Biochem - Diseases

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1.

22q11 deletion syndromes

Variable presentation, incl CATCH22: Cleft palate, Abnormal facies, Thymic aplasia / T-cell deficiency, Cardiac defects, Hypocalcemia (2ary to parathyroid aplasia), from microdeletion at chr 22q11. Due to aberrant development of 3rd / 4th branchial pouches. DiGeorge, Velocardiofacial syndromes. Aut-rec deficiency in apoB-100 (binds LDL receptor; mediates VLDL secretion) and apoB-48 (mediates chylomicron secretion), so can't synthesize lipoproteins. Sx appear in 1st months of life: FTT, steatorrhea, acanthocytosis (= RBC with spikes, "spur cells," membrane lipids messed up = puckered / spiky membrane), ataxia, night blindness Aut-dom cell-signaling defect in fibroblast growth factor receptor 3 (FGFr3). Dwarfism: short limbs but head/trunk normal. A/W advanced paternal age Converts adenosine to inosine in purine salvage pathway. Excess ATP, dATP in nucleotide pool = imbalance (feedback inhibition of ribonucleotide reductase, preventing DNA synthesis), so decreased lymphocyte count (major cause of SCID, severe combined immunodeficiency dz, e.g. "bubble boy") Variable inheritance (locus heterogeneity); vs ocular albinism (x-linked recessive). Congenital deficiency of either 1) tyrosinase (can't make melanin from tyrosine; aut-rec); 2) defective tyrosine transporters (dec. tyrosine = dec. melanin); can also be from lack of migration of neural crest cells. Inc. risk skin cancer. Aut-rec deficiency of homogentisic acid oxidase (degradative pathway of tyrosine), benign disease. Dark connective tissue, pigmented sclera, urine turnes black on standing, may have debilitating arthralgias.

7.

Alport's syndrome

Defects in type IV collagen synthesis; most common form X-linked recessive. Hereditary nephritis, deafness +/- ocular disturbances (type IV collagen important in BM of kidney, ears, eyes) Chr 15, normally active maternal (AngelMan = maternal) allele deleted. MR, seizures ataxia, inappropriate laughter ("happy puppet"). Other parent's allele inactivated / imprinted by methylation; can also be from uniparental disomy (2 copies of chr from 1 parent). Prader-Willi syndrome = paternal counterpart Adult polycystic kidney disease. Aut-dom, 90% from mutation in APKD1, chr 16 (16 letters in "polycystic kidney"). Always bilateral, big kidneys (lots of big cysts). Flank pain, hematuria, HTN, progressive renal failure. a/w polycystic liver dz, berry aneurysms, mitral valve prolapse. Infantile form is recessive Inhibits lipoic acid (required for pyruvate dehydrogenase complex, pyruvate to acetylcoA). Vomiting, rice water stools, garlic breath. X-linked mutated dystrophin. Less severe than Duchenne's. Onset: adolescence, early adulthood. Rare; from abx or excessive raw egg ingestion (avidin in whites binds biotin). Dermatitis, alopecia, enteritis. Biotin used in carboxylation enzymes. Microtubule polymerization defect (no lysosomal tracking). Decreased phagocytosis. Recurrent pyogenic infections, partial albinism, peripheral neuropathy. Aut-rec absence of galactose-1-phosphate uridyltransferase; toxic substances accumulate (e.g. galactitol in lens of eye). FTT, jaundice, hepatomegaly, infantile cataracts, MR. Tx: no galactose / lactose (glucose + galactose). Glycogen debranching enzyme (alpha-1,6 glucosidase) deficiency (type III glycogen storage disease). Like type I (Von Gierke's; glucose-6-phosphatase deficiency) but milder (gluconeogensis intact; normal blood lactate levels) Microdeletion of short arm of chr 5: 46,XX or XY, 5p-. Microcephaly, moderate/severe MR, high pitched crying/mewing (cry of the cat), epicanthal folds, cardiac abnormalities

8.

