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CV Final Material > Inherited CV Disease > Flashcards

Inherited CV Disease Flashcards

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1
Q

Central Dogma of genetics?

A

Cells have chromosomes which have genes on them which are made of DNA!!!! The DNA can be transcribed and translated into protein!

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2
Q

What is a proband?

A

person who is central to the family history/pedigree

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3
Q

What is autosomal dominant inheritance?

A
  • Gene is located on one of the non-sex chromosomes
  • Single copy of the gene mutation can cause disease
  • Affected parents have a 50% chance of having an affected child
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4
Q

What is autosomal recessive inheritance?

A
  • Gene is located on one of the non-sex chromosomes
  • Two copies of gene are mutated, causing disease
  • Parents with an affected child are carriers
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5
Q

What is x-link recessive inheritance?

A
  • Gene is located on the X chromosome

* Carrier mothers have a 50% chance of having an affected son and 50% chance of having a carrier daughter

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6
Q

What is genetic penetrance?

A

the proportion of individuals with a particular genetic variant who exhibit signs and symptoms of the genetic disorder

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7
Q

What happens in reduced genetic penetrance?

A

Less than 100% of individuals with a certain genotype actually express signs or symptoms

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8
Q

What is variable expressivity?

A

the signs and symptoms of a genetic condition differ among affected individuals

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9
Q

What is genetic heterogeneity?

A

a genetic disorder can be caused by more than one mutation in an allele

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10
Q

What is genetic pleiotrophy?

A

genetic variants in a particular allele can cause several signs or symptoms

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11
Q

What form of genetic inheritance do inherited CV diseases usually follow?

A

autosomal dominant

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12
Q

What are the 5 general categories of inherited CV disease?

A
  1. arrhythmia
  2. cardiomyopathy
  3. aneurysm syndromes
  4. familial hypercholesterolemia
  5. pulmonary arterial hypertension
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13
Q

What are some inherited arrhythmias?

A

– Long QT syndrome (LQTS)
– Brugada syndrome
– Catecholaminergic polymorphic ventricular tachycardia (CPVT)
– Familial atrial fibrillation

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14
Q

What are some inherited cardiomyopathies?

A 
– Hypertrophic cardiomyopathy (HCM)
– Dilated cardiomyopathy (DCM)
– Restrictive cardiomyopathy (RCM)
– Arrhythmogenic right ventricular dysplasia/cardiomyopathy(ARVD/C)
– Left ventricular noncompaction (LVNC)
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15
Q

What are some inherited aneurysm syndromes?

A

– Familial thoracic aortic aneurysm and dissection syndromes
– Marfan, Loeys-Dietz, and other connective tissue disorders
– Familial coronary artery disease and dyslipidemias
– Autosomal dominant polycystic kidney disease

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16
Q

What is the general cause on inherited arrhythmias?

A

channelopathies

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17
Q

What are clinical findings with arrhythmias?

A
  • Patients may be affected at any age
  • Syncope, sudden cardiac death (SCD) and sudden infant death syndrome (SIDS) are common findings
  • Distinct ECG patterns clarify disorders
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18
Q

What is the prevalence of long QT syndrome?

A

1:3,000 – 7,000

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19
Q

What do you see on an EKG for LQTS?

A

• Clinically identified by prolonged QT interval and T wave abnormalities on ECG and torsade de pointes (TdP)

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20
Q

How do LQTS pt present?

A

• Presents with syncope and SCD due to ventricular tachyarrhythmias, typically torsades de pointes (TdP)
– TdP also may cause seizures
– Syncopal episodes usually occur during exercise or high emotions, not as often during rest or sleep

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21
Q

What are two congenital causes of LQTS?

A

– Romano-Ward syndrome (RWS)

– Jervell and Lange-Nielson syndrome

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22
Q

What are some aquired causes of LQTS?

A

– Primary myocardial problems: myocardial infarction, myocarditis, cardiomyopathy
– Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia
– Autonomic influences
– Drug effects
– Hypothermia

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23
Q

How long does the QT interval have to be before you are sure it is LQTS?

A

> 470 msec in males

>480 msec in females

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24
Q

What is Romano-Ward syndrome (RWS)?

