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Genetics > Lecture 8: cardiovascular/melanoma > Flashcards

Lecture 8: cardiovascular/melanoma Flashcards

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1
Q

Hereditary Cardiomyopathy

A
  1. Cardiomyopathy: any condition in which the heart muscle is dysfunctional
  • increased risk for arrythmias and sudden cardiac death
  • categorized based on pathologic features of the heart tissue
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2
Q

2 most common types types hereditary cardiomyopathy

A
  1. familial hypertrophic cardiomyopathy (HCM)

2. arryhtmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)

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3
Q

Familial Hypertrophic Cardiomyopathy (5)

A
  1. A portion (typically the left ventricle) of the myocardium is hypertrophied (thickened)
  2. functional impairment cardiac muscle
  3. leading cause of sudden cardiac death in young athletes
  4. asymptomatic until sudden cardiac death
  5. dyspnea on exertion palpitations, chest pain and syncope
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4
Q

Diagnosis HCM (6)

A
  1. difficult
  2. personal and family hx 3. fatigue, arrhythmias, palpitations, presyncope, syncope, chest pain
  3. any of the above symptoms in someone 35 years or younfer
  4. family hx of sudden cardiac death
    - or unexplained death in first degree relative
  5. family hx of heart failure, hypertrophic cardiomyopathy, heart transplant, stroke, or blood clots in important in evaluation
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5
Q

Physical exam may reveal S4 heart sounds (3)

A
  1. S1: “lub” the sound produced during the closing of the AV valve
  2. S2: “dub” sound produced during closing of the semilunar valves
  3. S4: is a low-pitched sound immediately before S1
    - caused by stiffening of the walls of the ventricles-abnormally turbulent blood flow as atria contract to force blood into the ventricle
    - S4 usually inaudible
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6
Q

Familial Hypertrophic Cardiomyopathy Genetics (4)

A
  1. inherited as an autosomal dominant trait
  2. attributed to gene encoding sarcomere proteins
    - over 20 genes discovered
  3. genes most commonly responsible
    - MYH7
    - MYBPC3
    - TNNT2
    - TNNI3
  4. some mutations may have more malignant potential than others
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7
Q

sarcomere

A

basic unit of muscle

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8
Q

screening for HCM (3)

A
  1. electrocardiogram
  2. echocardiogram
  3. cardiac magnetic resonance image (CMR) is considered the gold standard for determining the physical properties of the left ventricular wall
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9
Q

Genetic testing HCM (5)

A
  1. 12 genes are commonly linked to HCM and mutation carriers should undergo close surveillance
  2. identify mutation in proband
  3. test at risk relatives
  4. mutation status cannot predict
    - age of onset
    - contellation or severity of symptoms
  5. mutation status can identify people who require close surveillance
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10
Q

Management and Treatment HCM (6)

A
  1. primary goal is to prevent arrhythmias, syncopal episodes and sudden cardiac death
  2. pharmacological therapies
  3. implantable defibrillators
  4. patients in atrial fibrillation-antigoaculation therapy to prevent thromboembolism
  5. avoid endurance training
  6. heart transplant
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11
Q

Arrhythmogenic Right ventricular dysplasia/cardiomyopathy ARVD/C (7)

A
  1. replacement of normal heart tissue in the right ventricle by fibrous, fatty tissue
  2. weakened muscle and impaired contractility
  3. arrhythmias, palpitations, chest pain and syncope
  4. increased risk for sudden cardiac death
    - second leading cause after HCM
  5. more common in individuals under 35
  6. autosomal dominant/rare form of autosomal recessive
  7. incidence is 1/1,000 in overall population
    - 4.4/1,000 in southern US and certain mediterranean populations
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12
Q

4 clinically observable phases of ARVD/C distinguished (4)

A
  1. concealed phase
  2. symptomatic arrhythmias
  3. right ventricular failure
  4. complete pump failure
    - left ventricular involvement can occur in any of these phases, there is risk for sudden cardiac death in all phases
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13
Q

