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MOD - 2 - Cells: Adaptation, Injury, and Death > Lecture - Ch. 5 - Genetics > Flashcards

Lecture - Ch. 5 - Genetics Flashcards

1
Q

there are 3 categories of human genetic disorders, what are they?

A

1) mutation in a single gene with large effects (aka mendelian disorders)
2) chromosomal DOs: structural or numerical alterations in autosomes and sex chromosomes
3) complex multigenic DOs (aka polymorphisms)

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2
Q

describe mendelian/ single gene mutations and give an example

A
  • rare, high penetrance
  • sickle cell anemia: strong selective forces maintain it in the population
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3
Q

describe chromosomals DOs

A

uncommon, high penetrance

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4
Q

what are examples of complex multigenic/ polymorphic DOs

A

atherosclerosis, diabetes, hypertension, autoimmune dzs, height and weight

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5
Q

what are mutations?

A

permanent changes in the DNA

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6
Q

what type of mutations give rise to inherited dzs?

A

germ cell mutations

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7
Q

what type of mutations give rise to cancer and congenital malformations?

A

somatic cell mutations

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8
Q

what is a missense mutation? give an example

A

alter meaning of sequence of protein encoded

eg: sickle cell: glutamic acid to valine in beta-globin chain of Hb

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9
Q

what is a nonsense mutation?

give example

A

stop codon

  • if it occurs in beta-globin chain = beta-not-thalassemia
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10
Q

what are transcription factors to be aware of when it comes to mutations in noncoding regions

A

MYC, JUN, p53

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11
Q

what happens if you get deletions or insertions of 3 base pairs?

A

reading frame is intact, you just get an abnormal protein

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12
Q

what is a trinucleotide-repeat?

A

amplilification of a sequence of 3 nucleotides;

almost all contain G and C

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13
Q

what is anticipation and what are some examples?

A

as genetic disorders are passed down to the next gen, the symptoms appear earlier and worsen in severity

eg: Huntingtons Disease, and myotonic dystrophy

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14
Q

what type of alterations occur in Cystic fibrosis? ABO blood type? and Tay sachs?

A

CF: 3 base deletion

ABO: single base deletion (frameshift)

Tay Sachs: 4 base insertion (frameshift)

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15
Q

what are Autosomal Dominant disorders to be aware of here?

A

nervous stystem: HD, neurofibromatosis, myotonic dystrophy

MSK: Marfan, EDS, and Osteogenesis imperfecta

Metabolic: Familial hypercholesteremia

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16
Q

how are AD DOs manifested?

A

in heterozygous state

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17
Q

where do new AD mutations come from?

A

seem to occur in germ cells of relatively older fathers

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18
Q

what is familial hypercholesterolemia an example of?

A

loss-of-function mutation

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19
Q

what is HD an example of?

A

gain of fx mutation

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20
Q

what are the 2 main patters of diseases that are AD? what patterns would tell you its an AD disorder?

A

1) affects regulation of complex metabolic pathways, subject to feedback inhibition
2) key structural proteins: collagen cytoskeleton etc

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21
Q

what is an example of an AD disease with a pattern of affected regulation of metabolic pathways?

A

Fam. Hypercholest.

  • LDL receptor concentration decreases by 50% -> secondarily incr. cholesterol -> atherosclerosis in affected heterozygots
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22
Q

what is an example of a key structural protein affected by AD?

A

osteogenesis imperfecta

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23
Q

in regards to onset, what gives it away that its an AD?

A

age of onset is delayed In many conditions; sx appear in adulthood

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24
Q

whats is the chance of an affected parents with an AD would pass it on?

A

50/50

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25
Q

Almost all inborn errors of metabolism are what?

A

AR

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26
Q

what are some examples of AR DOs?

A

CF; PKU

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27
Q

What if two parents who are carriers of AR disease have kids? whats their chance of passing it on?

A

1/4

50/50: carrier

1/4 unaffected

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28
Q

what are the 3 features of AR DOs?

A

1) parent is usually not affected
2) singlings have 1/4 chance of having the trait
3) if mutation is low frequency in general populations, consanguineous marriage increases the chances above 1/4

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29
Q

how do you differentiate AR from AD?

