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50 Cards in this Set

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Mendelian disorders
-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
Some autosomal mutations are?
partial expression in heterozygote and full expression in homozygote
Single gene mutations typically follow 3 patterns of inheritance:
1. Auto Dominant
2. Auto Recessive
3. X-linked
Pleotropism
single mutant gene causing many end effects
Genetic heterogeneity
mutations at several genetic loci producing the same effect
What 2 variations occur in autosomal dominant disorders?
1. Frequency w/ which the abnormal gene produces disease (penetrance)
2. the degree of abnormality seen in different individuals (expressitivity)
What are some examples of common X-linked disorders?
-Hemophilia A, Christmas dx, G6PD deficiency, Duchenne muscular dystrophy, Red-green color blindness
Marfan Syndrome
-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
Clinical features of Marfan syndrome
1. Skeletal abnormalities--> elongated habitus, long extremities, arachnytactyl, kyphoscoliosis, pectus excavatum, pigeon breasted deformity
2. Eye changes: bilat dislocation of lens***, retinal detachment
Cardiovascular Abnormalities of Marfan syndrome
-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
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
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
Heterozygotes vs. Homozygotes in FH
Heterozygotes--> cholesterol deposits in tendon sheaths, premature athero-->CAD
Homozygotes--> Xanthomas in childhood--> freq die of MI by 20
What are 4 diseases that are caused by mutations in enzyme proteins?
1. Phenylketonuria
2. Galactosemia
3. Lysosomal storage diseases
4. Glycogen storage diseases
Phenylketonuria (PKU)
-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
Clinical manifestations of PKU
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)
Galactosemia
-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
Clinical manifestations of Galactosemia
-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
What are 3 Lysosomal Storage Diseases?
-cause: inherited lack of functional lysosomal enzymes
1. Tay-Sach Disease
2. Gaucher Disease
3. Niemann-Pick disease
Tay-Sach Disease
-Enzyme Defect: Hexosaminidase
-Tissue: brain, retina
-Accumulation of GM2-ganglioside
*Blindness, Cherry-red spot in retina, death by 2-3 years
Gaucher Disease
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
Niemann-Pick disease
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
Mucopolysaccharidoses
-progressive disorders charcterized by involvement of multiple organs
-associated w/ coarse facial features, clouding of cornea, joint stiffness, hepatosplenomegaly, narrowwing of coronary arteries
Hurler syndrome
-Enz defect: L-Induronidase
-Tissue: skin, cornea, bone, heart, brain, liver, spleen
-auto recessive
-Accum: heparan and dermatan sulfate
-6-10 yrs
Hunter syndrome
-Enz defect: L-Iduronsulfate sulfatase
-Tissue: skin, bone, heart, brain
-X-linked
-Accum: heparan and dermatan
sulfate
-second decade to normal
Glycogenoses (Glycogen Storage Disorders)
deficiency of an enz--> defects in synth or catabolism of glycogen--> accum of glycogen in cytoplasm--> cells pale and distended--> dysfunct of affected cells
What are 3 examples of Glycogen Storage disorders?
1. von Gierke disease
2. Mc Ardle Syndrome
3. Pompe disease
Von Gierke disease
-Enz defect: gluc-6-phosphatase
-Tissue: liver, kidney
-Accum of glycogen--> enlarged liver or kidney
-hypoglycemia, bleeding, 50% mort
McArdle Syndrome
-Enz defect: muscle phosphorylase
-Tissue: skeletal muscle--> muscle craps after exercise
Pompe disease
-Enz defect--> glucosidase
-Heart most affected--> cardiomegaly--> cardiac failure by age 2
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
Neurofibromatosis 2
(Acoustic neurofibromatosis)
-rare
-**bilat acoustic neurofibromatosis
-many pt have peripheral neurofibromas and cafe au lait spots
-chromosome 22
Characteristics of diseases w/ multifactorial (polygenic) inheritance
-combo action of several genes at different foci
-height, body weight, hair color, BP
-1st degree relatives have 5-10% risk of developing disease
Examples of diseases w/ multifactorial (polygenic) inheritance
-diabetes mellitus, hypertension, CHD, gout, schizophrerenia, manic depression
Cytogenetic diorders
-karyotyping of metaphase spread, G-banding technique--> basic tools of cytogeneticist
-result from alterations in number or structure of chromosomes
Aneuploid
-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)
Monosomy involving an autosome =
incompatible w/ life
Trisomy of certain autosomes and monosomy involving sex chromosomes =
compatible w/ life
Mosaicism
presence of 2 or more populations of karyotypically distinct cell lines in the same individual (usually due to postzygotic mitotic nondisjunction)
Unbalanced translocation
-small fragments are lost (eg Robetsonian t)--> abnormal gametes and zygotes--> abnormal offspring
Isochromosomes
horizontal division at centromere--> 2 new chromosomes
What are 3 major causes of chromosomal disorders?
1. Increasing maternal age
2. Ionizing radiation- there is no "safe" low dose
3. Drugs (anticancer, thalidomide)
What are a few uncommon autosomal disorders?
Trisomies 18 and 13
-Deletion (Cri du chat = del 5p)
Down syndrome

Trisomy 21
-most common chromo disorder
-most common cause is meitotic nondisjunction (parents have normal karyotype)
-~95% (47XX+21 or 47XY+21)
Some statistics of Down Syndrome
-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)
Clinical features of Down Syndrome
-infant has upward slanting eyes and prominent epicanthal folds, mental retardation, congenital malformations especially heart defects (Ventricular Septal Def- VSD==> responsible for most deaths)
Klinefelter Syndrome
-male hypogonadism--> most pt w/ 47 XXY, ~15% show mosaic pattern (46XY/47XXY; 47XXY/48XXXY)
Clinical manifestations of Klinefelter Syndrome
smal testes, testicular atrophy w/ impaired spermatogenesis--> infertility
-mild mental retardation, reduced facial/body hair, low test, elevated urinary gonadotropin levels
Turner syndrome
Female hypogonadism--> ~55% absences of one X chromo, ~45% mosaics, some cells 45X and others 46XX
-diagnosis: estab by karotyping
Clinical manifestations of Turner Syndrome
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