Angelman's syndrome

2.

Abetalipoproteinemia

9.

APKD

3.

Achondroplasia

10.

Arsenic toxicity

4.

Adenosine deaminase deficiency

11.

Becker's muscular dystrophy Biotin deficiency

12.

13.

5.

Albinism

ChediakHigashi syndrome Classic galactosemia

14.

15.

Cori's disease

6.

Alkaptonuria (ochronosis)

16.

Cri-du-chat syndrome

17.

Cystic fibrosis

Aut-rec (CFTR gene, chr 7; CFTR channel secretes Cl- in lungs / GI, resorbes Cl- from sweat). Thick mucus - plugs lungs, pancreas, liver. Recurrent pulm infections (Pseudomonas, S aureus), chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption / steatorrhea), meconium ileus in newborns. Fatsol vit deficiencies (ADEK). Infertility in males (bilateral absence of vas deferens). FTT in infancy. #1 lethal genetic dz of Caucasians. Dx: inc [Cl-] in sweat test. Tx: N-acetylcysteine (Mucinex) - loosen mucous plugs by cleaving disulfide bonds w/in mucous glycoproteins Aut-rec, defect in renal tubular AA transporter (cysteine, ornithine, lysine, arginine in renal PCT). inc. cystine (2 cysteines w/ disulfide bond) in urine --> cystine kidney stones (cystine staghorn calculi). Common (1:7000); Tx with acetazolamide (alkalinize the urine) A 22q11 deletion syndrome. Thymic, parathyroid, cardiac defects. Microdeletion at chr 22q11. Due to aberrant development of 3rd / 4th branchial pouches. Trisomy 21; MR, flat facies, epicanthal folds, simian crease, gap btwn 1-2nd toes, duodenal atresia, congenital heart dz (esp septumprimum-type ASD), a/w inc risk ALL, Alz dz (>35 y/o). #1 cause congenital MR; #1 chr disorder (1:700). 95% from meiotic nondisjunction of homologous chr (a/w advanced maternal age, 1:25 > 45y/o), also Robertsonian translocation (4%). Screening: pregnancy quad screen (dec AFP, inc B-hCG, dec estriol, inc. inhibin A); U/S: inc. nuchal translucency B1 (thiamine) deficiency. Polyneuritis, symmetrical muscle wasting X-linked frame-shift mutation: deletion of dystrophin (DMD anchors mm fibers, esp. skeletal / cardiac. Longest gene: lots of spontaneous mutations). Accel. mm breakdown (weakness in pelvic girdle -> superiorly). Pseudohypertrophy of calf mm (fibrofatty replacement), cardiac myopathy, Gower's maneuver, onset < 5 y/o. Dx: inc. CPK, mm biopsy Trisomy 18 (E=election age), 1:8000. Severe MR, rockerbottom feet, congenital heart disease. Vs Patau's: micrognathia, low-set ears, clenched hands, prominent occiput. Death w/in 1 yr

24.

Ehlers-Danlos syndrome

Faulty collagen synthesis: hyperextensible skin, tendency to bleed (easy bruising), hypermobile joints. Mostly type III collagen. 6 types, inheritance / severity vary (AD/AR). A/w joint dislocation, berry aneurysms, organ rupture Lysosomal storage disease (a sphingolipidosis). X-linked recessive (all other sphingolipidoses AR); deficiency of alphagalactosidase A ceramide trihexoside accumulates. Peripheral neuropathy (hands / feet), angiokeratomas, CV / renal disease Aut-dom; mutation in APC gene (chr 5, "polyp" has 5 letters). Colon covered with adenomatous polyps after puberty. Progresses to colon cancer unless resected Aut-dom; defective / absent LDL receptor. Elevated LDL. Heterozygotes (1:500) have cholesterol = 300 mg/dL. Homozygotes (rare) chol > 700 mg /dL, severe atherosclerotic dz early in life, tendon xanthomas (classically Achilles); may have MI < 20 y/o. AKA hyperlipidemia type IIA Type IIa familial dyslipidemia. Autdom absence / decrease in LDL receptors. LDLs increased, blood cholesterol elevated. Macrocytic, megaloblastic anemia w/o neuro sx. #1 vitamin deficiency in USA; see in alcoholism / pregnancy (neural tube defects; supplement in early pregnancy), also drugs (phenytoin, sulfas, MTX). From FOLiage (leafy greens) with small reserve pool in liver. Converted to THF, CH3-transfer rxns (e.g. nitrogenous base synthesis) X-linked trinucleotide repeat disorder (CGG); affects methylation / expression of FMR1 gene, a/w chromosomal breakage. #2 cause of genetic MR (Down's is #1). Macroorchidism, long face + large jaw, large everted ears, autism.

