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50 Cards in this Set
- Front
- Back
Mendelian disorders
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-single gene mutations of large effect
-every individual is a carrier of 5-8 deleterious genes -85% of mutations are familial -some autosomal mutations -single gene mutations |
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Some autosomal mutations are?
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partial expression in heterozygote and full expression in homozygote
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Single gene mutations typically follow 3 patterns of inheritance:
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1. Auto Dominant
2. Auto Recessive 3. X-linked |
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Pleotropism
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single mutant gene causing many end effects
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Genetic heterogeneity
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mutations at several genetic loci producing the same effect
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What 2 variations occur in autosomal dominant disorders?
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1. Frequency w/ which the abnormal gene produces disease (penetrance)
2. the degree of abnormality seen in different individuals (expressitivity) |
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What are some examples of common X-linked disorders?
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-Hemophilia A, Christmas dx, G6PD deficiency, Duchenne muscular dystrophy, Red-green color blindness
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Marfan Syndrome
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-autosomal dominant disorder of CT
-defects in fibrillin--> a glycoprotein component of microfibrillar fibers which serve as scaffolding for deposition of elastin ***Chromosome 15 q21.1 |
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Clinical features of Marfan syndrome
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1. Skeletal abnormalities--> elongated habitus, long extremities, arachnytactyl, kyphoscoliosis, pectus excavatum, pigeon breasted deformity
2. Eye changes: bilat dislocation of lens***, retinal detachment |
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Cardiovascular Abnormalities of Marfan syndrome
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-most serious, frag of elasti fibers in tunica media of aorta--> dissecting aneurysm--> aortic rupture
-mitral and tricusp valves--> floppy valve syndrome -avg age of death 30-40 due to rupture of dissecting AA |
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Ehlers-Danlos Syndrome
Mutation in Structural proteins |
-defect of collagen synthesis, 10 subtypes--> majority auto dom
-hypermobile jts -hyperextensible and fragile skin -weakness of BV walls--> may lead to hemorrhage |
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Familial Hypercholesterolemia (FH)
Mutations in receptor/transport proteins |
-one of most common auto dom
-LDL receptor on cell surface is def --> overprod and maldistribution and accum of cholesterol in plasma |
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Heterozygotes vs. Homozygotes in FH
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Heterozygotes--> cholesterol deposits in tendon sheaths, premature athero-->CAD
Homozygotes--> Xanthomas in childhood--> freq die of MI by 20 |
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What are 4 diseases that are caused by mutations in enzyme proteins?
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1. Phenylketonuria
2. Galactosemia 3. Lysosomal storage diseases 4. Glycogen storage diseases |
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Phenylketonuria (PKU)
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-one of most com inborn errors of metabolism
-characterized by def/abs of hepatic enzyme phenyalaine hydroxylase (PAH)--> failure of conversion of dietary phenylalanine to tyrosine |
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Clinical manifestations of PKU
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mental retardation, uncoord movements, seizures, eczematous rashes, pale skin and hair (reduced melanin prod)
-early diagnosis is essential -abnormalities excreted in sweat and urine impart a strong mouselike odor (musty odor) |
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Galactosemia
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-def of galactose-1-phosphate uridyltransferase--> reduced conversion of galctose to glucose--> accum of galactose and its metbolites in liver--> increased blood galactose and galactosuria
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Clinical manifestations of Galactosemia
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-infants w/ disorder who are fed w/ milk rapidly develop hepatosplenomegaly, jaundice, and hypoglycemia
-cataracts and mental retardation -liver-->ext fat accum, bile duct prolif--> cirrhosis |
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What are 3 Lysosomal Storage Diseases?
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-cause: inherited lack of functional lysosomal enzymes
1. Tay-Sach Disease 2. Gaucher Disease 3. Niemann-Pick disease |
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Tay-Sach Disease
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-Enzyme Defect: Hexosaminidase
-Tissue: brain, retina -Accumulation of GM2-ganglioside *Blindness, Cherry-red spot in retina, death by 2-3 years |
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Gaucher Disease
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Enzy Defect: Glucocerebrosidase
Tissue: brain, ret, liv, spleen, BM Accum: cerebroside in RE cells--> large vacuolated cells Type 1: adults, brain not involved Typ 2: infnts: hepatosplenomeg; CNS--> mental deterioration, convulsions, young death |
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Niemann-Pick disease
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Enz defect: sphingomyelinase
Tissue: brain, liv, spleen, BM, lymph Accum: sphingomyelin in phagocytic cells and neurons -hepatosplenomeg, infilt of BM, death by 5, cherry red spot in ret |
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Mucopolysaccharidoses
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-progressive disorders charcterized by involvement of multiple organs
-associated w/ coarse facial features, clouding of cornea, joint stiffness, hepatosplenomegaly, narrowwing of coronary arteries |
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Hurler syndrome
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-Enz defect: L-Induronidase
-Tissue: skin, cornea, bone, heart, brain, liver, spleen -auto recessive -Accum: heparan and dermatan sulfate -6-10 yrs |
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Hunter syndrome
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-Enz defect: L-Iduronsulfate sulfatase
-Tissue: skin, bone, heart, brain -X-linked -Accum: heparan and dermatan sulfate -second decade to normal |
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Glycogenoses (Glycogen Storage Disorders)
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deficiency of an enz--> defects in synth or catabolism of glycogen--> accum of glycogen in cytoplasm--> cells pale and distended--> dysfunct of affected cells
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What are 3 examples of Glycogen Storage disorders?
