GENETICS_usmle success academy.pdf

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GENETICS

Keys to success in Gene9cs #1 – #2 – #3 – #4 – #5 -‐

Important terminology in Gene9cs Heteroplasmy: Variable expression: Incomplete penetrance: Loss of heterozygosity: Imprin9ng: Pleiotropy: An9cipa9on: Mosaicism:

PEDIGREE INTRODUCTION

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Autosomal Dominant Disorders

•  Defect of a single gene leads to the disease •  50% chance of inheritance of AD disorder

Autosomal Dominant Inheritance

Tuberous Sclerosis

•  Mul9 organ disorder •  Non-‐malignant tumors grow abundantly Hamar9a à Malformed 9ssues Hamartomas à Benign growths Muta9on of 2 genes: ________ & ________ Codes for proteins called: ___________ &______________

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Tuberous Sclerosis

•  Follows the 2-‐hit hypothesis Brain tumor associated with TS = ____________ Dermatological findings include: -‐  Ash-‐leaf spots [fair skinned pt use Wood’s lamp] à Renal angiomyolipoma

Marfan Syndrome Muta9on of _________ gene on Chrom ____. Encodes for the Fibrillin-‐1 protein. à Fibrillin-‐1 is a component of the ECM These situa9ons look like Marfan’s syndrome: -‐  Homocys9nuria -‐  Congenital contractural arachnodactyly -‐  Ehlers-‐Danlos syndrome -‐  S9ckler syndrome -‐  MEN 2B

Marfan Syndrome

Findings: à Above average height à Arachnodactyly à Spinal abnormali9es à Lens disloca9on (upper por9on: pa9ent has trouble seeing above eye level)

à Aor9c aneurysm OR dilated aorta à Dural ectasia

Neurofibromatosis

Type 1 à Von Recklinghausen disease -‐ Muta9on of _______________ 1 gene, which is found on Chrom _______. -‐  Tumor suppressor gene ________________ works to inhibit the p21 ras oncoprotein.

Type 2 à Central neurofibromatosis -‐ Muta9on of the ___________ protein found on Chrom ______.

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Neurofibromatosis Type 1

Diagnosed by finding: à Café-‐au-‐lait spots

à Neurofibromas

à Lisch nodules

Neurofibromatosis Type 2

Diagnosed by finding: à Bilateral acous9c neuromas (CN 8 aka Schwannoma)

Tumors can cause: -‐  HA -‐  Balance problems -‐  Facial weakness/paralysis (CN7 compression)

Hun9ngton’s Disease

•  Trinucleo9de repeat disorder (CAG) •  Demonstrates gene9c an9cipa9on •  CAG encodes for the AA _______________

Affected gene = _______________, and is located on Chrom _____. Affected gene encodes for the __________ protein.

Hun9ngton’s Disease

•  Hypermethyla9on of AA residues leads to the respression of transcrip9on

Gene9c muta9on leads to atrophy of the ______________ nucleus, which causes loss of GABAergic neurons. Diagnosis made by:

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Hun9ngton’s Disease 2 forms of the disease: 1.  Adult onset 2.  Early onset

Findings: -‐  Personality changes -‐  Chorea -‐  Muscle rigidity -‐  Writhing -‐  Psychomotor func9on worsens -‐  Impaired execu9ve planning -‐  Short & long-‐term deficits

Hun9ngton’s Disease Neuropsychiatric Manifesta9ons include: -‐  Anxiety -‐  Depression -‐  Blunted affect -‐  Aggression -‐  Compulsive behaviors

Management: No cure à Can regulate with CNS depressants

Re9noblastoma

Re9nal cancer caused by muta9on of the _______ gene on Chrom _____. à Re9noblastoma protein a regulator of the G1àS phase transi9on

Hyperphosphorylated protein = ____________ Hypophosphorylated protein = _____________

Re9noblastoma

•  Screening part of ‘well baby’ screening

Looking for the: 1.  Red reflex (red/orange re9nal reflec9on) 2.  Corneal light reflex (symmetrical reflec9on)

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Re9noblastoma

Findings: -‐  Leukocoria -‐  Deteriora9ng vision -‐  Irrita9on of the eye -‐  Concurrent glaucoma -‐  Enlargement of the eye

Myotonic Dystrophy

•  Chronic, slowly progressing mul9systemic disease characterized by:

