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What are the 4 types of collagen and what do they make?
1: bone, skin, tendon, cornea
3: skin, blood vessels, granulation tissue, uterus, RETICULIN
4: basement membrane
What step of collagen formation is inhibited in scurvy and why?
Hydroxylation (of proline and lysine residues of preprocollagen)
What step of collagen formation in inhibited in osteogenesis imperfecta?
Glycosylation (of alpha chains into procollagen/triple helix)
What step of collagen formation is inhibited in Ehlers-Danlos?
Cross-linking of collagen fibrils (tropocollagen)
What is Ehlers-Danlos syndrome?
Faulty collagen synthesis (TYPE 3 and 1) causing:
1. hyperextensible skin
2. easy bruising (tendency to bleed)
3. hypermobile joints
What is osteogenesis imperfecta?
Genetic bone disorder (brittle bone disease)
Most common in autosomal dominant (so will have family history)
Abnormal TYPE 1 collagen causing:
1. multiple fractures with minimal trauma (may look like child abuse)
2. blue sclerae due to translucency of tissue over veins
3. hearing loss (abnormal middle ear bones)
4. dental imperfections due to lack of dentin
What is Alport's syndrome?
Abnormal TYPE 4 collagen (basement membrane)
Progressive hereditary nephritis and deafness; may have ocular disturbances
What is elastin?
Stretchy protein within lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (vertebrae)
Rich in proline and lysine (nonglycosylated)
Broken down by elastase (normally inhibited by alpha-1-antitrypsin
What usually breaks down elastin? What inhibits that enzyme?
Broken down by elastase
Elastase inhibited by alpha-1-antitrypsin
What 2 diseases are associated with defects in elastin/its pathway to be broken down?
Marfan's and emphysema
Emphysema caused by alpha-1-antitrypsin deficiency results in what? What type of emphysema?
Results in excess elastase activity
Panacinar emphysema (all over acini, not just centralized)
A kid comes in with nephritis and deafness with a positive fam history of the same symptoms mostly in males. What disease?
Alport's sydrome (abnormal type 4 collagen)
What are fat soluble vitamins? What are they important for?
A - eye and skin
D - bones (calcium)
E - antioxidant
K - clotting factors
What vitamins are water soluble? What are they important for?
Bs, C, folate, B12
Bs - metabolic
C - collagen synthesis, antioxidant
folate - blood, neural development
B12 - blood, CNS
Where are fat soluble vitamins absorbed? What diseases can cause a fat soluble vitamin deficiency?
Absorbed in the ileum (so dependent on gut and pancreas to digest fats)
Malabsorption syndromes with steatorrhea (CF, celiac) can cause deficiencies
Vitamin A (retinol) is necessary for what? What is it found in?
Normal differentiation of epithelial cells into specialized tissue
Constituent of visual pigments
Found in liver and leafy veggies
What can vitamin A be used to treat? What must you do before prescribing it?
Used topically for wrinkles and acne; for APL
TERATOGENIC so pregnancy test must be done before giving it for skin probs
What is thiamine needed for in the body?
Cofactor for many enzymes (pyruvate dehydrogenase in glycolysis, alpha-ketoglutarate dehydrogenase in TCA cycle, transketolase in HMP shunt, branched-chain AA dehydrogenase)
A deficiency in thiamine can lead to what? What is it associated with?
Impaired glucose breakdown -> ATP depletion (worsens with glucose infusion), highly aerobic structures like brain and heart are affected first
Associated with malnutrition and alcoholism
A deficiency in thiamine can lead to what diseases?
Wernicke-Korsakoff (confusion, opthalmoplegia, ataxia, confabulation) -> damage to medial dorsal nucleus of thalamus and mamillary bodies
What brain structures are damaged in thiamine deficiency?
Medial dorsal nucleus of the thalamus (memory, organization) and mamillary bodies (memory)
What diseases are caused by riboflavin deficiency?