25.

Fabry's disease

18.

Cystinuria

26.

Familial adenomatous polyposis coli

19.

DiGeorge syndrome

27.

Familial hypercholesterolemia

20.

Down syndrome

28.

Familial hypercholesterolemia

21.

Dry beriberi Duchenne's muscular dystrophy

29.

Folic acid deficiency

22.

30.

Fragile X

23.

Edwards' syndrome

31.

Fructose intolerance

Aut-rec deficiency of aldolase B; fructose-1-P accumulates; dec. in phosphate = inhibition of glycogenolysis / gluconeogenesis. Hypoglycemia, jaundice, cirrhosis, vomiting. Tx: limit fructose, sucrose (gluc + fruc) intake. Aut-rec fructokinase deficiency. Can't P-late fructose, so can't enter cells. Benign, asymptomatic - just fructose in blood, urine. X-linked recessive. G6PD: G6P + NADP+ -> 6PG + NADPH; NADPH needed to reduce GSSG to 2GSH (glutathione reductase) for H2O2 to 2H2O conversion. Only pathway for making reduced GSH in RBC, so can't detoxify free radicals / peroxides (fava beans, sulfa drugs, primaquine, anti-TB drugs); leads to hemolytic anemia. More common in blacks (inc malaria resistance), #1 human enzyme deficiency. Heinz bodies (Hb precipitates in RBC) & Bite cells (macrophage phagocytosis of heinz bodies - bite out of cell) Aut-rec galactokinase deficiency. Galactitol can accumulate if galactose present in diet; relatively mild. Galactose in blood / urine, infantile cataracts (may not track objects, develop social smile. Lysosomal storage disease (a sphingolipidosis), Aut-rec deficiency of betaglucocerebrosidase; glucocerebroside accumulates. Hepatosplenomegaly, aseptic necrosis of femur, bone crises, Gaucher's cells (macrophages that look like crumpled tissue paper) Aut-dom; disorder of blood vessels. Telangiectasia, recurrent epistaxis, skin discolorations, AVMs. Incr. in Utah Mormons

39.

Homocystinuria

32.

Fructosouria

33.

G6PD deficiency

Aut-rec, 3 forms. All interfere with conversion of methionine to cysteine cysteine becomes essential; homocysteine accumulates. Causes: 1) cystathionine synthase deficiency (Tx: dec Met, inc. Cys intake. Inc B12 / folate in diet to drive conversion of extra homocystine back to methionine). 2) Decreased affinity of cystathionine synthase for pyridoxal phosphate (enzyme still works a bit - Tx w/ lots of B6; more pyridoxal phosphate drives rxn forward). 3). Homocysteine methyltransferase deficiency. Findings (all 3): inc. homocys in urine, MR, osteoporosis, tall stature, kyphosis, lens subluxed down & in, atherosclerosis (inc stroke, MI) Lysosomal storage disease (a mucopolysaccharidosis). X-linked rec deficiency of iduronate sulfatase; heparan sulfate, dermatan sulfate accumulate. Mild Hurler's phenotype (developmental delay, gargoylism (thickened gingiva + upturned nose), airway obstruction, hepatosplenomegaly) but with aggressive behavior and no corneal clouding. "Hunters see clearly (no corneal clouding) and hit the X (XR inheritance). Aut-dom; mutation of huntingtin (chr 4, "hunting 4 food"), CAG repeats. Depression, progressive dementia, choreiform movements, caudate atrophy; manifests 20-50 y/o. Dec GABA, ACh in brain. Lysosomal storage disease (a mucopolysaccharidosis). Aut-rec deficiency of alpha-L-iduronidase; heparan sulfate, dermatan sulfate accumulate. Developmental delay, gargoylism (thickened gingiva + upturned nose), airway obstruction, corneal clouding, hepatosplenomegaly. Vs. Hunter's (X-linked rec, milder, aggressive behavior, no corneal clouding)