à Was9ng of the muscles à Cardio disturbances à Endocrine disorders à Visual disturbances

2 types: Type 1 (Steinert diz) Type 2 (PROMM)

Myotonic Dystrophy

Type 1: DMPK gene à On long arm of chromosome _____ à Encodes _________________ protein kinase à Is a trinucleo9de repeat disorder (CTG)

Type 2: ZNF9 gene à Found on chromosome _____ à Tetranucleo9de repeat disorder (CCTG)

Familial Hypercholesterolemia

•  Muta9on of _____ gene that encodes the LDL receptor protein

•  Gene located on chromosome _____ located on the short arm of the chromosome.

Main findings: Xanthelasma, tendon xanthomas High risk of __________________, which may lead to CAD

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Adult Polycys9c Kidney Disease

•  Both AR and AD versions

AD version: 3 muta9ons in PKD-‐1, PKD-‐2, PKD-‐3 PKD-‐1 gene located on Chrom _____ and codes for a protein that regulates the cell cycle & intracellular transport of _______________ in epithelial cells.

Adult Polycys9c Kidney Disease Findings in the kidney: -‐  Mul9ple cysts on both kidneys

Extrarenal findings: -‐  Cerebral aneurysms -‐  Pancrea9c & hepa9c cysts -‐  Mitral valve prolapse -‐  Aor9c root dilata9on -‐  Colonic diver9cula

Von Hippel Lindau

•  Caused by muta9on of the ______ tumor suppressor gene located on Chrom ____.

Pa9ents develop: -‐  Benign & malignant tumors (MC In CNS) -‐  Capillary hemangioblastomas in re9na -‐  Clear cell renal carcinoma -‐  Pheocromocytoma -‐  Pancrea9c neuroendocrine tumors

Von Hippel Lindau

Diagnosis: Family hx + sx men9oned above Management: No cure à Rou9ne screenings important à Early recogni9on + symptoma9c tx can improve quality of life

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Achondroplasia

•  MCC of dwarfism

à Fibroblast growth factor receptor 3 (FGFR3) muta9on (at the epiphyseal growth plate)

à Results in abnormal car9lage forma9on

* No effect on intelligence

Achondroplasia

Findings: -‐  Short stature -‐  Large head-‐to-‐body size difference -‐  Prominent forehead -‐  Decreased muscle tone -‐  Bowed legs -‐  Spinal stenosis -‐  Kyphosis and lordosis

Acute Intermitent Porphyria •  Heme produc9on disturbed •  Porphobilinogen deaminase deficiency •  2nd MC porphyria (auer Cutanea Tarda)

Findings: -‐  Severe abdominal pain -‐  Peripheral neuropathy -‐  CNS signs ** NO RASH

Von Willebrand Disease

Type 1 & 2 = AD Type 3 = AR •  vWF deficiency •  vWF required for platelet adhesion •  vWF gene located on Chrom ____

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Von Willebrand Disease Presenta9on: -‐  Easy bruising -‐  Nosebleeds -‐  Bleeding gums -‐  Heavy menstrual periods (females)

Type 1: Quan9ta9ve defect in vWF (Majority of cases) Type 2a: Qualita9ve defect (normal quan9ty) Type 2b: Hyperbinding of vWF to glycoprotein 1 Type 3: Complete absence of vWF (most severe)

Von Willebrand Disease

Diagnosis: à Measure vWF quan9ty in a vWF an9gen assay à Measure vWF func9onality with any of (glycoprotein 1b binding assay’, collagen binding assay’, ristoce9n cofactor ac9vity’)

Mgmt: Desmopressin MOA: S9mulates release of vWF from Weibel Palade bodies of endothelial cells + increases vWF levels

Osteogenesis Imperfecta

•  Qualita9ve or quan9ta9ve deficiency of type 1 collagen (decreased structural quality of collagen)

•  Glycine is replaced with bulky amino acids


Type 1 – MILD… COL1A1 gene Type 2: LETHAL.. COL1A1 & COL1A2 gene Type 3: Progressive/deforming Type 4: Deforming, normal sclera Type 5: Similar to type 4 (histology = mesh-‐like) Type 6: Similar to type 4 (histology = Fish scale) Type 7: CRTAP gene, car9lage associated protein Type 8: Severe/lethal, Leprecan protein (LEPRE1 gene)