Cheilosis (inflammation of lips, scaling and fissures at corners of mouth)
THE 2 C's -> cheilosis and corneal vascularization
Deficiency of niacin is associated with what diseases?
1. Pellagra (dermatitis, diarrhea, dementia)
2. Hartnup - decreased tryptophan absorption
3. Malignant carcinoid syndrome - increased tryptophan metabolism due to increased 5-HT release
4. Isoniazid therapy (since decreases B6 and B6 is needed to make B3)
What is the function of B5/pantothenate?
Essential component of CoA (cofactor for acyl transfers) and fatty acid synthase
What is the function of B6/pyroxidine?
Cofactor used in transamination (ALT, AST), glycogen phosphorylase, heme synthesis
Required for synthesis of niacin from tryptophan
What symptoms are associated with B6 deficiency?
Convulsions, hyperirritability, peripheral neuropathies, sideroblastic anemia
Deficiency inducible by Isoniazid and birth control pills
What is the function of B12?
Cofactor for homocysteine methyltransferase (transfers methyl groups to methionine) and methylmalonyl-CoA mutase
What symptoms are associated with B12 deficiency?
Macrocytic, Megaloblastic anemia, hypersegmented PMNs, NEUROLOGIC SYMPTOMS due to abnormal myelin
Prolonged deficiency can lead to irreversible nervous system damage
What is the most common causes of B12 deficiency?
Malabsorption (celiac, enteritis, bacteria)
Pernicious anemia (lack of IF)
Lack of a terminal ileum (Crohn's, celiac)
What is the function of folic acid?
Coverted to THF, a coenzyme for 1-carbon transfer/methylation reactions
Important for synthesis of nitrogenous bases in DNA and RNA
What drugs can cause a folate deficiency?
Methotrexate, sulfonamides, phenytoin (inhibits intestinal absorption of folate)
What symptoms are associated with folic acid deficiency?
Macrocytic, megaloblastic anemia, hypersegmented neuts, NO NEUROLOGICAL DEFECTS
What substrate regenerates methionine (takes a methyl off to make homocysteine so it can be turned into methionine again)?
S-adenyl-methionine (SAM) - donates a methyl group
What substrate is required for the conversion of NE to epi?
SAM (S-adenosul-methionine) - transfers a methyl from methionine to generate it (makes homocysteine from methionine so homocysteine can get another methyl from B12 to make methionine)
What causes biotin deficiency? What are symptoms of a deficiency?
Excessive ingestion of raw eggs (binds biotin)
Symptoms = dermatitis, alopecia, enteritis (deficiency is relatively rare)
What is the function of vitamin C?
Facilitates iron absorption by keeping iron in Fe2+ reduced state (more absorbable)
Necessary for hydroxylation of proline and lysine in collagen synthesis
Necessary to convert DA to NE
What does a deficiency in vitamin C present as?
SCURVY! - swollen gum, bruising, hemarthroses, anemia, poor wound healing; weakened immune response
What is the function of vitamin d?
Increase intenstinal absorption of Ca and P
Increase bone resorption
What type of vitamin D is ingested from plants? What kind is found in milk? What kind is formed in sun-exposed skin?
Plants - D2
Milk - D3
Sun - D3
What diseases does vitamin D deficiency result in?
Children - rickets
Adults - osteomalacia
Both - hypocalcemic tetany (decreased threshold)
What disease commonly has an increase in vitamin D and consequently Ca?
Sarcoid (granulomatous tissue has 1-alpha hydroxylase, which forms active vitamin D)
What is the function of vitamin E?
Antioxidant (protects erythrocytes and membranes from free-radical damage)
What is the function of vitamin K?
Catalyzes gamma-carboxylation of glutamic acid residues on various proteins concerned with blood clotting
Synthesized by intestinal flora
What does a deficiency of vitamin K present like in a newborn? Why?
Neonatal hemorrhage with increased PT and PTT but normal bleeding time
Neonates don't have intestinal bacteria so they can't make vitamin K -> get a vitamin K shot after born
In vitamin K deficiency, what clotting pathway would be most effected?