PE ARVD/C (6)

A
  1. normal in at least 50% patients
  2. major diagnostic clue-extra heart sound such as a wide-split S2 or the presence of S3 or S3
  3. characteristic ECG findings are evident in as many of 90% affected individuals
  4. dilation of R ventricle can cause asymmetry of the chest wall
  5. pt diagnoses with ARVD/C are normally between 19-45
    - majority male
  6. diagnosis involved assessment of structural alterations, level of heat dysfunction, tissue characterization of family hx
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14
Q

Genetic Testing ARVd/C (5)

A
  1. 8 genes known to be assoc.
  2. autosomal dominant inheritance pattern
    - rarely autosomal recessive in families from greece
  3. testing for at risk individuals is routinely performed once a mutation is identified in a proband
  4. 1st degree family members of a proband should undergo initial screening with the onset of puberty and follow up exams every 2-3 years
  5. management same as with HCM
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15
Q

Phenotypic Features Marfan Syndrome (9)

A
  1. tall stature, long thin arms and legs
  2. spider-like features
  3. arm pan exceeds body height
  4. elongated, narrow face
  5. high arched palate, overcrowded teeth
  6. scoliosis
  7. hyperflexible joints
  8. chest deformities
  9. ocular disorders: myopia, lens displacement, cataracts, glaucoma
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16
Q

Genetics Marfan Syndrome

A
  1. FBN1: encodes fibrillar 1
    - comines with other structural proteins to form microfibrils
    - regulates growth and repair of various body tissues
    - -lend strength and flexibility to all connective, load bearing tissues
    - –fbn1mutations accompanies by excessive TGF-Beta signaling
  2. FBN1 is at 15q21.1
  3. mutation created abnormal protein
  4. FBN1 mutations vary widely among affected families and are scattered across gene
    - genetic heterogeneity
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17
Q

Genetic’s Marfan’s pt. II

A
  1. penetrance 100%
  2. variable expressivity is the degree of variation in symptoms assoc with disease
  3. marfan syndrome autosomal dominant
  4. genotypes other than mutations in FBN1 can cause phenotypic features similar to those found in marfan syndrome
18
Q

Loeys-Dietz Syndrome

A

syndrome involving mutation in TGF(beta)R2

-receptor protein of TGF-beta

19
Q

Genocopy

A

genotype that determines a phenotype which closely resembles the phenotype determined by a different genotype

20
Q

Dx Marfan syndrome

A
  1. based on family hx and the following physical examination findings
    - aortic dilation of dissection level of sinuses of valsalva
    - ectopia lentis
    - presence systemic features
21
Q

Genetic Testing and Counseling (3)

A
  1. utility of molecular genetic testing for FBN! mutation
    - component of clinical diagnosis
    - for prenatal diagnosis
    - predictive testing in families with known mutations
  2. clinical evaluation: medical history, family history, echocardiogram, when high suspicion for Marfan
  3. genetic studies
    - linkage analysis for families in which FBN1 mutation has been previously identified
22
Q

Management and treatment of marfan syndrome

A
  1. CV surveillance-manual echocardiograms or more frequent when the aortic root diameter is known to be enlarges above the threshold
    - exceeds expected rate of enlargement or aortic regurgitation develops
  2. avoidance of contact sports, isometric exercise, caffeine, and decongestants
  3. avoidance of breathing against resistance
    - playing brass instruments
  4. avoid negative-pressure ventilation for those at risk of pneumothorax
  5. drugs to lower BP to protect aorta
  6. surgical repair aorta, retina, breastbone
  7. correction for scoliosis
23
Q

Polycystic Kidney Disease

A
  1. genetic d/o where abnormal cysts develop and grow in kidneys
  2. multisystem d/o-cysts occur in liver, seminal vesicles, pancreases, arachnoid matter
  3. vascular anomalies-intracranial aneurysms as well as aortic dilation and mitral valve prolapse
    - 1:1,000
24
Q

