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Pathology > Mendellian Disorders and those with non-classical inheritance > Flashcards

Mendellian Disorders and those with non-classical inheritance Flashcards

0
Q

what 2 things are disfunctional in auto dom mendellian disorders

A
  1. structural proteins
  2. metabolic pathway receptors
  3. scaffolding proteins
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1
Q

mendellian disorders are…

A

single gene disorders

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2
Q

if its an auto recessive disorder what would you expect

A

mutation in enzyme

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3
Q

the 2 auto dom disorders with mutations in a structural protein

A
  1. Marfans syndrome

2. EDS= Ehlers-Danlos syndrome

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4
Q

if you hear auto dom mendellian disorder with a metabolic pathway receptor mutation, you think of

A

familial hyper-cholesterolemia

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5
Q

you hear mutation in enzymes, you think

A

auto rec.=

  1. PKU=phenyl-keton-uria
  2. galactosemia
  3. lysosomal diseases
  4. glycogen storage diseases
  5. alkaptonuria
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6
Q

which disorders come to mind when you hear lysosomal storage diseases

A
  1. Tay Sachs disease
  2. Niemann-Pick disease
  3. Gaucher’s disease
  4. MPS= mucopolysaccharidoses
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7
Q

think glycogen storage disease

A
  1. Von Gierke
  2. McArdle
  3. Pompe
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8
Q

non classic inheritance for disorders

A
  1. triplet repeat mutations
  2. mitochondrial gene mutations
  3. genomic imprinting
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9
Q

triplet repeat mutation

A

Fragile X syndrome

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10
Q

mitochondrial gene mutations

A

LHON= Leber Hereditary Optic Neuropathy

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11
Q

genomic imprinting

A
  1. Prader-Willi syndrome

2. Angelmann syndrome

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12
Q

MOA for Marfans syndrome

A

mutation–> scaffolding protein= fibrillin = major component of microfibrils in ECM (scaffolding)

abn. fibrillin 1 does not bind TGF B–> active TGF B–>
1. +fibroblasts
2. -re-epithelialization
get destruction of areas where fibrillin 1 is present= aorta, ligaments, and ciliary zone of lens

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13
Q

when you hear_____________________ you should think marfans

A

bilateral ectopia lentis= both eyes involved

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14
Q

what 3 areas are involved in marfans syndrome and how

A 
1. skeleton
	pectus excavatum= depression of chest
	pectus carinatum= pigeon chest
2. eye--> bilateral ectopia lentis
3. cardio
	aortic dissection--> get tears in wall, and blood flows out
		=hemo-pericardium--> death
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15
Q

issue with type 3 collagen synthesis and structure

A

Ehler-Danlos syndrome

gene= COL3A1

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16
Q

symptoms of Ehler Danlos syndrome

A

hyper-extensible skin
hyper mobile joints

type 3 collagen in blood vessels and bowel walls
see ruptures of colon and large arteries

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17
Q

MOA of familial hypercholesterolemia

A

problem with LDL receptor transport (mut. of class 2= most common)

  1. liver thinks cholesterol is low since it cant sense levels do to low # LDL receptors
    increases HMG CoA reductase which assists in production of cholesterol
  2. IDL–> LDL since IDL isnt getting recycled
  3. scavenger receptors (on macrophages and smooth m) take up the LDL/IDL
    resulting in increased foam cells
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18
Q

what symptoms do you see in someone with familial hypercholesterolemia

A
  1. atherosclerosis early in life
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19
Q

MOA of PKU

A

lack of phenyl-alanine hydroxylase which converts

phenyl-alanine–> tyrosine———–> melanin

no phenyl-alanine hydroxylase= increase phenyl-alanine–> accumulation of its metabolites (phenyl acids–> mousy odor)

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20
Q

if you see

  1. mental retardation
  2. decreased pigmentation
  3. depression
A

PKU= phenyl-keton-uria

phenylalanine= neurotoxin at high doses–> mental retardation
no phenylalanine= no tyrosine prod.= no melanin–> fair skin