What is the function of zinc?
Essential for activity of 100s of enzymes
Important for formation of zinc fingers (transcription factor motif)
What does a deficiency of zinc look like?
Delayed wound healing, hypogonadism, decrease in adult hair (axillary, facial, pubic), loss of taste and smell (dysgeusia and anosmia)
May predispose to alcoholic cirrhosis
What are the steps in ethanol metabolism?
Ethanol to acetaldehyde by alcohol dehydrogenase
Acetaldehyde to acetate by acetaldehyde dehydrogenase
Where are the steps in ethanol metabolism found in the cell?
1st step in cytosol
2nd step in mitochondria
What is fomepizole and what does it do?
Inhibits alcohol dehydrogenase and is antidote for methanol or ethylene glycol poisoning
What is the antidote for methanol or ethylene glycol poisoning? What does it do?
Fomepizole - inhibits alcohol dehydrogenase
What is disulfiram and what is it used for?
It's Antabuse -> inhibits acetylaldehyde dehydrogenase and gives alcoholics hungover feeling whenever they ingest alcohol
What drug inhibits acetylaldehyde dehydrogenase and why is it useful?
Disulfiram (Anatabuse) -> used for alcoholics since it inhibits the enzyme that takes away acetylaldehyde when alcohol is ingested
Acetylaldehyde is what causes hungover feeling
Alcohol dehydrogenase operates via what kind of kinetics?
Zero-order (operates independent of substrate concentration -> always detoxes 1 drink/hour no matter what)
How does alcohol abuse lead to hypoglycemia?
Ethanol metabolism increases NADH/NAD+ ratio in liver (metabolism uses NAD+ to make NADH), causing:
1. diversion of pyruvate to lactate
2. OAA to malate
Inhibits gluconeogenesis and stimulates fatty acid synthesis (why alcoholics have fatty livers)
What is Kwashiorkor?
PROTEIN deficiency resulting from:
M - malnutrition
E - edema
A - anemia
L - liver (fatty change due to decrease apolipoprotein synthesis)
What is Marasmus?
ENERGY malnutrition resulting in MUSCLE wasting, loss of subQ fat and variable edema
What is the difference between Kwashiorkor and marasmus?
Kwashiorkor - PROTEIN deficiency due to malnutrition, edema, anemia or liver (fatty)
Marasmus - ENERGY deficiency resulting in muscle wasting, loss of subQ fat, edema
What metabolic processes take place in the mitochondria?
Beta oxidation of fatty acids (matrix)
Acetyl CoA production (glycolysis) (matrix)
TCA cycle (matrix)
Oxidative phosphorylation (inner membrane)
What metabolic processes take place in the cytoplasm?
Fatty acid synthesis
Protein synthesis (rER)
Steroid synthesis (sER)
What metabolic processes take place in both in the mitochondria and the cytoplasm?
What does a "kinase" do?
Uses ATP to put a phosphate group onto another substrate
i.e. glucokinase puts a phosphate on glucose
What does a "phosphorylase" do?
Adds inorganic phosphate onto substrate without using ATP
i.e. glycogen phosphorylase
What is the rate determining enzyme of de novo pyrimidine synthesis?
Carbamoyl phosphate synthetase II
Carbamoyl phosphate synthetase II is the rate determining enzyme for what?
De novo pyrimidine synthesis
In chromatin structure, what is positively and negatively charged?
DNA is negatively charged
Histones are positively charged
Histones form an octomer around which DNA winds
What type of chromatin is able to be transcribed? What type is not?
Able to be copied = euchromatin
Unable to be copied = heterochromatin
What type of chromatin is condensed? What type isn't? What does that mean for transcription?
Condensed = heterochromatin -> unable to be copied
Not condensed = euchromatin -> able to be copied
What nucleotides are purines? What ones are pyridimines?
Purines = adenine and guanine
Pyridimines = cytosine, uracil, thymine
Which nucleotides have 2 rings? Which ones have only 1 ring?