Genetics PCKD

A
  1. ADPKD-autosomal dominant inheritance
  2. mutations in PKD1 and PKD2 genes produce abnormal proteins os polycystin-1 and polycystin-2
    - form protein complexes in primary cilia or renal tubules, cardiac, myocytes and myofibroblasts of heart valves and vessles
  3. 85% autosomal dominant disease expression is attributable to mutations in PKD-1 and 15% PKD-2
  4. 5% de novo mutations
25
Q

PKD-1

A

lies on chromosome 16

-mutations more severe clinically and earlier onset than PKD2

26
Q

PKD-2

A

Lies on chromosome 4

27
Q

Polyscystin 1 & 2

A

likely work together to help regulate cell growth and division, cell movement and interactions with other cells

28
Q

Environmental factors influence penetrance (4)

A
  1. hypertension before age 35
  2. hematuria before age 3
  3. hyperlipidemia at any age
  4. coexistence of sickle cell trait
29
Q

Other factors influencing presentation

A
  1. genetic modifier
    - ex sickle cell
  2. homozygous expression= spontaneous abortion
  3. penetrance is high: highest risk for PKD1 mutations
30
Q

Genetic modifer

A

inherited genes that alter expression of mutated genes

31
Q

anticipation

A

prediction of worsening disease due to the increased in the number of repeated units of the defective gene
-triplet repeat expansion

32
Q

Adult dx criteria PCKD with NO family hx (3)

A
  1. at least 2 unilateral or bilateral cysts in individuals < 30 years old
  2. 2 cysts in each kidney in individuals 30-39 years old
  3. 4 cysts in each kidney in individuals > 60 years old
33
Q

Dx criteria adults with positive family Hx (5)

A
  1. enlarged kidneys noted on physical exam
  2. enlarged liver noted on physical exam
  3. hypertension
  4. mitral valve prolapse
  5. abdominal wall hernia
34
Q

Children dx criteria PCKD

A
  1. large echogenic kidneys without distinct macroscopic cycts
    - regardless family hx
35
Q

Genetic testing and counseling PCKD (3)

A
  1. testing available for family members of patients with documented mutations
    - include prenatal testing of amniotic fluid
  2. testing indicated for relatives of proband in end stage renal disease when screening relatives for living-donor kidney transplant
  3. genetic counseling indicated for affected individuals and those as risk for PCKD due to a positive family hx
36
Q

Management and treatment PCKD(5)

A
  1. depend on disease manifestations at diagnosis
  2. lifestyle modifications and pharmacotherapy to treat hypertension
  3. renal-protective drugs-angiotensin-converting enzyme (ACE) inhibitors of angiotensin II receptor blockers (ARBS)
  4. decrease diatary protein consumption
  5. pain management
37
Q

Malignant Melanoma predictors (5)

A
  1. light complexion, inability to tan
  2. red hair
  3. number atypical nevi > 10
  4. anatomic location of atypical nevi, especially back
  5. freckles
38
Q

Genetics of Melanoma-familial atypical multiple mole and melanoma syndrome (FAMMM) (3)

A
  1. AKA dysplastic nevus syndrome (DNS) and atypical mole syndrome (AMS)
  2. characterized by the appearance of a large number of dysplastic nevi or atypical moles at an early age in combination with MM
  3. CDKN2A- 2 potential isoforms-mutations in either isoform of both can lead to melanoma susceptibility
39
Q

Genetics MM (4)

A
  1. mutation in CDKN2A affects development of melanoma
  2. 2 main transcripts encode INK4A and p14ARF
  3. INK4A controls progression through G1-S transition of the cell cycle
  4. ARF stabilized tumor suppressor protein p53
40
Q

CDK4

A

Gene involved in FAMM

-also involved in G1-S transition

41
Q

MC1R

A

melanocortin 1 receptor

  • found on surface of melanocytes
  • red hair and freckles assoc. with certain alleles of MC1R
  • phenotype is assoc. with increased rx MM

Genetics (14 decks)

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