genetics Flashcards
(61 cards)
1
Q
Oteogenisis inperfecta
A
gen bone dis. gene defect COLIA1 and COLIA, def collagen type1
BITE: Bones=multiple fractures I= (eye)= blue sclera Teeth=dental imperfection Ear=hearing loss
2
Q
Ehler-Danlos syndrome
A
faulty collagen synthesis causing hyperextensilble skin, cassical type (joint mobility and skin symptoms), mutation of type V collagen COL5A1, COL5A2,
vascular type:(fragile tissues including vessels eg AORTA and organ rapture type 3, procollagen eg COL3A1
3
Q
Menkes disease
A
impaired copper absorption,decreased lysyl oxidase
X-linked recessive connective tissue disease caused by impaired copper absorption and transport due to defective Menkes protein (ATP7A, vs ATP7B in Wilson disease). leads to decreased lysyl oxidase (copper is a nessary cofactor)—->defectice collagen, brittle, kinky hair, growth retardation, and hypotania
4
Q
Marfan syndrome is?
affected chromosome?
affected gene?
affected organs?
A
autosomal dominant cennective tissue disorder affecting skeleton, heart and eyes. FBN1 gene mutation on chromone 15 (fiteen) results in in defective fibrillin
5
Q
Rett syndrome
A
sporadic disorder seen almost exclusively in girls( affected males die in utero). de novo mutation of MECP2 and X-Chromosome—-loss of motor skills and speech
6
Q
Fragile X sy.
A
x-linked dominant. trinuclide repeat FMR1 gene, macroorchidism, large ears, long face, mitral valve prolapse
7
Q
trinuclide repeat expasion diseases are?
A
hutington, myotic dystrophy, fragile X, friedreich atxia
8
Q
down sy.
A
5 A’s: advanced maternal age, atrisia, ASD, alzheimer, AML/ALL
9
Q
edwars
A
Prince Edward, elction at 18, prominant occiput, rockerbottom feet, interlectual, clenched fist, ears
10
Q
patau is?
Chromosme?
organs affected?
A
you can wath a movie at 13, P’s, cleft liP/Palate, holoPracencephaly, Polydactyly, curis aPlasia, congnital (Pump) heart disease. PKD
11
Q
Which blotting procedures are there?
A
SNoW DRoP
Southwestern=DNA
Northern=RNA
Western=Protein
12
Q
what Roberson translocation are there?
A
13,14,15,21
13
Q
cri du chat
A
deletion on chromosome 5, microcephalis, intelectual, VSD
14
Q
williams
A
microdelition chrom 7 elfin face, friendly, intelectual
15
Q
prader willi
A
chrom 15, prader has no dad
16
Q
angelMan
A
UBE3A paternal derived gene silenced (imprinted) Maternal deletion, happy puppet: inappropriate laughter, seizures ataxia
17
Q
what is mosaism?
A
presence of genetical distinct cell line in the same individual, mutation arises from mitotic error and propagates through multiple organs/tissues
18
Q
locus heterogenietic
A
diff loci can produce the same phenotye, albinism
19
Q
allelic hetergenecity
A
diff mutation in the same loci produce the same phenotype
20
Q
heteroplasmy
A
presence of normal and mutated mtDNA, resulting invariable expression in mitochondrially inherited diseases
21
Q
uniparental distomy
A
offsping has 2 copies of chromosomes from 1 parent and no copies from the other parents. prader willi
22
Q
duchenne
A
x-linked disorder due to frameshift deletion or nonesense mutation
duchenne= deleted dystrophin
23
Q
ELISA
A
immulogic test used to detect the presence of an antibody. higly senstive and specific, but less specific than the western blott
24
Q
microassay
A
thousands of nucleic acds sequences are arrenge in a grid, detects the amound of complimentary binding, able to detect sigle nucleutide plymorhisms SNP’S and copy number varans (CNV’S). Application: genotyping, clinical genetic testing, foreign analysis, cancer mutations, and genetic linkage analysis
25
PCR
amplify DNA fragment.
denaturation: separate by heating 95°
annealing: add DNA primer 55°
elongation: compine primer with the DNA (polimerase) 72°
heat again and cooling cycles until enough DNA samle.
used neonate HIV, herpes encephalitis
26
reverse trascriptase pcr
PCR using reverse transcriptase
27
what are blots used for?
to find a particular sequence: of either DNA---RNA---Protein
28
what is the southwestern blot?
this is protein binding to DNA eg tracription factors
29
what is flow cytometry?