Purines have 2 rings
Pyridimines have 1 ring
Which nucleotide bases bond together? How many bonds are between each pair?
cytosine and guanine - triple bond
adenine and thymine/uracil - double bond
Ornithine transcarbamoylase deficiency affects which cycle(s)? What does it lead to?
Affects urea cycle and eventually the de novo pyridimine synthesis cycle
OTC deficiency leads to acculumation of carbamoyl phosphate -> converted to orotic acid
How does 5-fluorouracil affect nucleotide synthesis?
Inhibits thymidylate synthase (no dUMP -> dTMP)
How does methrotrexate affect nucleotide synthesis?
Inhibits dihydrofolate reductase (can't make dTMP)
How does trimethoprim affect nucleotide synthesis?
Inhibits bacterial dihydrofolate reductase (can't make dTMP)
What is orotic aciduria and what does it present like? How is it inherited? How is it different from OTC deficiency?
Inability to convert orotic acid to UMP (de novo pyrimidine synthesis) due to problems with orotic acid phosphoribosyltransferase or orotidine 5'-phoshate decarboxylase
Presents with increased orotic acid in blood and urine (leads to crystal formation), megaloblastic anemia (unresponsive to iron or B12), failure to thrive; NO HYPERAMMONEMIA
Different from OTC because doesn't have hyperammonemia (OTC has increased orotic acid and hyperammonemia since it's affecting urea cycle too)
What is adenosine deaminase deficiency? What is it assocaited with?
Purine salvage deficiency
Imbalanced feedback inhibition of ribonucleotide reductase -> prevents DNA synthesis and decreases lymph count
Adenosine is toxic to lymphs
Associated with causing SCID
What is Lesch-Nyhan syndrome? How is it inherited and how does it present?
Defective purine salvage
Due to absence of HGPRT (converts IMP -> GMP), increases uric acid production
Presents with MR, self-mutilation, aggression, hyperuricemia, gout, choreoathertosis
What is a silent mutation?
Same amino acid, often base change in 3rd position of codon (tRNA wobble)
What is the level of severity of silent, missense and nonsense mutation?
Nonsense > missense >silent
What is a frame shift mutation?
Change resulting in misreading of all nucleotides downstream, usually resulting in a truncated, nonfunctional protein
What does DNA polymerase III do?
In prokaryotes only
Adds nucleotides in 5'->3'
Proofreads with exonuclease activity in 3'->5'
What is the promoter for in gene expression?
Where RNA polymerase and transcription factors bind
Upsteam from gene locus
What is the enhancer for in gene expression?
Alters gene expression by binding transcription factors
What are the 3 RNA polymerases in eukaryotes?
RNA polymerase I - rRNA
RNA polymerase II - mRNA
RNA polymerase III - tRNA
What are the 3 things that happen in RNA processing?
1. capping on 5' end
2. poly-A tail on 3' end
3. splicing out of introns
capped and tailed transcript = mRNA
Do introns or exons contain the actual genetic info coding for the target protein?
Exons (exons EXIT, introns INTERFERE)
What are the sites on the ribosome and what happens in each?
A - holds incoming aminoacyl tRNA
P - holds growing peptide
E - holds empty tRNA
What tumor suppressors are responsible for regulating the cell cycle? At which breakpoint do they work?
Rb and p53
Control G1->S (once you go through S you have to complete the cycle)
What are permanent cell types? What are some examples?
Remain in G0
Regenerate from stem cells
Neurons, skeletal and cardiac muscle, RBCs
What are stable cell types? What are some examples?
Enter G1 from G0 when stimulated
What are labile cell types? What are some examples?
Never go to G0
Divide rapidly with a short G1
Bone marrow, gut epithelium, skin, hair follicles
What does the rough endoplasmic reticulum synthesize?
Secretory (exported) proteins
Nissl bodies make enzymes and peptide NTs
Free ribosomes make cytosolic and organellar proteins
What is I cell disease? What is the presentation? What organelle is the problem?
