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Sproule DM, Kaufmann P, Engelstad K, Starc TJ, Hordof AJ, De Vivo DC. Wolff-Parkinson-White Syndrome in Patients With MELAS. Arch Neurol. 2007;64(11):1625–1627. doi:10.1001/archneur.64.11.1625
Tissues with high energy demands, such as the heart, are susceptible to the effects of mitochondrial DNA point mutations.
To investigate the frequency of Wolff-Parkinson-White (WPW) syndrome among a phenotypically and genotypically homogeneous cohort of patients with MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) and the A3243G mutation most commonly associated with MELAS syndrome.
The Pediatric Neuromuscular Disease Center at Columbia University.
Thirty patients with the A3243G mutation and MELAS syndrome enrolled in a clinical trial to assess the effect of dichloroacetate on neurologic symptoms.
Medical histories and electrocardiograms were reviewed and DNA samples from fibroblasts, urine and cheek epithelial cells, leukocytes, and hair were analyzed to determine mitochondrial mutation abundance and estimate total mutation burden.
Four of 30 patients (13%) had a clinical history of, or electrocardiographic findings consistent with, WPW syndrome. In 2 patients, WPW syndrome preceded MELAS syndrome by 15 and 21 years. The tissue burden of mutant mitochondria was similar in patients with (49.4%) and without (39.1%) WPW syndrome.
The prevalence of WPW syndrome among patients with MELAS syndrome and the A3243G mutation appears much higher than in the normal population and may become manifest earlier than neurologic symptoms. Patients with WPW syndrome and neurologic abnormalities consistent with MELAS syndrome, such as seizures, deafness, short stature, and stroke, should be screened for the A3243G mutation. Moreover, patients with MELAS syndrome should be monitored for cardiac anomalies including cardiomyopathy and WPW syndrome.
Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is a maternally inherited disorder characterized by a progressive encephalopathy punctuated by episodes of focal brain injury.1,2 An A→G transition at nucleotide 3243 of the mitochondrial genome, affecting a mitochondrial leucine tRNA gene, is the most common underlying mutation and results in impaired oxidative phosphorylation.3 Multiple organs can be affected, but tissues with high energy demand are most vulnerable. Therefore, nervous system and muscle impairment often dominate the clinical picture.1-3 Cardiac involvement has been described in patients with MELAS syndrome, including hypertrophic and dilated cardiomyopathy,4,5 and conduction disturbances, including Wolff-Parkinson-White (WPW) syndrome.1,2,6 However, to our knowledge, no large case series has directly addressed the association, coincidence, and relative onset of these disorders among a genotypically well-described cohort.
Herein we describe the occurrence of WPW syndrome among a cohort of patients with MELAS syndrome and the A3243G mutation. The patients were enrolled in a clinical trial evaluating dichloroacetate as a treatment for MELAS.7 In addition, we attempt to characterize a temporal relationship in the clinical onset of WPW and MELAS among patients who are doubly affected and discuss why a mitochondrial DNA mutation such as the A3243G mutation might be associated with the WPW syndrome.
Patients for this study were participants in a clinical trial assessing the efficacy of dichloroacetate in the treatment of MELAS. Recruitment for this trial commenced on March 1, 2000, and included US patients who were evaluated at Columbia University Medical Center, who were referred by other physicians, or who learned of the trial through publications, Web sites, or nonprofit patient advocacy groups.
The methods and selection criteria used in this trial have been described previously.7 Criteria for inclusion required the presence of the MELAS syndrome (including seizures or strokelike episodes); confirmed A3243G mitochondrial DNA point mutation as assessed with polymerase chain reaction; and elevated lactate values in the ventricles as measured by magnetic resonance spectroscopy or in the cerebrospinal fluid as measured by lumbar puncture. Excluded were patients younger than 6 years, those with elevated serum transaminase levels (alanine aminotransferase or aspartate aminotransferase), and those with an inability to complete study procedures. All 30 patients enrolled in the clinical trial were included in this study. Age at onset of MELAS syndrome was described as the age at which the patient experienced his or her first seizure or strokelike event based on clinical history and medical records.
Electrocardiograms were obtained on all patients, concurrent with identification of any prior cardiac history, including past cardiac surgery or catheter ablations. In patients with a history of a past catheter ablation, case histories and preablation electrocardiograms were reviewed to confirm the history of WPW syndrome. Electrocardiograms were reviewed and analyzed independently by 2 pediatric cardiologists, one who interacted with the patients and was aware of the MELAS diagnosis (T.J.S.), and a second reviewer who was blinded to patient history (A.J.H.). In cases of discordance between the 2 reviewers, the blinded reviewer's opinion was accepted.
Tissue samples from patients enrolled in this study were obtained from skin fibroblasts, blood leukocytes, hair, oral mucosa, and urine sediment cells. Mutant mitochondrial DNA in each tissue type was quantified as a percentage of total mitochondrial DNA using polymerase chain reaction amplification and restriction fragment length polymorphism analysis of total DNA, which involved using a technique described previously.8 A total tissue burden was estimated using a mean of the percentage of mutant mitochondrial DNA in the 5 tissue types, where available.
Demographic characteristics and clinical features of the cohort are outlined in the Table. Patients with WPW syndrome tended to be younger and to have disease onset before age 40 years. A nonsignificant increase in the mean composition of mutant mitochondrial DNA was observed among patients with WPW (49.4%) compared with those without WPW (39.1%).
