S1M3 Genetics of Cardiopathies

  1. What are the five subtypes of cardiomyopathies?
    • hypertrophic cardiomyopathy
    • dilated cardiomyopathy
    • glycogen cardiomyopathy
    • restrictive cardiomyopathy
    • arrhythmogenic right ventricular cardiomyopathy
  2. What is a very common cardiomyopathy characterized by the absence of an increased load?
    NO change in the systolic pressures but impaired dystolic function
    • Hypertrophic cardiomyopathy
    • Assymmetrical in 2/3 of cases, septum is typically where the hypertrophy is located.
  3. Hypertrophic cardiomyopathy can be thought of as a disease of what component of the cardiac muscle?
    • The SARCOMERE!
    • It is an immense protein (z line to z line), consisting of thick/thin filaments which needs ATP and calcium to slide by one another.
    • Also needs to be anchored by dystrophin!
  4. What are the three most common gene mutations that result in familial hypertrophic cardiomyopathy?

    KNOW THESE THREE! If someone has a thickend ventricular septal wall, they probably have one of these cardiomyopathies!
    • B-myosin heavy chain -(50%)-part of the myosin motor unit
    • Cardiac troponin T - anchors troponins to tropomyosin
    • Cardiac myosin-binding protein C-anchors myosin to titin
  5. Your familial hypertrophic cardiomyopathies are examples of what type of heterogeneity?
    locus heterogeneity!

    Which remember is a single trait or disorder that is caused by mutations to genes at different chromosomal locations.
  6. What is allelic heterogeneity?
    Different mutations at the same locus or same gene that result in the same disorder.
  7. ***Some mutations of sarcomere proteins enhance contractile function and cause hypertrophic cardiomyopathy while others reduce the production of contractile force causing __________cardiomyopathy.
    • Dilated cardiomyopathy.
    • Example of locus heterogeneity, which is mutations of different genes at different loci that cause the same condition.
  8. A 25 year old comes into your office and has SOB and chest pain. The echocardiogram reveals thickened ventricular septal wall of 3.2 cm. What gene is mostly likely mutated?
    • Cardiac troponin T
    • B-myosin heavy chain
    • Cardiac myosin-binding protein

    CBC = your familial hypertrophic cardiomyopathies!!!!
  9. What are the clinical characteristics of Dilated cardiomyopathy (DCM)?
    • Left Ventricle Chamber Enlargement
    • Systolic Dysfunction
    • Normal or modest increase in ventricular wall thickness
    • 35% cases familial, so inherited, associated with 24 different loci/genes
    • Associated with life threatening atrial or ventricular arrhythmias!!!
  10. Dilated cardiomyopathy (DCM) mutations affect what part of the muscle?
    Mutations to the cardiac myocyte skeleton!


    Think the proteins that connect the sarcomere (z-z) to the sarcolemma and ECM to TRANSMIT force generated during contraction.
  11. Dilated cardiomyopathy (DCM) mutations...what do you need to think of?
    Disease of the cardiac (myocyte cytoskeleton) connecting the sarcomere to the sarcolemma and ECM.
  12. What is a glycogen cardiomyopathy?

    What is a common feature?
    • results from defects in genes of metabolism associated with the lysosome!
  13. What are the histological characteristics of glycogen cardiomyopathy?
    • Myocyte and myofiber disarray
    • Myocye hypertrophy
    • Fibrosis
    • ***Myocte vacuoles contain glycogen!
  14. What is characteristic of the myocytes in glycogen cardiomyopathy?
    • The contain lots of GLYCOGEN (because it is a lysosomal disease)
    • Myocytes/myofibers are in disarray!
    • Myocytes are hypertrophied!
    • Fibrosis
    • Causes electrophysiological dysfunction
  15. What are the four types of glycogen cardiomyopathies?
    • Pompe Disease
    • Danon Disease
    • Fabry Disease
    • PRKAG2
  16. What protein do you lack in Pompe disease?
    • recessively inherited deficency of lysosomal acid a-1,4-glucosidase (GAA)
    • POMPE think GAA...a-1,4-glucosidase

  17. What type of cardiomyopathy is Pompe disease?
    • It is a glycogen cardiomyopathy, resulting from defects in genes associated with lysosomes!
    • So you get glycogen deposition!
  18. Danon disease is what type of cardiomyopathy and is a lack of what protein?