A
  • expression of defect is more uniform
  • complete penetrance
  • onset is early In life
  • new mutations are rarely detected clinically (takes several gens)
  • many mutations Involve ENZYMES (Inborn metabolic errors) (enzyme may be normal but low in abundance, or defective)
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30
Q

what two bugs give you CF?

A

staphylococcus and psudomonas

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31
Q

what is the primary defect in CF?

A

abnormal function of an epithelial chloride channel protein

encoded by: CFTR gene

chromosome: 7q31.2

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32
Q

what symptoms do you expect to see? clinically, what should you keep an eye out for?

A

chronic lung disease (in kids!), male infertility (top two)

  • pancreatic insufficiency, steatorrhea, intestinal obstruction
  • cirrhosis, malnutrition
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33
Q

whats the incidence of CF?

A

1/2500 libe births,

most common lethal genetic disease In Caucasians (AR)

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34
Q

What are CF heterozygote carriers prone to?

A

resp and pancreatic disease

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35
Q

if you kiss a baby with CF, what do they taste like?

A

salt

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36
Q

what are key clinical findings of CF?

A

maconium Ileus

male urogentical abnormalities; pseudomonas aeruginosa infections

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37
Q

if babies have a diaper with a smell described as musty or mousy odor, what do you suspect?

A

PKU (phenylketonuria)

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38
Q

whats the incidence for PKU?

A

1/10,000 live births; caucasians

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39
Q

what is PKU and what are the clinical findings?

A

AR, deficiency of phenylalanine hydroxylase (PAH) leading to hyperphenylalaninemia

  • phenylalanine cant be converted to tyrosine
  • tyrosine is a precursor for melanin

normal at birth

at 6 months, severe mental retardation

hypopigmentation of hair and skin

eczema

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40
Q

what is the tx for PKU?

A

Dietary restriction

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41
Q

name some X linked DOs

A

G6PD def.

Fragile X syndrome

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42
Q

what are some things about X linked DOs to be aware of?

A
  • almost all men are recessive (located in male-specific region of Y)
  • males, usually infertile
  • all daugheters of affected male are carriers
  • hetero female dont express full phenotypic change cuz they got a normal paired allele
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43
Q

when taking a family history of X linked DO case, what will stand out?

A

all males affected, and skips a generation

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44
Q

what can you suspect if you give your pt a drug, and they come back with some sort of hemolytic reaction?

A

suspect G6PD deficiency

drug Induced hemolytic rxs

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45
Q

Describe the pedigree of X linked recessive if an affected father links w a normal mom; or an affected mom linking with a normal dad

A
  • affected dad, normal mom: sons are unaffected, daughters are carriers
  • reverse: both son and daughter have 50/50 of being unaffected; affected son = 25%; daughter carrier = 25%
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46
Q

describe mitochondrial inheritance:

A
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47
Q

what are mendelian disorders?

A
  • alterations to a single gene: leads to abnormal product, or decrease of a normal product
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48
Q

what are the 4 main catergories of mendelian DOs?

A
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49
Q

what are the consequences of a mutation in regards to an enzmye for Mendelian DOs?

A

decrease activity (abn fx) or decr. amount of NL enzyme

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50
Q

what are the 3 major consequences of having enzyme defects?

A

1) accumulation of substrate
2) decrease amount of end product
3) failure to inactivate a tissue damaging substrate

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51
Q

what is an example of #1)

A

galactosemia

  • galactose-1-phosphate uridyltransferase defeciency
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52
Q

what is an example of decreased amount of end product?

A
  • albinism: lack of tyrosinase leads to less melanin

lesch-nyhan: Incr. Intermediate product and their breakdown product Is toxic

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53
Q

what is an example of failure to inactivate a tissue-damaging substrate?

A

alpha1- antitrypsin defect:

  • unable to inactivate neutrophi elastase In lung -> EMPHYSEMA
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54
Q

what is the most common clinically significant mutation in regards to lung disease?