Laboratory technique to asses size, granularity and protein expression of cells, CD8, CD4
30
Vitamin A
Use all-trans retinoic acid to treat acute promyelocytic leukemia.
Isotretinoin is teratogenic
31
Vitamin B1
Also called thiamine.
FUNCTIONIn thiamine pyrophosphate (TPP), a cofactor for several dehydrogenase enzyme reactions (Be APT):
Branched-chain ketoacid dehydrogenase
α-Ketoglutarate dehydrogenase ( TCA cycle)
Pyruvate dehydrogenase (links glycolysis to TCA cycle)
Transketolase (HMP shunt)
DEFICIENCY
Impaired glucose breakdown----> ATP depletion worsened by glucose infusion; highly aerobic tissues (eg, brain, heart) are affected first.
In patients with chronic alcohol overuse or malnutrition, give thiamine before dextrose to risk of precipitating Wernicke encephalopathy.
Diagnosis made by increase in RBC transketolase activity following vitamin B1 administration.
Ber1Ber1
32
Vitamin B2
Also called riboFlavin.
FUNCTION
Component of flavins FAD and FMN, used as cofactors in redox reactions, eg, the succinate dehydrogenase reaction in the TCA cycle.
FAD and FMN are derived from riboFlavin
(B2≈2 ATP).
DEFICIENCY
Cheilosis (inflammation of lips, scaling and fissures at the corners of the mouth), “magenta” tongue, corneal vascularization.
The 2 C’s of B2
33
Vitamin B3
Also called niacin, nicotinic acid.
FUNCTIONConstituent of NAD+, NADP+ (used in redox reactions and as cofactor by dehydrogenases). Derived from tryptophan. Synthesis requires vitamins B2 and B6. Used to treat dyslipidemia ( decreases VLDL, increases HDL).
NAD derived from Niacin (B3≈3 ATP).
DEFICIENCY
Glossitis. Severe deficiency of B3 leads to pellagra, which can also be caused by
Hartnup disease, malignant carcinoid syndrome ( tryptophan metabolism serotonin synthesis), andisoniazid ( vitamin B6).
Symptoms of B3 deficiency (pellagra) (the 3 D’s):
Diarrhea, Dementia (also hallucinations), Dermatitis (C3/C4 dermatome circumferential “broad collar” rash [Casal necklace], hyperpigmentation of sun-exposed limbs A).
Hartnup disease—autosomal recessive. Deficiency of neutral amino acid (eg, tryptophan) transporters in proximal renal tubular cells and on enterocytes ----> neutral aminoaciduria and absorption from the gut ---->tryptophan for conversion to niacin----> pellagra-like symptoms. Treat with high-protein diet and nicotinic acid.
Deficiency of vitamin B3--->pellagra. Less B3.
34
Vitamin B5
Also called pantothenic acid. B5is “pento”thenic acid.
FUNCTION
Component of coenzyme A (CoA, a cofactor for acyl transfers) and fatty acid synthase.
DEFICIENCY
Dermatitis, enteritis, alopecia, adrenal insufficiency may lead to burning sensation of feet (“burning feet syndrome”; distal paresthesias, dysesthesia).
35
Vitamin B6
Also called pyridoxine.
FUNCTION
Converted to pyridoxal phosphate (PLP), a cofactor used in transamination (eg, ALT and AST), decarboxylation reactions, glycogen phosphorylase. Synthesis of glutathione, cystathionine, heme, niacin, histamine, and neurotransmitters including serotonin, epinephrine, norepinephrine (NE), dopamine, and GABA.
DEFICIENCY
Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and oral contraceptives), sideroblastic anemia (due to impaired hemoglobin synthesis and iron excess).
36
Vitamin B7
Also called biotin.
FUNCTION
Cofactor for carboxylation enzymes (which add a 1-carbon group):
Pyruvate carboxylase (gluconeogenesis): pyruvate (3C)---->oxaloacetate (4C)
Acetyl-CoA carboxylase (fatty acid synthesis): acetyl-CoA (2C) ------>malonyl-CoA (3C)
Propionyl-CoA carboxylase (fatty acid oxidation): propionyl-CoA (3C) methylmalonyl-CoA (4C)
DEFICIENCY
Relatively rare. Dermatitis, enteritis, alopecia. Caused by long-term antibiotic use or excessive ingestion of raw egg whites.“Avidin in egg whites avidly binds biotin.”
37
Vitamin B9
Also called folate.
