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Usha/Devendra Flashcards

1
Q

Allelic Heterogeneity

A
  • Multiple alleles @ a single locus
  • Due to: Allele residual function = congenital absence of VAS deferens & CFTR (CF)
  • Specific sub function of a protein more affected (Hb Kempsey & beta thal)
  • Unpredictable nature (alpha 1 antitrypsin & liver disease)
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2
Q

Locus Heterogeneity

A
  • Assocication of more than 1 locus w/specific clinical condition
  • Modifier genes = Disease causing alleles, rare benign variants modulate severity of genes.
  • Ex. APO-E alziemers & Beta/Alpha thall
  • CF = pulomary severity depends on modifier genes
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3
Q

Outline of Enzyme Def.

A
  • Mutations in genes for enzymes = enzymopathies
  • Activity of enzymes def or absent = inadequate for conversion of substrate to product
  • Enzyme def. of HEME synthesis are inherited in AD fashion
  • MOST are inherited in autosomal/X-linked recessive
  • ++ of substrates upstream of defect or def in products downstream to defect
  • ++ production of minor metabolites (due to accum of stubstrates) in connected pathways
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4
Q

Application of Enzyme Def.

A
  • Def. of multiple enzymes MAY occur
  • Def. of cofactor or coenzyme (BH4)
  • Mutation of subunit, activator or processing protein (sandhoff’s disease)
  • Enzymes processed by common enzyme is Def. (Icell disease)
  • Abnormalities in organelles (peroximal disorders)
  • Pathological effect = confined to tissue and substrate ++ IF it can NOT diffuse out = Muccopolusac
  • May be wide spead involving MANY organ systems IF small mol it can diffuse = pheylalanine
  • Pathology & symptoms can be similar IF function of def enzyme same area OR partilal/complete def of enzyme exsist
  • Ex. partial Def of HRPT = Gout & complete Def of HRPT = Lesch Nyhan syndrome
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5
Q

Aminoacidopathies

A
  • Characterized by HIGH lvls of AA in plasma(aminoacidemia) & Urine(aminoaciduia)
  • PKU, Alkaptonuria, Maple syrup disease, homocystinuria, Albinism
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6
Q

Phenylketonuria

A
  • Epitome or inborn errors of metab.
  • Excretion of phenylpyruvic acid (phenylketone) in urine
  • AR inheritance
  • Def. of phenylalanine hydroxylase = Increased LVLs of phenylalanine
  • BH4 is oxidized to qBH2 in activating PAH
  • Normal lvls = less than 1mM in PKU = 2-3 mM
  • Enzyme def = conversion of phenylalanin to Tyrosine (BH4 coenzyme) & maintained by recylcing (de-novo synthesis)
  • Enzyme Dihydropteridine reductase recylces BH4
  • BH4 is also required in synthesis of Catecholamines & serotonin (thyrosine hydroxylase & tryptophan hydroxylase)
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7
Q

Types of PKU

A
  • Severity of mutation on PAH gene=presentation of phenotype
  • Mutation @ residue 408 arginine to Tyrpsin - Allelic herteriogeneity
  • Classic PKU = Very low PAH level (homozygous cond): low phenyl alanine in diet and worst presentation
  • Variant PKU
  • Non-PKU hyperphenylalaninemia
  • Neurotoxic effects due to high lvl of phenylalanine = damages developing CNS
  • Underpigmentation due to tyrosine def & comp inhibition of Tyrosinase
  • Musty order due to ketoacid metabolites
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8
Q

Mutations that affect - PAH gene

A
  • Mutations in **genes encoding enzymes of BH4 metab **
  • Impaired terahydrobiopterin recycline (BH4) & synthesis
  • Due to this also have def in catecholamine & serotonin
  • Locus heterogeneity
  • This mutation responds to high LVLs of BH4
  • Malignant PKU
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9
Q

Alkaptonuira

A
  • AR
  • Def enzyme = homogentisate oxidase
  • Conv of homogentisic acid to maleylacetoacetate in catabolic pathway of tyrosine
  • Substrate homogentisic acid accumulates & auto oxidizes->polymerized form dark colored pigment in conn. tissue (alkaptan bodies)
  • Ochronosis = discoloration of ears/nose 4th decade of life
  • Hips, knees, & IVD affected MOST by degenerative arthritis
  • Treatment = HIGH lvl of Vit C due to high acidic creates basic enviroment
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10
Q

