Cardiac Disorders in Patients With Leber Hereditary Optic Neuropathy

Cardiac abnormalities have been described in patients with Leber hereditary optic neuropathy (LHON). Some are life-threatening because of the risk of ventricular fibrillation and sudden death. The purpose of our study was to better characterize the cardiac abnormalities in a large patient cohort with LHON. A retrospective study of the electrocardiogram (EKG) results performed on all patients with LHON evaluated at The Reference Center for Rare Diseases in Ophthalmology, Paris, France, from January 2015 to June 2017. Our series included 73 patients with LHON (9 women/64 men) with a mean age of 30.29 ± 14.48 years. Although only 1 patient had cardiac complaints, cardiac abnormalities were detected in 17 patients (23.2%): 9 patients had an excitation syndrome, 6 had atrioventricular block, and 2 had repolarization abnormalities. All patients harbored mtDNA point mutations 11778 or 3460. Cardiac abnormalities occur frequently enough in patients with LHON that a baseline EKG is warranted. However, further studies are needed to determine the true cardiac risk associated with specific LHON mtDNA mutations.

Original Contribution Cardiac Disorders in Patients With Leber Hereditary Optic Neuropathy Christophe Orssaud, MD Background: Cardiac abnormalities have been described in patients with Leber hereditary optic neuropathy (LHON). Some are life-threatening because of the risk of ventricular fibrillation and sudden death. The purpose of our study was to better characterize the cardiac abnormalities in a large patient cohort with LHON. Methods: A retrospective study of the electrocardiogram (EKG) results performed on all patients with LHON evaluated at The Reference Center for Rare Diseases in Ophthalmology, Paris, France, from January 2015 to June 2017. Results: Our series included 73 patients with LHON (9 women/64 men) with a mean age of 30.29 ± 14.48 years. Although only 1 patient had cardiac complaints, cardiac abnormalities were detected in 17 patients (23.2%): 9 patients had an excitation syndrome, 6 had atrioventricular block, and 2 had repolarization abnormalities. All patients harbored mtDNA point mutations 11778 or 3460. Conclusions: Cardiac abnormalities occur frequently enough in patients with LHON that a baseline EKG is warranted. However, further studies are needed to determine the true cardiac risk associated with specific LHON mtDNA mutations. Journal of Neuro-Ophthalmology 2018;38:466-469 doi: 10.1097/WNO.0000000000000623 © 2018 by North American Neuro-Ophthalmology Society V isual loss is the cardinal clinical manifestation of patients with Leber hereditary optic neuropathy (LHON). However, systemic abnormalities also have been described. Asymptomatic periventricular white matter lesions on T2 imaging, similar to those found in multiple Functional Unit of Ophthalmology, Reference Center for Rares Diseases in Ophthalmology OPHTARA, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France. The author had consultancy agreement/support for travel to meeting with Santhera Pharmaceuticals. Address correspondence to Christophe Orssaud, MD, Functional Unit of Ophthalmology, Reference Center for Rares Diseases in Ophthalmology OPHTARA, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, 20 Rue Leblanc, 75015 Paris, France; E-mail: [e-mail] 466 sclerosis, have been detected on MRI (1-3). "Leber-plus" refers to patients with LHON and neurological manifestations indistinguishable from those observed in multiple sclerosis (4,5). Bower et al (6) initially reported cardiac involvement in patients with LHON and in their unaffected relatives harboring 11778 mtDNA mutation. Other investigators documented preexcitation syndromes, such as Wolf-Parkinson-White syndrome (WPWS) and short PR interval duration in patients with LHON and their families (7) as well as abnormal QT interval on electrocardiogram (EKG) in patients with the 11778 mtDNA mutation (8). Subsequently, these abnormalities were reported with other point mtDNA mutations (9). The aim of our study was to better characterize and quantify the types of cardiac disorders in a large cohort of patients with LHON. PATIENTS AND METHODS We retrospectively reviewed the results of EKG testing in patients with LHON evaluated at The Center for Rare Diseases in Ophthalmology, Paris, France, from January, 2005 to June, 2017. The diagnosis of LHON was based on characteristic ophthalmologic features, electrophysiological testing, and results of mtDNA genetic testing. However, when a patient had a family history of LHON including a pathogenic mtDNA mutation, this was considered diagnostic for the whole pedigree. All EKGs were performed and analyzed by certified cardiologists. In addition, each cardiologist had the opportunity to perform a clinical examination of the patient, according to the EKG