    Autosomal or X linked?
    • It is a glycogen cardiomyopathy, it's X-linked
    • lysosome-associated membrane protein (LAMP2) deficency.
  19. Fabry disease is a lack what protein?

    • It is a glycogen cardiomyopathy, X-linked
    • lysosomal hydrolase a-galactosidase A (GLA) deficency.
  20. What is one glycogen cardiomyopathy that is cardiac specific? (has no extracardiac manifestations)
    PRKAG2--associated with glycogen storage disease, encodes the gamma-2 subunit of AMPK (AMP activated protein kinase)

    You get a build up of glycogen stores!!
  21. What is fabry disease's effect on the heart? on the skin?
    • Causes dilated cardiomyopathy (left ventricular)
    • Causes angiokeratomas on the leg, tiny, painless papules on the leg
  22. Danon disease is a lack of what protein?

    • Think Danon's LAMP
    • Lysosomal Associated Membrane Protein.
  23. What disease is due to a lack of a-1,4-glucosidase?
    Pompe Disease (glycogen cardiomyopathy)
  24. What disease is due to a lack of lysosome-associated membrane protein (LAMP2)?
    Danon's disease
  25. What disease is due to a lack of hydrolase a-galactosidase A (GLA)?
    Fabry's disease

    it is a glycogen cardiomyopathy!
  26. What disease is due to a lack of the gamma 2 subunit of the AMP-activated protein kinase (AMPK)?
    • PRKAG2
    • This disease is cardiac specific (gamma 2 is cardiac specific)
  27. What is characteristic of restrictive cardiomyopathy (RCM)?
    • bi-atrial enlargement
    • Impaired ventricular filling with restrictive physiology!
  28. What cardiomyopathy is characterized by bi-atrial englargement and impaired ventricular filling?
    Restrictive cardiomyopathy
  29. What cardiomyopathy is associated with a mutation to cardiac troponin I (TNNTI3)
    restrictive cardiomyopathy (RCM)
  30. Restrictive cardiomyopathy is associated with a mutation to?
    • cardiac troponin I (TNNTI3)
    • causes bi-atrial enlargement
    • impaired ventricular filling
  31. What cardiomyopathy involves the progressive loss of myocytes with fatty or fibrofatty tissue replacement in the RIGHT ventricle?
    Arrhythmogenic right ventricular cardiomyopathy (ARVC)

    Specific to the right ventricle (can also involve left v)
  32. Arrhythmogenic right ventricular cardiomyopathy(ARVC)
    right ventricular loss of myocytes and replacement with fatty tissue (can be in left ventricle also)
  33. Arrhythmogenic right ventricular cardiomyopathy(ARVC) is a disease of what structural component?
    Disease of the DESMOSOME.

    *remember desmosomes from special intercellular junctions that anchor IFs to cytoplasmic membrane adjoining cells. Involves the mutations of 5 genes!
  34. What is a cardiomyopathy that involves disease of the desmosomes?
    Arrhythmogenic right ventricular cardiomyopathy(ARVC)
  35. If a patient has an enlarged right ventricle and much of the heart muscle has been replaced by fibrofatty tissue what cardiomyopathy should you think of?
    ARVC = Arrhythmogenic right ventricular cardiomyopathy
  36. What are the key ion channels that underlie cardiac excitability?
    • K+ channels (mediate repolarization)
    • Na+ channels (mediate Na+ influx)
    • Ca2+ channels (mediate Ca2+ influx)
    • Na+/Ca2+ exchanger (transports three Na in 1 Ca out)
  37. What is the name of an abnormality of an ion cahnnel function that has really reallly really bad consequences that show up in ECGs and as arrhythmias?
    Cardiac Channelopathies!