Oculocutaneous Albinism

A
  • AR
  • Enzyme Def = Tyrosinase
  • Tyrosine to melanin (skin pigment)
  • Mutations on other loci may be involved
  • lack of pigment in skin, hair, iris, ocular fundus
  • Poor visual acuity (nystagmus) = pigment layer of retina helps w/light dispersion
  • Retinal fovea underdeveloped
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11
Q

Homocystinuria

A
  • AR
  • Def enzyme = cystathioneine beta-synthase
  • Also caused by methionine synthase & coenzyme def-
  • Pyridoxal phosphate (Vit B6) co enzyme for cystathio beta-synthase = Homocyst to cystathio
  • Folate & Vit B12 (methionine synthase) Homocyst to S-adenosymeth
  • Disorder could be due to defects in cobalamin absorbtion or transportation (B12)
  • High LVLs of homocysteine and methoionine metabolites
  • Mental retardation, seizures & osteoporsis
  • Can mimic marfan syndrome (dislocation of lenses)
  • Treat w/folate, B6 & B12 & restriction of methionine in diet (eggs, nuts, fish)
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12
Q

Maple Syrup Urine Disease

A
  • AR
  • Def Enzyme = Branched chain Alpha Keto acid Dehydrogenase
  • Works on branched chain AA = Valine, leucine & isoleucine
  • Mech of action is oxidative decarb of Branched chain Alpha keto acids correspoding to Acyl CoAs
  • Valine = propinyl CoA
  • Leucine = Acetoacetate/acetyl CoA
  • Isoleucine = propionyl CoA/acetyl CoA
  • Maple syrup odor urine
  • HIGH lvls of branched chain AA
  • Ketouria (lethargy, poor feeding)
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13
Q

Types of Maple Syrup Urine Disease

A
  1. Classic = present @ neonatal age almost NO activity for BCKD
  2. Intermediate = residual enzyme activity, age of onset varies = milder symptoms
  3. Intermittent = Normal early growth & development->episodic deompsensation when under metabolic stress
  4. Thiamin responsive= similar to intermediate BUT leucine tolerance improve w/Thiamine therapy
  • Treatment w/restriction of Branched-chain AA
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14
Q

Gylcogen Storage Disease

A
  • Affect glycogen metabolism and ALL enzymes involved in it and it’s regulation may be Def. = disease state
  • Can be abnormal in quantity or quality
  • Most common in liver & muscle
  • Liver = plasma glucose homeostatis & disorders associated w/hypoglycemia & heptomegaly
  • Muscle= Glycgogen needed to generate ATP ->contraction, muscle cramps, exercise intolerance, fatigue, progressive weakness
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15
Q

Von Gierke’s

A
  • Def enzyme = Glucose 6 phosphate
  • Clinical presentation = SEVERE hypoglycemia, heptomegaly, hyperlipidemia, hyperuricemia
  • Glycogen structure = NORMAL
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16
Q

Cori’s & Andersen’s

A
  • Cori’s = Debranching enzyme, Mild hypoglycemia, SHORTER outer branches, single glucose residue on OUTER branch
  • Andersen’s= Branching enzyme, infantile hypotonia, cirrhosis, very FEW branches toward periphery
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17
Q

Pompe’s

A
  • Def enzyme = Lysosomal Alpha-1,4 glucosidase
  • Clinical feature = Cardiomegaly (flabby heart), muscle weakness
  • Glycogen structure = glycogen like material inclusion bodies
  • Acid maltase Def leads to ++ of normal glycogen in lysosomes
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18
Q

Defects in Purine Synthesis (Lesch Nyhan)

A
  • HGPRT absolute def
  • X Linked Recessive
  • HGPRT part of salvage pathway of purines
  • Hyperuricemia = Nephrolithiasis (calculi in kidney) w/renal failure, gouty arthritis, & Tophi (deposit of urate under skin)
  • Neurological = extra pyramidal signs (dystonia) & pyramidal signs (spasticity/hyperflexia) due to purine imbalance
  • Behavioral problems = cognitive dysfunction, agressive, & impulsive behavior SELF mutilation
  • Orange sand in diapers = uric acid crystalluria & microhematuria
  • Partial mutations = hyperuricemia & gout = HGPRT activity 1-30% of normal
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19
Q

Alpha 1 Antitrypsin Def.