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Findings: -‐  Bone fragility -‐  Spinal curvature -‐  Loose joints -‐  Poor muscle tone -‐  Blue sclera (see underlying choroidal veins) -‐  Hearing loss

Hypokalemic Periodic Paralysis

•  Defect in CNA4A gene •  Defect in voltage-‐gated calcium channels (blood K+ levels fall rapidly)

Main findings: -‐  Muscle weakness/paralysis -‐  Lasts hours to days

Hypokalemic Periodic Paralysis

Management: -‐  Focuses on preven9ng future atacks -‐  Avoid high-‐carb meals, strenuous exercise, other triggers

à K+ sparing diure9c like ________________ can keep K+ levels elevated

Hereditary Spherocytosis

•  Defect in RBC’s cytoskeleton (due to Spectrin & Ankyrin abnormali9es)

Classic Manifesta9ons: -‐  Jaundice -‐  Hemoly9c anemia -‐  Splenomegaly

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Hereditary Spherocytosis

Findings: -‐  Oval-‐shaped RBCs (Elliptocytosis) -‐  RBC small/red, no central pallor -‐  Re9culocytosis / incr RDW / incr MCHC

Confirm with _____________ fragility test

Li-‐Fraumeni Syndrome

•  Early cancer development due to p53 gene muta9on

•  Requires inherited muta9on of p53 + soma9c muta9on of 2nd allele

à Look for mul9ple cancers in someone < 45yr of age

à MC tumors in breast, adrenal cortex, brain, blood, & sarcomas

Osler-‐Weber-‐Rendu Syndrome

•  Hereditary hemorrhagic telangiectasia

Findings: Telangiectasias in skin + mucus membranes of the lips/oronasopharynx/respiratory tract/GI tract/urinary tract à Rupture leads to epistaxis, GI bleeding, hematuria

Essen9al Tremor •  Worsens with ac9vity •  MC in upper extremity Classic finding: Improves with ___________ consump9on Management: _________________ MOA: Non-‐selec9ve beta blocker Why it works à Suppresses tremor through beta-‐2 blockade

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Autosomal Recessive Disorders

•  MC enzyme deficiencies •  There is a 25% chance of inheri9ng an AR disorder

Autosomal Recessive Disorders

Autosomal Recessive Inheritance

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CYSTIC FIBROSIS

•  Muta9on of _______________ gene •  Dele9on of 3 nucleo9des that code for ______ results in the loss of Phenylalanine

CFTR is an ______-‐binding transmembrane ion transporter.. Pumps __________ ions out of the epithelial cells.

Cys9c Fibrosis (Sweat Gland)

Cys9c Fibrosis (Lungs) Phenylketonuria (PKU) •  Deficiency of ______________ hydroxylase •  Cannot convert Phe à Tyr

If we can’t make Tyr, we wont get: -‐  DA -‐  NE -‐  EPI

If we can’t make Melanin, we see: -‐  Light skin -‐  Blonde hair -‐  Blue eyes

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PKU

Accumula9on of the following: à à à ** These account for the musty odor Mgmt: Eliminate _____ from the diet, add _____

Cys9nuria •  Get forma9on of cys9ne stones in the kidney, ureter, & bladder.

Muta9ons in _________ & _________ genes, which encodes for transporter protein in kidney. Findings: -‐  Flank pain -‐  Radia9ng pain to the groin

Mgmt: Fluids to dilate urine / lithotrypsy for big stones

Alkaptonuria

•  Deficiency of Homogen9sic acid oxidase •  Muta9on of ______ gene

Body cannot breakdown _______ & _______. Findings: Urine darkens upon standing (Dx factor) Infant à darkened urine in diaper Adults à Arthri9s, darkening of ear, dark spots on sclera

Galactosuria •  Benign spilling of galactose into the urine •  Deficiency of _______________ enzyme •  Due to muta9on of the _______ gene, located on Chrom _____.

Worrisome complica9on is CATARACTS, caused by accumula9on of ____________ in the lens. Mgmt: If cataracts we remove them… à Eliminate ____________ & ____________ from the diet.

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Galactosemia

•  Deficiency of _________________________ leads to accumula9on of Gal-‐1-‐Phosphate.

Lactase breaks down Lactose into these 2 sugars: 1. 2.

