FA biochem 2
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inhibits by binding to K+ site.
Cardiac glycosides name and MOA?
- digoxin and digitoxin
- directly inhibit the Na+-K+ ATPase,which leads to indirect inhibition of Na+/Ca2+ exchange inc. [Ca2+]i and inc. cardiaccontractility.
osteogenesis imperfecta type I defect in
- type I collagen Glycosylation (RER) which is Problems forming triple helix
Ehlers-Danlos syndrome Classical type (joint and skin symptoms) caused by
mutation in type V collagen
Ehlers-Danlos syndrome Vascular(vascular and organ rupture) type defect in
type III collagen, Cross-linking Outside fibroblasts, in normal:covalent lysine-hydroxylysine cross-linkage (by Cu2+-containing lysyl oxidase) to make collagen fibrils
Alport syndrome and Goodpasture syndrome
collagen type IV defective in Alport syndrome; targeted by autoantibodies in Goodpasture syndrome
Collagen synthesis happens in
RER Inside fibroblasts
Inside fibroblasts what r the steps of collagen synthesis?
- 1. Synthesis (RER)
- 2. Hydroxylation (RER)
- 3. Glycosylation (RER)
- 4. Exocytosis
collagen Synthesis (RER)
Gly-X-Y (X and Y are proline or lysine). Glycine content best reflects collagen synthesis (collagen is 1⁄3 glycine)
which step of collagen synth needs vit C?
scurvy happens in what stage of collagen synthesis?
Hydroxylation (RER) it requires vit C
what are the steps Outside fibroblasts in collagen synthesis?
- 5. Proteolytic processing
- 6. Cross-linking
Ehlers-Danlos syndrome associated with
joint dislocation, berry andaortic aneurysms, organ rupture
Connective tissue disease caused by impaired copper absorption and transport. Leads to activityof lysyl oxidase (copper is a necessary cofactor). Results in brittle, “kinky” hair, growth retardationand hypotonia.
Elastin Rich in
proline and glycine, nonhydroxylated forms.
Elastin Broken down by _____, which is normally inhibited by _______.
Marfan syndrome—caused by a defect in
fibrillin, a glycoprotein that forms a sheath around elastin
Emphysema—can be caused by
α1-antitrypsindeficiency, resulting in excess elastase activity
Wrinkles of aging are due to
collagen andelastin production
- Maternal imprinting: gene from mom is normally silent and Paternal gene is deleted/mutated. Results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia.
- 25% of cases due to maternal uniparentaldisomy (two maternally imprinted genes are received; no paternal gene received).
- Paternal imprinting: gene from dad is normally silent and Maternal gene is deleted/mutated.Results in inappropriate laughter (“happy puppet”), seizures, ataxia, and severe intellectual disability.
- 5% of cases due to paternal uniparental disomy(two paternally imprinted genes are received; nomaternal gene received).
- rickets—formerly known as vitamin D–resistant rickets. Inherited disorder resulting in phosphate wasting at proximaltubule. Results in rickets-like presentation
- X-linked dominant
Autosomal dominant polycystic kidney disease (ADPKD)
Formerly known as adult polycystic kidney disease. Always bilateral, massive enlargement of kidneys due to multiple large cysts. 85% of cases are due to mutation in PKD1 (chromosome 16;16 letters in “polycystic kidney”); remainder due to mutation in PKD2 (chromosome 4).
Familial adenomatous polyposis
Colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unlesscolon is resected. Mutations on chromosome 5 (APC gene); 5 letters in “polyp.”
Elevated LDL due to defective or absent LDL receptor. Leads to severe atherosclerotic disease earlyin life, and tendon xanthomas (classically in the Achilles tendon).
Hereditary hemorrhagic telangiectasia
Inherited disorder of blood vessels. Findings: telangiectasia, recurrent epistaxis, skin discolorations,arteriovenous malformations (AVMs), GI bleeding, hematuria. Also known as Osler-Weber-Rendu syndrome.
Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia;high MCHC. Treatment:splenectomy.
Huntington disease Findings
Findings: depression, progressive dementia, choreiform movements, caudate atrophy, and levels of GABA and ACh in the brain. Gene on chromosome 4; trinucleotide repeat disorder: (CAG)n. inc repeats lower age of onset. “Hunting 4 food.”
Marfan syndrome cardiac findings
cystic medial necrosis of aorta --> aortic incompetence and dissecting aortic aneurysms; floppy mitral valve
Multiple endocrine neoplasias MEN 2A and 2B are associated with ___ gene.
Neurofibromatosis type 1 (von Recklinghausen disease)
Neurocutaneous disorder characterized by café-au-lait spots and cutaneous neurofibromas. Autosomal dominant, 100% penetrance, variable expression. Caused by mutations in the NF1 gene on chromosome 17; 17 letters in “von Recklinghausen.”
Neurofibromatosis type 2
Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas. NF2 gene on chromosome 22; type 2 = 22.
Neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas. Incomplete penetrance, variable expression.
von Hippel-Lindau disease
Disorder characterized by development of numerous tumors, both benign and malignant. Associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p). Von Hippel-Lindau = 3words for chromosome 3.
Cystic fibrosis GENETICS
Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508. Most common lethal genetic disease in Caucasian population.
Cystic fibrosis PATHOPHYSIOLOGY
CFTR encodes an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands. Mutations --> misfolded protein--> protein retained in RER and not transported to cell membrane, causing dec. Cl- (and H2O) secretion; inc. intracellular Cl- results in compensatory inc. Na+ reabsorption via epithelial Na+ channels --> inc. H2O reabsorption -->abnormally thick mucus secreted into lungs and GI tract. high Na+ reabsorption also causes more negative transepithelial potential difference.
