Usha/Devendra Flashcards
(67 cards)
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)
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
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
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
5
Q
Aminoacidopathies
A
- Characterized by HIGH lvls of AA in plasma(aminoacidemia) & Urine(aminoaciduia)
- PKU, Alkaptonuria, Maple syrup disease, homocystinuria, Albinism
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)
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
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
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
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
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)
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)
13
Q
Types of Maple Syrup Urine Disease
A
- Classic = present @ neonatal age almost NO activity for BCKD
- Intermediate = residual enzyme activity, age of onset varies = milder symptoms
- Intermittent = Normal early growth & development->episodic deompsensation when under metabolic stress
- Thiamin responsive= similar to intermediate BUT leucine tolerance improve w/Thiamine therapy
- Treatment w/restriction of Branched-chain AA
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
15
Q
Von Gierke’s
A
- Def enzyme = Glucose 6 phosphate
- Clinical presentation = SEVERE hypoglycemia, heptomegaly, hyperlipidemia, hyperuricemia
- Glycogen structure = NORMAL
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
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
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
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)
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.
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:
- Metabolic turnover of intracell (autophagy)
- Extra cell substrates by phagocytosis (heteropahgy)
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
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
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
25
Gaucher's Disease
* 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)
26
Neimann-Pick Disease
* ++ 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
27
Sphingolipidoses (Fabry's)
* **_Fabry's disease:_**
* **X linked**
* Def. enzyme _Alpha galactosidase_
* I**NCREASED globosides**
* Reddish purple rash, Kidney/heart failure, PAIN in lower extermities
27
Il giorno
The day
28
Sphingolipidoses (Farber's)
* **_Farber's Disease:_**
* AR
* **Def enzyme cereminidase**
* Increase in ceramide
* Painful joint, subcut nodules
29
Mucopolysaccharidoses
* 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
MPS (Hurler/Hunters)
* **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
I-Cell Disease
* 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
Targeting of lysosomal proteins to Lysosomes
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
Cystic Fibrosis Outline
* 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
4 classes of mutations in CF
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
Phenotype of CF (sweat & lungs)
* 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
Phenotype of CF (Pancreas, GI, Bile duct)
* **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
CF Genocopy
* 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
Lipoproteins & Familial Hypercholes
* 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
HYPERLIPOPROTEINEMIA: FREDRICKSON CLASSIFICATION (I)
* 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
HYPERLIPOPROTEINEMIA: FREDRICKSON CLASSIFICATION (II A & B & III)
* _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
HYPERLIPOPROTEINEMIA: FREDRICKSON CLASSIFICATION (IV & V)
* _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
Familial Hypercholesterolemia (LDL receptor)
* _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
PCSK9 protease
* 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
X-Linked Dystrophies
* **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
DMD properties
* 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
DMD clinical & treatment
* 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
BMD
* 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
OI (osteogenesis imperfecta)
* Bone fragility
* Hearing loss
* Blue sclera
* Abnormality in teeth
* Due to mutations for genes that encode Type 1 Collagen
50
OI (Type 1 collagen)
* 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
Genetics of OI
* **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
OI (4 Types)
* 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
Alzheimer Disease (general)
* 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
Pathogenesis of AD
* _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
Beta-APP
* 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
AB42
* 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
APOE
* 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
Diseases due to Unstable repeat expansions
* 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
Pathogenesis of unstable repeat expansions
* _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
Fragile X syndrome
* 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
Huntington's
* **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
Freidreich Ataxia (FRDA)
* **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
Myotonic dystrophy
* **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
Treatment of genetic diseases (multifactorial)
* Enviromental factors can be modified
* Diet, lifestyle & habits
* _Medical treatment_ = Type 1 diabetes
* _Surgical treatment_ = cleft lip, palate
* _Avoidance of risk factor_ = smoking
65
Metachromatic Leukodystrophy (sphingo)
* **_Metachromatic leukodystrophy:_**
* AR
* Def. enzyme _Arylsulfatase A_
* **Increased sulfatides**
* Mental retard, demylination, paralysis, _Nerves STAIN yellowish brown w/cresyl violet_
66
Sphingolipdoses (Krabbe's)
* **_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
A-Beta Lipoproteinemais
* **MTP def.**
* LOW chylomicrons, VLDL, IDL
* Any protein associated with AB will NOT work properly
* **Fatty stools, Mal nutrition, Vit. Def**