abnormalities observed. Some patients had echocardiography as well. The number of each cardiac abnormality was quantified and correlated with the type of mtDNA mutation. WPWS was defined as a PR interval ,120 ms, QRS duration .120 ms, and slurred onset of the QRS complex (d wave) (10). EKG evidence of left ventricular hypertrophy and of atrioventricular block Orssaud: J Neuro-Ophthalmol 2018; 38: 466-469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Cardiac findings in patients with Leber hereditary optic neuropathy. was defined in accordance with standard criteria of the French Society of Cardiology. RESULTS Ninety-eight patients, 15 women and 83 men, were included in our study, but 25 did not have cardiac assessment. This left 73 patients with LHON (9 women/ 64 men), with a mean age of 30.29 ± 14.48 years and median age of 27.5 years. Sixty-seven patients carried the mutation 11778 and 7 the 3460 mutation. The mutations 14484 and 14482 were observed in 4 patients each. HowOrssaud: J Neuro-Ophthalmol 2018; 38: 466-469 ever, in 1 patient, the 14484 mutation was associated with 15257. In another patient, the 15257 mutation was the only mutation of mtDNA detected and in 1 patient, only the 14568 mutation was found. In the remaining patients, the mutation was confirmed in the maternal family, but because of the laws governing personal genetic data, we were unable to obtain the results. EKG testing was normal in 56/73 (76.71%) patients. Thus, 23.29% of our patients had cardiac abnormalities (Fig. 1). Two patients had a WPWS confirmed by EKG, both carrying the 3460 mtDNA mutation. These patients were referred to the cardiac electrophysiology department 467 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution for specialized studies (intracardiac recordings) and management. Treatment consisted radiofrequency ablation of the accessory pathway because of symptomatic arrhythmia for the first patient and modification of the EKG with an increase of cardiac troponin value for the second one. Seven patients had a short PR interval without other findings of WPWS. This occurred in patients with both 11778 and 3460 mtDNA point mutations. Atrioventricular block was observed in 6 patients of 5 different families. All these patients harbored the 11778 mutation. In addition, large T waves were detected in 1 patient with the 11778 mutation and asymptomatic posterior myocardial ischemia in another patient with the 11778 mutation. Only 1 patient, with WPWS, had cardiac symptoms. DISCUSSION In our study, 17/73 (23.29%) patients with LHON had cardiac abnormalities detected with EKG testing. All patients with cardiac abnormalities had mtDNA mutation 11778 or 3460. At least 4 types of cardiac abnormalities were observed, one of which has previously not been reported. WPWS and conduction abnormalities in the PR segment were found most frequently. Two patients had EKG abnormalities compatible with WPWS, both harboring the 3460 mtDNA mutation as previously described (7,9) and our findings support an association between LHON and WPWS or preexcitation syndrome (7). The prevalence of this syndrome in our patient cohort was 2.73%, which is approximately 9 times greater than in the general population (11-13). In our series, 8.22% of patients had atrioventricular blocks, although its prevalence in the general population is less than 1% in Caucasian populations before the age of 50 years and close to 3% in the same age group in African Americans (14,15). One patient had an asymptomatic posterior myocardial ischemia, but it is not possible to establish a causal link with an mtDNA mutation. Presence of large T waves on the EKG observed in another patient also is atypical for patients with LHON. But, in the absence of cardiac symptoms, no further work up was performed. Various cardiac abnormalities have been reported in patients with LHON including preexcitation syndrome, isolated EKG abnormalities of PR or QT segments, and hypertrophic cardiomyopathy (7,9,10,16,17). These have been most frequently treated in patients with mutations 11778 or 3460. When looked for, their frequency differs according to their type and depending on the series reported, the prevalence ranging from 15% to 50%. In a series of 24 patients, Sorajja et al (10) found more patients with left ventricular hypertrophy associated with point mutation 3460 than with the 2 other mtDNA mutations and only 1 case of left ventricular hypertrophy and ST segment abnormality in a 51-year-old patient with a 14484 mutation. 