Galactosemia Findings: -‐  Feeding problems -‐  Failure to thrive -‐  Liver damage/failure -‐  Bleeding -‐  Infec9ons

Without treatment, what happens to levels of ammonia? Mgmt: Restrict ______________ in the diet.

Gaucher’s Disease

•  MC lysosomal storage disease •  Dysfunc9onal metabolism of sphingolipids Deficiency of ____________________ enzyme. Defec?ve gene is the _____________________, which is on Chrom 1q21. à See accumula9on of _________________ in the lysosomes.

Gaucher’s Disease Three MC types: Type 1: MC form à  Non-‐neuropathic à  Hepatosplenomegaly

Type 2: Acute infan9le neuropathic à  Within 6 months of birth à  H/S megaly à  Neuro findings

Type 3: Chronic neuropathic form à  From childhood into adulthood à  Slowly progressing neuro sx

Mgmt: Type 1 & 3 = Replace enzyme

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Gangliosidoses

•  Lipid storage disorder whereby lipids are accumulated •  TWO types (GM1 & GM2)

GM1: Deficiency of Beta-‐Galactosidase Early infan?le: Neurodegenera9on, seizure, H/S megaly, coarsening of facial feat., skel abn. Late infan?le: Between 1-‐3 yr, (ataxia, seizure, demen9a, speech difficulty) Adult onset: Muscle atrophy, less severe/slower-‐developing neuro findings

Gangliosidoses

GM 2: Deficiency of Beta-‐Hexosaminidase à Enzyme found in lysosomes à Lipids accumulate in nervous 9ssue (leads to neuro findings)

Hartnup’s Disease Muta9on of _______________ gene on Chrom ____.

Affects absorp9on of non-‐polar AA’s (most importantly: __________) TRP needed because it converts to the following: -‐  Serotonin -‐  Melatonin -‐  Niacin

Hartnup’s Disease Findings: -‐  FTT -‐  Photosensi9vity -‐  Nystagmus -‐  Ataxis (intermitent) -‐  Increased AA in the urine -‐  Pellagra (4 D’s)

Mgmt: High ___________ diet (helps overcome deficiency of neutral AA’s) à Avoid sunlight & drugs that cause photosensi9vity Which drugs cause photosensi9vity?

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Hurler’s Syndrome

•  Lysosomal storage disease •  Defect in the ________ gene which is on Chrom _____.

Buildup of: -‐  GAGs (due to deficiency of _____________) -‐  ____________ & _____________ sulfate.

Hurler’s Syndrome

Findings: -‐  Progressive deteriora9on -‐  H/S megaly -‐  Dwarfism -‐  Progressive mental retarda9on -‐  Death by end of __st decade of life

Mgmt: Enzyme replacement

Krabbe’s Syndrome

•  Defect in sphingolipid metabolism •  Causes degenera9on of _________ sheath in the CNS

Muta?on of ________ gene located on chrom__ Deficiency of _________________ enzyme.

Krabbe’s Syndrome Findings: Start 3-‐6 months auer birth -‐  Irritability -‐  Fever -‐  Seizure -‐  Feeding difficulty -‐  Vomi9ng -‐  Mental/motor regression -‐  Muscle weakness -‐  Spas9city -‐  Deafness -‐  Op9c nerve atrophy

Mgmt: BM transplant

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Maple Syrup Urine Disease •  Deficiency of _________________________ Muta?on in 4 genes: 1.  BCKDHA 2.  BCKDHB 3.  DBT 4.  DLD This enzyme required to breakdown BCAA’s: à à à

Maple Syrup Urine Disease Findings: à Sweet-‐smelling urine -‐  Poor feeding -‐  N/V -‐  Dehydra9on -‐  Lethargy -‐  Hypoglycemia -‐  Ketoacidosis -‐  Neuro findings

Mgmt: Avoid BCAA’s & foods rich in them à Avoid nutrasweet

Metachroma9c Leukodystrophy

•  Lysosomal storage disease •  Deficiency of _______________ enzyme.

à Altered G&D of myelin à Build-‐up of Sulfa9des in 9ssue (destroys myelin sheath in CNS & PNS)

Several forms… focus on: Late infan9le, Juvenile form, Adult form

Metachroma9c Leukodystrophy Late Infan9le: MC form seen -‐  Difficulty walking around 2nd year

Juvenile Form: Between 3-‐10yr of age -‐  Progressive symptoms

Adult Form: Auer 16yr of age -‐  Psych disturbances -‐  Progress to demen9a

Mgmt: NO CURE (terminal illnesses)

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Ataxia Telangiectasia •  Defect in DNA repair genes •  The ______ gene is affected à This gene manages the cell’s response to stress induced _________ breaks.

