Inherited heart rhythm disturbance

The pumping action of the heart is caused by a flow of electricity through the heart that repeats itself in a cycle. If this electrical activity is disrupted, such as by a disturbance in the heart’s rhythm (known as an arrhythmia), it can affect the heart’s ability to pump properly. ¹ When this rhythm occurs, no blood is pumped out from the heart and the brain becomes quickly deprived of oxygen, causing sudden loss of consciousness (syncope) and in some cases, sudden death.

The medical term for an inherited heart rhythm disturbance is ion channelopathies. ¹ This is a group of uncommon diseases that can cause life-threatening arrhythmias. Ion channelopathies are uncommon genetic conditions that are caused by abnormalities of the DNA, known as ‘mutations’. They are usually inherited from parents but can occur for the first time. ¹ The mutations affect certain genes (specific segments of the DNA that are responsible for the production of ion channels in the heart). ¹

An ion is a chemical substance that carries an electrical charge and forms the basis of the movement of electricity through the heart muscle. ¹ An ion channel is the route that ions take in and out of the heart muscle cells to allow the movement of electricity. The ion channels control the flow of electrical charge. If these channels do not work normally, the electrical function of the heart becomes abnormal and the person can then be prone to arrhythmias. ^{1, 6} This can cause blackouts, cardiac arrest and in some cases, sudden death.

There are several different types of ion channelopathies including ¹:

• Long QT syndrome (LQTS)
• Brugada syndrome`
• CPVT (catecholaminergic, polymorphic ventricular tachycardia)
• PCCD (progressive cardiac conduction defect)
• Short QT syndrome (SQTS)
• Familial atrial fibrillation and
• Sodium channel disease.

Long QT syndrome

Long QT Syndrome (LQTS) is the most common and best understood type of channelopathy. It is estimated that its prevalence ranges from 1 in 2500 people to 1 in 7000. ^{1, 7} 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 number of people with LQTS, a sodium channel that regulates the flow of sodium ions from the outside to the inside of cells is affected. In people with potassium channel associated LQTS, the channels do not behave as efficiently as normal. They let potassium ions out of the cell too slowly. If the sodium channel is affected, too many sodium ions are allowed into the cell. In short, the potassium levels do not work properly or the sodium channel over-activates. ² This results in an electrical disturbance in the cells of the heart, called ‘prolonged repolarisation’. Repolarisation is the recharging of the electrical system after each heart beat. This can sometimes be seen on an ECG recording as a lengthening of the time period of a particular part of the heartbeat cycle, known as the ‘QT interval’. This is where the name Long QT syndrome comes from. Not everyone who has Long QT syndrome develops a dangerous heart rhythm. ⁶

There are two rare forms of LQTS- Timothy syndrome and Andersen-Tawil syndrome. Timothy syndrome is associated with calcium channel abnormalities and Andersen’s syndrome is associated with potassium channel abnormalities.

Timothy syndrome

Timothy syndrome was identified in 2004 by researchers in Children’s Hospital, Boston, Howard Hughes Medical Institute, University of Utah and University of Pavia, Italy. ¹⁰ Timothy syndrome is a rare childhood disorder which underlies a form of severe cardiac arrhythmia. ⁸ Research has shown that Timothy syndrome results from spontaneous genetic mutations that interfere with the calcium channels that regulate the excitation and contraction of the heart. ⁸ Specifically, there is a mutation in the Ca(v)1.2 calcium channel gene called CACNA1C. Calcium flow cannot be blocked at the appropriate time.

Children with Timothy syndrome have a problem with the flow of calcium in the body cells. Calcium is one of the most important molecules in the body, and disturbing its flow can cause a wide range of symptoms. These may include ^3,4,8,9:

• heart rhythm disturbances
• heart defects
• webbed fingers and toes (syndactyly)
• weakened immune system
• cognitive difficulties
• autism
• low blood sugar (hypoglycemia).

Any child born with webbed fingers or toes should be checked to see if he or she as a genetic disorder.¹⁵ An ECG will detect any abnormal heart rhythms. An echocardiogram (ultrasound of the heart) will detect any heart defects. ^{1, 15} The abnormal flow of calcium in the body can be treated with calcium-channel blocking medications such as Calan (verapamil) or Procardia (nifedipine).

