USMLE Biochemistry Notes PDF

**Alpha1 antitrypsin deficiency** - Inheritance: co-dominant not recessive - Causes emphysema but Is produced in the **liver** - Breaks down elastase; build up of elastase is seen - Sequestered in liver - Disease presentation: - **Young and non smoker** - Causes **hepati...

**Alpha1 antitrypsin deficiency** - Inheritance: co-dominant not recessive - Causes emphysema but Is produced in the **liver** - Breaks down elastase; build up of elastase is seen - Sequestered in liver - Disease presentation: - **Young and non smoker** - Causes **hepatic cirrhosis** - **Pan-acinar emphysema - in entire resp zone** - **Smoking** causes emphysema due to increased elastase activity - Cellular - PAS positive aggregates \--\> **misfolded glycoprotein** - **Accumulation of misfolded protein in endoplasmic reticulum \--\> hepatocyte death + cirrhosis** - **Increase elastase in lungs \--\> emphysema**   Abetalipoproteinemia - Deficiency of ApoB-48 and ApoB100 - ApoB48 allows for release of chylomicrons into circulation - **Fat droplets in the bowel wall** - **Decreased fat absorption, increased steatorrhea** - Decreased fat soluble vitamins: - Vitamin A: retinitis pigmentosa - Vitamin E: spinocerebellar degeneration - Leads to **acanthocytes (spur cells)** - **Remember spur cells = abetalipoproteinemia** - **Acanthocytes (spur cells) also seen in liver failure** Acanthocytes -- Cells and Smears   **Aldose reductase + sorbitol + galactitol** - Aldose reductase converts - glucose to sorbitol (glucose + NADPH \--\> sorbitol + NADP+) - Galactose to galactitol - Neuropathy and cataracts in diabetes \--\> osmotic injury to cells - Nephropathy, retinopathy and atherosclerosis \--\> non enzymatic glycosylation of endothelial cells by glucose - Cataracts in galactose disorders are due to galactitol not sorbitol - Cataracts + reducing sugars in urine or cataracts + hepatomegaly + jaundice (classic galactosemia) \--\> aldose reductase is responsible for the **cataracts**, product of reaction is galactitol - The cause of classic galactosemia is galactose 1 phosphate uridylytransferase \--\> jaundice, hepatosplenomegaly, cataracts and mental impairement   Alkaptonuria - Caused by **homogentistic oxidase**; enzyme needed for breakdown of **tyrosine to fumarate** - **Urine becomes dark/black upon standing** - **Painful joints, biopsy shows blue/black/brown connective tissue (orchronosis)**   **Angelman vs prader-willi syndromes** - Imprinting means receiving one allele from each parent but one is preferentially silenced - Maternal imprinting: mom\'s allele silenced - Uniparental disomy means both of an individuals alleles for a gene are received from the same parent - Prader willi (**maternal imprinting or maternal UPD)** - Chromosome 15 - Obese, mental impairement, hyperphagia - Due to maternal imprinting or maternal uniparental disomy - Mom\'s gene is received and silenced but dad\'s defective gene is responsible for the disease - Angelman syndrome (**paternal imprinting or paternal UPD)** - Chromosome 15 (UBE3A) - Paternal imprinting or paternal uniparental disomy - Mental impairement, easily made happy - Paternal imprinting and maternal gene deletion/mutation   Chronic Granulomatous disease (NAPDH oxidase deficiency) - NADPH oxidase deficiency - The substrate for NADPH oxidase is molecular oxygen - Respiratory burst is a series of reactions through which phagoocytes like neutrophils create reactive oxygen intermediates to kill invading microbes - NADPH, NADH and SH are reducing agents - NADP+, NAD+ are oxidizing agents - In chronic granulomatous disease there is increased susceptibility to catalase positive organisms - Mnemonic for organisms is **C shapes** - Candida, serratia, h pylori, actinomyces, pseudomonas, E coli and S. aureus - Presentation of CGD: aphthous ulcers (mouth ulcers), urogenital tract obstruction due to granulomas, crohn like symptoms (bleeding per rectum/malabsorption\_ - Diagnosis is made with a positive dihyrohodamine test - Treatment is IFN-y - **Note:** G6PD deficiency: susceptible to oxidizing drugs like dapsone and primaquine because their NADPH production is less efficient so they cant neutralize H2O2 and their RBC membranes are more prone to lysis   Myeloproxidase - Auder rods are seen in AML and they are composed of myeloperoxidase - Release of myeloperoxidase into blood during leukemia can lead to DIC - Myeloperoxidase gives sputum its colour!   Collagen I, osteogenesis imperfecta and osteopetrosis - Collagen I - Found in **skin and bone** - Important for **late wound repair** - Early repair: high collagen 3, low collage 1 - Late repair: collagen 3 replaced by collagen 1 - Type 1 collagen is also found in dentin and cornea - Osteogenesis imperfecta: - Deficiency of type 1 collagen (COL1A genes) - Autosomal dominant - Disease happens due to null allele affect (there is not enough type I collagen) - Type II or III osteogenesis imperfecta can be a dominant negative (abnormal type I collagen physically impairs the function of healthy collagen) - Occurs due to **defective hydrogen bonding** - **Multiple fracture, Blue sclerae and conductive hearing loss (don't respond when spoke to), abnormal dentition** - Note: if the child avoids eye contact, that's child abuse but not responding due to deafness, that's osteogenesis imperfecta - Osteopetrosis - Fracture disorder: increased bone density due to decreased osteoclast activity - Osteoclast activity is decreased due to deficiency of carbonic anhydrase II inside bone - In both osteoporosis and osteopetrosis calcium, phosphate, alp and pth are all normal   Collagen II, III and ehlers