40.

Hunter's syndrome

34.

Galactokinase deficiency

35.

Gaucher's disease

41.

Huntington's disease

36.

Hereditary hemorrhagic telangiectasia (OslerWeber-Rendu syndrome) Hereditary nonpolyposis colorectal cancer Hereditary spherocytosis

42.

Hurler's syndrome

37.

Mutation in mismatch repair genes (mismatched nucleotides in unmethylated / newly synthesized string recognized + removed) Aut-dom, defect in spectrin or ankyrin. Hemolytic anemia, increased MCHC (mean corpuscular hemoglobin concentration). Splenectomy is curative

38.

43.

Hyperammonemia

Acquired (e.g. liver dz) or hereditary (urea cycle enzyme deficiencies). inc. NH4 depletes alpha-keotglutarate, inhibiting TCA cycle. Ammonia intox tremor, slurred speech, somnolence, vomiting, cerebral edema, blurred vision. Tx with benzoate, phenylbutyrate (lower serum ammonia levels) Type I familial dyslipidemia. Lipoprotein lipase deficiency or altered apolipoprotein C-II (LPL cofactor) = can't degrade TG circulating in chylomicrons, VLDLs. Increased chylomicrons, elevated cholesterol / TGs in blood Type IV familial dyslipidemia. Hepatic overproduction of VLDL; VLDL increased; blood TGs elevated "Bear liver"guy, arthralgias, fatigue, headaches, skin changes, sore throat, alopecia. Also teratogenic (cleft palate, cardiac abnormalities) X-linked dominant disorder (M/F offspring of affected mom can be affected; all female offspring of affected father diseased). Inc. phosphate wasting at proximal tubule; rickets-like presentation Inclusion cell disease. Can't add mannose-6-P to lysosome proteins. Enzymes secreted outside of cell instead of targeted to lysosome. Lysosomal storage disorder. Coarse facial features, clouded corneas, restricted joint movement, high plasma levels of lysosomal enzymes. Often fatal in childhood. Immobile cilia (dynein arm defect). Infertility (M/F; sperm immotile), bronchiectasis, recurrent sinusitis (not pushing out bacteria / particles). A/W situs inversus

50.

