Long QT Syndrome (LQT Syndrome) is a cardiac disorder characterized by prolonged interval between two consecutive beats, referred to as the QT interval. A prolonged QT interval is not harmful per se. However, it may result in arrhythmia, which leads to cardiac arrests and sudden death. Many different forms of LQT syndromes are known, both inherited and acquired. Inherited types of LQT syndrome are of seven different types, based on the gene involved. LQT1, also known as Romano-Ward Syndrome, is the most common form of inherited LQT syndrome, affecting one in 7000 people worldwide. Approximately half of the patients affected with LQT do not show any external symptoms, and are identified only on the basis of their abnormal ECG pattern. The rest of the patients show typical symptoms, which include syncope and seizures. Syncope usually occurs when the heart beats erratically, due to physical exercise or emotional excitement. Sudden death can occur, if the situation is not immediately brought under control. A variant form of LQT1 is Jervell Lange-Nielsen Syndrome, which is characterized by severe prolongation of the QT interval, increased ventricular arrhythmias, and congenital deafness.
ECG is the easiest method to diagnose LQT. Genetic testing is also available to determine the susceptibility or to corfirm the diagnosis. Treatment for LQT involves limiting physical and emotional exertion, and medications such as beta blockers, which lower the heart beat rate. Patients who do not respond to the medications require either an artificial pacemaker or a cardioverter-defibrillator to be implanted under the skin of the chest. In addition, a surgical procedure can be performed to remove specific nerves of the body's sympathetic nervous system, which regulate the heart rhythm. With the modern therapy available, it has been able to reduce the mortality due to LQT to 3-5% from 60-70%.
LQT1 syndrome has been found to be caused due to mutations in the Potassium Channel, Voltage-Gated, KQT-Like Subfamily, Member 1 (KCNQ1) gene. The product of this gene, KvLQT1 is a voltage gated potassium channel, expressed mainly in the heart, where it helps in the transport of potassium and sodium across the cell walls.
Vurgese et al. (2006) described a 35-year old Arab patient who presented with fleeting pain and tingling sensations in all limbs, and mild weakness in the lower limbs. He had a history of admission with complaints of syncope and palpitations. Three of his siblings and a first-degree relative had died suddenly after complaining of syncope and palpitation. Examination revealed mild hypotonia in the lower limbs, positive mycoplasma serology, elongated Q-T interval at 505 msec, elevated cardiac marker Troponin I, and abnromal CSF glucose level (3.76 mmol/L). Nerve conduction studies showed slowing of conduction, prolongation of distal latencies and F-wave, and conduction blocks suggestive of demyelinating polyneuropathy. The observations prompted Vurgese et al. (2006) to make the extremely rare diagnosis of Guillain Barre syndrome in comorbidity with Romano Ward syndrome. The patient was closely monitored and treated with IV immunoglobulin and beta blockers, and discharged without any neurological deficit. He was advised to get an automated cardioverter defibrillator implanted.
[Vurgese T, Mapkar OA, Surrun SK. Guillain-Barre syndrome in a patient with Romano-Ward syndrome: a case report. Kuwait Med J. 2006; 38(1):53-5.]
Schulze-Bahr et al. (1997) performed haplotype analysis with microsatellite markers in a Lebanese family with Jervell Lange-Nielsen syndrome, but failed to detect linkage at LQTS 1. Using this approach, Schulze-Bahr et al. (1997) also excluded two other ion-channel genes involved in autosomal-dominant LQTS, HERG (LQTS2) and SCN5A (LQTS3).
Subramanyan and Venugopalan (2002) reported a family with a malignant form of long QT syndrome. A member of this family with consanguineous parents presented at the age of two months with fever and convulsions, which recurred after a month but without the fever and continued for 24 hours. Clinically, he had no neurological or cardiovascular abnormalities and was a normally growing infant. Investigations revealed a prolonged QT interval of 0.53-0.62 seconds on ECG, along with T wave alternas (alternating in direction), which also varied in size, shape and duration. Ambulatory ECG revealed heart rate range of 62 to 118/min with no significant arrhythmia. Normal cardiac anatomy and function were detected by an echocardiography which also showed abnormal left ventricular posterior wall movement with prolonged thickening and a double-peak anterior movement in systole. Biochemical and hematological investigations were normal and so was an audiometry, which excluded neural deafness. The patient was diagnosed with Long QT syndrome and was started on propranolol but while on therapy, the convulsions recurred one month later, so in addition to propranolol, a permanent ventricular epicardial demand pacemaker (VVI) was implanted. At the age of six years, the pacemaker was changed to an endocardial VVI system and he remained asymptomatic through out the eight years of follow up. Within this family, four children had died at ages of one to four years from convulsions or syncope which had been diagnosed as epilepsy while other two children had convulsions and dizzy spells, respectively. Screening of the parents and the other nine children had shown that six of the children had evidence of long QT syndrome, and the mother, although asymptomatic had mild prolonged QT interval in ECG. The siblings were started on propranolol and only one required further management with a pacemaker. After screening and appropriate management, there were no deaths, convulsions, or syncopal attacks in any member of this family.