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1. von Gierke disease
2. Mc Ardle Syndrome 3. Pompe disease |
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Von Gierke disease
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-Enz defect: gluc-6-phosphatase
-Tissue: liver, kidney -Accum of glycogen--> enlarged liver or kidney -hypoglycemia, bleeding, 50% mort |
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McArdle Syndrome
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-Enz defect: muscle phosphorylase
-Tissue: skeletal muscle--> muscle craps after exercise |
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Pompe disease
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-Enz defect--> glucosidase
-Heart most affected--> cardiomegaly--> cardiac failure by age 2 |
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Neurofibromatosis Type 1
(von Recklinghausen disease) |
-about 90%
3 features: multiple neurofibromas, pig skin lesions (Cafe au lait spots), pig iris hamartomas (Lisch nodules) -*most serious comp--> transformation of neurofibroma into malignant tumor -Affected gene chromo 17 |
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Neurofibromatosis 2
(Acoustic neurofibromatosis) |
-rare
-**bilat acoustic neurofibromatosis -many pt have peripheral neurofibromas and cafe au lait spots -chromosome 22 |
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Characteristics of diseases w/ multifactorial (polygenic) inheritance
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-combo action of several genes at different foci
-height, body weight, hair color, BP -1st degree relatives have 5-10% risk of developing disease |
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Examples of diseases w/ multifactorial (polygenic) inheritance
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-diabetes mellitus, hypertension, CHD, gout, schizophrerenia, manic depression
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Cytogenetic diorders
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-karyotyping of metaphase spread, G-banding technique--> basic tools of cytogeneticist
-result from alterations in number or structure of chromosomes |
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Aneuploid
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-any number of chromosomes that is noneuploid (not an exact multiple of n) --> Trisomy or monosomy
-main cause of aneuploidy is nondisjunction (failure of chromosomes to separate) |
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Monosomy involving an autosome =
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incompatible w/ life
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Trisomy of certain autosomes and monosomy involving sex chromosomes =
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compatible w/ life
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Mosaicism
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presence of 2 or more populations of karyotypically distinct cell lines in the same individual (usually due to postzygotic mitotic nondisjunction)
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Unbalanced translocation
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-small fragments are lost (eg Robetsonian t)--> abnormal gametes and zygotes--> abnormal offspring
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Isochromosomes
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horizontal division at centromere--> 2 new chromosomes
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What are 3 major causes of chromosomal disorders?
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1. Increasing maternal age
2. Ionizing radiation- there is no "safe" low dose 3. Drugs (anticancer, thalidomide) |
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What are a few uncommon autosomal disorders?
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Trisomies 18 and 13
-Deletion (Cri du chat = del 5p) |
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Down syndrome
Trisomy 21 |
-most common chromo disorder
-most common cause is meitotic nondisjunction (parents have normal karyotype) -~95% (47XX+21 or 47XY+21) |
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Some statistics of Down Syndrome
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-1 in 1550 live births in women <20
-1 in 25 for mothers > 45 ~4% due to Robertsonain translocation (14;21) ~1-2% mosaics (milder manifests) |
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Clinical features of Down Syndrome
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-infant has upward slanting eyes and prominent epicanthal folds, mental retardation, congenital malformations especially heart defects (Ventricular Septal Def- VSD==> responsible for most deaths)
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Klinefelter Syndrome
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-male hypogonadism--> most pt w/ 47 XXY, ~15% show mosaic pattern (46XY/47XXY; 47XXY/48XXXY)
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Clinical manifestations of Klinefelter Syndrome
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smal testes, testicular atrophy w/ impaired spermatogenesis--> infertility
-mild mental retardation, reduced facial/body hair, low test, elevated urinary gonadotropin levels |
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Turner syndrome
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Female hypogonadism--> ~55% absences of one X chromo, ~45% mosaics, some cells 45X and others 46XX
-diagnosis: estab by karotyping |
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Clinical manifestations of Turner Syndrome
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short stature, webbing of neck, broad chest w/ widely spaced nips, lymphedema, congen malform such as coarctation of aorta, horseshoe kidneys
-primary amenorrhea, rud ovaries presenting as fribrous streaks, high pit gonadotrophin |