Findings: -‐  Cerebellar atrophy -‐  Oculocutaneous telangiectasia -‐  Telangiectasia -‐  Immune deficiency -‐  Increased cancer risk

Chediak-‐Higashi Syndrome

à Diagnosed in childhood Nuero defects include: Immunodeficiencies include: Skin findings include:

Leukocyte Adhesion Deficiency

•  Gene9c absence of CD___ •  Disturbs forma9on of Integrins

What are Integrins needed for?

Leukocyte Adhesion Deficiency

Findings: -‐  Late separa9on of _________________ (which is the major sign)

-‐  Poor wound healing -‐  Recurring skin infec9ons -‐  Gingival inflamma9on

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Kartagener’s Syndrome

AKA “primary ciliary dyskinesia” Dynein protein defect leads to dynein arm defect. Findings: Any structure depending on mo9lity is nega9vely affected… -‐  Sperm -‐  Cilia à Situs invertus

Hemochromatosis

•  Muta9on to _____ gene on Chrom ____. •  Abnormally high absorp9on of _____ in the GI

Where is the most important site for HFE gene expression?

Hemochromatosis

Iron overload in the following: -‐  Heart -‐  Pancreas -‐  Liver

TWO most worrisome complica?ons: à Liver cirrhosis à Hepatocellular carcinoma

Wilson’s Disease

•  Toxic accumula9on of Copper •  Muta9on of the _______ gene on Chrom ____

Neuropsych sx: -‐  Parkinsonism -‐  Seizure/migraine -‐  Demen9a

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Wilson’s Disease

Organ-‐specific findings: Eyes: Kayser-‐Fleischer rings (Copper deposi9on in Descemet’s membrane) Heart: Cardiomyopathy Kidneys: Renal tubular acidosis Endocrine: Parathyroid dysfunc9on

Wilson’s Disease Overview of pathophysiology…. Normal physiology: à Copper membrane transporter (CMT1) allows for absorp9on in

stomach & duodenum à Once in the liver is incorporated into an alpha-‐2 globulin (forms

ceruloplasmin).. Via ATP7B protein à Released into plasma as circula9ng Copper

Pathophysiology: à Defect in ATP7B protein à Copper not incorporated into Ceruloplasmin à Copper accumulates in liver (leads to oxida9ve damage)

Wilson’s Disease Making a diagnosis: -‐  Abnormal ______ -‐  Bilirubin is _______ -‐  AST is _______ -‐  Albumin is ____________ -‐  PT is ________________ -‐  Ceruloplasmin levels are _______________ -‐  Serum copper is _____, urine copper is ______ à  Confirm diagnosis when liver sample contains at least _____ug of copper

per gram of dried liver 9ssue.

Mgmt: Diet low in copper-‐containing foods à Copper chelator ___________________ binds to copper and is excreted through the urine.

Sickle Cell Disease

MC AR disease in African Americans Main findings: 1.  Hemolysis 2.  Vaso-‐occlusive sx 3.  Infec9ons

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X-‐linked dominant diseases

•  X-‐linked dominant diseases and transmited through both parents

•  All female offspring of an affected father will be affected

•  Both male and female offspring of an affected female may be affected

X-‐linked dominant inheritance

X-‐linked dominant diseases

•  Alport’s syndrome •  Ret’s syndrome •  Vitamin D resistant rickets/Hypophosphatemic rickets

Alport’s Syndrome

Muta9on of _______, ________, & _________ genes, located on Chrom ____. Muta9ons lead to improper produc9on of type ____ collagen, which is required for basement membrane forma9on. Ini9al presenta9on is ouen ______________.

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Alport’s Syndrome Diagnosis: Based on finding 4/10 criteria… 1.  Bilateral sensorineural hearing loss 2.  Muta9on in COL4An (n=3,4,5) 3.  Family hx of nephri9s 4.  Persistent hematuria 5.  Immunohistochemical evidence 6.  Ocular lesion 7.  Gradual ESRD 8.  Macrothrombocytopenia or granulocy9c inclusinos 9.  Diffuse leiomyomatosis of the esophagus 10.  Glomerular BM abnormali9es

Mgmt: ACEI’s for proteinuria, no known cure.