Gorgels et al. (1998) described a 2-year old boy who was diagnosed with a rare condition of LQTS with impaired AV conduction. The patient was referred with a history of spells, sudden attacks of cyanosis, and loss of consciousness. The child was found to be tachypeic with muffled heart sounds. ECG showed mild dilatation, and impaired contractility of the left ventricle and mitral valve regurgitation. Detailed investigations revealed relative sinus bradycardia, a long QT interval of 700 msec, and occasionally, 2:1 AV conduction with impaired RBB and LBB conduction, decremental conduction in the His-Purkinje axis, sinus pauses, and accelerated AV junctional escape beats. ECG studies of parents and all four siblings were normal. Gorgels et al. (1998) opined that the condition could have been produced by a sporadic mutation in one of the genes associated with repolarization. A VVI pacemaker was inserted in the patient, and he was started on Propranolol. During the follow up period of 6-months, no TdP or fainting spells were observed. ECGs showed relative sinus bradycardia, 1:1 AV conduction, narrow QRS complexes, and persistently prolonged QT interval.
Bhuiyan et al. (2009) described two Saudi families with long QT syndrome 1, with an autosomal recessive pattern of inheritance. The first family had a 3-year-old boy; who suffered from an episode of loss of consciousness while swimming. His hearing was normal and there was no history of deafness in the family members. The second family had a 16-year-old boy who developed generalized seizures with cyanotic lips when he was 1-year-old. He had multiple seizure attacks till he was 4 years old. There were no seizure attacks after he was prescribed propranolol. The family history showed sudden unexplained death of several family members. The same homozygous mutations in the KCNQ1 gene were identified in the two patients. Both families originated from the Assir region, although they were not knowingly related. Haplotype analyses lend credence to the theory that mutations in both families originated from the same ancestor.
Shinwari et al. (2013) studied a large Saudi family with Long QT Syndrome. The proband in this family was a 25-year old female who presented with a history of syncope, and was found to have a prolonged QTc interval of 550 ms. Her brother also had repeated syncope, requiring the implantation of an ICD. The family members in this extended family were assessed. Of the 26 members in this family who underwent assessment, only two were clinically symptomatic. However, gene sequencing identified a novel heterozygous c.773A>C (p.His258Pro) mutation in the KCNQ1 gene in 12 family members. The mutation showed incomplete penetrance, with only two of the 12 mutation carriers being clinically symptomatic. However, Shinwari et al. (2013) cautioned that seven of these 12 carriers were children, and were at risk of developing symptoms later.
Benhorin et al. (1993) referred to the unpublished work of Kerem and colleagues who indicated the existence of more than one genetic form of LQT and excluded linkage with HRAS1 in a very large affected Jewish family originating from the island of Jerba near Tunis and later residing in Israel. The studied family is probably the largest family with LQT outside the United States. Five years later, Benhorin et al. (1998) indicated that sudden cardiac death has been documented in five members of the family who were not alive at the initiation of their study. They studied many members (n=131) of the LQT-affected Jewish kindred and identified tight linkage between the LQT-affected status and LQT3 (lod score 6.13, with an estimated recombination fraction of zero). They also identified a new point-mutation, A to G substitution at nucleotide 5519 of the SCN5A gene, changing the aspartate 1840 to glycine, D1840G. The mutation was identified in all affected individuals (n=23), and not identified in any of the unaffected family members (n=40), or in 200 chromosomes of healthy control individuals. The mutation was identified in 3/12 individuals with equivocal phenotype, thus, providing an accurate diagnostic tool for all family members.