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21
Q

if you suspect PKU what test can you run

A

guthrie test

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22
Q

how can maternal PKU hurt her baby

A

if phenyl-alanine builds up in the mom it will cross the placenta and go to the baby

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23
Q

galactose-1-phosphate uridyl transferase mutation

A

= GALT mutation=galactosemia

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24
Q

MOA of galactosemia

A

galactose-1-phosphate/galactitol (alt pathway) builds up

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25
Q

signs of galactosemia

A
  1. failure to thrive
  2. HEPATOMEGALY–> liver enlargement and jaundice that develops in 1st week of life
  3. CATARACTS W/I 1ST WEEK OF LIFE
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26
Q

if baby has galactosemia what shouldnt you do

A

give formula or breast fee–> you want to remove all galactose from diet for first 2 years of life

27
Q

when you hear Tay Sachs you think

A

defect in hexos-aminidase A–> buildup of GM2 gangliosides (due to the fact that the gangliosides cant be degraded

IN ASHKE-NAZI JEWS

28
Q

MOA of Tay- Sachs disease

A

gangliosides build up in cytoplasmic vacuoles in neurons–> foamy neurons
stain + for fat= oil red stain

29
Q

symptoms of tay sachs disease

A
  1. motor and mental deterioration
  2. dementia
  3. blindness–> from ganglioside build up in n. of eye
  4. cherry red spot in macula–> due to swollen ganglion cells @ margin of macula
  5. DEATH BY 2-3 YO
30
Q

Why are babies with Tay Sachs disease normal at birth

A

up until 6 mo they still have enzymes from the mother

once they hit 6 mo they no longer have anything left from mother–> deterioration

31
Q

type A and B Niemann-Pick disease have mutations in

A

sphingomyelinase

32
Q

MOA of Niemann-Pick syndrome A and B

A

since sphingomyelin isnt being broken down it accumulates in phagocytic cells–> foamy cells and stain + fat using oil red
see zebra bodies

33
Q

symptoms of Niemann-Pick Syndrome A

A
  1. MASSIVE SPLEEN–> protuberant abdomen
  2. cherry red spot on macula
  3. at 6 mo
    fail to thrive, vomit, fever, lymphadenopathy
  4. DEATH BY 1-2 YO
34
Q

how are the symptoms of type B Niemann-Pick syndrome different from type A

A

type B= less severe deficiency of sphingomyelinase
ORGANOMEGALY–> BUT NO CNS INVOLVEMENT
usually survive til adulthood

35
Q

MOA for Neimann-Pick type C

A 
NPC gene--> which encodes for cholesterol trafficking
	cells accumulate
		1. cholesterol
		2. GM1 gangliosides
		3. GM2gangliosides
36
Q

symptoms for Niemann Pick disease type C

A
  1. psych and motor issues
  2. presents in childhood
  3. hydrops fetalis
  4. stillbirth
37
Q

MOA for Gaucher’s disease

A

mutation in glucocerebrosidase
leads to accumulation of glucocerbrosides in phagocytes which stimulates macrophages to release IL2, IL 6, TNF
distended lysosome

38
Q

symptoms of Gauchers diesease (LSD)

A
  1. HEPATOSPLENOMEGALY
  2. skeletal lesions
  3. slight decrease in life expectancy
    no CNS involvement= chronic non-neuronopathic form
39
Q

MOA of mucopolysaccharidoses (LSD)

A

deficient degradation of mucopolysaccharides

impaired degradation HEPARAN SULFATE= mental deficiency
impaired degradation of the following sulfates–> mesenchymal abnormalities
1. DERMATAN
2. CHONDROITIN
3. KERATAN

40
Q

symptoms of muco-polysaccharidoses (LSD)

A
  1. ORGANOMEGALY
  2. coarse facial features
  3. short stature
  4. skeletal deformities
  5. valvular lesion
  6. corneal clouding

progressive and involves many organs

41
Q

MOA alkaptonuria

A

deficiency in HGO= homogentisic acid oxidase/ homogentisate-1,2- dioxygenase

N: HA (homogentisic acid)–> maleyl-aceto-acetic acid via HGO

no HGO= increased HA–> which oxidizes to benzo-quinones with time
this causes black urine