Ret Syndrome •  MC due to spontaneous muta9nos •  Spora9c cases due to muta9on to the _______ gene, located on the X

chromosome.

Findings: -‐  motor/language regression (at ~ 6-‐18mnth) -‐  Au9sm-‐like behavior

ReZ specific findings: -‐  Inconsolable crying fits -‐  Screaming fits -‐  Emo9onal inversion -‐  Speech regression -‐  Sensa9on problems

Ret Syndrome Symptoms worsen and may include… à Hypotonia à Gait difficulty à Dystonia à Chorea à Bruxism

Mgmt: -‐  Surveillance for back problems -‐  Social skills development/work

Vitamin D Resistant Rickets •  Muta9on in the _______ gene sequence on Chrom Xp___.

•  Leads to inac9vity in the _______ protein.

** Not responsive to vitamin D supplementa9on Males à develop outward bowing of knees Females à inward bowing of legs Mgmt: Oral ____________ + _______________

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X-‐linked recessive diseases

•  No male-‐to-‐male transmission •  Sons of a heterzygous (carrier) mother have a 50% chance of transmission

•  Affected males always pass one diseased x gene to the daughters (makes them a carrier)

•  ONLY MALES ARE AFFECTED

X-‐linked recessive pedigree

Red-‐Green Color Blindness

•  Inability to discriminate red & green hues Cause à Absence of red or green re9nal photoreceptors * Males >>>>> Females

Duchenne Muscular Dystrophy •  Muta9on of ____________ gene, which is located on the ____ chromosome.

•  Codes for protein ___________, an important structural component of muscle 9ssue.

à Dystrophin connects cytoskeleton of each muscle fiber to underlying basal lamina

Microscopically: varia9ons in muscle fiber shape & size, visualize regenera9ng fibers, see increased amounts of connec9ve 9ssue.

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Duchenne Muscular Dystrophy Main PHYSICAL sx: Seen 1st 9me they walk -‐  Eventually lose muscle func9on from neck down Gower’s Maneuver à crawls hands up legs to straighten torso Toe Walking à compensatory adapta9on to extensor muscles of the legs Muscle contractures Progressive walking difficul?es à eventual loss by 12yr Pseudohypertrophy of calves à muscle replaced by faty 9ssue

Duchenne Muscular Dystrophy Diagnosis: -‐  Gower’s sign -‐  Elevated crea9ne kinase -‐  EMG demonstrates muscle weakness (not nerve weakness) -‐  Gene9c tes9ng to ID Xp21 gene errors -‐  Muscle biopsy (ID absence of Dystrophin)

Mgmt: To control sx & improve quality of life -‐  Steroids -‐  Beta2 agonists -‐  No-‐impact ac9vi9es -‐  Orthopedic appliances -‐  Respiratory support

Prognosis: Max 25yr lifespan

Becker’s Muscular Dystrophy •  Similar but less severe than Duchenne •  Muta9on in ____________ gene that encodes Dystrophin Important difference: Only less Dystrophin made (Duchenne there is none made) à Progressive muscle weakness à Toe-‐walking à Modified Gower’s maneuver

Diagnosis: EMG + Check CPK levels

Hemophilia A •  Deficiency of clo�ng factor 8 •  Sx vary with severity

Most serious bleeding occurs into: -‐  Joints -‐  Muscles -‐  GI -‐  Brain

Diagnosis: Increased PTT, normal PT & normal bleeding 9me. Mgmt: Severe cases required IV recombinant or plasma concentrate factor ___. Mild cases managed with _________________, which works by released stored factor 8 from the endothelial walls.

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Hemophilia B •  Muta9on of Factor 9 gene, leading to Factor 9 deficiency •  Less common than Hemophilia A •  Aka “Christmas Disease”

Findings: -‐  Nosebleeds -‐  Easy bruisability -‐  Blood in urine & stool -‐  Excessive bleeding with minor injury

Diagnosis: Low factor 9, abnormal PTT, normal PT & normal bleeding 9me. Mgmt: Infusion of factor ____.