Inheirited lysosomal storage disorder so that the enzymes are secreted outside the cell instead of being targeted to the lysosome after packaging in the golgi (doesn't put in mannose-6-phosphate)
Presents with coarse facial features, clouded cornears, restricted joint movement, high plasma levels of lysosomal enzymes (often fatal in childhood)
Golgi targeting enzymes to lysosomes is the problem
What are microtubules put in/important for?
Incorporated into flagella, cilia, mitotic spindles
Important for axoplasmic transport in neurons
What are the proteins responsible for transporting things to microtubules?
Dynein = retrograde transport
Kinesin = anterograde transport
What are 5 drugs that act on microtubules?
1. mebendazole (antihelminthic)
2. griseofulvin (antifungal)
3. vincristine (anti-cancer)
4. paclitaxel (anti-breast cancer)
5. colchicine (anti-gout)
What is Chediak-Higashi syndrome and how does it present?
Microtubule defect resulting in decreased phagocytosis
Presents with recurrent pyogenic infections, partial albinism, peripheral neuropathy
What is Kartagener's syndrome? How does it present?
Immotile cilia due to a dynein arm defect
Results in male and female infertility (immotile sperm), bronchiectasis, recurrent sinusitis (bacteria and particles are not pushed out)
Associated with situs inversus
What cytoskeletal elements are associated with actin and myosin?
Microvilli, muscle contraction, cytokinesis, adherens junctions
What cytoskeletal elements are associated with microtubules?
Cilia, flagella, mitotic spindle, neurons, centrioles
What cytoskeletal elements are associated with intermediate filaments?
Vimentin, desmin, cytokeratin, glial fibrillary acid proteins (GFAP), neurofilaments
How does increased cholesterol and long saturated fatty acids affect the plasma membrane?
Increases the melting temperature but decreases fluidity
What is the ion movement in the Na/K ATPase? Where is the ATP site located?
3Na out for 2K in
ATP site is on cytoplasmic side
How do cardiac glycosides work?
Inhibit Na/K ATPase which leads to indirect inhibition of Na/Ca exchange -> increased Ca means increased cardiac contractility
Na not pumped out of cell so there's not enough Na outside of the cell to be exchanged in for Ca out -> more Ca in cell
What is PCR used for? What are the 3 steps?
Used to amplify a desired fragment of DNA
3. elongation (replication)
Then put on agarose gel electrophoresis
What are microarrays used for?
Profile gene expression levels of 1000s of genes simultaneously to study diseases and treatments
What is an ELISA used for?
Rapid immunologic technique testing for antigen-antibody reactivity
Test antigen to see if body recognizes it or test antibody to see if certain antigen is present
What is FISH used for?
Used for specific localization of genes and direct visualization of anomalies at molecular level (when too small to see by karyotype)
Fluorescence = gene is present
No fluorescence = gene has been deleted
What is karyotyping? What stage are the chromosomes in? Samples from where can be used?
Used to diagnose chromosomal imbalances; sorted by morphology, size, arm-length ratio and banding pattern
Samples from blood, bone marrow, amniotic fluid or placental tissue can be used
What is variable expression?
Nature and severity of phenotype vary between individuals
Neurofibromatosis type 1
What is pleiotropy?
1 gene has >1 effect on an individual's phenotype
PKU (has tons of seemingly unrelated symptoms)
What is imprinting?
Differences in phenotype depend on whether mutation is of maternal or paternal origin
Prader-Willi and Angelman's
What is anticipation?
Severeity of disease worsens or age of onset of disease is earlier in succeeding generations
What is loss of heterozygosity?
If patient inherits/develops mutation in tumor suppressor gene, other allele must be deleted/mutated before cancer develops
NOT true of proto-oncogenes (or p53)
What is dominant negative mutation?
Exerts a dominant effect -> heterozygote produces nonfunctional protein that also prevents normal gene product from functioning
What is linkage disequilibrium?
Tendency for certain allels at 2 linked loci to occur together more often than expected by chance
Measured in POPULATION, not family
Varies in different populations
What is mosaicism?
