FA biochem 2

inhibits by binding to K+ site.

• digoxin and digitoxin
• directly inhibit the Na+-K+ ATPase,which leads to indirect inhibition of Na+/Ca2+ exchange Ž inc.  [Ca2+]i Žand inc.  cardiaccontractility.

• type I collagen Glycosylation (RER) which is Problems forming triple helix
• AD

mutation in type V collagen

type III collagen, Cross-linking Outside fibroblasts, in normal:covalent lysine-hydroxylysine cross-linkage (by Cu2+-containing lysyl oxidase) to make collagen fibrils

collagen type IV defective in Alport syndrome; targeted by autoantibodies in Goodpasture syndrome

RER Inside fibroblasts

• 1. Synthesis (RER)
• 2. Hydroxylation (RER)
• 3. Glycosylation (RER)
• 4. Exocytosis

Gly-X-Y (X and Y are proline or lysine). Glycine content best reflects collagen synthesis (collagen is 1⁄3 glycine)

Hydroxylation (RER)

Hydroxylation (RER) it requires vit C

• 5. Proteolytic processing
• 6. Cross-linking

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.

proline and glycine, nonhydroxylated forms.

• elastase
• α1-antitrypsin

fibrillin, a glycoprotein that forms a sheath around elastin

α1-antitrypsindeficiency, resulting in excess elastase activity

 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

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).

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).

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.

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 Žlower age of onset. “Hunting 4 food.”

cystic medial necrosis of aorta -->Ž aortic incompetence and dissecting aortic aneurysms; floppy mitral valve

ret

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.”

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.

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.

Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508. Most common lethal genetic disease in Caucasian population.

CFTR encodes an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands. Mutations Ž--> misfolded protein-->Ž 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 Ž --> inc. H2O reabsorption -->Žabnormally thick mucus secreted into lungs and GI tract. high Na+ reabsorption also causes more negative transepithelial potential difference.

 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.

Recurrent pulmonary infections (e.g., Pseudomonas), chronic bronchitis and bronchiectasisŽ --> 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).

N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins),dornase alfa (DNAse) to clear leukocytic debris.

• "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

Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle

Gower maneuver

Usually, X-linked point mutation in dystrophin gene (no frameshift).

CTG trinucleotide repeat expansion in the DMPK gene

abnormal expression of myotonin protein kinase Ž --> myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia.

X-linked defect affecting the methylation and expression of the FMR1 gene

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.

Huntington disease, myotonic dystrophy,Friedreich ataxia, fragile X syndrome.

• "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.

anticipation (disease severity and age of onset  in successive generations).

intellectual disability, flat facies,prominent epicanthal folds, single palmar crease, gap between 1st 2 toes,

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).

• 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"

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.

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.

Findings: severe intellectual disability, rocker bottomfeet, microphthalmia, microcephaly,cleft liP/Palate, holoProsencephaly,Polydactyly, congenital heart disease. Deathusually occurs within 1 year of birth.

First-trimester pregnancy screen shows:  low freeb-hCG, low PAPP-A, and high nuchal translucency

chromosome pairs 13, 14, 15,21, and 22.

Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p-).

Findings: microcephaly, moderate to severe intellectual disability, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD).

Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene).

distinctive “elfin” facies, intellectual disability, hypercalcemia ( sensitivity to vitamin D),well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.

DiGeorge syndrome— or Velocardiofacial syndrome

Variable presentation, including Cleft palate,Abnormal facies, Thymic aplasia Ž T-cell deficiency, Cardiac defects, Hypocalcemia 2°to parathyroid aplasia, due to microdeletion atchromosome 22q11.