A
  • Primary electrophysiologic disorder due to ion channel abnormalities
  • Autosomal dominant disorder with Reduced penetrance: 50% of individuals with a disease-causing mutation will not show symptoms & heterogeneity: 10 genes known to be associated with RWS
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25
Which channelopathy is most common in RWS?
K channel in >60%
26
What treatments are available to pt with LQTS?
* Beta blockers * Pacemakers * Access to defibrillators * Implantable cardioverter-defibrilators (ICDs) for individuals resistant to medications
27
What is Jervell and Lange-Nielson syndrome?
Congenital, profound, bilateral sensorineural deafness and QT prolongation often >500 ms – increased risk for SIDS & >50% of untreated children with JLNS die prior to age 15
28
How is Jervell and Lange-Nielson syndrome inherited?
Autosomal recessive inheritance – 2 genes known to be associated with JLNS (KCNQ1 causes 90%)
29
Why do you genetic test for LQTS?
* Molecular confirmation of a clinical diagnosis in symptomatic individuals * Risk assessment of asymptomatic family members of a proband with arrhythmia * Differentiation of hereditary arrhythmia from acquired arrhythmia * Recurrence risk calculation
30
What is the current detection rate for RWS with genetic testing?
75%
31
Does a negative genetic test rule out a genetic cause?
No!!! There could still be other unidentified genes
32
What percentage of RWS pt will have two genetic mutations?
up to 10%
33
What is brugada syndrome?
* Cardiac conduction abnormalities ST-segment elevation in the right precordial leads (V1-V3), high risk for ventricular arrhythmias * Presents as syncope, SIDS or sudden unexpected nocturnal death syndrome (SUNDS)
34
What is the prevalence of brugada syndrome?
1:2000
35
What is the best way to diagnose brugada?
75% of cases are based on clinical history and ECG results
36
What is the major genetic defect in brugada?
Majority occur in SCN5A (alpha subunit of cardiac sodium channel) and 25-30% of cases are found to have a gene mutation in 16 genes encoding ion channels
37
What is Catecholaminergic polymorphic ventricular tachycardia (CPVT)?
* Prevalence: 1 in 10,000 * Distinct bidirectional or polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and cause sudden death
38
How does CPVT present?
Syncope caused by exercise or acute emotion in an individual without structural heart disease
39
What genes are important for CPVT?
55-65% of cases will have a gene mutation in the RYR2 (cardiac ryanodine receptor channel) or CASQ2 (calsequestrin, calcium buffering protein of the sarcoplasmic reticulum) genes
40
How are RYR2 and CASQ2 genes of CPVT inherited?
– RYR2 are inherited in an autosomal dominant | – CASQ2 are inherited in an autosomal recessive
41
Should we use single gene testing or genetic panels when looking for arrhythmia genes?
moving toward panels which have become more cost effective and allow for sequencing of multiple genes
42
What are the 4 main proteins that can be mutated in cardiomyopathies?
cytoskeletal desmosomes sarcomeres nuclear envelope proteins
43
What is cardiomyopathy?
• Diseases of the myocardium – Causes the heart to become enlarged and dilated, thickened, and/or stiffened – Weakens the heart causing it to becomes inefficient and incapable of pumping blood and maintaining a normal rhythm – This can lead to heart failure, arrhythmia or sudden death
44
What is among the leading indications for heart transplant?
cardiomyopathy >26,000 deaths in the United States per year
45
How is cardiomyopathy diagnosed?
Diagnosed based on echocardiogram and ECG
46
What is the prevalence of hypertrophic cardiomyopathy (HCM)?
Prevalence: 1:500
47
What is a major cause of sudden cardiac death (SCD) in the young (<30 years of age) and most common cause of SCD in young athletes?
HCM
48
When do we diagnose HCM?
Unexplained left ventricular hypertrophy (LVH) in the absence of another cardiac or systemic disease (e.g. hypertension or aortic stenosis)
49
How does HCM usually present?
Clinical spectrum is diverse with variable age of onset – Typically includes chest pain, exertion-related dyspnea, or syncope – Others experience progressive exercise intolerance, thromboembolic disease, heart failure or unexpected SCD – Majority of individuals remain asymptomatic
50
HCM is a disease of what structures in the heart?
sarcomeres 50-60% of individuals with a family history of HCM will have a sarcomere gene mutation & 20-30% of individuals without a family history of HCM will have a sarcomere gene mutation
51
In HCM, there is some genotype-phenotype correlations what are they?
– MYH7: classic presentation – MYBPC3: later age of onset – TNNT2: mild or absent LVH, higher risk for arrhythmia, SCD