Cystic fibrosis DIAGNOSIS
high Cl- concentration (>60 mEq/L) in sweat is diagnostic. Can present with contraction alkalosis and hypokalemia (ECF effects analogous to a patient taking a loop diuretic) because of ECF H2O/Na+ losses and concomitant renal K+/H+ wasting.
Cystic fibrosis COMPLICATIONS
Recurrent pulmonary infections (e.g., Pseudomonas), chronic bronchitis and bronchiectasis --> reticulonodular pattern on CXR, pancreatic insufficiency, malabsorption and steatorrhea, nasalpolyps, and meconium ileus in newborns. Infertility in males (absence of vas deferens, absent sperm). Fat-soluble vitamin deficiencies (A, D, E, K).
Cystic fibrosis TREATMENT
N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins),dornase alfa (DNAse) to clear leukocytic debris.
X-linked recessive disorders
- "Be Wise Fucking HOes Have GOLD "
- Bruton agammaglobulinemia,
- Wiskott-Aldrich syndrome,
- Fabry disease
- Hunter Syndrome,
- Ornithine transcarbamylase deficiency Hemophilia A and B,
- G6PD deficiency
- Ocular albinism,
- Lesch-Nyhan syndrome,
- Duchenne (and Becker) muscular dystrophy
X-linked frameshift mutation
Muscular dystrophies Duchenne what do u see in muscle?
Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle
patients use upper extremity tohelp them stand up. is called?
Usually, X-linked point mutation in dystrophin gene (no frameshift).
Myotonic type 1 gene defect in
CTG trinucleotide repeat expansion in the DMPK gene
expansion in the DMPK gene results in?
abnormal expression of myotonin protein kinase --> myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia.
Fragile X syndrome defective gene
X-linked defect affecting the methylation and expression of the FMR1 gene
Fragile X syndrome cc
The 2nd most common cause of genetic intellectual disability(after Down syndrome). Findings: post pubertal macroorchidism (enlarged testes),long face with a large jaw, large everted ears,autism, mitral valve prolapse.
Trinucleotide repeat expansion diseases
Huntington disease, myotonic dystrophy,Friedreich ataxia, fragile X syndrome.
what are Trinucleotide repeat expansion in each diseases ?
- "X-Girlfriend’s First Aid Helped Ace My Test."
- Fragile X syndrome = (CGG)n.
- Friedreich ataxia = (GAA)n.
- Huntington disease = (CAG)n.
- Myotonic dystrophy = (CTG)n.
Trinucleotide repeat expansion diseases May show genetic
anticipation (disease severity and age of onset in successive generations).
Down syndrome(trisomy 21), 1:700 Findings:
intellectual disability, flat facies,prominent epicanthal folds, single palmar crease, gap between 1st 2 toes,
Down syndrome(trisomy 21), 1:700
duodenal atresia, Hirschsprung disease, congenital heart disease (most commonly ostium primum-type atrial septal defect [ASD]), Brushfield spots.Associated with risk of ALL, AML, andAlzheimer disease (> 35 years old).95% of cases due to meiotic nondisjunction of homologous chromosomes (associated with advanced maternal age; from 1:1500 in women< 20 to 1:25 in women > 45 years old).4% of cases due to Robertsonian translocation.1% of cases due to mosaicism (no maternal association; post-fertilization mitotic error).
Down syndrome First-trimester ultrasound and serumcommonly shows:
- First-trimester ultrasound commonly shows: high nuchal translucency and hypoplastic nasal bone; serum PAPP-A is dec , free β-hCG is inc .
- Second-trimester quad screen shows: low α-fetoprotein, high β-hCG, low estriol, high Inhibin A. "HIGH are high"
Edwards syndrome (trisomy 18), 1:8000 findings
severe intellectual disability, rocker bottom feet, micrognathia (small jaw), low-set Ears, clenched hands, prominent occiput,congenital heart disease. Death usually occurswithin 1 year of birth.
Edwards syndrome first trimester findings
PAPP-A and free b-hCG are low in first trimester.Quad screen shows: low α-fetoprotein, low β-hCG, low estriol, low or normal inhibin A.
Patau syndrome(trisomy 13),1:15,000 Findings
Findings: severe intellectual disability, rocker bottomfeet, microphthalmia, microcephaly,cleft liP/Palate, holoProsencephaly,Polydactyly, congenital heart disease. Deathusually occurs within 1 year of birth.
microphthalmia First-trimester findings
First-trimester pregnancy screen shows: low freeb-hCG, low PAPP-A, and high nuchal translucency
commonly involve chromosome pairs Robertsonian translocation
chromosome pairs 13, 14, 15,21, and 22.
Cri-du-chat syndrome what defect?
Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p-).
Cri-du-chat syndrome Findings:
Findings: microcephaly, moderate to severe intellectual disability, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD).
Williams syndrome what Congenital defect?
Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene).
Williams syndrome findings:
distinctive “elfin” facies, intellectual disability, hypercalcemia ( sensitivity to vitamin D),well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.
22q11 deletion syndromes
DiGeorge syndrome— or Velocardiofacial syndrome
22q11 deletion syndromes Variable presentation
Variable presentation, including Cleft palate,Abnormal facies, Thymic aplasia T-cell deficiency, Cardiac defects, Hypocalcemia 2°to parathyroid aplasia, due to microdeletion atchromosome 22q11.
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