danlos syndrome - Type II collagen is found in cartilage, nucleus pulposus and viterous body - Stickler syndrome: - Defect in type II collage; Mutations in COL2A1 - Deafness and ocular problems - Type III collagen - Found in granulation tissue (early wound healing) - Also in blood vessels, uterus and fetal tissue - Collagen III is a main component of retiulin - Keloid scars also have increased type III collagen - Ehler\'s danlos syndrome - Due to type III collagen defects or procollagen peptidase deficiency - Hyperextensible skin, joint hypermobility and joint subluxations - Increased risk of aortic aneurysm, mitral valve prolapse, aortic regurg and willis berry aneurysms leading to subarachnoid hemorrhage   Collagen IV, alport and good pasture syndromes - Found in basement membranes, basal lamina, lens of the eye, alveoli and glomerulous - Laminin binds to type IV collagen - Alport syndrome - Mutation in type IV collagen (COL4) - Xlinked - Presentation: ear/eye problems in a male with red urine - Goodpasture syndrome - Autoantibodies against IV collagen (anti-glomerular basement membran; anti GBM Abs) - Type II hypersensitivity due to autoantibodies against alpha 3 chains of type IV collagen (2,3,4) - Presentation: hemoptysis + hematuria in male in 40s - On biopsy: **linear immunofluorescence, fibrin crescents seen if it progresses to rapidly progressive glomerular nephritis** - In summary - **Alport syndrome = mutations in type IV collagen** - **Goodpasture syndrome = autoantibodies against IV collagen**   **Collagen production** - **Glycine** is the most abundant amino acid in collagen, translation of glycine X-Y repeats happens at rough RER - Preprocollagen \--\> Hydroxylation (vitamin C is needed) \--\> glycosylation \--\> triple helix formation (called procollagen) \--\> procollagen is exocytosed from cell \--\> tropocollagen \--\> collagen fibrils \--\> collagen fibrils are crosslinked via lysyl oxidase to make mature collagen - Lysyl oxidase is copper dependent and deficiency of copper can lead to menkes syndrome - Wrinkles due to aging are caused due to decreased fibril production   Cystinuria - 2 cystine molecules bound together by a disulfide bond - Cystinuria: pct of kidney cant reabsorb cysteine so buildup of it leads to **hexagonal ** cystine stones in renal tubes - Part of a pathology called **COLA **(inability to absorb cystine, ornithine, lysine arginine) - Citrate is the treatment as it alkalinizes the urine or pencillamine - Note: **pencillamine ** is used in copper chelation therapy in Wilson disease and causes SLE with positive anti histone antibodies - If a patient with cystinuria develops calcium phosphate stones, its because of citrate (HCO3) which is used for treatment of cystinuria. - In both cystinuria and homocystinuria, a patient will have **positive nitroprusside cyanide test or their urine becomes purple/blue/magenta** Cystic fibrosis vs kartagener syndrome - Cystic fibrosis - Autosomal recessive, chromosome 7 - Deletion of phenylalanine in CFTR - CFT is cAMP regulated and ATP gated chloride channel - Camp activates protein kinase A which catalyzes ATP hydrolysis, CFTR has 12 transmembrane compoents - Increased chloride inside cells, sodium moves into cells vis ENAC and leads to drying up or inspissation - In CF there is increased activation of **ENaC** - **Mutated cftr leads to production of cftr channel that is retained as a misfolded protein in the RER** - **Which diuretics causes similar effects to CF? Loop Diuretics** - **Dignosis:** sweat chloride testing (more accurate than genotyping) - CF is a allelic heterogeneity condition as different alleles cause the same disease - In CF, the nasal TEPD is less than 40 mV - In CF, **pseudomonas and staph infections** are most common - Over 10 yrs \--\> pseudomonas - Under 10 \--\> staph aureus - Nasal polyps and bronchiectasis and clubbing are seen with CF - Malbsorption and deficiencies of vitamin ADEK and B12 are also seen - Diabetes mellitus is a common morbidity of CF - CF also causes congenital bilateral absence of vas deferens; there are no sperm seen in ejaculate and leads to infertility - Failure to pass meconium is also common in CF; its called meconium ileus - **Treatments of CF** - N-acetylcystein - Guifenesin - Ivacaftor: binds to misfolded channel and increases probability that it will open - Karagener syndrome (primary ciliary dyskinesia) - Immotile dysfunctional cilia resulting in sperm immotility and defective fallopian tube mediated ovum transport - Cilia are immobile because of dynein arm defect - **Associated with situs inversus and chronic respiratory tract infections** - Leads to male and female infertility and ectopic pregnancy - In summary - **Sperm in sample \--\> kartagener syndrome** - **No sperm in sample \--\> cystic fibrosis**   Down, Edward and Patau syndromes - Down syndrome - Due to meiotic non disjunction, robertsonian translocation (14q;21q), **post fertilization error** leading to mosaicism - Non disjunction is associated with **35 years old and over** - **Features:** epicanthal folds, slanted palpebral fissures, **flat facies**, atrioventricular septal defect (AVSD), ostium primum type atrial septal defect, increased risk of mitral and tricuspid regurg and increased risk of pulmonary hypertension - The errors in endocardial cushion development is due to **failure of neural crest cell migration** - Associated conditions: trachoesophageal fistula, duoenal atresia, hirschsprung disease, ALL, AML, hypothyroidism, eustachian tube dysfunction, early alzheimers - Most common cause of mental retardation across the entire population is FAS but