X-‐Linked Mental Retarda9on

•  MC in males •  Around ______ genes involved in this type of mental retarda9on

à In MALES, XL mental retarda9on accounts for around ___% of all cases.

X-‐Linked SCID

•  MCC of SCID •  2nd MCC of SCID is __________________ def. Defec?ve gene à IL2-‐RG, located at ________ on the X chromosome

à Litle produc9on of ___ cells and ____ cells. à Also leads to defect in B cells

Glucose-‐6-‐Phosphate DH Deficiency

•  Disorder of the HMP shunt •  The amount of ____________ produced within the RBCs is

low… impairs ___________-‐mediated inac9va9on of free radicals

Findings: -‐  Hemoly9c anemia

Other Causes: drugs, fava beans, infec9ons Microbiology: Peripheral smear demonstrates ______ cells & Heinz bodies.

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Ornithine Transcarbamoylase Deficiency

•  Is XLR •  Urea cycle defect •  Due to a few muta9ons in OTC gene

à Body cannot eliminate ammonia à Oro9c acid builds up

Ornithine Transcarbamoylase Deficiency

Findings: -‐  Lethargy -‐  Anorexia -‐  Temp/breath regula9on difficulty Mgmt: Low protein diet à Maintain adequate hydra9on à Nitrogen-‐scavenging meds (Sodium Benzoate, Sodium Phenylbutyrate)

à Bio9n supplementa9on

Mitochondrial diseases

•  Transmission is only through the mother •  Father doesn’t pass mitochondrial material •  All offspring of an affected female may show signs of being diseased

Mitochondrial diseases

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High-‐Yield mitochondrial diseases

•  Leber’s hereditary op9c neuropathy •  DM + Deafness (DAD) – a combina9on •  Leigh syndrome •  MERFF syndrome (myoclonic epilepsy with ragged red fibers)

Leber’s Hereditary Op9c Neuropathy

à Any of 3 muta9ons in maternal mitochondrial DNA (ND1, ND4, or ND6) genes of complex 1 of the oxida9ve phosphoryla9on chain •  Degenera9on of re9nal ganglion cells & their axons

•  Leads to acute or subacute loss of central vision

Leber’s

Findings: -‐  Acute onset of visual loss (one eye at a 9me) -‐  Usually in younger adults -‐  Females present 5yr earlier than males -‐  Severe op9c atrophy + permanent visual acquity disturbances

Mgmt: Idebenone

DAD Syndrome

•  Associated with ___________ gene Causes: -‐  DM -‐  Sensorineural deafness

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Leigh Syndrome

à AKA ‘subacute necro9zing encephalomyelopathy’

à _______-‐1 gene is affected

Findings: -‐  Dystonia -‐  Motor findings (tremor, rigidity, chorea) -‐  Later finding is renal/resp impairment

MERFF Syndrome •  Several genes involved à MT-‐TK, MT-‐TL1, MT-‐TH, MT-‐TS1, MT-‐TS2, MT-‐TF

Findings: -‐  Progressive myoclonic epilepsy -‐  Ragged red fibers -‐  Hearing loss -‐  Lac9c acidosis -‐  Short stature -‐  Exercise intolerance

Mgmt: No cure

TRINUCLEOTIDE REPEAT DISORDERS

Trinucleo9de repeat disorders •  Diseases that result from trinucleo9de repeat expansions

•  The genes are expanded beyond the point which allows them to be stable

•  Trinucleo9de repeat disorders demonstrate the phenomenon of ‘an9cipa9on’

An?cipa?on: MOA:

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MC trinucleo9de repeat diseases

•  Hun9ngton’s disease (discussed earlier) •  Spinocerebellar ataxia •  Fragile x syndrome •  Friedreich’s ataxia •  Myotonic dystrophy (DM1 = trinucleo9de, DM2 = tetranucleo9de)

Spinocerebellar Ataxia

•  Several varia9ons of this disease •  Many genes involved (SCA1, SCA2, SCA3) •  All forms of the disease are polyglutamine diseases (CAG repeat)

•  Both AD varie9es & AR varie9es

Spinocerebellar Ataxia Findings: -‐  Slow progression of uncoordinated gait -‐  Poor coordina9on of hands/speech/eyes -‐  Inten9on tremor -‐  Cerebellar atrophy -‐  Lack of fine-‐motor coordina9on