FUNCTION
Converted to tetrahydrofolic acid (THF), a coenzyme for 1-carbon transfer/methylation reactions.Important for the synthesis of nitrogenous bases in DNA and RNA.Found in leafy green vegetables. Also produced by gut flora. Absorbed in jejunum. Folate from foliage.Small reserve pool stored primarily in the liver.
DEFICIENCY
Macrocytic, megaloblastic anemia; hypersegmented polymorphonuclear cells (PMNs); glossitis; no neurologic symptoms (as opposed to vitamin B12 deficiency).Labs: homocysteine, normal methylmalonic acid levels. Seen in chronic alcohol overuse and in pregnancy
Deficiency can be caused by several drugs (eg, phenytoin, sulfonamides, methotrexate).
Supplemental folic acid at least 1 month prior to conception and during early pregnancy to risk of neural tube defects. Give vitamin B9 for the 9months of pregnancy.
38
Vitamin B12
Also called cobalamin.
FUNCTION
Cofactor for methionine synthase (transfers CH3 groups as methylcobalamin) and methylmalonyl-CoA mutase. Important for DNA synthesis.Found in animal products.Synthesized only by microorganisms. Very large reserve pool (several years) stored primarily in the liver. Deficiency caused by malabsorption (eg , sprue, enteritis, Diphyllobothrium latum,achlorhydria, bacterial overgrowth, alcohol overuse), lack of intrinsic factor (eg, pernicious anemia, gastric bypass surgery), absence of terminal ileum (surgical resection, eg, for Crohn disease), certain drugs (eg, metformin), or insufficient intake (eg, veganism).
B9 supplementation can mask the hematologic symptoms of B12 deficiency, but not the neurologic symptoms.
DEFICIENCY
Macrocytic, megaloblastic anemia; hypersegmented PMNs; paresthesiasand subacute combined degeneration (degeneration of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts) due to abnormal myelin. Associated with serum homocysteine and methylmalonic acid levels, along with 2° folate deficiency. Prolonged deficiency irreversible nerve damage.
39
Vitamin C
Also called ascorbic acid.
FUNCTION
Antioxidant; also facilitates iron absorption by reducing it to Fe2+ state. Necessary for hydroxylation of proline and lysine in collagen synthesis. Necessary for dopamine β-hydroxylase (converts dopamine to NE).
Found in fruits and vegetables.Pronounce “absorbic” acid.Ancillary treatment for methemoglobinemia by reducing Fe3+ to Fe2+.
DEFICIENCY
Scurvy—swollen gums, easy bruising, petechiae, hemarthrosis, anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, “corkscrew” hair. Weakened immune response.
Deficiency may be precipitated by tea and toast diet.Vitamin C deficiency causes sCurvy due to a Collagen hydroCylation defect.
40
Vitamin D
D3 (cholecalciferol) from exposure of skin (stratum basale) to sun, ingestion of fish, milk, plants.D2 (ergocalciferol) from ingestion of plants, fungi, yeasts.Both converted to 25-OH D3 (storage form) in liver and to the active form 1,25-(OH)2 D3 (calcitriol) in kidney.
FUNCTION
↑intestinal absorption of Ca2+ and PO43–.
↑bone mineralization at low levels.
↑bone resorption at higher levels.
REGUlATION
↑PTH, decreased Ca2+, decreased PO43–> increasing 1,25-(OH)2D3 production.
1,25-(OH)2 D3 feedback inhibits its own production.
↑PTH, increases---->Ca2+ reabsorption and decreases PO43– reabsorption in the kidney.
DEFICIENCY
Rickets in children (deformity, such as genu varum “bowlegs” A), osteomalacia in adults (bone pain and muscle weakness), hypocalcemic tetany. Caused by malabsorption, decreased sun exposure, poor diet, chronic kidney disease (CKD), advanced liver disease. Give oral vitamin D to breastfed infants. Darker skin and prematurity predispose to deficiency.
EXCESS
Hypercalcemia, hypercalciuria, loss of appetite, stupor. Seen in granulomatous diseases ( activation of vitamin D by epithelioid macrophages).
41
Vitamin E
Includes tocopherol, tocotrienol.
FUNCTION
Antioxidant (protects RBCs and membranes from free radical damage).
DEFICIENCY
Hemolytic anemia, acanthocytosis, muscle weakness, demyelination of posterior columns ( proprioception and vibration sensation) and spinocerebellar tract (ataxia).Neurologic presentation may appear similar to vitamin B12 deficiency, but without megaloblastic anemia, hypersegmented neutrophils, or serum methylmalonic acid levels.