over age 40 is downsyndrome - Lab findings: - First trimester: increased nuchal translucency, decreased PAPP-A and increased beta-hcg, nasal bone hypoplasticity - Second semester: AFP down in down syndrome, decreased estriol, increased bhcg and inhibin A - Testing for down syndrome - CVS - at 10-12 weeks, most dangerous - Amniocentesis \--\> 14-16 weeks - Cell freen DNA - at 10 weeks, least dangerous - Edward syndrome (18) - Features: low set ears, micrognathia, prominent occiput, clenched hands and rocker bottom feet, omphalocele, meckel diverticulum and gut malrotation - Decreased AFP, estriol, b-hcg and inhibin A - Summary - Flatened facies + hypoplastic nasal bone + increased nuchal translucency = down syndrome - Low set ears + rocker bottom feet \_ prominent occiput + omphalocele = edward syndrome - Low set ears + clubbed feet + flattened facies = potter sequence - Patau syndrome (13) - Presentation: holoprosencephaly, cleft lip/palate, polydactyly - Differential dignosis for holoprosencephaly: **severe fetal alcohol syndrome, patau syndrome, homeobox gene mutation** - Differential diagnosis for cleft lip/palate: digeorge, patau syndrome, vitamin A teratogenicity (maternal use of isotretinoin) - Fetal alcohol syndrome - Flat facies and elongated philtrum   Duchenne vs becker muscular dystrophy - Both are x-linked recessive disorders caused by mutations in the dystrophin gene (DMD) - DMD gene is the longest human gene, so it can undergo spontaneous mutation easily - Dystrophin is a large cytoskeletal protein inside skeletal muscle that stabilizes the cytoskeleton within the extracellular matrix; it binds to a protein called **beta-dystroglycan** - Duchene is a frameshift mutation - Becker is a missense or deletion/insertion - Duchenne is worse than becker - Duchene presents with **gower maneuver: walking backwards with the arms in order to stand up** - In both disorders, there is **pseudohypertrophy** which is due to fibroadipose deposition in the muscle, there is weakness and kyphoscoliosis - Ther eis variation in fiber diameter and increased number of internalized nuclei and fiber degeneration - **First location affected is the hips then the calves** - Cause of death for both diseases is **cardiomyopathy/heart failure**     **Electron transport chain** - 2,3-dinitrophenol, ethanol, aspirin and thermogenin are uncoupling agents (DEATH) - Uncoupling agent destroys H+ gradient within the inner mitochondrial membrane so compensatory over activation measures to restore H+ gradient yield heat - Uncoupling agent \--\> protons leak back into inner mitochondrial space \--\> more protons needed to pump into intermembrane space to achieve the same atp production \--\> more o2 required to generate the same number of ATP - **Uncoupling agents increase O2 consumption/atp production ratio** - **Cyanide** causes inhibition of electron transfer to molecular oxygen - Treatment = amyl nitrite + sodium thiosulfate - Methomoglobinemia = chocolate brown blood; fe 3+ hemoglobin cant bind oxygen so saturation is decreased - Cherry red blood = bright red lips/face/nail beds = CO poisoning - CO posinoining is treated with hyperbaric oxygen - CO posinoing shows normal saturation on pulse oximetry - Potential post surgery complication in neonates is hypothermia - Rotenone inhibits complex I and antimycin A inhibits complex III   Familial dyslipidimias  - 1 LP, 2 LD, b adds v, 3 is E, 4 gets more - Type 1: hyperchylomicronemia - LPL deficiency or Apoc II - chylomicron (triglycerides + cholesterol) accumulation - Pancreatitis - Type 2a: hypercholesterolemia - LDL receptor deficiency - LDL buildup - xanthoma of achilles tendon or eyelid - Corneal arcus - Type 2b - Everything 2a and VLDL - Type 3 - apoE deficiency - Remnant buildup (chylo +VLDL) - Palmar xanthoma - Type 4: hyper triglyceridemia - Increased isolated Triglycerides - Hepatic VLDL overproduction - Pancreatitis - In summary - Type 1 - High levels of triglycerides and LDL \--\> type 1 familial dyslipedemia due deficiency of Apo-CII or LPL - LPL is usually located on endothelial cell surfaces - Type 2 - Autosomal dominant - LDL level of 300 \--\> heterozygous - LDL level of 700 \--\> homozygous - Treat with statins (**competitively and reversibly inhibits HMG-Coa reductase \--\> leading to increased HMG coa reductase Mrna expression** - **Statins** also lead to increased synthesis of LDL receptor exppression on vascular endothelium. Stations also have an antioxidant effect on endothelial cells - **Side effect of statin: hepatotoxicity** - Type 4 - **Isolated** increase of triglycerides due to **hepatic overproduction of VLDL** - **Fibrates (**fenofibrate, gemfibrozil) are the best drugs for lowering TGAs - Fibrates can cause myopathy but myopathy is decreased when it is combined with statin due to cytochrom inhibition - **Pancreatitis and abdominal pain are most important symptom**     Fructose disorders - A close-up of a sign Description automatically generated - Fructose disorder are usually presented as an infant who has just been introduced to fruit, honey or juice - **Essential fructosuria = deficiency of fructokinase = asymptomatic presentation** - Completely normal enfant with reducing sugar in urine - **Hereditary fructose intolerance = deficiency of aldolase b = severe presentation** - Build up of fructose 1 phosphate, leading to jaundice, cirrhosis and hypoglycemia - More severe presentation due to trapping of phosphate in liver - A person with fructose disorder needs to **avoid table sugar,** since its sucrose = glucose +fructose   Galactose disorders -  - Galactokinase deficiency = deficiency of galactokinase = milder presentation - Galactokinase deficiency will show up as **infantile cataracts and galactose in urine, infants will have trouble seeing or leukocoria + reducing sugar in urine** - Classic galactosemia = deficiency of GALT = severe presentation - Hepatosplenomegaly, jaundice and mental impairment - Phosphate trapping is seen in the liver - Child must stop breast feeding if diagnosed because lactose in breast milk is catabolized to glucose + galactose - In galactose disorders, galactitol causes cataracts because **aldolase reductase** turns galactose into galactitol - **E.coli sepsis in neonates is associated with classic galactosemia**     Gluconeogenesis - A diagram of a blood glucose cycle Description automatically generated   4 steps: 1. Pyruvate carboxylase a. Converts pyruvate \--\> OAA b. **Biotin (vitamin B7) dependent enzyme** c. **Acetyl coA is a positive regulator** 1. **PEP carboxykinase** a. Converts OAA back to PEP, then pep can work its way up to glucose 1. Fructose 1,6 biphosphate a. Rate limiting enzyme of gluconeogenesis 2. Glucose-6-phosphatase a. Enables G6P to go back to glucose b. Deficiency causes **von gierke disease (glycogen stroage disease type I)** c. **G6Pase are not found in skeletal muscle which is why skeletal muscle doesn't partake in gluconeogenesis**   - **Propionyl CoA carboxylase** converts propionyl CoA \--\> methylmalonyl Coa via biotin (b7) - Methylmalonyl CoA mutase then converts methylmalony CoA to succinyl Coa in the TCA cycle, this reaction requires b12 - B12 deficiency - Leads to buildup of methylmalonyl coa in B12 deficiency leadingto subacute combined degeneration - Involves corticospinal, dorsal columns and spinocerebellar tract   Glycogen storage disease - All autosomal recessive - **Von gierke disease (type I)** - Decrease in glucose-6-phosphatase enzyme - Most severe glycogen storage disease - Hepatomegaly, fasting hypoglycemia, **increased blood lactate** - **You will see lactic acidosis, bicarb is low** - **Glucose levels don't rise after giving fructose because gluconeogenesis is impaired** - **Cori disease (type III)** - Decrease in alpha 1,6 glucosidase (debranching enzyme) - Glucose levels rise after giving fructose since gluconeogenesis is intact - Pompe disease - Decreased lysosomal debranching alpha 1,4 glucosidase - Heart problem in glycogen storage disease = pompe disease - Only enzyme deficiency located in lysosome, the others are in cytosol - McArdle disease - Decrease in myophosphorylase (muscle glycogen phosphorylase - Teen, intense exercise which results in painful muscle cramps and red/dark urine - Hyperkalemia secondary to rhabomyolysis is seen - Dipstick of the urine will be positive for blood but urinalysis will reveal no RBCS - Acute tubular necrosis is also seen = muddy brown granular casts, sloughed off PCT tubular cells   Hartnup disease and Fanconi syndrome - Hartnup disease - Decreased ability to absorb nonpolar amino acids mainly tryptophan in the PCT - Tryptophan is a precursor to both serotonin and niacin - Hartnup disease \--\> decreased tryptophan \--\> decreased niacin \--\> pellagra - Increase serotonin production (carcinoid syndrome) \--\> decreased tryptophan \--\> decreased niacin \--\> pellagra - Note: pellagra is dementia, dermatitis and diarrhea which can happen due to impaired tubular reabsorption of dietary amino acid - Fanconi syndrome - Patient will have tryptophan and charged amino acids in urine - Note that tryptophan is neutral amino acid - In fanconi syndrome, there is a decreased reabsorption of amino acids, glucse, bicarb and phosphate in the PCT - Because there is decreased bicarb reabsorption, it's a cause of renal tubular acidosis type II - Fanconic syndrome can also be caused by consumption of expired teracyclines - Tetracycline MOA: 30s ribosomal subunit inhibitor; inhibits aminoacyl tRNA from binding to the A site   Hexose monophosphate (HMP) shunt -  - Glucose-6-phosphate which can normally proceed through glycolysis can be shunted here to make NADPH - NADPH is important for the respiratory burst and regneration of glutathione; reduced glutathione is protective against oxidizing agents and helps keep RBC membranes stable - Rate limiting enzyme in HMP shunt is glucose 6 phosphate dehydrgenase - G\^PD deficiency \--\> decreased NAPDH \--\> hemolysis in the event of stressors like **drugs, fava beans, DKA, infection, trauma** - Transketolase is used to recycle excess HMP intermediates back to fructose 6 phosphate in glycolysis; this enzyme is thiamine dependant - In general the four thiamine dependent enzymes are - Pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase, alpha ketoacid dehydrogenase, transketolase   Homocystinuria - Autosomal recessive disease, characterized by buildup of homocysteine due to deficiency of cystathionine synthase - A diagram of a chemical reaction Description automatically generated - Patient will present as a child with marfanoid body habitus and thrmbotic events - Ie tall and lanky 12 year old girl with scoliosis and len dislocation and thrmbotic event or myocardial infarction - Also associated with early onset osteoporosis - Cysteine is essential in homocystinuria but methionine is present in excess - Possible treatments are cysteine and pyridoxine (vitamin B 6) since it's a cofactor for cystathionine synthase - Pyroxidine can be used for decarboxylase reactions, heme synthesis, histamine synthesis and hepatic ALT/AST reactions   Kwashiorkor vs Marasmus vs Cretinism - **Marasmus** is total calorie deficiency presenting as diffuse wasting - Kwashiorkor **is protein malnutrition, the lack of protein** results