease phenylalanine in diet and increase tyrosine in diet |
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Alkaptonuria
(ochronosis) |
Congenital deficiency of homogentisic acid oxidase in the degradative pathway of tyrosine.
Resulting alkapton bodies cause urine to turn black on standing. Also have dark connective tissue because homogentistic binds to collagen(ears, nose, cheeks) Benign disease but may have debilitating arthraligias |
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Albinism
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Congenital deficiency of either of the following:
1. Tyrosinase - inability to synthesize melanin from tyrosine- autosomal recessive 2.Defective tryrosine transporters (decrease amt of tyrosine then you decrease amt of melanin) |
Can result from a lack of migration of neural crest cells
*Lack of melanin - increase risk of skin cancer *Variable inheritance due to locus heterogeneity |
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Homocystinuria
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3 forms (all autosomal recessive)
1.Cystathionine synthase deficiency (treatment: dec-Met and inc- Cys and B12 and folate in diet) 2.decrease affinity of cystathionine synthase for pyridoxal phosphate (treat: inc-viatmins B6 in diet) 3. Homocysteine methyltransferase deficiency |
All forms result in excess homocystine and cysteine becomes essential
*Can cause mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation (down and in), and atherosclerosis (stroke and MI). |
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Cystinuria
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Common (1:7000) inherited defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, and arginine in the PCT of the kidneys.
Excess cystine in urine can lead to precipitation of cystine kidney stones |
Treatment: acetazolamide to alkalinize the urine
*Cystine is made of two cystines connected with a disulfide bond |
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Maple syrup urine disease
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Blocked degradation of branched amino acids (Ile,Val, Leu) due to a decrease alpha-ketoacid dehydrogenase
Causes increase in alpha-ketoacids in the blood, especially Leu. Causes severe CNS defects, MR, and death |
Urine smells like maple syrup
I Love Vermont maple syrup. Ile, Leu, Val |
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Adenosine deaminase deficiency
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ADA deficiency can cause SCID (Severe Combined Immunodeficiency disease). Excess ATP and dATP imbalances nucleotide pool via feedback inhibition or ribonucleotide reductase. This prevents DNA synthesis and thus decrease lymphocyte count.
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1st disease to be treated by experimental gene therapy
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Lesch-Nyhan syndrome
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Purine salvage problem owing to absence of HGPRT, which converts hypoxanthine to IMP and guanine to GMP. X-linked recessive. Results in excess uric acid production. Findings: retardation, self-mutilation, aggression, hyperuricemia, gout, and choreoathetosis
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He's Got Purine Recovery Trouble
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Where is Insulin made?
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Beta cells of the pancreas - in response to ATP from glucose metabolism acting on K+ channels and depolarizing cells. Required for adipose and skeletal muscle uptake of glucose
*INsulin moves glucose INto cells |
Don't need insulin for glucose uptake: BRICK L
B:Brain R:RBCs I:Intestine C:Cornea K:Kidney L: Liver |
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Where are GLUT 1, GLUT 2, and GLUT 4 receptors found?