Mgmt: no defini9ve cure à Manage symptoms as they occur

Fragile X Syndrome

•  MCC of mental retarda9on in males •  2nd MCC of congenital mental retarda9on (auer Down’s)

•  Due to expansion of the ______ trinucleo9de repeat on the _______ gene, on the _______ arm of the X chromosome

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Fragile X Syndrome Findings: -‐  Short-‐term memory deficits -‐  Visual memory deficits -‐  Visual-‐spa9al rela9onship difficul9es •  Verbal abili9es rela9vely normal

Other Findings: -‐  Mild to severe mental retarda9on -‐  Elongated face -‐  Short height -‐  Joint laxity -‐  Scoliosis -‐  High-‐arched palate -‐  Large protruding ears -‐  Hypotonia -‐  Macroorchidism -‐  MVP

Friedreich’s Ataxia •  GAA repeats of the _____ gene •  Affects the _____________ protein, which is an iron-‐binding protein

•  Sclerosis & degenera9on of the dorsal root ganglion, spinocerebellar tracts, lateral CS tracts, & posterior columns

What does a low level of Frataxin lead to? Where is the primary site of pathology?

Friedreich’s Ataxia Signs & Anatomical Problems: In the limbs à Dorsal columns à LMN lesions à Pyrimidal à Cerebellar findings à Cardiac à Endocrine à Skeletal à * Death on average by 35th year of age

Myotonic Dystrophy

•  Chronic, slow-‐progressing, mul9systemic •  2 types (1 = Steinert disease, 2 = Proximal myotonic myopathy)

Characterized by: -‐  Muscle was9ng -‐  Cardio/endocrine/visual disturbances

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Myotonic Dystrophy Type 1: Steinert’s disease -‐  Affected gene is the _______ gene on the long arm of Chrom _____

-‐  Encodes the myotonic dystrophy protein kinase -‐  CTG triplet repeat

Type 2: PROMM -‐  Defect in the ______ gene on Chrom ____ -‐  Tetranucleo9de repeat disorder of CCTG nucleo9des

MONOSOMIES & TRISOMIES

MONOSOMIES – Turner Syndrome •  45XO (one x chromosome is missing) •  MCC is non-‐disjunc9on

Common findings: à à à à à

MONOSOMIES – Cri-‐du-‐chat syndrome

•  Par9al dele9on of short arm of chromosome 5 •  MCC by spora9c muta9on

Findings: à à à à à à

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TRISOMIES – Patau Syndrome

•  Extra copy of chromosome 13 •  Caused by Robertsonian transloca9on

Findings: à à à à

TRISOMIES – Edward’s Syndrome

•  Trisomy 18 •  Rocker-‐botom feet

Findings: à à à à

TRISOMIES – Down’s Syndrome

•  Trisomy 21 •  MC chromosomal abnormality •  2nd MCC of mental retarda9on

à Triple test at 16-‐18 weeks gesta9on… we are looking for low levels of ____________

Organ-‐Specific Findings… Cardiac :

Vascular: Cancer:

Thyroid:

Gastrointes9nal:

Infer9lity:

Neurological:

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Klinefelter Syndrome •  47XXY karyotype •  Due to meio9c non-‐disjunc9on during gametogenesis

Will cause: à Eunuchoid body habitus: à Cogni?ve findings: à

DiGeorge Syndrome

•  Dele9on of long arm of chromosome 22 (22q11.2) •  Thymic aplasia and failure of parathyroid forma9on •  Caused by defec9ve embryonic development of the 3rd and 4th pharyngeal pouches

Findings: Ini?al presenta?on: CATCH 22:

IMPRINTING

HY Imprin9ng

Beckwith-‐Wiedemann: Angelman syndrome: Prader-‐Willi:

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ALZHEIMER’S DISEASE

Alzheimer’s Disease •  Early onset (<60yr) •  Late onset (>60yr)

Muta?ons associated with early onset: 1. 2. 3. Muta?ons associated with late onset: à ε4 allele of Apolipoprotein E (causes senile plaques)

HARDY-‐WEINBERG GENETICS

Assump9ons

In order to maintain HW equilibrium, we assume the following: 1. 2. 3. 4.

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Major viola9ons to the HW equilibrium

Inbreeding: Small pop’n size: Assor9ve ma9ng:

Hardy-‐Weinberg Equilibrium

HWE p = q = p^2 = q^2 = 2pq =

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