A

PiZ; homozygots for the PiZZ protein have alpha1-AT levels that are only 10% of normal

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55
Q

what are two examples of defects in receptors and transport systems?

A

1) familial hypercholsterolemia: decr. synthesis or decr in fx of LDL receptor = defective transport of LDL into cells = secondary incr in cholesterol synthesis
2) CF: chloride ion transport

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56
Q

what are some examples in alterations in structure, fxs or quantity of non-enzyme proteins?

A

sickle cell disease: globin structure defect

  • thalassemias: globin GENE affects amount of globin chains made
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57
Q

what medication can surface as adverse reactions to drugs in regards to mendelian DOs?

A

primaquine (anti-malerial) -> severe hemolytic anemia = G6PD def.

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58
Q

whats the genetic scoop on Marfan?

A

AD

  • FBN1*, chr. 15Q21.1
  • FABN2,* CHR. 5q23.31 (less common)
  • defect in (extracell. glycoprotein) fibrillin-1
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59
Q

whats the marfan syndrome incidence?

A

1 in 5K

70-85% familial

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60
Q

what are the 2 fundamental mechanisms by which loss of fibillin leads to clinical findings?

A

1) loss of structural support (where microfibril is rich)
2) excessive activation of TGF-beta signaling

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61
Q

what are physical/ clinical findings of Marfan Syndrome?

A
  • tall, exceptionally long extremeties
  • “double jointed,” thumb can be hyperextended to wrist

ectopia lentis (dislocation of lens)

aortic dissection, mitral valve prolapse

cystic medial necrosis

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62
Q

whats the scoop on Ehlers-Danlos syndromes?

A

EDS

  • defect in synthesis/structure of fibrillar collagen
  • skin is hyperextensible, joints are hypermobile
  • extra stretchy skin, extremely fragile and vulnerable to trauma

*gaping defects, caused by minor injury. surgery is difficult cuz they lack normal tensile strength

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63
Q

because EDS is a basic defect in connective tissue, whats serious internal complications can you expect?

A
  • rupture of colon and large arteries (vascular EDS)
  • rupture of cornea and retinal detachment (kyphoscholiosis EDS)
  • and diaphragmatic hernia (Classic EDS)
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64
Q

what are the clinical findings of Classic EDS and its gene defects?

A

COL5A1, COL5A2

Skin and joint hypermobility, atrophic scars, easy bruises

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65
Q

what are the clinical findings and gene defects for vascular EDS?

A

COL3A1

  • thin skin
  • arterial or uterine rupture
  • bruising
  • small joint hyperextensibility
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66
Q

what are the clinical findings and gene defects for

kyphoscholiosis EDS?

A

lysyl hydroxylase

hypotonia, joint laxity, congenital scoliosis, ocular fragility

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67
Q

what should lead you to the suspicion of familial hypercholesterolemia?

A

MI before 20 yo

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68
Q

facts on familial hypercholesterolemia?

A
  • receptor dz
  • mutation in receptor for LDL
  • one of the most frequent mendelian DOs

1/500 from birth have 2-3 fold Increase In cholesterol and dfvelope tendinous xanthomas

- Incr. cholesterol leads to premature atheroschlerosis leading to increased risk of MIs

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69
Q

what if someone is homozygous for FH?

A

5-6 times the plasma cholesterol

  • skin xanthomas (as well as coronary and cerebral and vascular atherosclerosis at a young age; MI BEFORE 20 yo
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70
Q

what does the LDL receptor recognize? where does the LDL come from? explain that train

A

liver cell secretes VLDL (with ApoC, ApoB-100, ApoE) –> lypolysis of VLDL –> IDL with ApoE and ApoB-100 —> conversion of IDL to LDL (with ApoB-100),

LDL RECEPTOR ON LIVER RECOGNIZES ApoB-100

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71
Q

what happens in lysosomal storage Dzs?

A

catabolism of subsrates of the missing enzyme remains incomplete, leading to the accumulation within the lisosomes = primary accumulation

  • lysosomes are also used for autophagy, so when THAT is the route that is taken, the impaired autophagy gives rise to secondary accumulation of autophagic substrates
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72
Q

what are the 3 approaches to treating lysosomal dzs?