52
What is the most common gene mutation for HCM?
beta myosine heavy chain (MYH7) and myosin binding protein C (MYBPC3) in about 70% of all HCM
53
When does dilated cardiomyopathy (DCM) usually occur?
Clinical onset usually occurs in the adult years (30s to 50s) but varies widely, occasionally even presenting in infants, small children, and the elderly
54
What are the clinical features of DCM?
``` congestive heart failure reduced CO arrhythmia/conduction system disease thromboembolic disease some pt have muscle weakness or dystrophy ```
55
What are the general causes of DCM?
* Acquired * Idiopathic DCM: after exclusion of all identifiable causes (except genetic) * Familial DCM: two or more closely related family members that meet the criteria for idiopathic DCM
56
What are some aquired causes of DCM?
``` – Ischemic injury from myocardial infarction (MI) or coronary artery disease (CAD) – Congenital heart disease – Toxins – Thyroid disease – Inflammatory conditions – Myocarditis – Severe chronic hypertension (HTN) – Radiation – Iron overload ```
57
What kind of inheritance does DCM usually show?
Majority of cases show autosomal dominant inheritance – but can also have X-linked, autosomal recessive and mitochondrial inheritance
58
Is DCM causes by a certain genetic mutation?
Extensive genetic heterogeneity with mutations in more than 20 genes involved in the sarcomere, Z-disc, nuclear lamina, intermediate filaments, sarcoplasmic reticulum, desmosome and dystrophin-associated glycoprotein complex
59
LMNA mutation can lead to DCM how?
Prominent conduction disease, with or without supraventricular or ventricular arrhythmias, leading to DCM and heart failure
60
LMNA has pleiotrophy what other diseases it involved in?
``` – Muscular dystrophy: Skeletal muscle involvement indicated by elevated creatine kinase – Neuropathy – Lipodystrophy – Hutchinson-Gilford Progeria syndrome – brachydactyly ```
61
How do you manage/treat cardiomyopathy?
* Pharmacologic therapy – ACE inhibitors & Diuretics * Lifestyle modifications– Avoiding competitive sports & Healthy lifestyle * Mechanical devices: pacemakers, ICD * Surgical intervention like Septal myectomy & Alcohol ablation * Cardiac transplantation
62
How does familial hypercholesterolemia present?
• Significant elevationsin total serum cholesterol and LDL cholesterol early in life – Xanthomas : yellowish cholesterol-rich material in tendons or other body parts – Atheromas: accumulation of debris containing cholesterol in the artery walls (plaques)
63
Is FH common?
yes! Prevalence 1:200-500
64
What are cholesterol levels like in untreated pt with FH?
* Untreated adults: LDL-C > 190 mg/dL or total cholesterol > 310 * Untreated children/adolescents: LDL-C > 160 mg/dL or total cholesterol > 230
65
How is total cholesterol in pt with homozygous FH?
really bad total cholesterol > 500 mg/dL
66
What does FH predispose pt to?
Premature coronary heart disease (CHD) and CVD
67
What is the inheritance pattern for FH?
Autosomal dominant (HeFH) and autosomal recessive (HoFH) inheritance – Homozygotes have earlier age of onset and more severe disease
68
What gene is most commonly mutated in FH?
LDLr in 60-80% of cases
69
How do you treat pt with FH?
* Risk-factor modification before onset of disease – Diet/lifestyle changes * Pharmacotherapy: statin – HoFH not responsive to monotherapy; multiple medications and apheresis * Early screening and therapy for elevated cholesterol levels
70
What are ethical, legal and societal implication of genetic testing?
* Diagnostic testing vs predictive testing * Privacy of genetic information * Insurance discrimination – GINA 2008 * Psychosocial impact * Genetic testing in children * Uncertainty in interpreting results and utility for clinical management
71
When do you suspect hereditary component to a CV disease?
– Common diseases that present at younger ages with a more severe or progressive phenotype – Family history: Non-traditional autosomal dominant inheritance, Incomplete penetrance, Variable expression
72
What are benefits of genetic testing?
– Provides risk information for individuals and families – Provides information useful for medical management – Leads to early detection and minimize complications – May relieve anxiety
73
What are risks of genetic testing?
– Emotional (increased fear/anxiety) | – Insurance discrimination: State and Federal Laws
74
What are the limitations of genetic testing?
– Genetic testing is not able to detect all causes of cardiovascular disease – Continued risk for cardiovascular disease – Some management strategies not proven effective

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