in hypoalbuminemia, decreased intravascular oncotic pressure and ascites (pot belly) - Treated with leucine, lysine and tryptophan - Cretinism - Also had protruding abdomen but with **severe mental impairement, large tongue, impaired linear bone growth, impaired myelin synthesis \--\> congenital hypothyroidism** - **Note:** worldwide most common cause of hypothyroidism is iodine deficiency whereas in the western worls its hashimotos       Lactase deficiency - Lactase breaks down lactose into glucose and galactose - Lactase is located on the surface of enterocytes, predominant in the jejunum and it's a brush border enzyme - Biopsy should show normal appearing villi - Normal villi = lactose intolerance - Blunting of villi = celiacs - There are anti endomysial and IgA anti tissue transglutaminases - Dermatitis herpetiformis is also associated with celiacs - Celiacs disease is also associated with increased risk of T cell lymphoma - Gastroenteritis can lead to transient (secondary) lactose intolerance due to shedding - /inflammation of the itnestinal epithelium \--\> due to rotavirus - Rotavirus is dsRNA segmented virus causing watery diarrhea in kids - Kid with osmotic diarrhea, bloating and cramps following consumption of dairy products - Stool will demonstrate low pH and breath shows high hydrogen content - Lactose is also regered to as glactosyl beta 1,4 glucose     **Lactulose vs Neomycin** - Both used in the tx of hyperammonemia - Lactulose increases gut excretion of ammonia by enabling its conversion to ammonium - Neomycin, an aminoglycoside, kills urease positive organisms thereby decreasing ammonia production - Aminoglycoside moa: 30s ribosomal subunit inhibitor; causes disruption of initiation complex and causes misreading of mRNA   Maple syrup urine disease - Increased levels of alpha ketoacids of leucine, isoleucine and valine because there is a deficiency of alpha ketoacid dehyrodgenase, a thiamine (vitamin b1) dependant enzyme - Leucine, isoleucine and valine are all branched amino acids - The mother may notice the smell of burnt sugar in her infants diaper - Treatment: restrict intake of leucine, isoleucine and valine - Its most prelevalent in ashkenazi jews - Since alpja ketoacid dehydrogenase is a thiamine dependant enzyme, thiamine can help mitigate metabolic derangement - Symptoms: hypotonia, mental impairement and metabolic acidosis and hypoglycemia   Marfan Syndrome - Autosomal dominant, chromosome 15, FBN1/2 which codes for fibrillin, which is a glycoprotein that forms a sheath around elastin - Marfan syndrome is NOT a collagen disorder - Features of marfan - Tall lanky, arm span greater than height, pectus excavatum, increase risk of spontaneous pneumothorax, scoliosis, mitral valve prolapse, aortic regurg - Lens dislocation happens due to defective microfibrils within suspensory ligaments - Aortic regurg happens due to weakening of tunica media - Mitral vale prolapse happens because of myxomatous degeneration of the mitral valve - Marfanoid body habitus means the patient looks like he has marfan syndrome but doesn't - Homocystinuria: school age child with marfanoid body habitus, history of thrombotic event and blurry vision or lens dislocation - MEN2B: marfanoid body habitus, pheochromocytoma, medullary thyroid carcinoma, mucosal neuroma   Menkes Syndrome - Menkes syndrome is x linkedrecessive, there is a decreased ability to absorb copper in the gut due to a defective transporter - Whereas wilsons disease is too much copper due to inability to secrete copper into bile - copper is usually absorbed in the duodenum and is excreted through bile - Why do we need copper? - It's a cofactor for lysyl oxidase, which is the final enzyme necessary in collagen synthesis - Therefore, there is lesser activity of lysyl oxidase in menkes syndrome - Menkes presentation - Connective tissue weakness, brittle kinky hair, truncal hypotonia, seizures   Mitochondrial disorders - Strict maternal inheritance - Presentation: **ragged red fibres,** visual, hearing problems, hypotonia and lactic acidosis - Heteroplasmy is seen in mitochondrial genetics - Heteroplasmy is the presence of more than one type of mitochondrial dna in the same individual - Mitochondrial disease vary in severity among individuals because of varying ratios of disease vs wild type mitochondrial gene inherited - Side notes about other genetic terms - Incomplete penetrance: not everyone with the mutation will go on to have the condition - Variable expressivity: everyone with diseased genotype has disease phenotype but individuals vary in presentation. For example, those with NF1 can have café au lait spots and lisch nodules whereas others have axillary/groin freckling - Myoclonic epilepsy with ragged red fibres - Mitochondrial disorder with **seizures, ataxia, hearing loss and myopathy**   Phenylketonuria (PKU) - Deficiency of phenylalanine hydroxylase = classic phenylketonuria - Deficiency of tetrahydrobiopterin = malignant phenylketonuria - Treatment: decrease phenylalanine and increase tyrosine in diet - Problem with malignant PKU is that once tyrosine is given as a treatment, it cant be converted to LDOPA and dopamine therefore: - In malignant PKA, galactorrhoea (hyperprolactinemia) can result from decreased dopamine secondary to decreased LDOPA - In classic PKU, there is no hyperprolactinemia because tyrosine can still be converted to L-DOPA - In both forms of PKU, there is mental impairment if phenylalanine (aspartame) is not removed from diet - PKU presentation: eczema, fair skin, musty or mousy body Odor - Maternal PKU: when the foetus doesn't have pku but the mother