A

1) enzyme replacement therapy
2) substrate reduction therapy
3) some random shit based on our understanding of the molecular basis of the deficient enzyme (not even mentioned)

73
Q

what is the enzyme deficient and major accumulating metabolites for tay sachs disease?

A

enzyme: alpha-subunit of hexosaminidase
metabolite: G-M2 ganglioside

74
Q

what is the defective enzyme and accumulated metabolite in Gaucher dzs?

A

glucocerebrosidase

  • glucocerebroside
75
Q

what is the defective enzyme and major accumulated metabolite in Niemann-Pick disase (type A and B)

A

sphingomyelinase

sphingomyelin

76
Q

what is the defective enzyme and major accumulated metabolite in muchopolysaccharidoses (MPS): MPS I

A

AKA HURLER Dz

alpha-l-iduronidase

dermatan sulfate, heparan sulfate

77
Q

what is the defective enzyme and major accumulated metabolite in MPS II

A

aka Hunter Dz

l-iduronosulfate sulfatase

dermatan sulfate, heparan sulfate

78
Q

whats Tay Sachs aka

A

Gm2 gangliosidosis: hexosminidase alpha-subunit deficiency)

79
Q

where does the tay sachs mutation occur?

A

alpha-subunit locus on chromosome 15 –> severe deficiency of hexosaminidase A

80
Q

what is the incidence and clinical presentation for tay sachs?

A
  • eastern european (Ashkenazic Jews): 1 In 30 carrier rate
  • normal at birth; 6month = motor and mental detrioriation
  • by 1-2 years: vegetative state; deathy by 2-3 yo
  • CHERRY RED SPOT IN MACULA
81
Q

where do you find accumulations of Gm2 ganglioside?

A

neurons, retina,

heart, spleen, liver

82
Q

what are the cytoplasmic inclusions for tay sachs?

A

fat stains on oil red O

and Sudan black B are positive

83
Q

describe the Niemann-Pick Dz, types A and B

A
  • lysosomal acumulations of sphingomyelin due to Inherited def. of sphingomyelinase
84
Q

what do you see in a histo slide of Niemann-Pick Dz?

A

foamy cytoplasm

85
Q

what are the raw stats on niemman-pick dz/

A

ashkenazi jews

AR

chr- 11p15.4

86
Q

describe type A, B, C

A

A: severe Infantile form, complete lack of enzyme, missense mt; extensive neuro, sx by 6m, death before 3yo

B: No CNS involvenemt, reach adulthood

C: most common, NPC1, progressive neuro damage, ataxia

87
Q

if you see zebra bodies, what is it?

A

NP diease

88
Q

what are some other clinical findings of NP dz?

A
  • massive splenomegaly (10x normal weight)
  • 33-50% have cherry red retinal spot
89
Q

whats the scoop on Gaucher Dz?

A
  • AR
  • glucocerebrosidase mutation
  • accum of glucocerebroside In phagocytes
  • this accumulation leads to activation of macrophages -> secrete IL-1, IL-6, TNF
90
Q

what is the most common lysosomal storage disorder?

A

gaucher

91
Q

what are the 3 types?

A

type I: chronic, 90% of cases, european jews, NO CNS

TII: ACUTE NEUROPATHIC; Infantile cerebral pattern, early death, NOT JEWISH

TIII: intermediate; progressive CNS, begins in adolescence of early adulthood

92
Q

whats the morphology of Gaucher?

A

distended phagocytic cells = gaucher cells in liver, spleen, bone marrrow (bone erosion –> pathologic fx), LN,

93
Q

whats it look like under a scope?

A

crumpled tissue paper

94
Q

what organ is enlarged in gaucher dz?

A

spllen, more than 10kg;

also, pancytopenia or thrombocytopenia

95
Q

whats the defect in mucopolysaccharidoses?

A

def enzymes degrading glycosaminoglycans

96
Q

whats some facts on MPS?