Krabbe's disease

Lysosomal storage disease (a sphingolipidosis). Aut-rec deficiency of galactocerebosidase; galactocerebroside accumulates. Peripheral neuropathy, developmental delay, optic atrophy, globoid cells (multinucleated). Protein malnutrition. Skin lesions, edema, liver malfunction (fatty change). Small child, swollen belly. Age dep or hereditary lactose intolerance (blacks / Asians); lose brush-border enzyme. Bloating, cramps, osmotic diarrhea. Avoid dairy / use lactase pills. Mitochondrial inheritance (only transmitted via mom); degeneration of retinal ganglion cells / axons; acute loss of central vision X-linked recessive, absence of HGPRT (hypoxanthine to IMP, guanine to GMP in purine salvage pathway). Can't salvage purines, so increased elimination = incr uric acid production. Retardation, self-mutilation, aggression, hyperuricemia, gout, choreoathetosis Dec alpha-ketoacid dehydrogenase activity = blocked degradation of branched amino acid (Ile, Leu, Val = I Love Vermont; maple trees w/ branches). Increased alpha-ketoacids in blood (esp Leu). Severe CNS defects, MR, death. Urine smells like maple syrup Energy malnutrition. Tissue / muscle wasting, loss of subQ fat, variable edema. Aut-dom, Fibrillin defect (scaffolding for elastin formation - stretchy protein for lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava). Connective tissue disorder: skeleton, heart, eyes affected. Tall, long extremities, pectus excavatum, hyperextensive joints, arachnodactyly (long, tapering fingers / toes). Cystic medial necrosis of aorta -> aortic incompetence, dissecting aortic aneurysms; floppy mitral valve; subluxation of lenses. Skeletal muscle glycogen phosphorylase deficiency (normally breaks down glycogen to 4-glucose residue branched "limit dextrans"). Type V glycogen storage disease. Incr. glycogen in mm, but can't break down (mm cramps, myoglobinuria with strenuous exercise). McArdle = Muscle

51.

Kwashiorkor

44.

Hyperchylomicronemia

52.

Lactase deficiency

53.

Leber's hereditary optic neuropathy Lesch-Nyhan Syndrome

45.

Hypertriglyceridemia

54.

46.

Hypervitaminosis A

55.

47.

Hypophosphatemic rickets

Maple syrup urine disease

56.

Marasmus Marfan's syndrome

48.

I-Cell disease

57.

49.

Kartagener's syndrome

58.

McArdle's disease

59.

Metachromic leukodystrophy

Lysosomal storage disease (a sphingolipidosis). Aut-rec deficiency of arylsulfatase A, cerbroside sulfate accumulates. Central / peripheral demyelination, ataxia, dementia. Aut-dom; I/II/III, familial tumors of endocrine glands (pancreas, parathyroid, pituitary, thyroid, adrenal medulla). II / III a/w ret gene Aut-dom; mutation on long arm of chr 17 (17 letters in "von recklinghausen") cafe-au-lait spots, neuronal tumors, Lisch nodules (pigmented iris hamartomas). Skeletal disorders (eg scoliosis), optic pathway gliomas, pheochromocytoma, increased tumor susceptibility. Aut-dom; mutation of NF2 gene (chr 22: "type 2 = 22"). Bilateral acoustic neuromas, juvenile cataracts. Lysosomal storage disease (a sphingolipidosis). Aut-rec deficiency of sphingomyelinase; sphingomyelin accumulates. Progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foam cells. X-linked rec; most common urea cycle disorder (others aut-rec). Can't eliminate ammonia; often dx'd perinatally but can be later. Dx: orotic acid in blood / urine (excess carbamoyl phosphate converted to orotic acid), dec. BUN, hyperammonemia sx (tremor, slurred speech, somnolence, vomiting, cerebral edema, blurred vision) per age Aut-rec; can't convert orotic acid to UMP in de novo pyrimidine synthesis pathway (defect in orotic acid PRT or orotidine 5''-P-decarboxylase. Incr. orotic acid in urine, megaloblastic anemia (that doesn't get better with B12 / folate supplements), FTT in babies. No hyperammonemia (vs OTC deficiency - incr orotic acid + hyperammonemia). Tx with oral uridine administration (bypass UMP block).

66.

Osteogenesis imperfecta

60.

