Symptoms and signs associated with syncope in young people with primary cardiac arrhythmias.

BACKGROUND: It is often reported that clinical symptoms are useful in differentiating cardiac from non-cardiac syncope. Studies in the young are rare. This study was designed to capture the symptoms and signs reported by patients with cardiac syncope before the patients or their attending clinicians knew the final diagnosis. METHODS: Retrospective case-note review of 35 consecutive unrelated gene-positive probands with a proven cardiac channelopathy. RESULTS: The presentation leading to diagnosis of cardiac channelopathy was resuscitated sudden cardiac death in 7 patients; syncope in 20; collapse with retained consciousness in 2; palpitations in 1 and an incidental finding in 5. For the 20 patients with syncope (LQTS 18, Brugada syndrome 2), median age at presentation was 13.9 years (1.8 day to 40.8 years). Of the 17 patients able to describe the onset of syncope, 11 (65%) had at least one symptom prior to collapse, though none reported nausea. Dizziness or lightheadedness was the most frequent symptom, being experienced by 8 (47%). Nine (of 20) patients (45%) had witnessed seizure-like activity and 8 (40%) had urinary incontinence. Nineteen patients were capable of describing the post-syncopal period, of whom 15 (79%) reported symptoms, the most common (12; 65%) being drowsiness or exhaustion. CONCLUSIONS: Cardiac syncope in the young frequently presents with symptoms and signs that are typically associated with other causes of transient loss of consciousness, including vasovagal syncope and seizure disorders. The presence of symptoms may not be as helpful in differentiating arrhythmic from non-arrhythmic events as is often supposed. A thorough history, appropriate investigations and a high index of suspicion remain essential in the assessment of syncope.

Misdiagnosis of long QT syndrome as epilepsy at first presentation.

STUDY OBJECTIVE: Long QT syndrome has significant mortality, which is reduced with appropriate management. It is known that long QT syndrome masquerades as other conditions, including seizure disorders. We aim to evaluate a series of patients with genetically confirmed long QT syndrome to establish the frequency of delayed recognition. We also examine causes and potential consequences of diagnostic delay. METHODS: A consecutive case series of patients with long QT syndrome was identified through the Cardiac Inherited Disease Registry in New Zealand between 2000 and 2005. Detailed retrospective review of 31 cases was undertaken. The primary outcome was the time from first presentation with sudden loss of consciousness to a diagnosis of long QT syndrome. If the diagnosis was not made at the initial presentation, it was considered delayed. For the patients with a delayed diagnosis, the median duration of delay was compared between the subgroup of patients initially misdiagnosed with epilepsy and the others. RESULTS: Genetic mutations in 31 probands were consistent with long QT type 1 in 18 (58%) patients, long QT type 2 in 10 (32%) and long QT type 3 in 3 (10%). Median age at diagnosis was 21 years (1 day to 54 years). Thirteen patients (39%) experienced diagnostic delay after presentation with syncope or seizure: median delay 2.4 years (2 months to 23 years). Electroencephalograms were obtained in 10 patients; 5 were diagnosed with epilepsy. For those labeled epileptic, diagnostic delay was significantly longer than with other misdiagnoses: estimated median difference 9.75 years (95% confidence interval 7.6 to 20.7 years). During the delay period, 4 sudden unexplained deaths reportedly occurred in young relatives. Ten of the 13 had an ECG before diagnosis, with unrecognized pulse rate-corrected QT interval prolongation in 8 cases (range 0.47 to 0.65 seconds). CONCLUSION: Delayed diagnosis of long QT syndrome is frequent. Symptoms are often attributed to alternative diagnoses, most commonly seizure disorder. Patients labeled as epileptic experience a particularly long diagnostic delay. ECGs were frequently requested, but interpretation errors were common. Given the potentially preventable mortality of long QT syndrome, emergency physicians investigating syncope and seizure should maintain a high index of suspicion.

Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome.

BACKGROUND: Sequencing or denaturing high-performance liquid chromatography (dHPLC) analysis of the known genes associated with the long QT syndrome (LQTS) fails to identify mutations in approximately 25% of subjects with inherited LQTS. Large gene deletions and duplications can be missed with these methodologies. OBJECTIVE: The purpose of this study was to determine whether deletions and/or duplications of one or more exons of the main LQTS genes were present in an LQTS mutation-negative cohort. METHODS: Multiplex ligation-dependent probe amplification (MLPA), a quantitative fluorescent approach, was used to screen 26 mutation-negative probands with an unequivocal LQTS phenotype (Schwartz score >4). The appropriate MLPA kit contained probes for selected exons in LQTS genes KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2. Real-time polymerase chain reaction was used to validate the MLPA findings. RESULTS: Altered exon copy number was detected in 3 (11.5%) patients: (1) an ex13-14del of the KCNQ1 gene in an 11-year-old boy with exercise-induced collapse (QTc 580 ms); (2) an ex6-14del of the KCNH2 gene in a 22-year-old woman misdiagnosed with epilepsy since age 9 years (QTc 560 ms) and a sibling with sudden death at age 13 years; and (3) an ex9-14dup of the KCNH2 gene in a 12 year-old boy (QTc 550 ms) following sudden nocturnal death of his 32-year-old mother. CONCLUSION: If replicated, this study demonstrates that more than 10% of patients with LQTS and a negative current generation genetic test have large gene deletions or duplications among the major known LQTS susceptibility genes. As such, these findings suggest that sequencing-based mutation detection strategies should be followed by deletion/duplication screening in all LQTS mutation-negative patients.

Long QT and Brugada syndrome gene mutations in New Zealand.

BACKGROUND: Genetic testing in long QT syndrome (LQTS) is moving from research into clinical practice. We have recently piloted a molecular genetics program in a New Zealand research laboratory with a view to establishing a clinical diagnostic service. OBJECTIVE: This study sought to report the spectrum of LQTS and Brugada mutations identified by a pilot LQTS gene testing program in New Zealand. METHODS: Eighty-four consecutive index cases referred for LQT gene testing, from New Zealand and Australia, were evaluated. The coding sequence and splice sites of 5 LQTS genes (KCNQ1, HERG, SCN5A, KCNE1, and KCNE2) were screened for genomic variants by transgenomics denaturing high-performance liquid chromatography (dHPLC) system and automated DNA sequencing. RESULTS: Forty-five LQTS mutations were identified in 43 patients (52% of the cohort): 25 KCNQ1 mutations (9 novel), 13 HERG mutations (7 novel), and 7 SCN5A mutations (2 novel). Forty patients had LQTS, and 3 had Brugada syndrome. Mutations were identified in 14 patients with resuscitated sudden cardiac death: 4 KCNQ1, 5 HERG, 5 SCN5A. In 17 cases there was a family history of sudden cardiac death in a first-degree relative: 8 KCNQ1, 6 HERG, 2 SCN5A, and 1 case with mutations in both KCNQ1 and HERG. CONCLUSION: The spectrum of New Zealand LQTS and Brugada mutations is similar to previous studies. The high proportion of novel mutations (40%) dictates a need to confirm pathogenicity for locally prevalent mutations. Careful screening selection criteria, cellular functional analysis of novel mutations, and development of locally relevant control sample cohorts will all be essential to establishing regional diagnostic services.