A

All of the syndromes are AR, except Hunter syndrome (X-linked recessive)

  • coarse facial features, clouding of the cornia, joint stiffness, mentally retarded
97
Q

facts on hurler:

A

MPS 1-H;

normal at birth, hepatosplenomegaly at 6-24 months, death by 6-10 yo due to cardiovasc complications

**corneal clouding; dwarfism

98
Q

facts on Hunters syndrome

A

MPS II; X-LINKED;

NO CORNEAL CLOUDING (mild clinical course)

99
Q

where do you find the mucopolysaccharides in MPS?

what are common histo findings?

A

mononuclear phagocytic cells

balloon cells + zebra bodies

100
Q

what is common to all MPS?

A

hepatosplenomegaly; (esp. coronary deposists); brain lesions

101
Q

what is the COD for MPS?

A

myocardial infarction and cardiac decompensation

102
Q

what is glycogenoses?

A

glycogen storage disease

103
Q

what does glygenoses result in?

A

glycogen storage in the liver or muscle

104
Q

what are the 3 types?

A

hepatic form: von Gierke

myopathic form: McArdle

Misc: Pompe Dz

105
Q

for von gierke (type I) what enzyme is deficient, what can you expect to see in the clinic?

A

deficiency of: glucose-6-phosphatase

Increased glycogen storage in liver = low blood glucose (hypoglycemia)

—-

clinic: hyperlipidemia, hyperuricemia; convulsions; gout and skin xanthomas; bleeding tendency

106
Q

in Mc Ardle dz, what is the defective enzyme and major accumulated metabolite in ?

A

muscle phosphorylase deficiency

no Incr. In blood lactate after exercise

leads to muscle cramps and weakness after exercise

107
Q

in Pompe Dz, what is the defective enzyme and major accumulated metabolite in?

A

glucosidase (acid maltase) deficiency

also, lack of branching enzymes

early death

cardiomegaly

108
Q

what can be said about complex multigenetic disorders?

A

they are of multifactorial inheritance = Implies interaction of environmental influences with two or more genes

most common genetic cause of congenital malformations

109
Q

what can you suspect from a cleft lip, cleft palate and neural tube defects?

A

there was a reduced intake of folic acid preconceptionally

110
Q

what type of severity can you expect frmo multifactorial inheritance’?

A

variable expressivity

reduced penetrance of a single mutant gene

111
Q

euploid

A

any exactl multiple of haploid number (23)

112
Q

aneuploid; how do they occur?

A

NOT an exact multiple of 23

  • nondisjunction: gametes have +/- 1 chromosome
  • anaphase lag: one normal cell + one monosomy cell
113
Q

when monosomy occurs, whats the fate?

A

monosome doesnt form

trisomies do happen tho

114
Q

whats mosaicism?

A

mitotic errors; gives rise to two or more populations of cells with different chromosomal complements

115
Q

where is mosaicism common?

A

sex chromosomes

116
Q

whats a ring chromosome?

A

where breaks occur at both ends of chrmosomes and the ends fuse

117
Q

whats inversion? what are the two examples?

A
  • 2 breaks occur within a single chromosomes with reincorporation of the Inverted Intervening segment

1) paracentric: only one arm involved

2) pericentric: breaks are on opposite sides of the centromere

118
Q

whats isochromosome?

A

on arm of the chromosome is lost, and the remaining arm duplicates

  • chromo has either 2 short arms or two long arms
119
Q

whats translocation?

A

segment of one chromosome is transferred to another one

120
Q

whats balanced reciprocal translocation?

A

single breaks in each of 2 chromosomes; but NO LOSS OF MATERIAL

NORMAL PHENOTYPE

121
Q

What is an example of a Robertsonian translocation?

A

Trisomy 21

122
Q

what are the 2 physical give aways of trisomy 21?

A

slanted palpebral fissures

single palmar crease

123
Q

what is the most common chromosomal disorder?

A

trisomy 21

124
Q

what is the number one cause of mental retardation?

A

trisomy 21

125
Q

what is the US incidence of trisomy 21?

A

1 in 700; 95% of affected individuals have trisomy 21, 47 chromosomes

126
Q

what is the strongest influence on incidence for trisomy 21?

A

maternal age

127
Q

what are the diagnostic clinical features of trisomy 21?

