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The Ion Channelopathies are rare disorders that affect the sodium, potassium and calcium channels, which are present in the heart muscles and are responsible for regulation of inflow and outflow of the electrical current in the cells.
The channels are coded on particular genes in the chromosomes. Any mutations in these genes produce abnormal channels, which might cause abnormal heart rhythms that can cause sudden death. Since these channels are microscopic and are not visible to the naked eye, the heart appears normal during post-mortem examination. The following are the common disorders that affect ion-channels:
Long QT Syndrome Brugada Syndrome Progressive Cardiac Conduction Defect (Lev-Lenegre's Syndrome) Idiopathic Ventricular Fibrillation (without Brugada ECG changes) Catecholaminergic Polymorphic VT
The proteins involved in the Long QT Syndrome consist of two of the potassium "channels" which regulate the behaviour of potassium ions moving from the inside to the outside of the cell. In addition, a sodium "channel" is also affected and this regulates the behaviour of sodium ions that move from the outside to the inside of cells. The same sodium channel protein has also been found to have mutations in Brugada Syndrome, Lev-Lenegre’s Syndrome and Idiopathic Ventricular Fibrillation without Brugada ECG changes. Catecholaminergic Polymorphic VT has been associated
very recently with another protein (hRyR2) that is found inside the cell
and regulates the release of calcium ions into the rest of the cell.
Romano-Ward syndrome: Romano-Ward syndrome is the most common form of congenital long QT syndrome, which purely affects cardiac ion channels to produce prolonged QT interval. It does not affect any other systems unlike Jervell and Lange-Nielsen syndrome. It is inherited in an autosomal dominant fashion which means that one parent with the culprit gene is sufficient to produce an affected child.
Jervell and Lange-Nielsen syndrome has more malignant course than Romano-Ward syndrome. With the advent of molecular genetics, congenital Long QT Syndrome has been classified into 7 groups (Long QT1-Long QT7). Long QT 1-3 comprises 95% of all cases of congenital Long QT Syndrome. Long QT 1 and 2 are due to mutations in potassium channels, whereas Long QT 3 is as a result of mutation in sodium channels.
Symptoms Blackouts are the most common problem, although palpitations, dizzy spells and chest pain can also be reported. More often, patients may not report any symptoms at all, and sudden death could be their first presentation. There is however, a wide spectrum of severity and these vary according to the type of gene involved, sex, age and length of the QT interval. Most commonly, sudden death in Long QT 1 is seen after physical exertion (athletes are at risk), whereas in Long QT 2 sudden death or syncope is usually seen during emotional stress, which may be brought on by loud noises, the crying of a baby in the middle of the night, ringing of a phone or alarm clock etc. In Long QT 3, sudden death has been increasingly seen during sleep. Signs There are no physical signs of the condition. Diagnosis This involves observation of the ECG for the lengthening of the QT interval and abnormality of other parts of the ECG that represent repolarisation. These are the T Waves. Unfortunately, the wide spectrum of the condition means that many individuals might be carriers but not exhibit any ECG changes. It may require repeated ECGs, exercise tests and 24-48 hour tape monitoring to see any hint of the condition. There does not appear to be much role for more aggressive tests such as electro-physiological studies. Future diagnosis might be improved however, by genetic testing. Unfortunately, this is limited, because only 50% of known Long QT patients have mutations of the previously mentioned genes. Also, negative genetic testing does not rule out the condition, as only 70% of those affected show positive results. There is an additional problem in that families with identified mutations appear to have a specific change to the DNA code, which is not found in other families (known as a "private" mutation). This is further complicated because each individual
carrier of the same mutation may be affected with differing severity, even
if they are from the same family. This makes decisions on management of
the condition very difficult. Management If it is decided that the risk to an individual is great enough that treatment is required, then drugs are invariably used. The commonest drug is a beta-blocker. This blocks the affects of adrenaline and associated natural chemicals in the body that have an action on the heart. This does appear to be successful in reducing the risk of sudden death. There are other more recent trends in drug treatment that have yet to be clarified that appear promising. These involve using specific classes of drugs that block disturbances in the heart rhythm that cause sudden death (known as antiarrhythmics). If the risk is felt to be great enough, special devices may be used in addition to medication. Pacemakers that control the heart rate have been used successfully, as have cardiac defibrillators (ICDs). The ICDs are given to patients who are believed to be at high risk of sudden death (which is decided through various testing as mentioned above; considering family history; and symptoms). These are similar to Pacemakers, except they are also able to shock the heart when a rhythm disturbance occurs that might be life threatening. In addition to these measures, we do advise patients with Long QT Syndrome to avoid excessive exercise or strenuous athletic activities.
Symptoms Blackouts, palpitations and sudden death. Signs There are no physical signs associated. Diagnosis This is again, on the basis of the ECG appearance, which may be present or absent. If it is absent then there are tests that can bring it out. These are known as provocation tests that use short injections of drugs that are "anti-arrhythmic", i.e. attempt to control the heart's rhythm. There is some controversy now as to how reassuring a negative result is. The role for electro-physiological testing is still to be determined. Because of the small proportion of sufferers have been
identified with these mutations, genetic testing is limited in its
application. Management The condition can carry a poor prognosis, particularly in those who are symptomatic, i.e. at least a 10% death rate per year. It is therefore standard practice at present to use an ICD to protect most patients. Drug therapy has not appeared to be successful but there may be a role for electro-physiological studies to differentiate those people who do or do not require an ICD. This is another very rare condition where the heart's
conduction of electrical impulses is affected. This results in the gradual
development over time of heart block that may result in death due to the
cessation of the heart rhythm - i.e. asystole, or escape rapid rhythm
disturbances (ventricular arrhythmias). Only certain cases have had
sodium channel mutations associated with them, so again genetic testing is
of limited use. Symptoms Blackouts and dizziness are the usual symptoms and the
findings may be detected on ECG or 24-48 hour Holter monitoring.
Electro-physiological study may also assist in diagnosis. Management The successful treatment appears to be permanent pacemakers, which stop the heart slowing excessively, although this may not prevent the ventricular arrhythmias. Therefore, additional medical treatment with tablets may be appropriate or even an ICD. Idiopathic Ventricular Fibrillation There has been one report about patients with this condition - which is similar to Brugada, but without the associated ECG changes - who also had sodium channel mutations. The treatment again revolves around the use of ICDs. Catecholaminergic Polymorphic VT In early 2001, two research groups reported mutations in the hRyR2 protein mentioned above. This is a rare condition found in young people who can black out or die suddenly when exerting themselves. The diagnosis only appears to be easily made when these rhythm disturbances have been recorded and recognised. The sufferers respond dramatically to beta-blockers and a restriction of exercise, and have a much better outlook following treatment.
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