does; if the mother doesn't watch her diet, then the child can get mental impairment as the phenylalanine can cross the placenta - But if the mother doesn't have the disease and the foetus does, the diet doesn't matter and there are no symptoms - The heel prick tests for PKU and must have high sensitivity, low false negative rate and high true positive rate   Phakomatoses - Phakomatoses are neurocutaneous disorders and refer to NF1, NF2, TSC, VHL and sturge-weber - Neurofibromatosis type 1 - Chromosome 17, AD - Neurofibromas - **Cafe au lait spots** - **Pheochromocytoma** - **Optic nerve glioma** - Lisch nodules - Neurofibromatosis type 2 - Chromosome 22, AD - **Bilateral acoustic schwannomas** - Congenital cataracts - Meningioma, ependymoma - Tuberous sclerosis - TSC1 on chromosome 9 coding for hamartin protein and chromosome 16 for tuberin protein - Autosomal dominant - Angiofibromas; skin colored papules in a butterfly distribution on face and in the nasolabial folds - **Cardiac rhabdomyoma** - **Renal angiomyolipoma** - Von hippel lindau - Chromosome 3, AD - Cerebellar and retinal hemangioblastomas - Bilateral renal cell carcinoma - Sturge weber syndrome - Not hereditary; caused by mosaic, somatic mutation in GNAQ gene - Unilateral facial port wine stain birthmark (but may also present as cutaneous violaceous papules in an ophthalmic trigeminal nerve distribution) - Seizure - glaucoma     Trinucleotide repeat disorders - Fragile X (CGG) - X linked recessive; FMR1 gene - Karyotyping is performed on leukocytes in a folate and thymidine deficient medium - Presentation: large, everted ears, long jaw and macroorchidism, scoliosis and pes planus and mental retardation - **Note: if you get a question with a philtrum that is flat, long or smooth, then that is FAS not fragile X** - Huntington disease (CAG) - AD and on chromosome 4 - Presenation: chorea, athetosis (slow writhing movement), progressive dementia - The caudate nuclei and putamen are affected; there is dilation/widening of the anterior horns of lateral ventricles - The most common cause of death is pneumonia secondary to aspiration from decrease muscle coordination - You must do genetic councelling before doing genetic testing - The disease also shows complete penetrance, if a patient has 40 or more repeats, there is a 100% chance they will develop the disease - Brain biopsy will show long strands of glutamine since CAG codes for glutamine - Hormonally: huntingtons will show decrease GABA and acetylcholine and increased dopamine - Treatment: - Treated with amine depleting drugs that inhibit VMAT like terabenazine and reserpine - Typical antipsychotics like haloperidol are also used in treatment of huntings associated psychosis - Friedreich ataxia (GAA) - AR on chromosome 9 on gene called frataxin - Cardiomyopathy, early onset T2DM, kyphoscoliosis, pes cavus, ataxia, bainski reflexes, dysarthria and hammer toes - Myotonic dystrophy (CTG) - AD on chromosome 19 - Abnormal expression of myotonin protein kinase - Presentation: sustained muscle contraction, muscle wasting, baldness, cataracts and testicular atrophy; they will show inability to relax their muscles - They cant let go of a golf club or doorknob and have extra long handshakes - They all show anticipation \--\> increase number of repeats = incraese severity of condition and decrease age of onset   Urea cycle, orotic aciduria, OTC deficiency - The last enzyme in the urea cycle is arginase and it's the one that makes urea - Arginine + h2o = urea + ornithine - N-acetylglutamate is also a positive allossteric regulator of carbamoyl phosphate synthetase I, the rate limiting step of urea cycle - If a patient has hyperammonemia, there is increased ornithine and the urea cycle enzymes are normal, the answer is n-acetylglutamate deficiency - Ornithine transcarbamylase (OTC) is also an x linked recessive disorder - OTC vs orotic aciduria - In both conditions there is increased serum orotic acid - Normal MCV, hyperammonemia, decreased BUN \--\> OTC deficiency (xlinked) - Increased MCV, normal ammonia and BUN \--\> orotic aciduria (AR) - In orotic aciduria there is impairement of pyrimidine synthesis so there is slowed bone marrow production of nucleated erythrocyte precursors - There is no impaired pyrimidine synthesis in OTC   Lab Techniques - Southern blot \--\> for DNA ie paternity testing - Northern blot \--\> RNA - Western blot \--\> for protein, usually used as a confirmatory test for HIV or lyme disease etc - Southwestern blot \--\> type of western blot, protein ran on gel then visualized with oligonucleotide probe. Its great for **identiifying dna binding proteins** - DNA finger printing: used for paternity testing and forensics, looks at variable number of tandem repeats (VNTRs) - DNA microarray: used to detect SNPs - Sequencing: uses dideoxynucleotides to randomly terminate growing strands of DNA then the DNA is sepereated on a gel and read by the other of the bands on the gel - Reverse transcription PCR is used to detect mRNA levels; mRNAs is first converted to cDNA then pcr is done - ELISA: - Sensitive test and is used for screening - Ie elisa is the screening test for hiv and western blood is the confirmatory test - Two main types - Direct elisa: you are trying to detect antigen in the patients serum - Indirect elisa: you are trying to detect antibody in patients serum - Direct ELISA: - Trying to detect antigen, you need the plate to coated to cover with known antibody - This means the secondary antibody binds the patients antigen - Indirect elisa - Trying to detect antibody in patients serum, you need the plate to initially be coated with