EXCESS
Risk of enterocolitis in infants.High-dose supplementation may alter metabolism of vitamin K--->enhanced anticoagulant effects of warfarin.
Includes tocopherol, tocotrienol.FUNCTIONAntioxidant (protects RBCs and membranes from free radical damage).
DEFICIENCY
Hemolytic anemia, acanthocytosis, muscle weakness, demyelination of posterior columns ( proprioception and vibration sensation) and spinocerebellar tract (ataxia).Neurologic presentation may appear similar to vitamin B12 deficiency, but without megaloblastic anemia, hypersegmented neutrophils, or serum methylmalonic acid levels.
EXCESSRisk of enterocolitis in infants.High-dose supplementation may alter metabolism of vitamin K enhanced anticoagulant effects of warfarin.
42
Vitamin K
Includes phytomenadione, phylloquinone, phytonadione, menaquinone.
FUNCTION
Activated by epoxide reductase to the reduced form, which is a cofactor for the γ-carboxylation of glutamic acid residues on various proteins required for blood clotting. Synthesized by intestinal flora. K is for Koagulation. Necessary for the maturation of clotting factors II, VII, IX, X, and proteins C and S. Warfarin inhibits vitamin K–dependent synthesis of these factors and proteins.
DEFICIENCY
Neonatal hemorrhage with
PT and aPTT but normal bleeding time (neonates have sterile intestines and are unable to synthesize vitamin K). Can also occur after prolonged use of broad-spectrum antibiotics.
43
Zinc
FUNCTION
Mineral essential for the activity of 100+ enzymes. Important in the formation of zinc fingers (transcription factor motif).
DEFICIENCY
Delayed wound healing, suppressed immunity, male hypogonadism, adult hair (axillary, facial, pubic), dysgeusia, anosmia. Associated with acrodermatitis enteropathica (A, defect in intestinal zinc absorption). May predispose to alcoholic cirrhosis.
44
Protein-energy malnutrition
Kwashiorkor
Protein malnutrition resulting in skin lesions, edema due to plasma oncotic pressure (due to low serum albumin), liver malfunction (fatty change due to apolipoprotein synthesis and deposition). Clinical picture is small child with swollen abdomen A.
Kwashiorkor results from protein-deficient MEALS:
Malnutrition
Edema
Anemia
Liver (fatty)
Skin lesions (eg, hyperkeratosis, dyspigmentation)
Marasmus
Malnutrition not causing edema. Diet is deficient in calories but no nutrients are entirely absent.
Marasmus results in muscle wasting
45
Phenylketonuria
Caused by phenylalanine hydroxylase or tetrahydrobiopterin (BH4) cofactor (malignant PKU). Tyrosine becomes essential.
increase phenylalanine-----> increased phenylketones in urine.
Findings: intellectual disability, microcephaly, seizures, hypopigmented skin, eczema, musty body odor. Treatment: phenylalanine and tyrosine in diet, tetrahydrobiopterin supplementation
46
Maple syrup urine disease
Blocked degradation of branched amino acids (Isoleucine, leucine, valine) due to branched-chain α-ketoacid dehydrogenase (B1). Causes increased α-ketoacids in the blood, especially those of leucine.
Treatment: restriction of isoleucine, leucine, valine in diet, and thiamine supplementation.
47
Alkaptonuria
homogentisate oxidase
Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate--->pigment-forming homogentisic acid builds up in tissue. Autosomal recessive. Usually benign.Findings: bluish-black connective tissue, ear cartilage, and sclerae (ochronosis); urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage).
48
Homocystinuria
Causes (all autosomal recessive):
Cystathionine synthase deficiency (treatment: decrease methionine, increase cysteine, increased B6, B12, and folate in diet)
decreased affinity of cystathionine synthase for pyridoxal phosphate (treatment: increase B6 and increase cysteine in diet)
Methionine synthase (homocysteine methyltransferase) deficiency (treatment: increases methionine in diet)
Methylenetetrahydrofolate reductase (MTHFR) deficiency (treatment: increases folate in diet)All forms result in excess homocysteine.
HOMOCYstinuria:
increased Homocysteine in urine, Osteoporosis, Marfanoid habitus, Ocular changes (downward and inward lens subluxation), Cardiovascular effects (thrombosis and atherosclerosis--->stroke and MI), kYphosis, intellectual disability, hypopigmented skin. In homocystinuria, lens subluxes “down and in” (vs Marfan, “up and fans out”)
49
Cystinuria
Hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cystine, Ornithine, Lysine, and Arginine (COLA).
