18.04.12 Inherited Cardiac Genetics

Question 1

There are broadly two classes of inherited cardiac conditions. What are they?

Answer 1

Cardiomyopathies and inherited cardiac arrhythmias

Question 2

What is cardiomyopathy and what are some of the phenotypic features?

Answer 2

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.

Question 3

What are cardiomyopathies?

Answer 3

Disorders of the heart muscle

Question 4

Give some examples of different types of cardiomyopathies.

Answer 4

Dilated cardiomyopathy (DCM)
Hypertrophic Cardiomyopathy (HCM)
Restricted cardiomyopathy (RCM)
Arrythmogenic Right Ventricular Cardiomyopathy (ARVC)
Left Ventricular Non-Compaction (LVNC)

Question 5

Give some examples of inherited cardiac arrhythmias

Answer 5

Long QT Syndrome (LQT)
Brugada Syndrome (BS)
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Short QT syndrome (SQT)

Question 6

What are cardiac arrthymias? What are some of the presenting features?

Answer 6

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.

Question 7

What are some of the presenting features of cardiac arrthymias?

Answer 7

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)

Question 8

What is the physiology and presentation of DCM?

Answer 8

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

Question 9

How is DCM diagnosed?

Answer 9

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

Question 10

What is the genetic spectrum of DCM?

Answer 10

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.

Question 11

What is the physiology and presentation of HCM?

Answer 11

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.

Question 12

How is HCM diagnosed?

Answer 12

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.

Question 13

What is the genetic spectrum of HCM?

Answer 13

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.

Question 14

What are the differential diganoses for HCM?

Answer 14

Fabry disease, athlete’s heart, Noonan and LEOPARD syndrome, Friedrich’s ataxia.

Question 15

What is the physiology and presentation of restrictive cardiomyopathy (RCM)?

Answer 15

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

Question 16

How is RCM diagnosed?

Answer 16

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

Question 17

What is the genetic spectrum of RCM?

Answer 17

Genes involved in HCM are also involved in some cases of RCM. (Families with HCM can also have RCM individuals)

Question 18

What is the presentation and physiology of arrhymogenic right ventricular cardiomyopathy (ARVC)?

Answer 18

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

Question 19

How is ARVC diagnosed?

Answer 19

Based on detection of abnormalities of structure and rhythm, family history

CMR, echo

Question 20

What is the genetic spectrum of ARVC?

Answer 20

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.

Question 21

What is the physiology and presentation of LVNC (Left ventricular non-compaction)?

Answer 21

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

Question 22

How is LVNC diagnosed?

Answer 22

Based on structural changes seen on CMR, ECG

Question 23

What is the genetic spectrum of LVNC?

Answer 23

AD, X-linked and mitochondrial inheritance

Heterogeneous - Multigenic -each with a small contribution

Include G4.5, RYR2, LMNA and FKPB12

Question 24

What is the physiology and presentation of longQT syndrome?

Answer 24

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).

Question 25

How is longQT syndrome diagnosed?

Answer 25

ECG - but won’t detect many carriers. Often exercise-ECG tests and 24-48 hour ECG monitoring may be needed before any hint of the condition is seen

Exists as two hereditary variants: Jervell and Lange-Nielsen syndrome (JLN; LQT5) and Romano-Ward syndrome (RW; LQT1). The former is associated with deafness and shows AR inheritance. Also most severe of LQT

Subdivided into types (based on genes in which mutations occur - currently 13 types).

Types 1+2 = mutns in K+ channels and 3=mutns in Na+ channels. Types 1-3 account ~75% of LQT.

Question 26

What is the genetic spectrum of longQT?

Answer 26

AD and AR inheritance

AD: Mutations in genes KCNQ1, KCNH2, and SCN5A.

AR: Mutations in KCNQ1 and KCNE1.

Question 27

What is the physiology and presentation of Brugada syndrome?

Answer 27

Physiology: Ventricular fibrillation caused by cardiac conduction abnormalities due to ST segment abnormalities on ECG. Associated with mutations in the sodium channel, but this appears to account for only 1 in every 5 people with the condition.

Presentation: Asymptomatic to SCD (mean age of SCD = 40yrs). Not a common condition in the western world, but seems to be much more common in South East Asia

Question 28

How is Brugada syndrome diagnosed?

Answer 28

The changes may appear on ECG continuously or intermittently, or they may not show at all. Having a high temperature can sometimes bring out the ECG changes.

May require a drug provocation test (using an arrhthymogenic drug called ajmaline in controlled environment) known as a “reveal”.

Question 29

What is the genetic spectrum of Brugada syndrome

Answer 29

Mutations only found in small number of patients. Frequently no genetic association - can be medication induced.

AD inheritance - at least 8 genes linked.

SCN5A , GPD1L, CACNA1C , CACNB2 , KCNE3 , SCN1B , SCN10A and HEY2

Question 30

What is the physiology and presentation of catecholaminergic polymorphic ventricular tachycardia (CPVT)?

Answer 30

Physiology: Arrhythmogenic disease characterised by cardiac electrical instability during exercise or acute emotion. Not due to a structural cardiac abnormality

Presentation: Syncope during exercise, SCD. Rare condition found in young people and children. There are no physical signs.

Question 31

How is CPVT diagnosed?

Answer 31

Characteristic of CPVT, while the person is doing exercise-ECG

Can be associated with exercise and swimming in particular

Question 32

What is the genetic spectrum of CPVT?

Answer 32

AD and AR inheritance

AD: RYR2 gene mutations. 50-55% of all CPVT. Large gene; exon dosage may also be causative; Manchester lab run RYR2 MLPA.

AR: CASQ2 and TRDN

Question 33

What are some management options for patients with ICC?

Answer 33

Management is varied and can include use of drug treatments (e.g. beta blockers), risk management (e.g. stopping competitive sports, swimming) or avoiding alarm clocks, corrective cardiac surgery and procedures, use of pacemakers and internal deliberators, LVAD, etc. ICCs are a leading cause of heart failure, and ultimately, heart transplant.