a known antigen. This means the secondary antibody binds the patients antibody   Vitamin A, zinc, selenium - Vitamin A in general - Vitamin A converts 11 cis retinal to 11 trans retinal in phototransduction, any night blindness is due to vitamin A deficiency - Supports proper immune functioning (deficiency of vita A = increase infections) - Enables differentiation of tissues (ie prevents skin cancer by inhibiting squamous metaplasia) - Vitamin A as a treatment - **All trans retinoic acid (**a vitamin A derivative) can treat acute promyelocytic leukemia; this is because vitamin A induces differentiation of leukemic cells into mature neutrophils - Vitamin A deficiency = increase suceptibility to measles (rna virus; enveloped; SS (-) sense - For acne - Topical retinoids \--\> topical benzoyl peroxide \--\> topical clindamycine \--\> tetrcacyline \--\> oral isoretinoin - **Isoretinoin,** used for sever eacne is a high dose vitamine A that is teratogenic - **Vitamin A (retinoids) helps with acne** because it's a transcription factors and it shuts of sebum production - Where benzoyl peroxide opens poors and kills bacteria - Vitamin A deficiency - Vit A deficiency and excess both cause xerosis cutis (dry skin) - Bitot spots (Grey plaques on conjucntiva) and corneal metaplasia can also be seen in vita a deficiecny - Vitamine A deficiency can also lead to risk of measles andsquamous cell carcinoma - Hypervitaminosis A (toxicity) - Toxicity can happen due to isoretinoin and consumption of ursine (bear) liver - Toxicity can lead to increased intracranial pressure (pseudotumor cerebri\_, papilledema and cerebral edema - Note: whereas other fat soluble vitamines are stored in adipocytes, vitamin A is concetrated in the hepatic stellate cells (ito cells) of liver - Vitamin A teratogenicity results in = cleft lip/palate - Vitamin A causes teratogenecity due to disruption of homeobox gene - Selenium - Selenium is a cofactor for glutathione peroxidase - Glutathione peroxidase converts H2O2 + reduced glutathione \--\> H20 + oxidized glutathione - The h202 from this reaction is made in respiratory burst - Zinc - Zinc deficiency: **anosmia, dysgeusia (decreased ability to taste), decreased wound healing** - Zinc deficiency also leads to acrodermatitis enteropathica (decrease zinc absorption, dermatitis of orifices/limbs, diarrhea and alopecia) - Zinc deficiency also causes infertility: zinc stabilizes dna containing chromatin spermatazoa     Side note on translocations and leukemia - T(15;17) is the cause of APL - T(9;22) causes chronic myelogenous leukemia (CML); philadelphia chromosome - T(8;14), t(2;8) and t (8;22) all cause burkitt lymphoma - T(14;18) is follicular lymphoma - T(11;14) is mantle cell lymphoma     Vitamin B1 (thiamine)+ wernicke korsakoff - Thiamine dependent enzymes - Pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase, branched chain amino acid dehydrogenase and transketolase - Remember that thiamine is usually a cofactor for dehydrogenase reactions - Thiamine deficiency - Usually seen in chronic alcoholism due to dietary deficiency - Dry beriberi (neuropathy) \--\> classically numbness of the hands and feet - Wet beriberi (dilated cardiomyopathy) \--\> lateralized apex beat, S3 heart sound, increased pulmonary capillary wedge pressure - Thiamine deficiency and chronic alcoholism can both cause dilated cardiomyopathy that are distinct from each other - Alcohol damage can cause rhabdomyolysis leading to non megaloblastic macrocytic anemia - **Wernicke encephalopathy also happens in thiamine defiicnecy** - A COW = ataxia, confusion, opthalmoplegia, wernicke - If glucose is given before giving thiamine, anterograde amnesia happens - Never give glucose without thiamine if they are thiamine deficienct, as wernicke encephalopathy will get worse - The mammillary bodies and medial dorsal nucleus of the thalamus are frequently damaged in W-K   Vitamin B2 (riboflavin) and B3 (Niacin) - Vitamin B2 - Cofactor for reactions with FAD/FADH2, oxidation/reduction reactions - FADH2 is produced via succinate dehydrogenase in the conversion of succinate \--\> fumarate in the TCA cycle - Vitamin B3 (Niaicin) - Its used in reactions involving NADH/NAD+ - Its also a lipid improving agent - It increases HDL - It decreases hepatic export of VLDL (decreases triglycerides) - Niacin can cause the following so its not given as a treatment - Flushing of face and body \--\> due to prostaglandings and is treated with aspirin - Hyperglycemia due to insulin resistance: if a patient is taking niacin and they have diabetes, their med doses need to be increased - Gout due to hyperuricemia (niacin is contradicted inthose with gout) - **Niacin deficiency causes** - Hartnup disease (decrease tryptophan reabsorption in the kidney \--\> decreased niacin synthesis because tryptophan is the precursor) - Carcinoid syndrome (tryptophan is the precursor of both niacin and serotinin. Increased serotonin synthesis leads to depletion of tryptophan leading to decreased niacin synthesis - Pellagra = dementia, dermatitis, diarrhea - Patient has low HDL \--\> best initial management is lifestyle changes but most effective is niacin   Vitamins B5, B6 and B7 - Vitamin B 5( pantothenic acid) - Used for coenzyme-A (CoA) reactions - Deficiency causes adrenal insufficiency and burning feet syndrome - Vitamin B6 (pyridoxine) - Depleted with isoniazid (INH) use for TB; Ie seizures or neuropathy in the setting of TB treatment = B6 deficiency - Seizures caused by vitamin B6 deficiency secondary to INH use are due to decreased GABA - Cystathionine synthase requires B6 as a cofactor; vitamin B6 is used for