A
  • flat facial profile
  • oblique palpebral fissures
  • epicanthic folds

40% of pts have congenitcal heart disease (ASD and VSD); responsible for majority of deaths in infancy

128
Q

what are they at risk of developing?

A

10 to 20 fold incr. risk of developing acute leukemia

129
Q

what are the 3 trisomies?

A

down: tri 21
patau: tri 13 (1 in 15,000 births)
edwards: tri 18 ( 1 in 8K)

130
Q

what is the DiGeorge syndrome chromosome that is deleted?

A

Ch. 22q11.2

1/4K births

131
Q

what can you expect from DiGeorge syndrome?

A
  • congenital heart defects
  • abnormalities of the palate,

facial dysmorphisms

developmental delays

T-cell Immunodeficiency (gets viral Infections) and hypocalcemia

132
Q

what clinical findings do you find with DiG synd.

A

thymic hypoplasia = T-cell immunodef.

parathyroid hypoplasia = HYPOcalcemia, cardiac malformations

velocardiofacial syndrome: long face, narrow palpebral fissures, overfolded ear helix, pear shaped nose, cleft palate

CATCH 22

133
Q

whats worse, imabalances of sex chromosomes or autosomal imbalances?

A

sex chromosomes are better tolerated

134
Q

what two factors are peculiar to the sex chromosomes?

A

lyonization (inactivation) of all but one X chromosome

  • modest amount of genetic material carried by the Y chromosome
135
Q

whats the Lyon hypothesis?

A

1) only one X chromosome is genetically active
2) other X undergoes heteropyknosis, rendered Inactive
3) inactivation occurs at random
4) inactivation of same X chromo persists in cells derived from each precursor cell

136
Q

what is a Barr body?

A

inactive X can be seen in the interphase nucleus as a darkly staining small mass in contact with the nuclear membrane

137
Q

what determines the presence of the male sex?

A

presence of a single Y

138
Q

when are sex chromosomes usually detected?

A

at puberty; they are suble, and chronic problems related to sexual development and fertility

139
Q

what increases your chances of mental retardation?

A

an incr in X chromosomes

140
Q

what is the most common cause of hypogonadism in males?

A

klinefelter syndrome: 47, XXY

141
Q

what is the indicence of KS?

A

1 in 660; usually not detected til puberty

142
Q

what are people with klinefelter syndrome at an increased risk of getting?

A

type 2 diabetes and metabolic syndromes

  • 50% of them have mitral valve prolapse
  • osteoporosis

lack of secondary male characteristics: deep voice, beard, and male distribution of pubic hair

20X incr risk of breast cancer; incr risk of lupus

143
Q

what else does klinfelter syndrom cause?

A

male infertility and reduced spermatogenesis

144
Q

buzzword for Kleinfelter?

A

gynecomastia

145
Q

buzzwords for Turner syndrome?

A
  • webb neck
  • broad chest with spaced nipples

STREAK OVARIES

146
Q

What is the karyotype for Turner syndrome?

A

45, X

*complete or partial monosomy of X chr; hypogonadism in phenotypic females

other karyotypes: 45, X/ 46, XX;

45,X/ 46, XY;

45,X / 47, XXX;

147
Q

What is the most common sex chromosomal abn in females?

A

turner syndrome; 1/2,500 births

148
Q

what is cystic hygroma?

A

infant with edema; swelling of the neck due to lymph statis; it subsides but leaves behind bilateral neck webbing

149
Q

what is turner syndrome the single most important cause of?

A

primary amenorrhea (1/3 of the cases)

150
Q

what are the clinical findings of turner syndrome?

A
  • congential heart disease (25-50% of pts; coarctation of aorta)
  • cardiovasc. abn. are most important cause of incr. mortality
  • shortness of stature
  • amenorrhea
  • streak ovaries (atrophi ovaries = fibrous strands, devoid of ova and follicles)
  • hypothyroidism
  • glucose intolerance, obesity, and insulin resistance
151
Q

true hermaphrodite vs pseudo

A

true: presence of both ovaries and testis

psudo:

  • female pseudohermaphro: ovaries, but a dick
  • male pseudoherm: testis, but a vagina
152
Q

what are the 4 categories of single-gene disorders with nonclassical inheritance

A
  • diseases causing trinucleotide-repeat mts
  • dos caused by mutations in mitochondrial genes
  • genomic Imprinting

- gonadal mosaicism

153
Q

what is the repeated sequence in fragile X syndrome?