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GLUT1: RBCs and brain
GLUT2: (bidirectional) beta islet cells, liver, and kidney GLUT4: (insulin responsive): adipose tissue and skeletal muscle. |
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Effects of Insulin
(anabolic) |
-Inhibits glucagon release by the alpha cells of the pancreas
Anabolic effects: 1. increase glucose transport 2.increase glycogen synthesis and storage 3.increase triglyceride synthesis and storage 4.increase Na+ retention (kidneys) 5. increase protein synthesis (muscles) 6. increase cellular uptake of K+ |
When glucose is high in the blood stream - ATP is produced in the mitochondria which inhibits the K+ release out of the cell, This causes a depolarization and Ca+2 comes into cell releasing insulin
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Regulation of Glycogen Synthase
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Liver: + Insulin, Glucose
- Glucagon, Epinephrine Muscle: + insulin - epinephrine |
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Regulation of Glycogen Phosphorylase
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Liver: +epinephrine, +glucagon
- insulin Muscle: +AMP, Epinephrine - ATP, Insulin |
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Glycogen in Skeletal muscle
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Glycogen undergoes glycogenolysis to form glucose which is rapidly metabolized during exercise
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Branches have 1-6 alpha bonds
linkages have alpha 1-4 bonds |
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Glycogen in Hepatocytes
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Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels
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Glucose- Glucose6P-Glucose1P-UDP-Glucose
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Glycogen Storage Diseases
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12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen wihtin cells
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Von Gierke's Disease (Type 1)
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*Deficient enzyme: Glucose 6 Phosphatase
Severe fasting hypoglycemia, increase glycogen in liver, increase blood lactate, hepatomegaly |
Glucose 6 phosphatase
separates the glucose from the phosphate Glucose goes through T2 and Phosphate through T3 |
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Pompe's Disease (Type II)
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*Deficiency enzyme: Lysosomal alpha1-4 glucosidase
Cardiomegaly and systemic findings leading to early death Failure to mobilize glycogen from the lysosome and accumulation of intracellular glycogen |
Pompe's disease trashes the Pump (heart, liver, muscle)
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Cori's disease (Type III)
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*Deficient enzyme: Debranching enzyme alpha 1,6-glucosidase
Milder form of type I with normal blood lactate levels |
Gluconeogenesis is intact
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McArdle's disease (type V)
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*Skeletal muscle glycogen phosphorylase
increase glycogen in muscle, but cannot break it down, leading to painful muscle cramps, myoglobinuria with strenuous exercise. |
McArdle's = Muscle
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Fabry's disease
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*deficient enzyme = alpha-galactosidase A
Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease |
Accumulated substance:Ceramide trihexoside
Inheritance: XR |
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Angiokeratomas
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begnin cutaneous lesions of capillaries resulting in small marks of red and blue color and characterized by hyperkeratosis
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Hyperkeratosis - thickening of the stratum corneum with abnormal keratin
Due to Vitamin A deficiency or exposure to arsenic |
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Gaucher's disease
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(most common)
*Deficient enzyme: Beta glucocerebrosidase Hepatosplenomegaly, aseptic necrosis of femur, bone crises, Gaucher's cells(macrophages that look like crumpled tissue paper) |
Accumulated substance:Glucocerebroside
Inheritance: AR |
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Niemann-Pick disease
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*Sphingomyelinase
Progressive neurodegeneration, hepatosplenomegaly, cherry-red spot (on macula), foam cells |
Sphingomylein
AR |
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foam cells
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cells in the atheroma that are derived from both smooth muscle cells and macrophages that have accumulated LDL by endocytosis
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Tay-Sachs disease
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*Hexosaminidase A
Progressive neurodegneration, developmental delay, cherry-red spot on macula, lysosomes with onion skin |
GM2 ganglioside
AR |
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Krabbe's disease
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*Galactocerebrosidase
Peripheral neuropathy, developmental delay, optic atrophy, globoid cells |
Galactocerebroside
AR |
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Globoid cells
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cells that have more than 1 nucleus
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Metachromatic leukodystrophy
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*Arylsulfatase A
Central and peripheral demyelination with ataxia, dementia |
Cerebroside sulfate
AR |
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Hurler's syndrome
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* alpha-L-iduronidase
Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly |
Heparan sulfate, dermatan sulfate
AR |
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Hunter's syndrome
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*Iduronate sulfatase
Mild Hurler's + aggressive behavior no corneal clouding |
Heparan sulfate, dermatan sulfate
XR |
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gargoylism
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a condition characterized by coarsened facial features associated with Hurler and Hunter syndromes
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Fatty acid metabolism sites
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Citrate shuttle to move acetyl-CoA out
Carnitine shuttle- to more Acyl-CoA into mitochondria |
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Ketone Bodies
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in liver, fatty acid and aa are metabolized to acetoacetate and beta-hydroxybutyrate. In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcoholism, excess NADH shunts oxaloacetate to malate. Both processes stall the TCA cycle, which shunts glucose to FFA to ketone bodies. Excreted in urine. Made from HMG-CoA. Ketone bodies are metabolized by the brain to 2 molecules of acetyl-CoA
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Breath smells like acetone (fruity odor)
Urine test for ketones does not detect Beta-hydroxybutyrate (favored by high redox state) |
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Cholesterol synthesis
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Rate limiting step is catalyzed by HMG-CoA reductase, which converts HMG-CoA to mevalonate. 2/3 of plasma cholesterol is esterifed by lecithin-cholesterol acyltransferase (LCAT)
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Statins inhibit HMG-CoA reductase
Mevalonate-Isoprene-Squalene- Cholesterol |
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Essential Fatty Acids
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Linoleic and linolenic acids
Arachidonic acid, if linoleic acid is absent |
Eicosanoids are dependent on essential fatty acids
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Apolipoproteins
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A-I - activates LCAT
B-100- Binds to LDL receptor, mediates VLDL secretion C-II- Cofactor for lipoprotein lipase B-48- mediates chylomicron secretion E- mediates extra uptake |
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Lipoprotein functions
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Lipoproteins are composed of varying proportions of cholesterol, triglycerides, and phospholipids
LDL and HDL carry most cholesterol |
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LDL
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"Lousy"
transports cholesterol from liver to tissue |
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HDL
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Healthy
transports cholesterol from periphery to liver |
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Chylomicron
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Delivers dietary triglycerides to peripheral tissues. Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their triacylglycerols. Secreted by intestinal epithelial cells. Excess causes pancreatitis, lipemia retinalis, and eruptive xanthomas.