Cystine is made of 2 cysteines connected by a disulfide bond.
Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones A.
Treatment: urinary alkalinization (eg, potassium citrate, acetazolamide) and chelating agents (eg, penicillamine) solubility of cystine stones; good hydration; diet low in methionine.
Autosomal recessive. Common (1:7000). Cystinuria detected with urinary sodium-cyanide nitroprusside test and proton nuclear magnetic resonance spectroscopy of urine.
50
Propionic acidemia
Methylmalonic acidemia
Propionic acidemia
Deficiency of propionyl-CoA carboxylase-----> propionyl-CoA, methylmalonic acid.
Methylmalonic acidemia
Deficiency of methylmalonyl-CoA mutase or vitamin B12.
Treatment: low-protein diet limited in substances that metabolize into propionyl- CoA: Valine, Odd-chain fatty acids, Methionine, Isoleucine, Threonine (VOMIT).
51
Von Gierke disease(type I
Glucose-6-phosphatase
Severe fasting hypoglycemia, increased Glycogen in liver and kidneys, increased blood lactate, increased triglycerides, increased uric acid (Gout), and hepatomegaly, renomegaly. Liver does not regulate blood glucose
52
Pompe disease (type II)
Lysosomal acid α-1,4-glucosidase (acid maltase) with α-1,6-glucosidase activity.
Pompe disease (type II) Cardiomyopathy, hypotonia, exercise intolerance, and systemic findings lead to early death.
Pompe trashes the pump (1st and 4th letter; heart, liver, and muscle).
53
Cori disease (type III)
Debranching enzymes (α-1,6-glucosidase and 4-α-d -glucanotransferase.
Similar to von Gierke disease, but milder symptoms and normal blood lactate levels. Can lead to cardiomyopathy. Limit dextrin–like structures accumulate in cytosol.
54
Andersen disease (type IV)
Branching enzyme. Neuromuscular form can present at any age
Most commonly presents with hepatosplenomegaly and failure to thrive in early infancy.Other findings include infantile cirrhosis, muscular weakness, hypotonia, cardiomyopathy early childhood death.
55
McArdle disease (type V)
Skeletal muscle glycogen phosphorylase (myophosphorylase).
Characterized by a flat venous lactate curve with normal rise in ammonia levels during exercise.
increases glycogen in muscle, but muscle cannot break it down---->painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities. Second-wind phenomenon noted during exercise due to muscular blood flow.
Blood glucose levels typically unaffected.
McArdle =muscle.
56
Tay-Sachs disease
| Sphingolipidoses
Hexosaminidase A (“TAy-Sax”).
GM2 ganglioside.
AR
Progressive neurodegeneration, developmental delay, hyperreflexia, hyperacusis, “cherry-red” spot on maculaA (lipid accumulation in ganglion cell layer), lysosomes with onion skin, no hepatosplenomegaly (vs Niemann-Pick).
57
Fabry disease
| Sphingolipidoses
α-galactosidase A.
Ceramide trihexoside (globotriaosylce-ramide).
XR
Early: triad of episodic peripheral neuropathy, angiokeratomasB, hypohidrosis.Late: progressive renal failure, cardiovascular disease.
58
Gaucher disease
Sphingolipidoses
Glucocerebrosidase (β-glucosidase);
treat with recombinant glucocerebrosidase.
Glucocerebroside.
AR
Most common.
Hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of femur, bone crises, Gaucher cellsC(lipid-laden macrophages resembling crumpled tissue paper).
59
Niemann-Pick disease
Sphingolipidoses
Sphingomyelinase.
Sphingomyelin.
AR
Progressive neurodegeneration, hepatosplenomegaly, foam cells (lipid-laden macrophages) D, “cherry-red” spot on macula A.
60
Mucopolysaccharidoses
Hurler syndrome
α-l-iduronidase.
Heparan sulfate, dermatan sulfate.AR
Developmental delay, skeletal abnormalities, airway obstruction, corneal clouding, hepatosplenomegaly.
61
Mucopolysaccharidoses
Hunter syndrome
Iduronate-2 (two) -sulfatase.
Heparan sulfate, dermatan sulfate.
XR
Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive)
Mild Hurler + aggressive behavior, no corneal clouding.