A
  • AR
  • High risk of chronic obstructive lung disease & cirrhosis of liver
  • Alpha 1 = serine protease inhibitors (serpins) on chrom 14
  • Role of A-1 is inhibit elastase production, specific neutrophil elastase lower resp tract
  • Liver major factory for A-1
  • Z/Z homozygotes have a high risk of presenting w/neonatal jaundice & cirrhosis
  • Z protein under goes structrural changes = long bead like necklaces of mutant becomes trapped in rough ER of heptocytes = _Conformational disease _
  • Lung disease presents due to balance between elastase & A-1=progressive degradation of elastin in alveolar walls=**Emphysema **
  • Ecogenetic disorder = can be worsened by interaction of enviromental factors (smoking)
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20
Q

Acute intermittent Porphyria

A
  • AD
  • neurological dysfunction
  • Def. in porphobilinogen deaminase (enzyme in heme synthesis)
  • Works on PBG (single pyrole) to tetrapyrole (uroporphyrinogen 1)
  • Can be triggered by: Barbiturates, steroid hormones (puberty), Catabolic states (reducing diets, illness) ANYTHING that induces Cytochrome P450
  • Synthesis of ALA synthase UPregulated NO (-) feedback
  • Presents w/abdom pain, vomiting, mental disturbance.
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21
Q

Lysosomes

A
  • Membrane bound organelles
  • Contain large set of hydrolytic enzymes (acid hydrolases) to help breakdown variety of complex macromol.
  • Lysosomal hydrolases = made in ER & modified in golgi (glycosylation + mannose-6 phosphate to oligosacc side chains)
  • Mannose-6 binds to specific receptors on inner surface of golgi
  • Receptor enzymes are pinched off into vesicles & fuse w/lysosomes
  • Lysosomal acid hyrdolases 2 types of macromol substances:
  1. Metabolic turnover of intracell (autophagy)
  2. Extra cell substrates by phagocytosis (heteropahgy)
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22
Q

Lysosomal Storage Disorders

A
  • Def. of acid hydrolases
  • ++ of substrates w/in lysosomes = organelle enlargement
  • Enlargement = no normal cell function = cell death
  • Liver & spleen are rich in cells of phagocytic system = ++lysosomes
  • Gradual accumaltion of substrate & eventual breakdown of organ
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23
Q

GM2 Sphingolipidoses

A
  • Degraded in lysosomes by acid hydrolases
  • GM2 def = Tay Sachs & Sandhoff’s=++ of GM2 in lysosomes mainly neuronal
  • Symptoms are similar only told apart by enzyme analysis
  • Tay Sach’s = Alpha subunit mutations Def. Hex A
  • Sandhoff’s = Beta subunit mutations combined with Def. in Hex A/B
  • Activator Def = GM2 def NORMAL Hex A/B but inability to make GM2/GM2 activator complex
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24
Q

GM2 Sphingolip Tay-Sachs

A
  • ++ of complex lipids in phagocytes in CNS & neurons of ANS
  • Ganglion cells in retina swollen at margins of macula = Cherry Red spot
  • Infants normal @ birth symptoms @ 6 months
  • Exaggerated response to LOUD noises, motor & mental degradation, vegetative state followed by death @ 2-3
  • Can be caused by premature STOP codon or defective mRNA splicing
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25
Q

Gaucher’s Disease

A
  • AR gene that codes for glucocerebrosidase
  • Most common
  • ++ of Glucocerebroside
  • Located in phagocytic cells of body ALSO in some in CNS
  • Distended phagocytic cells = Gaucher cells = “crumpled tissue paper”
  • ++ mostly in Liver, spleen & bone marrow
  • Symptoms: Pain, fatigue, jaundice, bone damage, anemia
  • Signs: hepto/spleomegaly, osteoporosis bone mineral density reduced (marrow replaced by gaucher cells)
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26
Q

Neimann-Pick Disease

A
  • ++ of sphingomyelin & Def. of sphinomyelinase
  • Type A=Severe infantile form w/neuro involvement
  • Type B=NO CNS involvement
  • Small vacuoles created in uniform size imparting a foaminess in Cytoplasm
  • @ birth to 6 months
  • Protuberant abdomen = hepto/splenomegaly
  • Vomiing, fever, lymphadenopathy (disease of lymph), & psychomotor function
  • Find ++ of sphingomyelin in Bone marrow & liver biopsy
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27
Q