42
Q

Symptoms of alkaptouria

A
  1. o-chronosis= blue-black pigment in CT (ears, eyes, sclera)
    due to HA depositing in CT
  2. deterioration of cardiac valves= due to increased HA in heart
  3. degenerative arthropathy= due to increased HA in joints
  4. black urine–> due to HA in urine which oxidizes to benzoquinones
43
Q

MOA of Von Gierke= glycogen storage disease

A

N: glucose-6-phosphate–> glucose + Pi via
GLUCOSE-6-PHOSPHATASE= deficient enzyme
–> increased glucose-6-phosphate

HEPATIC= liver enlargement and hypoglycemia (due to decreased glucose production)

44
Q

MOA McArdle disease= glycogen storage disease

A

= MYOPATHIC

N= glycogen–> glucose-1-phosphate via phosphorylase

DEFICIENT PHOSPHORYLASE

45
Q

symptoms of McArdles diease

A
  1. decreased energy production–> m. weakness
  2. m. cramps after exercise due to serum lactate not increasing after exercise

MYOGENIC

46
Q

MOA Pompe disease= glycogen storage disease

A

N= glycogen–> glucose + Pi via acid maltase

ACID MALTASE= deficient enzyme

glycogen gets stored in lysosomes

CARDIOMEGALY

47
Q

most triplet repeats are

A

C-G rich

48
Q

triplet repeat mutations end up

A

G-G start base pairing together–> this prevents DNA polymerase from going any further
introns get spliced out

49
Q

what is an ex of a triplet repeat mutation disease

A

Fragile X syndrome

50
Q

MOA of fragile X syndrome

A

mutation in: FMR1= familial mental retardation
which has a role in shuttling RNA to final destination in neurons

get amplification of repeats in X chromosome during oogenesis
in UTR–> expansion of repeats causes methylations
methylation silences region of gene
increase in methylation leads to increased severity

51
Q

define anticipation

A

worsening of disease in later generations

seen with fragile X syndrome

52
Q

what is the 2nd most common genetic cause of mental retardation

A

fragile X syndrome

53
Q

Symptoms of fragile x syndrome

A
  1. macro-orchidism= big balls
  2. slight facial dysmorphism= large mandible and ear
  3. varying mental retardation
54
Q

fragile X syndrome=

A

X linked recessive

55
Q

MOA of LHON= leber hereditary optic neuropathy

A

defect in mtDNA from mom–> deficient enzymes for oxidative phosphorylation
ND1 for complex 1 in oxidative phosphorylation pathway

56
Q

main symptom of LHON

A

progressive BILATERAL loss of CENTRAL VISION between 15-35

eventually leads to blindness

57
Q

which chromosome is the issue with the 2 cases of genomic imprinting

A

chromosome 15

58
Q

how do you inactivate genes during gametogenesis

A

methylate them

59
Q

to imprint a gene means to

A

silence it

60
Q

the prader-willi gene is normally

A

imprinted/silenced on mom

61
Q

the angelmann gene(UBE3A) is normally

A

imprinted/silenced on dad

62
Q

what is the issue with prader-willi syndrome

A

fathers active locus is deleted and the mothers gene is imprinted like normal

or

the child gets 2 chromosome 15s from the mom

63
Q

**symptoms of prader willi syndrome****

A
  1. mental retardation
  2. short stature
  3. hypotonia
  4. obesity–> due to hyperphagia
  5. hypo-gonadism
64
Q

what is the issue with angelmann syndrome

A

N= dads gene is imprinted/silenced

angelmann= deletion in maternal gene

65
Q

symptoms of angelmann syndrome

A
  1. mental retardation
  2. ataxic gait= profound
  3. INAPPROPRIATE LAUGHTER–> HAPPY PUPPET SYNDROME

Pathology (6 decks)

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