adjunct therapy for homocysteinuria - Needed for heme synthesis; deficiency leads to sideroblastic anemia - The first step of heme synthesis \--\> succinyl-CoA + glycine \--\> aminolevulinic acid via vitamin B6 - Needed for dercarboxylase reactions - B6 is needed for B3 (niacin) synthesis - B6 is also needed for hepatic transminase reactions - Vitamin B7 (Biotin) - Needed for decarboxylase reactions - Pyruvate to oxaloacetate - Acetylcoa to malonylcoa - Propionyl-CoA to methylmalonyl Coa - Deficiency is caused by consumption of raw egg whites due to binding of B7 with avidin   Vitamin B9 (folate) + B12 - Dietary folate (B9) is converted to tetrahydrogolate (THF) - B9 is also found in dark green leafy vegetables - Ie if there is a women on a tea and toast diet and her MCV is elevated, she has a folate deficiency - **B9 and b12 deficiency also cause megaloblastic anemia and hypersegemented neutrophils** - **Maternal deficiency of B9 in the first three pregnancies leads to neural tube defects** - Antiepileptic meds llike phenytoin, valproic acid, and carbamazepine can cause folate deficiency by impairing gut absorption - Folate deficiency is the most common vitamin deficiency - Vitamin B12 is involved in two reactions - Homocysteine \--\> methionine - Methylmalonyl-CoA \--\> succinyl-Coa - Patients with increasing MCV - Serum methylmalonyl-CoA elevated? Yes \--\> B12 deficiency - Serum methylmalonyl-CoA elevated? No \--\> B9 deficiency - Hemolysis (increase unconjugated bilirubin) + normal serum methylmalonyl-Coa \--\> vitamin E deficiency - Causes of B12 deficiency - Pernicious anemia - Veganism - Surgery - Diphyllobothrium latum - Crohn disease - Menetrier disease - Schilling test - Tests for b12 deficiency     **Vitamin C and E** - **Vitamin C** - Vitamin C is necessary for collagen synthesis; required for hydroxylation of proline and lyrinse residues within preprocollagen - Deficiency of C leads to scurvy - leads to perifollicular hemorrhages (bleeding around hair follicles) and bleeding from gums and ill appearing patient - Scurvy also shows metaphyseal thickening, corkscrew shaped hair, brusied joints, petechiae, iron deficiency anemia - Scurvy \--\> corkscrew hair - Menkes \--\> kinky hair - Vitamin c is also needed for catecholamine synthesis - Vitamin C is required for duodenal absorption of iron - Hypervitaminosis C can cause calcium oxlatate stones - Vitamin E (tocopherol) - Protects RBCs from hemolysis - Vitamin E deficiency leads to hemolytic anemia - Hypervitaminosis E can cause bleeding as it increases INR   Vitamin D - Synthesized in **stratum basale** - **Vitamin D** deficiency leads to decreased cholecalciferol with normal levels of 7 dehydrocholesterol -  - The 25-OH hydroxylation step happens in the liver - An alcoholic who has vitamin D deficiency will have decreased hepatoc hydroxylation - Parathyroid hormone induces 1 alpha hydroxylation in the PCT of the kidney - Induces coversion of 25-hydroxyD3 to 1,25-OH-D3 - Hypoparathyroidism causes decreases 25-OH-D3 and decreased 1,24-OH-D3 - Vitamin D deficiency causes decreased calcium and phosphate in the serum - Vitamin D deficincy (rickets/osteomalacia): decreased calcium, phosphate, increased ALP and PTH - Rickets/osteomalacia \--\> harrison sulci (indentation of lower ribs), carbiotabes (softening of the skull), and rachitic rosary (bony prominences at the costochondral junctions), boweing of the tibias (genu varum), widened wrists/ankles, pseudofractures - Hypervitaminosis D is due to granulomatous diease - High vitamin D happens due to sarcoidosis \--\> nonceaseating granulomas that secrete 1 alpha hydroxylase; this increases the active form of vitamin D and leads to hypercalcemia and hyperphosphatemia - Micellaneous - Breast milk has low vitamin D - William syndrome: hypercalcemia secondary to increased vitamin D sensitivity; and have elfin like facies - Calcipotriene is a topical vitamin D used in treatment of plaque psoriasis   Vitamin K and Warfarin - A diagram of a complex of vitamin k Description automatically generated - Medical term for vitamin k1 isphytonadione - Warfarin inhibits vitamin K epoxide reductase therefore, warfarin inhibits the recycling of vitamin K1 to its active form - Gamma-glutamyl carboxylase - Vitamin K1 is a cofactor for gamma glutamyl carboxylase; this the enzyme that activates factors 2,7,9,10 and protein C and S - Which enzyme has decreased activity in vitamin K deficiency\> gamma glutamyl carboxylase - Which enzyme has decreased activity with warfarin use? Vitamin K epoxide reductase - Vitamin K deficiency and warfarin increase PT and aPTT - Vitamin k deficiency can happen in newborns and with chronic antibiotic use - Warfarin is broken down by CYP2C9 - Ciprofloxacin (a fluroroquinoline), macrolides and sulfa drugs and metronidazole are known to cause bleeding diathesis in patients on warfarin - Skin necrosis is an adverse effect of warfarin in those who have hereditary protein C deficiency - Patients who are deficienct of protein are more hypercoagulable - Treatment for vitamin K deficiency and reversal of warfarin - If there is no bleeding then vitamin k is given - If there is active bleeding, then fresh frozen plasma then vitamin k are given - Vitamin k deficiency can occur in patients who are on chronic broad spectrum antibiotics. Patients on antibiotics require lower dose of warfarin to achive the same INR target range because there is decrease in colonic normal flora - Sources of vitamin K - Veggies - Most of the vitamin k is made by synthesis by colonic normal flora - Greeny leafy vegetables \--\> folate - Colonic normal flora \--\> vitamin K