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lipemia retinalis
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A creamy appearance of the retinal blood vessels that occurs when the concentration of lipids in the blood surpasses five percent.
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Eruptive Xanthomas
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Eruptive xanthomas are associated with hypertriglyceridemia, particularly that associated with types I, IV, and V (high concentrations of VLDL and chylomicrons). They may also appear in secondary hyperlipidemias, particularly in diabetes
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Eruptive xanthomas most commonly arise over the buttocks, the shoulders, and the extensor surfaces of the extremities. Rarely, the oral mucosa or the face may be affected. The lesions typically erupt as crops of small, red-yellow papules on an erythematous base
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VLDL
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Delivers hepatic triglycerides to peripheral tissues. Secreted by liver. Excess causes pancreatitis
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IDL
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Formed in the degradation of VLDL. Delivers triglycerides and cholesterol to the liver, where they are degraded to LDL
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LDL
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Delivers hepatic cholesterol to peripheral tissues. Formed by lipoprotein lipase modification of VLDL in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis. Excess causes atherosclerosis, xanthomas, and arcus corneae.
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Arcus Corenae
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A disease of the cornea which sometimes appears as white arcs on the cornea. The white arcs are due to abnormal deposits of phospholipids and cholesterol. It is usually caused by high blood lipid levels or eye defects
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HDL
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Mediates centripetal transport of cholesterol (reverse cholesterol transport, from periphery to liver). Acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism). Secreted from both liver and intestine.
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Type I of Familial dyslipidemias
Hyperchylomicronemia |
Increased: chylomicrons
Elevated blood levels- TG, cholesterol Path: Lipoprotein lipase deficiency or altered apolipoprotein C-II |
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Type II of Familial dyslipidemias
Hypercholesterolemia |
Increased LDL
Elevated blood levels of Cholestrol Path: decrease in LDL receptors |
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Type IV of Familial dylipidemias
Hypertriglyceridemia |
Increased VLDL
Elevated blood levels of TG Path: Hepatic overproduction of VLDL |
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Heme Synthesis
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8 Succinyl-CoA + 8 Glycine = 8 ALA (B6 is a cofactor)
Underproduction of heme causes microcytic hypochromic anemia. Accumulation of intermediates causes porphyrias. |
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Porphyrias
Lead poisoning |
*affected enzyme: Ferrochelatase and ALA dehydratase
Accumulated substrate in urine: Coproporphyrin and Delta-ALA |
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Porphyrias
Acute intermittent porphyria |
Affected enzyme: Porphobilinogen deaminase
Accumulated substance in urine: Porphobilinogen and delta-ALA |
Symptoms are the 5Ps:
Painful abdomen Pink urine Polyneuropathy Psychological disturbances Precipitated by drugs |
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Porphyrias
Porphyria cutanea tarda |
Affected enzyme: Uroporphyrinogen decarboxylase
Accumulated substance in urine: Uroporphyrin (tea-colored) |
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Heme Catabolism
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Heme is scavenged from RBCs and Fe+2 is reused. Heme- biliverdin-bilirubin. Bilirubin is removed from blood by liver, conjugated with glucuronate and excreted in bile.