Sphingolipidoses (Fabry’s)

A
  • Fabry’s disease:
  • X linked
  • Def. enzyme Alpha galactosidase
  • INCREASED globosides
  • Reddish purple rash, Kidney/heart failure, PAIN in lower extermities
27
Q

Il giorno

28
Q

Sphingolipidoses (Farber’s)

A
  • Farber’s Disease:
  • AR
  • Def enzyme cereminidase
  • Increase in ceramide
  • Painful joint, subcut nodules
29
Q

Mucopolysaccharidoses

A
  • Heterogenous disorder = mucopolysacc ++ in lysosome
  • AR (Hunter’s X linked)
  • Mucco & glycosaminoglycans = made in connective tissue cells & degradation in lysosomes
  • Single enzyme may be involved in catabolism of more than 1 GAG leading to mucopolysaccharidoses
  • GAGs appear in urine
  • Chronic multisystem involvement, organomegaly, dysotosis multiplex (defect in ossification), Joint mobility
  • SEVERE mental retardation = Hurler, Hunter & sanfilippo
30
Q

MPS (Hurler/Hunters)

A
  • MPS 1(Hurler): Allelic heterogeneity due to diff mutations in gene
  • MPS 1H
  • MPS 1 S
  • **MPS 2 (Hunter’s): X linked **
  • Def enzyme: Iduronate sulfatase
  • Symptoms same as Hunter’s BUT no corneal clouding
  • MPS 3 (Sanfilippo’s syndrome) A-D
  • AR
  • Def enzymes in removal of N-sulfated/N-acylated glucosamine
  • A=Heparan sulfa def
  • B=N-acetylglucosamin def
  • C=N-acetyltransf def
  • D=N-acetylglucosamine def
31
Q

I-Cell Disease

A
  • Problems w/targeting of lysosomal proteins to lysosomes
  • Proteins have phosphorylated Mannose tag
  • Phosophor catalyzed by 2 golgi specific enzymes
  1. Phosophotransferase + GlcNAc-1 phosphate to C-6 of mannose
  2. GlcNAc removed leaving mannose-6phosphate
32
Q

Targeting of lysosomal proteins to Lysosomes

A
  1. TGN has mannose 6 phosphate receptors
  2. Packaged in clathrin-coated vesicles & sent to endosomes
  3. Endosomes mature & receptors release enzymes
  • I-cell disease = fibroblasts release lysosomal enzymes extracell due to LACK of mannose 6 phosphate tags = DEFECTIVE phosphotransferase
  • Mucolipodosis 2 = similar to hurler BUT presents eariler and NO mucopoly in unrine
  • Abnormal lysosomal enzyme transport in extracell instead to lysosome
  • Lysosomal enzymes are increased in blood
  • Affected cells show dense “inclusions” = I cell disease
33
Q

Cystic Fibrosis Outline

A
  • AR
  • Gene affected CFTR = codes for reg. Cl- channel located in apical membrane epithelial cells
  • Properties of CFTR: Large integral membrane protein & belongs to ABC family of transport proteins (ATP binding), leads to phospho of Protein kinase A
  • Located @ bile ducts, lungs, epithelium, pancreas
  • Cl- channels help w/Na & Cl exchange which also brings H2O w/it to thin out mucus
34
Q

4 classes of mutations in CF

A
  1. Defects in protein production (premature stop codon)
  2. Defective protein processing due to misfolding (Delta = deletion @ Phenyl alanine residue 508)
  3. Mutations disrupt regulation of protein
  4. Mutations membrane spanning protein (NBD1)
  • Most common is defective processing due misfolding (3 Bp deletion)
  • Use PCR to diagnosis
  • Complete misfolding @ deltaF508 NULL alleles = pancreatic insuff
  • IF partial & some alleles for CFTR protein WILL have pancreatic suff.
  • Modifier gene TGFB1 helps w/pulmonary function and depending on how many are active will help in severity of lung function
35
Q

Phenotype of CF (sweat & lungs)

A
  • Elevated Na/Cl in sweat = Greater than 60 mEq/L
  • Due to loss of function of CFTR=Cl- in duct can NOT be reabsored
  • Pulmonary disease: Starts as Obstructive (easily collasped airways) & Later bronchiectasis (irrever dialation of airways)
  • Hyperabsorption = Na+ & decreased Cl- secretion = depletion of airway surface liquid = THICK secretions = Bacterial infection which are recurrent
36
Q

