18.04.12 Inherited Cardiac Genetics Flashcards
(33 cards)
There are broadly two classes of inherited cardiac conditions. What are they?
Cardiomyopathies and inherited cardiac arrhythmias
What is cardiomyopathy and what are some of the phenotypic features?
Diseases in which heart muscle disease and/or measurable deterioration of cardiac muscle function occurs due to various causes, such as inherited and sporadic mutations of muscle proteins, as well as external factors such as hypertension, ischemia, and inflammation.
Phenotypical variability - asymptomatic to severe. Include palpitations, shortness of breath, chest pain and blackouts and SCD.
Overlap between different cardiomyopathies.
What are cardiomyopathies?
Disorders of the heart muscle
Give some examples of different types of cardiomyopathies.
Dilated cardiomyopathy (DCM) Hypertrophic Cardiomyopathy (HCM) Restricted cardiomyopathy (RCM) Arrythmogenic Right Ventricular Cardiomyopathy (ARVC) Left Ventricular Non-Compaction (LVNC)
Give some examples of inherited cardiac arrhythmias
Long QT Syndrome (LQT)
Brugada Syndrome (BS)
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Short QT syndrome (SQT)
What are cardiac arrthymias? What are some of the presenting features?
Inherited arrhythmia syndromes result from disorders in the heart’s electrical system
In cases of SCD caused by cardiac arrhythmia, the heart may appear structurally and histologically normal at post mortem,
Also known as ion channelopathies.
What are some of the presenting features of cardiac arrthymias?
Symptoms can include palpitations, dizziness, blackouts and sudden death.
Disorders of the heart’s electrical system. May get tachycardia (fast), bradycardia (slow) or arrhythmia. A leading cause of sudden cardiac death (SCD)
What is the physiology and presentation of DCM?
Physiology: Increase in myocardial mass and a reduction in ventricular wall thickness. Globular shape to heart, diffuse endocardial thickening, decreased force of contraction.
Presentation: Most prevalent cardiomyopathy and reason for cardiac transplantation in adults and children. Range from asymptomatic, arrhythmia, reduced cardiac output, stroke, heart failure, SCD. Mainly adult onset disease. May also have skeletal myopathies e.g. DMD
How is DCM diagnosed?
DCM - based on left ventricular enlargement and systolic dysfunction; cardiac MRI (CMR), echocardiogram (echo)
Idiopathic DCM - All acquired forms are excluded
Familial DCM - 2 or more relatives with IDCM or SCD occurs at a young age within family
What is the genetic spectrum of DCM?
Inheritance is variable - AD, AR, X-linked and mitochondrial
Heterogeneous - genes involved in the nuclear envelope, contractile apparatus, the force transduction apparatus (e.g., Z-disk and costamere), gene transcription and splicing machinery, and calcium handling. >40 genes described.
Titin (TTN) accounts for approx. 1/3 of inherited cases; huge gene, poorly characterized diagnostically (see refs).
Mutations in some of the same genes as HCM but in DCM the mutations have the opposite effect. E.g. mutations in MYH7 reduce motor function.
MYH7 and lamin A each account for 5-8% of all FDCM mutations.
What is the physiology and presentation of HCM?
Physiology: Usually this is an asymmetric thickening of heart muscle, involving the inter-ventricular septum (2/3 cases). 25% of individuals demonstrate an obstruction to the outflow of blood from the left ventricle during rest. 70% of patients obstruction can be provoked under certain conditions (dynamic outflow obstruction).
Presentation: Angina, palpitations, jerky pulse, presyncope, syncope. Can range from asymptomatic, progressive heart failure to SCD (=caused by ventricular fibrillation/tachycardia). Common cause of SCD in young athletes.
How is HCM diagnosed?
Unexplained hypertrophy of the left ventricle (+sometimes of the right ventricle; CMR, echo)
Usually with predominant involvement of the interventricular septum.