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Some urobilinogen, an intestine intermediate, is reabsorbed into blood and excreted as urobilin into urine. Biliverdin gives bruises their blue-green color.
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Hemoglobin
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Hemoglobin is composed of 4 polypeptide subunits (2 alpha and 2 beta) and exists in two forms:
1. T (taut) form that has low affinity for O2 2. R (relaxed form) has high affinity for O2 (300x). |
increased Cl-, H+, CO2, and 2-3BPG and temperature favor the T form over R, shifts dissociation curve to the right leading to increased O2 unloading
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Fetal Hemoglobin
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Has 2 alpha and 2 gamma and has lower affinity for 2,3-BPG than adult hemoglobin and thus has higher affinity for O2
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CO2 Transport in the blood
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CO2 that is transported in blood and not bound to hemoglobin is primarily in bicarbonate from.
CO2 binds to aa in globin chain at N terminus, but not to heme. CO2 binding favors T from of hemoglobin - promoting unloading of O2 |
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Hemeglobin Modifications
Methemoglobin |
Oxidized form of hemoglobin (Fe+3) that does not bind O2 as readily, but does have increased affinity for CN-
Iron in hemoglobin is normally in the reduced state (Fe+2) |
To treat cyanide poisoning, use nitrates to oxidze hemoglobin to methemoglobin, which binds cyanide, allowing cytochrome oxidase to function. Use thiosulfate to bind this cyanide, forming thiocyanate, which is renally excreted.
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Carboxyhemoglobin
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Form of hemoglobin bound to CO in place of O2.
CO has 200x affinity that O2 for hemoglobin |
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Polymerase Chain Reaction (PCR)
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Used to synthesize many copies of a desired fragment of DNA
1. DNA is denatured by heating to generate 2 separate strands 2. During cooling, excess premade DNA primers anneal to a specific seq. on each strand to be amplified 3. Heat-stable DNA polymerase replicates the DNA sequence following each primer |
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Southern Blot
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A DNA sample is electrophoresed on a gel and then transfered to a filter. Filter is soaked in a denaturant and then exposed to a labeled DNA probe that recognizes and anneals to its complementary strand. Then exposed on a film
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Northern Blot
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RNA
like Southern but involves a radioactive DNA probe binding to sample RNA |
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Western Blot
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Sample protein is separated via gel eletrophoresis and transferred to a filter. Labeled antibody is used to bind to relevant protein
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Microarrays
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Thousands of nucleic acid sequences are arranged in grids on glass or silicon. DNA or RNA probes are hybridized to the chip, and a scanner detects are hybridized to the chip, and a scanner detects the relative amounts of complementary binding
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Enzyme-linked immunosorbent assay (ELISA)
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Rapid immunologic technique for antigen-antibody reactivity
1. Test antigen- to see if immune system recognizes it 2. Test antibody- to see if a certain antigen is present If either is present the sample will have an intense color reaction |
ELISA is used to determine whether a particular antibody (i.e. anti-HIV) is present in the a patient's blood sample. Both for sensitivity and specificity
Both false + and - do occur |
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Fluorescence in situ hybridization (FISH)
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Fluorescent probe binds to specific gene site of interest
Specific localization of genes and direct visualization of anomalies at molecular level |
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Cloning Methods
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1. DNA fragments are inserted into bacterial plasmids that contain antibiotic resistance genes.Restriction enzymes cleave and allow insertion of the fragment
2. Tissue mRNA is isolated and exposed to reverse transcriptase, forming a cDNA (lacks intron) library |
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Sanger DNA sequencing
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Dideoxynucleotides halt DNA polymerization at each base, generating sequences of various lengths that encompass the entire original sequence. The terminated fragments are electrophoresed and the original sequence can be deduced.