Wolff-Parkinson-White syndrome was reported in 4 of 30 patients (13%) enrolled in this study. Of the 4 cases, 1 was identified by electrocardiography demonstrating a short PR interval, delta wave, and ST-segment changes, with a clinical history of tachycardia. This patient had no history of electrocardiographic abnormalities and was identified via review of his enrollment electrocardiogram. Three additional cases were determined through patient history of past documented WPW syndrome treated with catheter ablation of a bypass tract. Diagnosis and treatment in these 3 cases was made before, and independent of, the initial diagnosis of MELAS syndrome at a mean age of 10 years (range, 12 weeks to 14 years). The frequency of WPW syndrome in this cohort is significantly higher than in the general population (P < .001 vs historical control of 1.5 to 3.1 per 1000 persons using Fisher exact test9).
In 3 individuals with a history of WPW syndrome, this diagnosis preceded the diagnosis of MELAS syndrome. In 1 patient, WPW syndrome was diagnosed after the development of episodic tachycardia at 10 years of age. Within a few months of this diagnosis, this patient developed intractable seizures and was determined to have MELAS syndrome. In the other 2 patients, WPW syndrome became clinically apparent years before the development of MELAS syndrome. One patient was diagnosed as having WPW syndrome at 14 years of age and underwent an ablation at 24 years. He did not develop clinical manifestations of MELAS syndrome until he was 35 years of age. The other was diagnosed as having WPW syndrome at 12 weeks of age and underwent ablation at 12 years, but did not manifest MELAS syndrome until age 15 years.
In this study, we documented WPW syndrome in 4 of 30 patients with MELAS syndrome and the A3243G mutation. Wolff-Parkinson-White syndrome has been noted in previous case series on MELAS syndrome.1,2,6 In their review of published cases, Hirano et al2 noted that 6 of 43 patients with WPW syndrome and another 3 of 47 patients presented with cardiac conduction block. Okajima et al6 reported WPW syndrome in 3 of 11 pediatric patients with MELAS syndrome (10 of whom carried the A3243G mutation). The present study supports these previous observations of the association between the WPW and MELAS syndromes. This study examines an older cohort of patients with MELAS syndrome who exclusively express the A3243G mutation and, in so doing, incorporates a study group with distinctly different characteristics than the patient group studied by Okajima et al.
With a previously noted prevalence of approximately 1.5 to 3.1 per 1000 persons in Western countries, WPW is a common cause of supraventricular tachycardia.9 A mutation of the PRKAG2 gene, an adenosine monophosphate–activated protein kinase mapped to the locus 7q34-q36,9 has been linked to the development of WPW syndrome in 2 families with an autosomal dominant form of the disorder.9 The adenosine monophosphate–activated protein kinase encoded by the PRKAG2 gene has been described as a “cellular fuel gauge.”10 Aberrant energy metabolism in the developing fetus, leading to an altered cellular responsiveness to energy-depleting stressors, has been proposed as a possible mechanism underlying the pathogenesis of this mutation.9 Perhaps it is the failure of this gauge to properly regulate energy metabolism that underlies the development of this disorder. A mitochondrial defect may act in a similar manner to create a relatively energy-depleted state, preventing the normal maturation of the insulating ring, thus leading to the generation of an abnormal conductive circuit. Why WPW has not been reported in increased frequency in other mitochondrial DNA-associated syndromes such as myoclonus epilepsy associated with ragged-red fibers (MERRF), neuropathy, ataxia, and retinitis pigmentosa (NARP), and Leigh syndrome is unknown.
An understanding at the molecular and cellular levels of the importance of energy utilization and mitochondrial disease in the development of WPW syndrome remains a direction for future research. Although limited in sample size and retrospective in design, our study describes the possibility of WPW syndrome to precede the manifestation of MELAS syndrome in cases in which the 2 syndromes are present concurrently. Therefore, in patients with WPW syndrome and a clinical or family history suggestive of possible mitochondrial DNA disease, an underlying A3243G mutation should be considered. Also, given the potential for significant morbidity and mortality, patients with MELAS syndrome should be closely monitored for the development or existence of cardiac anomalies including cardiomyopathy, cardiac defects, and preexcitation syndromes such as WPW.
Correspondence: Darryl C. De Vivo, MD, Neurological Institute, 710 W 168th St, Room 2-201, New York, NY 10032.
Accepted for Publication: January 8, 2007.
Author Contributions:Study concept and design: Kaufman, Starc, and De Vivo. Acquisition of data: Sproule, Kaufman, Engelstad, Starc, and De Vivo. Analysis and interpretation of data: Sproule, Kaufman, Starc, Hordof, and De Vivo. Drafting of the manuscript: Sproule, Kaufman, Engelstad, and De Vivo. Critical revision of the manuscript for important intellectual content: Kaufman, Starc, Hordof, and De Vivo. Statistical analysis: Starc. Obtained funding: De Vivo. Administrative, technical, and material support: De Vivo. Study supervision: Kaufman, Starc, Hordof, and De Vivo.
Financial Disclosure: None reported.
Funding/Support: This study was supported by grant K12 RR017648 (Dr Kaufmann) from the National Institutes of Health, grant PO1-HD32062 (Dr De Vivo) from the National Institute of Child Health and Human Development, and by the Colleen Giblin Foundation (Dr De Vivo). Dr Kaufmann is the recipient of an Irving Research Fellowship.