Andersen-Tawil syndrome

Andersen-Tawil syndrome is a multisystem disorder that affects skeletal and facial features. Andersen-Tawil syndrome or Andersen syndrome, is a rare disorder that is characterised by a triad of distinctive dysmorphic features ¹¹:

• episodic flaccid muscle weakness
• ventricular arrhythmias and prolonged QT interval and
• common anomalies such as low-set ears , small mandible, syndactyl (webbing), short stature, and scoliosis.

Affected individuals can also present cardiac symptoms (palpitations and/or syncope), or weakness that occurs spontaneously following prolonged rest or following rest after exertion. ¹¹

The movement of potassium ions through channels is critical for maintaining the normal functions of skeletal muscles which are used for movement and cardiac muscle. ^{13, 14} Mutations in the KCNJ2 gene alter the usual structure and function of potassium channels or prevent the channels from being inserted correctly into the cell membrane. Many mutations prevent a molecule called PIP2 from binding to the channels and effectively regulating their activity. These changes disrupt the flow of potassium ions in skeletal and cardiac muscle. ¹⁴

Andersen-Tawil syndrome causes attacks of muscle weakness and irregular heart rhythms. ¹² Patients may experience brief episodes of localised weakness in a hand, foot, jaw or limbs, or they may experience generalised paralysis. The episodes of weakness often occur during rest after exercise, and they may occur on awakening in the morning. The heart rhythm irregularities include a prolonged QT interval which makes the heart more likely to experience tachycardia (a regular but too rapid heart rate) or dangerous irregular heart rates.

Symptoms of LQTS

LQTS varies greatly in severity.^1,2 Symptoms vary according to

• the type of channel involved,
• whether the person is male or female
• the person’s age and
• the length of the QT interval on the ECG.

Males are more likely to have symptoms before puberty, while females are more likely to have them in adolescence and early adulthood. Symptoms typically appear in pre-teen to teenage years but may occur in newborns and can appear as late as middle-age. ⁵

The most common symptom of LQTS is blackouts, caused by a heart rhythm disturbance. ^1,2 Sometimes the person can experience palpitations due to extra or ‘ectopic’ heartbeats.^{1, 2} Dizzy spells and chest pains have also been reported.² Often, patients may not report any symptoms at all. There is, however, a wide spectrum of severity.

There are no physical signs of LQTS. However, people with Andersen’s syndrome may also have muscle weakness or minor abnormalities of the skull, chin, fingers and toes. Children with Timothy syndrome often have many other problems that are present from birth and make it easier to diagnose the condition. Sudden death can be seen in LGTS. Irregular heart rhythms can be triggered in LQTS after physical exertion and during emotional stress which can be brought on by loud noises. ^{2, 6, 7} Sudden death has also been seen during sleep. ^{2, 6, 7}

Diagnosis

The diagnosis of LQTS involves having an ECG. ¹ Sometimes it is clear which ion channel has been affected just by looking at the ECG recording. However, in many people who might be carriers, the ECG does not show any sign of the condition. Repeated ECGs, exercise tests and ECG monitoring may be needed before any hint of the condition is seen. Even then, there may be no clear sign of the condition.

Genetic testing can sometimes identify carriers of LQTS. ¹ Unfortunately, this form of testing is of limited use at the moment, as 3 in every 10 people who are known to have LQTS do not have mutations of the genes known to be associated with LQTS. This can make it difficult to decide whether a mutation is causing the disease or not. People with the same mutation can also have effects that vary greatly in severity.

All of this can make it difficult for doctors to decide on the best way to treat people with this condition. It is essential that the expert medical opinion of a specialist in inherited heart conditions is obtained.

Treatment

The level of risk of sudden death helps decide on the need for treatment. Those who are statistically at greatest risk of sudden death are people with one or more of the following¹:

• a previous cardiac arrest
• blackouts
• a very long QT interval on the ECG
• sodium channel mutations
• are a young adult women.

Children who are most at risk tend to be young boys before puberty, and girls who are passing into puberty.¹

Drugs

The first line of treatment is with drugs. ^{1, 2, 4} The most commonly used drugs are beta-blockers. Beta-blockers block the effects of adrenaline and associated natural chemicals in the body that make the heart pump harder and faster. They, therefore, also block the effects of exercise on the heart. They are effective in the most common forms of LQTS, as they reduce symptoms and the risk of sudden death. However, they are less effective in people with the sodium channel form of LQTS. There are other more recent trends in drug treatment, but their longterm benefits are unknown. These involve using different anti-arrhythmic drugs. These drugs block disturbances in the heart rhythm that can cause sudden death. Potassium supplement pills have also been tried, with occasional success.