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Model systems
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Transgenic strategies in mice involves:
1. Random insertion of gene into mouse genome 2. Targeted insertion or deletion of gene through homologous recombination with mouse gene |
RNAi-dsRNA is synthesized that is complementary to the mRNA sequence of interest When transfected into human cells, the dsRNA separates and promotes degradation of the target mRNA, knocking down gene expression
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Codominance
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Neither 2 alleles is dominant (blood groups)
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Variable expression
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Nature and severity of the phenotype caries from 1 individual to another
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Incomplete penetrance
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Not all individuals with a mutant genotype show the mutant phenotype
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Pleiotropy
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1 gene has>1 effect on an individual's phenotype
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Imprinting
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Differences in phenotype depend on whether the mutation is a maternal or paternal origin
(angelman and prader-willi) |
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Anticipation
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Severity of disease worsens or age of onset of disease is earlier in succeeding generations
(Huntington's disease) |
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Loss of heterozygosity
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if a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes
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Dominant negative mutation
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Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning.
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Linkage disequilibrium
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Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. Measured in a population, not in a family, and often varies in different populations
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Mosaicism
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Occurs when cells in the body have different genetic makeup
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Locus heterogeneity
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mutations at different loci can produce the same phenotype
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Heteroplasmy
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Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease.
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Uniparental disomy
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offspring receive 2 copies of a chromosome from 1 parent and no copies from the other parent
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Hardy-Weinburg Population Genetics
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Disease prevalence: p2 + 2pq + q2 =1
Allele: p+q = 1 2pq= heterozygote prevalence The prevalence of and X-linked recessive disease in males = q and in females = q2 |
1.No mutation
2. no selection 3. random mating 4. no migration 5. infinitely large population |
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Imprinting
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at a single locus, only 1 allele is active; the other is inactive (imprinting)
Deletion of the active allele- disease |
Prader-Willi - deletion of normally active paternal allele
Angelman's - deletion of normally active maternal allele *can also be due to uniparental disomy |
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Prader-Willi Syndrome
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MR, obesity, hypogonadism, and hypotonia
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Angelman Syndrome
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MR, seizures, ataxia (lack of coordination) ,inappropriate laughter
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Autosomal Dominance
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Often due to defects in structural genes. Many generations, both male and female affected
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Family history crucial to diagnosis, and many case present after puberty
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Autosomal recessive
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25% of offspring from 2 carrier parents are affected. Often due to enzyme deficiencies. Usually seen in only 1 generation
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commonly more severe than dominant disorders; patients often present in childhood
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X-linked recessive
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Sones of heterozygous mothers have a 50% chance of being affected. No male to male transmission
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Commonly more severe in males. Heterozygous females may be affected
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X-linked dominant
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Transmitted through both parents. Either male or female offspring of the affected mother may be affected, while all females offspring of the affected father are diseased.
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Mitochondrial Inheritance
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Transmitted only through the mother. All offspring of affected females may show sings of disease.
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variable expression in population due to heteroplasmy
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Adult polycystic kidney disease
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Always bilateral, massive enlargement of kidneys due to multiple large cysts. Patients present with pain, hematuria, hypertension, progressive renal failure, 90% of cases are due to mutation in chromosome 16.
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Associated with polycystic liver disease, berry aneurysms, mitral valve prolapse. Juvenile form is recessive
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Familial hypercholesterolemia
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elevated LDL owing to defective or absent LDL receptor. Heterozygotes (1:500) have cholesterol = 300 mg/dL. Homozygotes (very rare) have cholesterol = 700 mg/dL, severe atheroscleotic disease early in life, and tendon xanthomas (classically in Achilles); MI may develop before age 20.
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Marfan's Syndrome
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Fibrillin gene mutation- connective tissue disorder
Skeletal abnormalities- tall with long extremities, pectus excavatum, hyperextensive joints, and long tapering fingers and toes Cardiovascular- cystic medial necrosis of aorta - aortic incompetence and dissecting aortic aneurysms |
pectus excavatum- is the most common congenital deformity of the anterior wall of the chest, in which several ribs and the sternum grow abnormally. This produces a caved-in or sunken appearance of the chest. It can either be present at birth or not develop until puberty.