Occurs when cells have different genetic makeup
Can be germ-line mosaic, which may produce disease not carried by parent's somatic cells
Lyonization = random X inactivation in females
What is locus heterogeneity?
Mutations at different loci can produce same phenotype
Marfan's, MEN2b and homocystinuria all cause marfanoid habitus
What is heteroplasmy?
Presence of both normal and mutated mtDNA = variable expression in mitochondrial inherited disease
What is uniparental disomy?
Offspring receives 2 copies of chromosome from 1 parent and no copies from the other parent
What are the 2 classic imprinting diseases? What chromosome is affected?
Prader-Willi = deletion of PATERNAL chrom 15 allele
Angelman's = deletion in MATERNAL chrom 15 allele
What are the presentations of Prader-Willi vs Angelman's?
Prader-Willi = MR, HYPERPHAGIA!!!!, obesity, hypogonadism, hypotonia
Angelman's = MR, seizures, ataxia, INAPPROPRIATE LAUGHTER ("happy puppet")
What is the Hardy-Weinberg equation for the prevalance of an x-linked recessive disease in males and females?
Males: prevalence = q
Females: prevalence = q^2
How do you calculate the expected frequency of affected individuals in the next generation?
Multiple frequency of heterozygote (carrier) by 1/4
What is gene flow vs genetic drift?
Gene flow = gene exchange between different populations
Genetic drift = change in gene frequency over generations due to finite population
What are the keys to an autosomal dominant inheritance?
Every generation is affected
Both males and females are affected
What are the keys to an autosomal recessive inheritance?
25% of offspring from 2 carrier parents are effected
Usually seen in only 1 generation
Patients often present in childhood
What are the keys to an x-linked recessive inheritance?
Sons of heterozygous mothers have a 50% chance of being affected
No male-to-male transmission
What are the keys to an x-linked dominant inheritance?
Transmitted through both parents
Either male or female offspring of affected mother may be affected
ALL female offspring of affected father have disease
ex = hypophosphatemic rickets (vit D resistant rickets)
What are the keys to a mitochondrial inheritance?
Transmitted only through mother
All offspring of affected females may show signs of disease
May have variable expression due to heteroplasmy
ex = mitochondrial myopathies -> Leber's herediary optic neuropathy
What is hypophosphatemic rickets and what kind of inheritance does it have?
aka vitamin D-resistant rickets
Increased phosphate wasting at proximal tubule
What is Leber's hereditary optic neuropathy and what kind of inheritance does it have?
Degeneration of retinal ganglion cells and axons -> leads to acute loss of central vision
What is achondroplasia and what kind of inheritance does it have?
Cell-signaling defect of fibroblastic growth factor (FGF) receptor 3
Results in dwarfism but head and trunk are normal size
Associated with advanced paternal age
What is polycystic kidney disease and what kind of inheritance does it have?
ALWAYS BILATERAL, massive enlargement of kidneys due to multiple large cysts
Presents with flank pain, hematuria, hypertension, progressive renal failure
90% associated with mutation in APKD1 on chom 16
Associated with BERRY ANEURYSMS, polycystic liver disease
What disease is associated with a mutation in APKD1 on chromosome 16?
Polycystic kidney disease
16 letters in polycystic kidney
What is familial adenomatous polyposis and what kind of inheritance does it have?
Colon becomes covered in 100s of polyps after puberty
Will progress to colon cancer unless resected
Deletion of APC gene on chrom 5
What disease is assocaited with deletion of APC gene on chromosome 5?
Familial adenomatous polyposis
5 letters in polyp
What is familial hypercholesterolemia and what kind of inheritance does it have?
Elevated LDL due to absent/defective LDL receptor
Tendon xanthomas in Achilles tendon
MI may develop before 20yo
What is hereditary hemorrhagic telangiectasia and what kind of inheritance does it have?
aka Osler-Weber-Rendu syndrome
Inherited disorder of blood vessels -> telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations
What is hereditary spherocytosis and what kind of inheritance does it have?