Pacemakers and ICDs

If a person is at high risk or if drugs have failed to control symptoms, a doctor may advise a person to have a pacemaker or an implantable cardioverter defibrillator (ICD) fitted, in addition to taking medication. ^{1, 4}  A pacemaker and an ICD both consist of an electronic box containing a battery. This is inserted under the skin and attached to the heart by special electrical ‘leads’. 

A pacemaker controls the heart rate and stops any excessive slowing of the heart that could trigger an arrhythmia. 1 The pacemaker is usually implanted just under the left collarbone. An ICD acts in the same way as a pacemaker, but it can also identify any dangerous arrhythmias and deliver an electrical shock to ‘reset’ the heart.¹ It may have to be positioned under the chest wall muscle, below the left shoulder.

Surgery

Surgery can be performed to disrupt the nerves that release adrenaline and related chemicals into the heart. ¹ This is known as cervical sympathectomy. It involves operating on the left side of the neck and removing the nerves.

References

1. British Heart Foundation (2009) Inherited Heat Conditions. London: British Heart Foundation
2. Cardiac Risk in the Young (2009) Conditions that can cause young cardiac death. [online]. Available from: http://www.c-r-y.org.uk/medical_conditons.htm  [Accessed 16 July 2009]
3. National Center (sic) for Biotechnology Information (2008) Timothy Syndrome. [Online]. NCBI. Available from: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601005  [Accessed 16 July 2009]
4. National Center (sic) for Biotechnology Information (2009) Timothy Syndrome. [Online]. NCBI. Available from: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=timothy . [Accessed 16 July 2009]
5. BBC (2009) Long QT Syndrome. [online]. BBC. Available from: http://www.bbc.co.uk/health/conditions/longqt1.shtml [Accessed 16 July 2009]
6. National Heart Lung and Blood Institute (2007) Long QT Syndrome. [online] NHIBI. Available from: http:// www.nhlbi.nih.gov/health/dci/Diseases/qt/qt_whatis.html . [Accessed 17 July 2009]
7. Levine et al (2008) Congenital Long QT Syndrome: Considerations for Primary Care Physicians. Cleveland Clinic Journal of Medicine. 75 (8), 591-600
8. Howard Hughes Medical Institute (2004) Researchers Pinpoint Cause of a Severe Cardiac Arrhythmia. [online]. HHMI. Available from: http://www.hhmi.org/news/keating6.html . [Accessed 17 July 2009]
9. Slawski et al (2005) Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proceedings of the National Academy of Sciences of the United states 102 (23): 8089–96.
10. National Organisation of Rare Disorder (2008) Timothy Syndrome. [online] NORD. Available from: http:// www.rarediseases.org/search/rdbdetail_abstract.html?disname=Timothy%20Syndrome . [Accessed 17 July 2009]
11. Rimoin et al (2006) Emery and Rimoin’s Principles and Practice of Medical Genetics (5 eds) [ebook] London: Churchill Livingston. Available at: http://books.google.co.uk/books?id=G-KTmwJdiFIC&pg=PA1234&lpg=PA1234&dq=timothy+syndrome+diagnosis&source=bl&ots=sSL-MCFDQ2&sig=cOrgdtrKRvTWFGTdl-1YKd02Q&hl=en&ei=G2tgSvzwEaSQjAeWvMjFDg&sa=X&oi=book_result&ct=result&resnum=6. [Accessed 17 July 2009]
12. Periodic Paralysis News Desk (2009) Frequently Asked Questions About Andersen-Tawil Syndrome. [online]. Periodic Paralysis News Desk. Available from: http://www.hkpp.org/faq/andersens.html . [Accessed 17 July 2009]
13. Tawil, R. and Venance, S. (2007) Andersen-Tawil Syndrome. [online]. Gene Reviews. Available from: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=acpp . [Accessed 17 July 2009]
14. Smith et al (2006) Review Article: Andersen-Tawil Syndrome. Indian Pacing and Electrophysiology Journal 6(1): 32-43
15. Hannigan, S. (2007) Inherited Metabolic Diseases. [ebook] London: Radcliffe Publishing Ltd. Available from: http://books.google.co.uk/books?id=lQvUH3ALdJcC&printsec=frontcover . [Accessed 20 July

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