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Neurofibromatosis type I (von Recklinghausen's disease)
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Findings: cafe-au-lait spots, neural tumors, Lisch nodules (pigmented iris). Also marked by skeletal disorders, increase tumor susceptibility. On long arm of chromosome 17, 17 letters in Recklinghausen
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Neurofibromatosis type 2
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Bilateral acoustic neuroma, juvenile catracts. NF2 gene on chromosome 22
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Tuberous sclerosis
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findings: facial lesions, hypopigmented "ash leaf spots" on skin, cortical and retinal hamartomas, seizures, MR, renal cysts and renal angiomyolipomas, cardiac rhabdomyomas increase incidence of astrocytomas
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Incomplete penetrance, variable expression
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von Hippel-Lindau disease
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Findings: hemangioblastomas of retina/cerebellum/medulla; about half of affected individuals develop multiple bilateral renal cell carcinomas and other tumors.
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Associated with deletion of VHL gene (tumor suppressor) on chromosome 3
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Huntington's disease
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Findings: depression, progressive dementia, choreiform movements, caudate atrophy, and decrease levels on GABA and ACh in he brain. Symptoms manifest in affected indivdiuals between the ages of 20 and 50.
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Gene for Huntington's is located on chromosome 4
triplet repeat disorder |
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Familial adenomatous polyposis
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Colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unless resected. Deletion on chromosome 5
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Hereditary spherocytosis
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Spheroid erythrocytes; hemolytic anemia; increase MCHC.
Splenectomy is curative |
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Achodroplasia
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Autosomal-dominant cell signaling defect of fibroblast growth factor receptor 3
Results in dwarfism, short limbs, but head and trunk are normal size Associated with advanced paternal age |
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Cystic Fibrosis
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Autosomal recessive defect in CFTR gene on chromosome 7. delta 508 common deletion
CFTR channel actively secretes Cl- in lungs and GI tract and actively reabsorbs Cl- from sweat defective Cl- channel- secrete abnormally thick mucus |
infertility in males due to bilateral absence of vas deferens
Can present as failure to thrice in infancy Treatment: N-acetylcysteine to loosen mucus |
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X-linked disorders
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Bruton's agammaglobulinemia
Wiskott-Aldrich syndrome Fragile X G6PD deficiency Ocular albinism Lesch-Nyhan syndrome Duchenne's muscular dystrophy Hemophilia A and B Fabry's disease Hunter's syndrome |
Be Wise, Fool's GOLD Heeds False Hope
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Duchenne's Muscular dystrophies
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X-linked
deletion of dystrophin gene- accelerated muscle breakdown onset before age 5 weakness begins in pelvic girdle muscle and progresses superiorly |
Duchenne's = Deleted Dystrophin Diagnose muscular dystrophies by increase CPK and muscle biopsy
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Becker's muscular dystrophy
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mutated dystrophin gene is less severe than Duchennes's
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Fragile X syndrome
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X-linked defect affecting the methylation and expression of the FMRI gene. Associated with chromosomal breakage. The 2nd most common cause of genetic mental retardation (1st being Down's). associated with macro-orchidism (enlarged testes), long face with a large jaw, large everted ears, and autism
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Triplet repeat disorder (CGG) that may show genetic anticipation
-germline expansion in females |
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Trinucleotide repeat expansion disease
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Huntington's disease, myotonic dystrophy, Friedreich's ataxia, fragile X syndrome
*May show anticipation |
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Chromosomal inversions
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Pericentric- involves centromere; proceeds through meiosis
Paracentric- does not involve centromere; does not proceed through meiosis |
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Cri-du-chat syndrome
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Congenital deletion of short arm of chromosome 5
Findings: microcephaly, severe MR, high pitched crying/mewing, epicanthal folds, and cardiac abnormalities |
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22q11 syndromes
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Cleft plate, Abnormal facies, thymic aplasia- T cell deficiency, cardiac defects, hypocalcemia secondary to parathyroid aplasia, microdeletion at chromosome 22q11. variable presentation as DiGeorge syndrome or velocaridofacial syndrom
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DiGeorge syndrome
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thymic, parathyroid, and cardiac defects
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22q11
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Velocardiofacial syndrome
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palate, facial, and cardiac defects
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22q11
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Alport Syndrome
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Abnormal type IV collagen
X- linked Recessive Progressive Hereditary: Nephritis, deafness, and ocular disturbances * Basement membrane of the EARS, EYES, KIDNEYS |
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