Multiple endocrine neoplasias

Brittle bone disease; genetic bone disorder. Variety of gene defects. Type II fatal in utero, neonatal. Most common form: AD with abnormal type I collagen (bone): multiple fractures w/ minimal trauma (e.g. during birth), blue sclerae (translucent connective tissue over choroid), hearing loss (ossicles messed up), dental imperfections (no dentin). Trisomy 13 (P = puberty age), 1:15,000. Severe MR, rockerbottom feet, congenital heart disease. Vs. Edwards': cleft lip / Palate, holoProsencephaly, Polydactyly (P's), micropthalmia, microcephaly. Death w/in 1 yr Severe vitamin B3 (niacin) deficiency (less severe = glossitis). Diarrhea, dementia, dermatitis. Can be caused by Hartnup disease (dec. tryptophan absorption), malignant carcinoid syndrome (inc tryptophan metabolism) (B3 made from tryptophan) and INH (dec vit B6, needed for B3 synthesis). Aut-rec deficiency of phenylalanine hydroxylase / THB (cofactor), so can't convert phenylalanine to tyrosine. Results: accumulate phenylalanine (excess phenylketones in urine); tyrosine becomes essential AA. Dx: MR, growth retardation, seizures, eczema, musty body odor ("aromatic" amino acids). Tx: don't eat phenylalanine (aspartame=Nutrasweet, etc), increase tyrosine in diet. Screening: 2-3 days after birth. Maternal PKU (no proper diet therapy during pregnancy) - baby has microcephaly, MR, growth retardation, congenital heart defects. Lysosomal alpha-1,4-glucosidase (acid maltase) deficiency (type II glycogen storage disease. Lysosomal degradation of glycogen impaired (1,4 = linkages, not branches). Cardiomegaly, systemic findings (liver, muscle) leading to early death. Pompe's trashes the Pump (heart) Chr 15, normally active parental (Prader = parental) allele deleted. MR, hyperphagia, obesity, hypogonadism, hypotonia. Other parent's allele inactivated / imprinted by methylation; can also be from uniparental disomy (2 copies of chr from 1 parent). Angelman's = maternal counterpart

61.

Neurofibromatosis type I (von Recklinghausen's disease)

67.

Patau's syndrome

68.

Pellagra

62.

Neurofibromatosis type II Niemann-Pick disease

63.

69.

Phenylketonuria

64.

Ornithine transcarbamoylase (OTC) deficiency

65.

Orotic aciduria

70.

Pompe's disease

71.

Prader-Willi syndrome

72.

Pyruvate dehydrogenase deficiency

(Pyruvate + NAD+ + CoA --> acetylCoA + CO2 + NADH; 3 enzymes, requires B1,2,3, CoA, lipoic acid). Pyruvate, alanine accumulate --> lactic acidosis (pyruvate to lactate). Congenital or acquired (e.g. alcoholics, B1 deficiency - lactic acidosis!). Neuro deficits. Treat with ketogenic nutrients (high fat content or lots of keotgenic AA: lysine, leucine) body relies on ketone metabolism for energy; also cofactor supplementation Peroxisomal disease; no alpha-oxidation of branched-chain FA like phytanic acid. Neuro sx; Tx = avoid chlorophyll Lysosomal storage disease (a sphingolipidosis). Aut-rec deficiency of hexosaminidase A; GM2 ganglioside accumulates. Progressive neurodegeneration, developmental delay, cherry-red spot on macula, lysosomes with "onion skin" Aut-dom. Facial lesions (adenoma sebaceum), hypopigmented "ash-leaf spots" on skin, cortical / retinal hamartomas, seizures, MR, renal cysts, renal angiomyolipomas, cardiac rhabdomyomas. Inc. incidence astrocytomas. Incomplete penetrance w/ variable presentation A 22q11 deletion syndrome. Palate, facial, cardiac defects. Microdeletion at chr 22q11. Due to aberrant development of 3rd / 4th branchial pouches. Night blindness, dry skin Cheilosis, corneal vascularization (the 2 C's) Facial flushing (niacin "flushing" in pharm doses for hyperlipidemia treatment). Pantothenate; in CoA. Dermatitis, enteritis, alopecia, adrenal insufficiency Pyridoxine = B6. Convulsions, hyperirritability, peripheral neuropathy. Deficiency inducible by INH, oral contraceptives. Converted to pyridoxal phosphate: used in transamination (ALT, AST, etc), decarboxylation, glycogen phosphorylase, heme synthesis; needed for niacin (B3) synthesis from tryptophan

82.