Phenotype of CF (Pancreas, GI, Bile duct)

A
  • Pancreas: maldigestion syndrome due to Def. secretion of enzymes, ATROPHY of acini (enzyme secreting cells)
  • Intestine: Obstruction present in neonatal period seen in meconium ileus (first stool of infant embryonic fluid)
  • Blie duct: obstruction = jaundice
37
Q

CF Genocopy

A
  • Similar in its appearance BUT different mech
  • DUE to mutation in epithelial Na channel gene SCNN1
  • Less severe intestinal disease
  • SAME elevated Na in sweat & pulmonary infections
  • SCNN1 interacts with CFTR gene
38
Q

Lipoproteins & Familial Hypercholes

A
  • Lipids insoluble in water & carried throughout body as soluble protein complexes = Lipoprotein
  • Core = insoluble (nonpolar) chelosterol esters & TAGs
  • Outside = proteins, phospholipids, free cholesterols w/polar body outside
  • Classes of lipoptoteins = VLDL, IDL (VLDL rem.), LDL, HDL
39
Q

HYPERLIPOPROTEINEMIA: FREDRICKSON CLASSIFICATION (I)

A
  • classified on changes in lipoprotien electrophoretic profile
  • Primary = Hereditory disorder in lipid metab
  • Secondary = endocrine or other disorders
  • Class I = chylomicron band @ origin, familial lipoprotien lipase or APoC2 def.
  • SLOW chylomicron clearance and LOW LDL/HDL - NO increased risk of coronary heart disease but HIGH risk of pancreaitis due to High LVLs of TAGs
  • PCSK 9 is GAIN of function protein mutation
  • Eruptive Xanthomas
40
Q

HYPERLIPOPROTEINEMIA: FREDRICKSON CLASSIFICATION (II A & B & III)

A
  • Class IIA:
  • High lvls of Beta band = High Chelosterol lvls
  • Familial Hypercholesterolemia & reduced LDL clearance
  • Class IIB:
  • High Pre-beta & Beta = High VLDLs & LDL
  • High TAGs & chelosterol
  • Class III:
  • One board thick band @ linking Pre-beta & Beta (vldl & ldl)
  • **Defect in IDL metab = APOe def **
  • Athersclerosis (hardening of arteries), xanthomas
41
Q

HYPERLIPOPROTEINEMIA: FREDRICKSON CLASSIFICATION (IV & V)

A
  • Class IV
  • Pre beta elevated = high TGL levels
  • Familial HYPERtriacylglyceromia
  • ELEVATED production of VLDL = Insulin resistance = diabetes (most common)
  • Class V
  • High chylomicron @ origin & pre-beta = HIGH TGL
42
Q

Familial Hypercholesterolemia (LDL receptor)

A
  • Elevated LDL
  • Deposistion of LDL in tendons/skin = Xanthomas
  • In arteries = atheromas
  • Cornea = arcus cornea
  • Heterozygotes: 2x increase in cholesterol (350-550) Above symptoms develop 3rd/4th decade of life
  • Homozygotes: SEVERE cholesterol lvls (650-1000) Xanthomas, coronary disease and MI are possible by 2nd decade of life
  • LDL receptor is located @ liver =
  1. receptor endocytosis
  2. delivery to lysosomes
  3. LDL degraded & cholesterol released
  • LDL receptor faulty = excess LDL deposited in scavenger cells = Xanthomas, etc…
44
Q

PCSK9 protease

A
  • Reg. mech decrease LDL receptor #s & prevent excess uptake of cholesterol
  • Gain of function mutation = Decrease in LDL receptors below normal
  • HIGH circulating LDL = lower risk of coronary heart disease (prevents reuptake of cholesterol into cells)
45
Q

X-Linked Dystrophies

A
  • DMD (duchenne) = lethal in males, fitness 0 die in early age, Some are NEW mutations & the rest are from carrier mothers
  • BMD (Becker) = mutations @ locus, fitness HIGH
  • Female Carriers can be slightly affected depending on non-random X inactivation
  • MAJOR clinical sign is elevated CK MM
46
Q

DMD properties

A
  • Gene is LARGE, 79 exons and 7 tissue promoters
  • Protein affected is Dystrophin acts as ANCHOR in membrane of skeletal muscle to cytoplasm & defects = destruction of muscle
  • Cardiac, Skeletal, and Brain
  • Most common is DELETION
  • Deletion = Frameshift = TOTAL loss of function
  • DMD & BMD express allelic hetero
47
Q