    due to mutations in genes coding for specific ion channels.
  38. What is are examples of Cardiac Channelopathies?
    • long-QT syndrome (LQTS)
    • short-Qt syndrome (SQTS)
    • Brugada syndrome
    • Conduction disease
    • sinus node dysfunction
    • catecholaminergic polymorphic ventricular tachycardia (CPVT)
  39. What channels are involved in the repolarization of a cardiomyocyte?
    K+ channels
  40. What is the name of a channelopathy that causes syncopal episodes, lethal tachyarrthmias, and ventricular tachyarrthmias that is autosomal dominant or recessive?
    Long-QT syndrome (LQTS)
  41. Long-QT syndrome (LQTS) does what to the QT segment?
    QT indicates the ventricular repolarization or recovery, therfore the QT interval is significantly prolonged, ventricular repolarization is delayed, leading to increased risk of ventricular tachyarrhythmias.
  42. The majority of the genes involved with LQTS (long QT-syndrome) involve what ion channel??

    Because K+ channels are a huge part of ventricular repolarization, if you have problems with K+ channels, you have prolonged ventricular repolarization, and a longer QT interval.
  43. LQT Syndrome involves mutations to what ion channels?
    K+ - Potassium channels subunits = KCNQ1, KCNH2, KCNE1


    Mutations in SCN5A, which is a sodium, Na+ channel, leading to an increase inward Na+ current = prolonged repolarization!!!
  44. Short-QT syndrome is caused by a quickened flux of what?
    enhanced outward current during repolarization, mostly due to K+ channels!

    Recognize these: KCNH2, KCNQ1, KCNJ2
  45. Gain-of-function mutations in K+ potassium channel genes (KCNH2, KCNQ1 ect.) are characterisitc of what cardiac channelopathy?
    Short-QT syndrome!

  46. In Short-QT syndrome repolarization of the ventricle is?
    Hastened by enhanced outward current! due to gain of function mutations in K+ (postassium) channels, which shorten the QT interval.
  47. You note your patients QT interval is shorter than it should be, what kind of mutation is the most likely to have caused this heart problem?
    A mutation that decreases the repolarization time
  48. What channelopathy is characterized by an ST interval elevation in the right precordial leads (V1,V2)?
    Brugada syndrome = THINKS SUDS (Sudden Unexpected Death Syndrome)
  49. What are the functional effects of Brugada syndrome?
    on the sodium currents, opposite of LQTS, so not enough Na+ leaving, not a good depolarization of the membrane
  50. Brugada syndrome is a loss-of-function mutation to what gene?
  51. A mutation to SCN5A causes what?
    • Brugada syndrome
    • ST ELEVATION!!!!!!
  52. SCN5A
    • a pore forming cardiac Na+ channel
    • mutation to this gene causes Brugada syndrome!
  53. Mutations to HCN4 cause what?
    • autosomal dominant sinus node dysfunction
    • HCN4 encodes cadiac pacemaker channels
  54. HCN4
    cardiac pacemaker channels!
  55. Mutations of SCN5A lead to what?
    LOSS of Na+ channel function, and a recessive form of sick sinus syndrome
  56. Loss of Function mutations in SCN5A and SCN1B lead to?
    problems with cardiac Na+ channel complex, and cardiac conduction disease!
  57. What cardiac channelopathy is caused by mutations in the gene encoding the ryanodine receptor channel (RYR2)?
    Catecholaminergic polymorphic ventricular tachycardia (CPVT)
  58. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is usually xlinked or autosomal?
    Autosomal dominant
  59. A recessive form of Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a homozygous mutation of the CASQ2 gene which encodes ?
    Calsequesterin, a protein that serves as a major Ca2+ resevoir within the lumen of the SR.

    Symptoms are more severe in CASQ2 homozygosity than in CPVT.
  60. You have a patient with a mutation in a RyR receptor channel....what is the disease?
    Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Card Set
S1M3 Genetics of Cardiopathies
S1M3 Genetics of Cardiopathies