Vitamin B12 deficiency

Cobalamin = B12. macrocytic, megaloblastic anemia. Neuro sx: paresthesias, subacute combined degeneration from abnormal myelin. Prolonged deficiency = irreversible nervous system damage. Found in animal products; synthesized only by microorganisms. Large reserves (several years) in liver. Deficiency from malabsorption (sprue, enteritis, diphyllobothrium latum = fish tapeworm), lack of intrinsic factor (pernicious anemia / gastric bypass surgery), absence of terminal ileum (e.g. Crohn's) Scurvy - swollen gums, bruising, anemia, poor wound healing. In fruits / vegetables. Facilitates Fe absorption: keeps Fe2+ reduced state, more absorbable. Also involved in hydroxylation of proline, lysine in collagen synthesis; antioxident; needed for dopamine B-hydroxylase (DA to NE conversion) Rickets in children (bending bones); osteomalacia in adults (soft bones). Also hypocalcemic tetany. Hypercalcemia, hypercalciuria, loss of appetite, stupor. Seen in sarcoidosis (inc. activation of vitamin D by epithelioid macrophages). Hemolytic anemia (inc fragility of erythrocytes vit E is antioxidant, protects erythrocytes / membranes from free-radical damage). Muscle weakness, neurodysfunction tooo. Bleeds (gamma-carboxylation of glutamic acid residues on factors II, VII, IX, X, protein C, S). Neonatal hemorrhage (inc PT, aPTT, normal bleeding time - sterile intestine in newborn, can't synthesize vitK - synthesized by intestinal flora give vitK injection @ birth to prevent). Also after prolonged broad-spectrum abx use. Glucose-6-phosphatase deficiency (type I glycogen storage disease). Can't de-plate G6P (glycogenolysis & gluconeogenesis). Severe fasting hypoglycemia, inc. glycogen in liver, inc. blood lactate (gluconeogenesis impaired), hepatomegaly. Aut-dom; deletion of VHL gene (tumor suppressor) on chr 3 (3 words for chr 3). Results in constitutive expression of HIF (transcription factor), activation of angiogenic growth factors. Hemangioblastomas of retina / cerebellum / medulla, 50% get multiple bilateral renal cell carcinomas, other tumors. High output cardiac failure (dilated CM), edema Microdeletion of long arm of chr 7 (incl. elastin gene). "Elfin" faces, MR but good verbal skills, cheerful disposition, extreme friendliness w/ strangers, CV problems

73.

Refsum disease

83.

74.

Tay-Sachs disease

Vitamin C (ascorbic acid) deficiency

84.

Vitamin D deficiency Vitamin D excess Vitamin E deficiency

75.

Tuberous sclerosis

85.

86.

76.

Velocardiofacial syndrome

87.

Vitamin K deficiency

77.

Vitamin A deficiency Vitamin B2 (riboflavin) deficiency Vitamin B3 excess Vitamin B5 deficiency Vitamin B6 deficiency

78.

88.

Von Gierke's disease

79.

80.

89.

81.

von HippelLindau disease

90.

Wet beriberi Williams syndrome

91.

92.

Xeroderma pigmentosum Zellweger syndrome Zinc deficiency

Mutation in nucleotide excision repair proteins (endonucleases that release oligonucleotides containing damaged bases; DNApol + ligase fill in). Can't repair thymidine dimers (UV light). Dry skin with melanoma + other cancers ("children of the night") Peroxisomal disease; can't metabolize very long chain FA (VLCFAs) or branched-chain FAs (e.g. phytanic acid, via alpha-oxidation). Can't form myelin in CNS. Hypotonia, seizures, hepatomegaly, MR, early death. Delayed wound healing, hypogonadism, dec. adult hair (axillary / facial / pubic); ?predispose to alcoholic cirrhosis?

93.

94.