DMD clinical & treatment

A
  • Age of onset 3-5 progessive muslce weakness
  • Awkward gait, inability to climb stairs
  • Pseudohypertrophy of calves due to muscle being replaced by fat & fiborous connective tissue
  • Show “Gower’s sign” = having to rise pushing from hands, supporting knees & thighs
  • Wheel chair boung & Death by cardiorespitory failure
  • High CK MM (type 3) = creatine kinase
  • Lumbar lordosis = degen of SC
48
Q

BMD

A
  • Similar to DMD properties BUT less aggresive
  • Higher life expectancy
  • age of onset @ 11 in some cases even until adult life
  • Reduced staining in myocytes in DMD complete absence of staining
49
Q

OI (osteogenesis imperfecta)

A
  • Bone fragility
  • Hearing loss
  • Blue sclera
  • Abnormality in teeth
  • Due to mutations for genes that encode Type 1 Collagen
50
Q

OI (Type 1 collagen)

A
  • Major structural protein of Bone & fiborous tissue formation
  • Made of 2 pro alpha 1 chains & 1 pro alpha 2 chain (A1/A2)
  • Glycine fits in restricted site where 3 alpha chains come together** = MAJOR disruption to helical structure**
  • Alpha chain assembly BEGINS @ Carboxyl term end towards Amino end
  • Mutations @ carboxyl end lead to SEVRE OI
  • Unassembled amino ends are modified, This leads to slow production & interferes w/formation of collagen fibrils, DEFECTIVE mineralization
51
Q

Genetics of OI

A
  • Null mutations = promoter mutations, splice signal, mRNA stability mutation
  • Missense glycine mutations = phenotype more severe:
  1. Glycine mutations near carboxyl end of alpha chains
  2. Substituted AA is Charged AA (Asparate)
  3. Substituted AA is Bulkier than glycine
  • Dominant negative effect = Defective A1 chains & 3/4 affected due to the fact they make BULK of collagen triple helix = MOST SEVERE
52
Q

OI (4 Types)

A
  • Classified on Phenoypic presentation
  • ALL AD
  • Type 1 = MILD, NO bone deform, Partial deafness, # of good Aplha 1 chains (only) made is LESS, Due to Null mutation
  • Type 2 = LETHAL, Misense mutation of glycine @ Carboxyl term end, Can affect BOTH A1/A2 & can present as NEW mutation
  • Type 3 = Progessive deform, Missense mutation of glycine @ many parts of helix (C & AA end) & on both A1/A2
  • Type 4 = NORMAL scelrae & mild bone deform, & same genetic properties as TYPE 3
53
Q

Alzheimer Disease (general)

A
  • Most common neurodegen disease
  • Presents in 6th to 9th decade of life
  • Due to neurons degrading in hippocampus
  • 4 genes associated w/AD
  1. APP (located on Chromosome 21) = BAPP-Needs to be cleaved by 3 enzymes
  2. PSEN 1 = presenilin 1
  3. PSEN 2 = presenilin 2
  4. APOE = E4 gene associated w/non-familial AD & infulences age of onset
54
Q

Pathogenesis of AD

A
  • Amyloid/senile plaques = extracellular depositions contain fibrillary protein AB & APOE
  • Neurofibrillary tangles = intracellular (intraneuronal) hyperphosphorylated Tau proteins
  • Tau protein = Promotes assembly & stability of microtubules (hyperphosphorylation IMPAIRS this function)
  • mutations NOT associated w/AD
55
Q

Beta-APP

A
  • Has 3 proteolytic fates:
  1. Alpha secretase & Beta secretase = cell surface secretases
  2. Gamma secretase = Atypical protease
  • Alpha & Beta secretase cleavage = AB40 NON_TOXIC
  • Gamma secretase clevage = AB42 NEUROTOXIC in accumulation
  • Majority of cleavage is done by ALPHA
56
Q

AB42

A
  • Normally Ab42 is contained in small amounts
  • Mutations increase presenilin 1 production leads to increase in Ab42
  • Presenilin 1 is CO-factor for gamma secretase
  • Down syndrome pts have 3 copies of BAPP gene (chromosome 21) HIGHER risk for early onset AD
  • AB42 increase w/pts that have mutations in BAPP gene
57
Q