Spheroid RBCs due to spectrin or ankyrin defect
Hemolytic anemia, increased MCHC
Splenectomy is curative
What is Huntington's disease and what kind of inheritance does it have?
Neurodegenerative disease -> depression, progressive dementia, choreiform movements, caudate atrophy, decreased levels of GABA and ACh in brain
Trinucleotide repeat disorder on chrom 4
What is Marfan's syndrome and what kind of inheritance does it have?
Mutuation in fibrillin gene (extracellular matrix protein, part of microfibrils)
What is MEN and what kind of inheritance does it have?
Familial tumors of endocrine glands
MEN2a and 2b associated with RET mutations
What is neurofibromatosis type 1 and what kind of inheritance does it have?
Presentation = cafe-au-lait spots, neural tumors, pigmented iris hamartomas, skeletal disorders, optic pathway gliomas
On chrom 17
What disorder is associated with autosomal dominant inheritance on chromosome 17?
Neurofibromatosis type 1
What is neurofibromatosis type 2 and what kind of inheritance does it have?
Bilateral acoustic -omas (persistent ringing in ears), juvenile cataracts
Mutation of NF2 gene on chromosome 22
What disease is associated with a mutation in the NF2 gene on chromosome 22?
Neurofibromatosis type 2
What is tuberous sclerosis and what kind of inheritance does it have?
Facial lesions, hypopigmented "ash lead spots" on skin, cortical and retinal hamartomas, seizures, ME, renal cysts, cardiac rhabdomyomas
Incomplete penetrance, variable presentation
What is von Hippel-Lindau disease and what kind of inheritance does it have?
Hemangioblastomas of retina/cerebellum/medulla, bilateral renal cell carcinomas
Associated with deletion of VHL gene (tumor suppressor) on chrom 3 -> constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors
What disease is associated with a deletion of VHL gene on chromosome 3?
No VHL = too much HIF = angiogenesis
What gene is affected in cystic fibrosis and where is it located?
CFTR gene on chromosome 7
Position 508 is affected
Mutation causes abnormal protein folding, resulting in degradation of channel before reaching cell surface
How does cystic fibrosis present?
Thick mucous in lungs (recurrent infections), pancreas (malabsorption of fat-soluble vitamins) and liver
Infertility in males due to bilateral absence of vas deferens
Increased concentration of Cl- ions in sweat test is diagnostic
What is the difference in the genetic abnormalities in Duchenne's and Becker's muscular dystrophies?
Duchenne's = X-linked frame-shift mutation leading to a deletion of dystrophin gene (Duchenne's = Deletion)
Becker's = X-linked mutation in dystrophin gene
What disease is due to abnormal methylation and expression of the FMR1 gene?
Fragile X syndrome
Associated with chromosomal breakage
What is the presentation of Fragile X syndrome?
Macro-orchidism, long face with a large jaw, large everted ears, autism, mitral valve prolapse
What are 4 trinucleotide repeat expansion disorders?
1. Huntington's (CAG)
2. Myotonic dystrophy (CTC)
3. Fragile X (CGC)
4. Friedreich's ataxia (GAA)
Do trinucleotide repeat expansion disorders show genetic anticipation?
Disease severity increases and age of onset decreases in successive generations
Germline expansion in females
What is the presentation of Down's?
MR, flat facies, prominent epicanthal folds, simian crease, gap between 1st 2 toes, duodenal atresia, congenital heart disease
Increased risk of ALL and Alzheimer's
What are the results of a quadruple screen in a fetus with Down's? What does a US show?
Increased inhibin A
US shows increased nuchal translucency
What is the presentation of Edward's syndrome?
Severe MR, rocker-bottom feet, MICROGNATHIA, low-set ears, CLENCHED HANDS, prominent occiput, congenital heart disease
Death usually occurs within 1 yr of birth
What is the presentation of Patau's syndrome?