A

CGG

protein: FMRP

154
Q

what is the repeat in HD?

A

CAG

  • huntingtin
155
Q

what can you expect from trinucleotide-repeat mutations

A

neuro disorders

156
Q

what are the 3 general principles of trinucleotide-repeat mutations?

A

1) asscted with expansion of a stretch of trinucl., usually include G and C
2) shit depends on sex of transmitting parent
3) the unstable repeats cause disease (via 3 mechanisms)

157
Q

what are the 3 mechanisms by which unstable repeats cause disease?

A

1) loss of fx
2) toxic gain of fx
3) toxic gain of fx mediated by mRNA

158
Q

what is a morphologic hallmark of trinucleotide-repeats?

A

accumulation of aggregated mutant proteins in large intranuclear inclusion

159
Q

fragile X syndrome

A

loss of fx

trainscriptional silencing

CGG triplet in UTR

160
Q

fragile-X tremor ataxia

A

accumulation of toxic mRNA

  • transcriptional dysregulation

CGG triplet in UTR

161
Q

friedreich ataxia

A

loss of fx

transcriptional silencing

GAA triplet

intron

162
Q

HD

A

toxic gain of fx

polyglutamine expansions with misfolding

CAG triplet in exon

163
Q

what is the second most common genetic cause of mental retardation?

A

fragile X syndrome

164
Q

where does the trinucleotide mutation occur in FXs?

A

FMR1

(familial mental retardation-1)

  • normal pop: 6-55 repeats;
  • affected pop: 200-4000 repeats

*when FMR1 gene exceeds about 230 repeats, the DNA of that region becomes super methylated = silencing of the FMR protein

165
Q

what is the incidence of Fragile X syndrome?

A

1 in 1550 men

1 in 8000 women

166
Q

phenotype for fragile X syndrome

A

long face, large mandible

large ears,

macro-orchidism (affects more than 90% of males)

  • hyperextensible joints
  • high arched palate
  • mitral valve prolapse
167
Q

fragile X lazy slide

A
168
Q

HD facts

A
  • 15 years of life after dx
  • AD disease
  • dementia and progressive jerky movemnts
  • HTT located on chromonome 4p16.3

anticipation

169
Q

affected mothers of mitochondrial diseases pass the mutations to who?

A

all their children

170
Q

mitochondrial fathers pass mito mutations to who?

A

no one

171
Q

what is LHON?

A

progressive bilateral loss of central vission; first noted between ages 15-35, leading to eventual blindness

172
Q

whats heteroplasmy and threshold effecct?

A

tissues have both normal and mutatnt mtDNA

  • minimum number of mutant mtDNA needed in cell to give rise to disease
173
Q

what is genomic imprinting?

A

selective inactivation of either maternal or paternal allele

174
Q

when and where does imprinting occur?

A

in ovum or sperm, before fertilization

175
Q

what are the 3 mechanisms of genomic impriting?

A

1) deletions: 70% of cases: eg: 15q12
2) Uniparental disomy: eg: prader-willi syndrome; they have two maternal copies of ch 15
3) defective Imprinting: 1-4% of prader-willi folks, the paternal chromo carries the maternal imprin

reverse is true for angelman syndrome

176
Q

prader-willi syndrome

A

mental retardation

short statur

  • hypotonia

profound hyperphagia

obesity

small hands and feet

hypogonadism

deletions of 15 (q11.2;q13)

177
Q

angelman syndorme

A

same deletion but derived from mothers

  • ataxic gait, seizures, happy puppets
178
Q

what will deletion of maternal chromosome render? paternal?

A

angelman

prader

179
Q
A

MOD - 2 - Cells: Adaptation, Injury, and Death (10 decks)

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