APOE

A
  • E4 allele of gene is linked with risk factor of AD
  • Associated w/early onset 10-15 years early
  • It is dose dependent = MORE E4 allele earlier onset
  • E2 allele of APOE has a protective effect of neurodegeneration
58
Q

Diseases due to Unstable repeat expansions

A
  • Tetranucleotide repeat expansion or trinucleotide repeat disorder:
    1. Myotonic dystrophy 2 (genocopy of myotonic dystrophy) = repeat of CCTG
  • Pentanucleotide repeat expansion:
    1. Spinocerebellar atrophy 10=repeat of ATTCT
59
Q

Pathogenesis of unstable repeat expansions

A
  • Class 1: Expansion of noncoding repeats=loss of protein function=impairing transcription of preRNA from affected gene
  • Ex. Fragile X (CGG) or Friedrich ataxia (GAA)
  • Class 2: **Expansions of noncoding repeats confer novel prop on RNA **
  • Ex. Myotonic dystrophy (CTG)1/2 & Fragile X tremor/ataxia
  • Class 3: Expansions of codons confer novel properties on affected protein
  • Ex. Huntington’s (CAG) & spinocerebellar ataxia
60
Q

Fragile X syndrome

A
  • Mech of inactivation of FMR1 gene = CGG repeats in 5’ UT region & Threshold = 60
  • 60-200 repeats = premutation
  • above 200 = full mutation = hypermethylation of 5’ UTR & promoter = SHUT down of transcription
  • LOSS of FMRP protein = clinical phenotype (large testis, ears, etc)
  • FMRP = RNA-binding protein:
  • Assoc w/polyribosomes to surpress translation of proteins from RNA targets
  • RNA target involved in cytoskeletal structure, synaptic transmission, neuronal maturation
61
Q

Huntington’s

A
  • Gene affected Huntingtin
  • Polyglutamine tract starts @ residue 18 & followed by polyporline region
  • ABNORMAL = CAG repeat translated to stretch of glutamine residues
  • When expanded interacts w/# of transcriptional regulators like TATA box binding proteins = CHANGES in transcription of proteins
  • Presents w/insoluble aggregates of mutant proteins & other polypeptides clustered in nuclear inclusions = cellular reponse to MISFOLDING of huntingtin gene
  • Soluble mutant huntingtin = pathogenesis
62
Q

Freidreich Ataxia (FRDA)

A
  • GAA repeat on FRDA gene choromsome 9
  • FRDA gene encodes for frataxin = mt iron binding protein, reg. iron homeostatis in mt
  • GAA expansion=impairs gene fnx by impairing transcriptional elongation
  • Leads to loss of function of frataxin
  • Increased lvls of mt iron & impaired heme synthesis (NOT in rbc)
  • Reduced activity of Fe-2 containing protein like complex 1-3
63
Q

Myotonic dystrophy

A
  • CTG repeat
  • DM2 is genocopy of DM1 BUT NO congenital form
  • DM2 = CCTG expansion
  • CUG present in DM1 & DM2 = phenotypes
  • CUG repeats bind to RNA binding proteins=pleiotropy of DM (multisystem)
  • RNA binding proteins = regulators of splicing
64
Q

Treatment of genetic diseases (multifactorial)

A
  • Enviromental factors can be modified
  • Diet, lifestyle & habits
  • Medical treatment = Type 1 diabetes
  • Surgical treatment = cleft lip, palate
  • Avoidance of risk factor = smoking
65
Q

Metachromatic Leukodystrophy (sphingo)

A
  • Metachromatic leukodystrophy:
  • AR
  • Def. enzyme Arylsulfatase A
  • Increased sulfatides
  • Mental retard, demylination, paralysis, Nerves STAIN yellowish brown w/cresyl violet
66
Q

Sphingolipdoses (Krabbe’s)

A
  • Krabbe’s Disease:
  • AR
  • Def. Enzyme galactosylceramide
  • Increase in galactocebrosides
  • Retardation, blindness, deafness, paralysis
  • TOTAL absence of myelin, globoid bodies in white matter of brain
67
Q

A-Beta Lipoproteinemais

A
  • MTP def.
  • LOW chylomicrons, VLDL, IDL
  • Any protein associated with AB will NOT work properly
  • Fatty stools, Mal nutrition, Vit. Def

Genetics Block 2 (2 decks)

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