Severe MR, rocker-bottom feet, CLEFT LIP/PALATE, HOLOPROSENCEPHALY, POLYDACTYLY, congenital heart disease
Death usually within 1yr of birth
What are the 3 ways a trisomy can occur?
1. Meiotic nondisjunction (associated with advancing maternal age)
2. Robertsonian translocation
What is a Robertsonian translocation and what chromosomes are associated with it?
Nonreciprocal chromosomal translocation when long arms of 2 acrocentric chromosomes fuse at centromere and short arms are lost
Balanced don't usually cause phenotype probs
Unbalanced cause probs
Associated with chroms 13, 14, 15, 21, 22
What is Cri-du-chat syndrome and what is the presentation?
Congenital microdeletion of 5p
Presentation = microcephaly, moderate-severe MR, high-pitched crying, epicanthal folds, cardiac abnormalities
What is Williams syndrome and what is the presentation?
Congenital microdeletion of 7q (includes elastin gene)
Presentation = "elfin" facies, MR, hypercalcemia (increased sensitivity to vitamin D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems
What are the 2 22q11 deletion syndromes? What is the presentation? What branchial pouch is the problem?
Microdeletion at 22q11.2
1. DiGeorge syndrome - thymic, parathyroid and cardiac defects
2. Velocardiofacial - palate, facial and cardiac defects
Presentation = Cleft palate, Anormal facies, Thymic aplasia (leads to T cell deficiency), Cardiac defects, Hypocalcemia (secondary to parathyroid aplasia) = CATCH-22
Problematic branchial pouches = 3rd and 4th
What diseases are associated with abberant development of the 3rd and 4th branchial pouches?
22q11 deletion syndromes (DiGeorge and Velocardiofacial)
What is the deficient enzyme, accumulated substrate and the findings of Gaucher's disease?
Enzyme = beta-glucocerebrosidase
Substrate = glucocerebroside
Findings = hepatosplenomegaly, bone crises, pancytopenia, Gaucher's cells (macrophages that look like crumpled paper)
What is the deficient enzyme, accumulated substrate and the findings of Niemann-Pick disease?
Enzyme = sphingomyelinase
Substrate = sphingomyelin
Findings = Progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foam cells
What is the deficient enzyme, accumulated substrate and the findings of Tay-Sachs disease?
Enzyme = hexosaminidase A
Substrate = GM2 ganglioside
Findings = Progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosomes with onion skin, NO HEPATOSPLENOMEGALY (in contrast to Niemann-Pick)
What 3 lysosomal storage disorders are associated with Ashkenazi Jews?
Gaucher's, Niemann-Pick and Tay-Sachs
What is the deficient enzyme, accumulated substrate and the findings of Hurler's syndrome?
Enzyme = alpha-L-iduronidase
Substrate = heparan sulfate
Findings = Developmental delay, coarse features, corneal clouding, airway obstruction, coronary artery disease
What is the deficient enzyme, accumulated substrate and the findings of of Hunter's syndrome?
Enzyme = Iduronate sulfatase
Substrate = heparan sulfate
Findings = mild Hurler's with aggressive behavior, NO CORNEAL CLOUDING (vs Hurler's)
What is the inheritance pattern for lysosomal storage disorders and mucopolysaccharidoses? What are the exceptions?
Usually they are autosomal recessive
Fabry's (lysosomal) and Hunter's (muco) are x-linked recessive
What is the deficient enzyme and the findings of von Gierke's disease?
Enzyme = glucose-6-phosphatase
Findings = severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, HEPATOMEGALY
What is the deficient enzyme and the findings of Pompe's disease?
Enzyme = lysosomal alpha-1,4-glycosidase
Findings = cardiomegaly and systemic, MR, hypotonia
Pompe's trashes the Pump -> heart, liver and muscle
What is the deficient enzyme and the findings of Cori's disease?
Enzyme = debranching enzyme (1,6 bonds)
Findings = Milder form of type I (von Gierke) without elevated lactate, have abnormal glycogen structure
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