Cardiomyocyte disarray and fibrosis by histology.Typically AD with variable penetrance
Heterogenous - most mutations in genes coding for sarcomeric proteins- involved in contraction (see table below)
30% of HCM patients do not have sarcomere gene mutations - probably involve genes involved downstream of muscle contraction
5-10% patients have multiple sarcomeric gene mutations - dose dependent severity.
What is the genetic spectrum of HCM?
Typically AD with variable penetrance
Heterogenous - most mutations in genes coding for sarcomeric proteins- involved in contraction (see table below)
30% of HCM patients do not have sarcomere gene mutations - probably involve genes involved downstream of muscle contraction
5-10% patients have multiple sarcomeric gene mutations - dose dependent severity.
What are the differential diganoses for HCM?
Fabry disease, athlete’s heart, Noonan and LEOPARD syndrome, Friedrich’s ataxia.
What is the physiology and presentation of restrictive cardiomyopathy (RCM)?
Physiology: Ventricles become stiff, but not necessarily thickened, so they resist normal filling with blood.
Presentation: Fatigue, shortness of breath, oedema and abdominal enlargement, blood clots, arrhythmia and palpitations
How is RCM diagnosed?
Rhythmicity and contractility of the heart may be normal
Blood flow is reduced, and blood volume that would normally enter the heart is backed up in the circulatory system. In time, restrictive cardiomyopathy patients develop diastolic dysfunction and eventually heart failure; CMR, echo.
Can be a symptom of other conditions e.g. Churg-Strauss syndrome, cystinosis, lymphoma, Gaucher’s disease, hemochromatosis, Fabry’s disease
What is the genetic spectrum of RCM?
Genes involved in HCM are also involved in some cases of RCM. (Families with HCM can also have RCM individuals)
What is the presentation and physiology of arrhymogenic right ventricular cardiomyopathy (ARVC)?
Physiology: Progressive loss of cardiomyocytes (mainly in right ventricle but also left) caused by either massive or partial replacement of myocardium with fatty or fibro-fatty tissue. Provides conditions for electrical instability
Presentation: Ventricular arrhythmias, heart palpitations, syncope, SCD - more common in adolescents and young adults; may be precipitated by exertion. Mean age of diagnosis = 31 years
How is ARVC diagnosed?
Based on detection of abnormalities of structure and rhythm, family history
CMR, echo
What is the genetic spectrum of ARVC?
50% AD inheritance with incomplete penetrance.
Heterogeneous (>8 genes)
Include mutations in genes involved in intercellular connections e.g. desmoplakin (DSP) and genes involved in calcium homeostasis e.g. RYR2. Can get compound heterozygosity (e.g. PKP2) and digenic mutations e.g. PKP2 and DSG2.
What is the physiology and presentation of LVNC (Left ventricular non-compaction)?
Physiology: Left ventricle appears to be spongy and “non-compacted” and consists of a meshwork of numerous muscle bands called trabeculations
Presentation: Range from asymptomatic to heart insufficiency-related disorders e.g. fatigue, oedema in lower extremities, breathlessness, arrhythmia, increased risk of blood clots in heart
How is LVNC diagnosed?
Based on structural changes seen on CMR, ECG
What is the genetic spectrum of LVNC?
AD, X-linked and mitochondrial inheritance
Heterogeneous - Multigenic -each with a small contribution
Include G4.5, RYR2, LMNA and FKPB12
What is the physiology and presentation of longQT syndrome?
Physiology: There is a delay at the end of each heartbeat, and the heart takes longer than it should to repolarise. This delay can be seen on the “Q through T” wave of an ECG . In most cases, two of the potassium channels that regulate the movement of potassium ions from the inside to the outside of the cells are affected. In a small proportion of cases a sodium channel that regulates the flow of sodium ions from the outside to the inside of cells is affected.
Presentation: Arrhythmogenic syncope, ventricular tachycardia, cardiac arrest and SCD - usually occur in conditions of either physical or emotional stress in otherwise healthy young individuals (mostly children and teenagers).