468 None of our patients had evidence of cardiac hypertrophy. Patients reported by Finsterer et al (9) had more severe cardiac involvement with echocardiographic findings of myocardial thickening and left ventricular hypertrabeculation. The basis for an association of cardiac abnormalities and LHON remains unknown. However, cardiac and neuroophthalmic abnormalities have been reported in other mitochondrial disorders such as Friedreich ataxia (18-20), but preexcitation syndrome and cardiac arrhythmias are infrequent in these disorders. Given the results of both our study and preview reports, we recommend that all patients with LHON should undergo cardiac evaluation. EKG seems to be the most effective strategy for screening for cardiovascular disease in asymptomatic patients. It is more sensitive than personal history or physical examination (16). Depending on the results obtained, a more comprehensive cardiac assessment may be warranted. In addition, it would be interesting to systematically look for cardiac dysfunction in relatives of patients with LHON, considered to be "unaffected carriers" of the mtDNA mutations. REFERENCES 1. Meire FM, van Coster R, Cochaux P, Obermaier-Kusser B, Candaele C, Martin JJ. Neurological disorders in members of families with Leber's hereditary optic neuropathy (LHON) caused by different mitochondrial mutations. Ophthalmic Genet. 1995;16:119-126. 2. Lev D, Yanoov-Sharav M, Watemberg N, Leshinsky-Silver E, Lerman-Sagie T. White matter abnormalities in Leber's hereditary optic neuropathy due to the 3460 mitochondrial DNA mutation. Eur J Paediatr Neurol. 2002;6:121-123. 3. Honda H, Tsujihata M, Ochi M, Satoh A, Tomita I, Fujikawa A. Hyperintense optic nerve lesion on T2-weighted MRI imaging in the acute stage of Leber's hereditary optic neuropathy: a case report. Rinsho Shinkeigaku. 2006;46:294-296. 4. Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, McDonald WI, Compston DA. Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain. 1992;115:979-989. 5. Matthews L, Enzinger C, Fazekas F, Rovira A, Ciccarelli O, Dotti MT, Filippi M, Frederiksen JL, Giorgio A, Küker W, Lukas C, Rocca MA, De Stefano N, Toosy A, Yousry T, Palace J; MAGNIMS Network. MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86:537-542. 6. Bower SP, Hawley I, Mackey DA. Cardiac arrhythmia and Leber's hereditary optic neuropathy. Lancet. 1992;339:1427- 1428. 7. Nikoskelainen EK, Savontaus ML, Huoponen K, Antila K, Hartiala J. Pre-excitation syndrome in Leber's hereditary optic neuropathy. Lancet. 1994;344:857-858. 8. Ortiz RG, Newman NJ, Manoukian SV, Diesenhouse MC, Lott MT, Wallace DC. Optic disk cupping and electrocardiographic abnormalities in an American pedigree with Leber's hereditary optic neuropathy. Am J Ophthalmol. 1992;113:561-566. 9. Finsterer J, Stollberger C, Michaela J. Familial left ventricular hypertrabeculation in two blind brothers. Cardiovasc Pathol. 2002;11:146-148. 10. Sorajja P, Sweeney MG, Chalmers R, Sachdev B, Syrris P, Hanna M, Wood ND, McKenna WJ, Elliott PM. Cardiac abnormalities in patients with Leber's hereditary optic neuropathy. Heart. 2003;89:791-792. Orssaud: J Neuro-Ophthalmol 2018; 38: 466-469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 11. Lu CW, Wu MH, Chen HC, Kao FY, Huang SK. Epidemiological profile of Wolff-Parkinson-White syndrome in a general population younger than 50 years of age in an era of radiofrequency catheter ablation. Int J Cardiol. 2014;174:530-534. 12. Pelliccia A, Adami PE, Quattrini F, Squeo MR, Caselli S, Verdile L, Maestrini V, Di Paolo F, Pisicchio C, Ciardo R, Spataro A. Are Olympic athletes free from cardiovascular diseases? Systematic investigation in 2352 participants from Athens 2004 to Sochi 2014. Br J Sports Med. 2017;51:238-243. 13. Davenport ED, Rupp KAN, Palileo E, Haynes J. Asymptomatic Wolff-Parkinson-white pattern ECG in USAF aviators. Aerosp Med Hum Perform. 2017;88:56-60. 14. De Lazzari C, Genuini I, Gatto MC, Cinque A, Mancone M, D'Ambrosi A, Silvetti E, Fusto A, Pisanelli DM, Fedele F. Screening high school students in Italy for sudden cardiac death prevention by using a telecardiology device: a retrospective observational study. Cardiol Young. 2017;27:74-81. 15. Upshaw CB Jr. Comparison of the prevalence of first-degree atrioventricular block in African-American and in Caucasian patients: an electrocardiographic study III. J Natl Med Assoc. 2004;96:756-760. Orssaud: J Neuro-Ophthalmol 2018; 38: 466-469 16. Harmon KG, Zigman M, Drezner JA. The effectiveness of screening history, physical exam, and ECG to detect potentially lethal cardiac disorders in athletes: a systematic review/meta-analysis. J Electrocardiol. 2015;48:329-338. 17. Newman NJ, Yu-Wai-Man P, Sadun AA, Karanjia R, Carelli V. Management of ophthalmologic manifestations of mitochondrial diseases. Genet Med. 2017;19. doi: 10.1038/gim.2017.171. 18. Marin-Garcia J, Goldenthal MJ, Filiano JJ. Cardiomyopathy associated with neurologic disorders and mitochondrial phenotype. J Child Neurol. 2002;17:759-765. 19. Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med. 1996;335:1169-1175. 20. Sidi D, Le Bidois J, Piéchaud JF, Da Cruz E, Marchal C, Gournay V, Kachaner J, Rustin P, Chrétien D, Munnich A. Activités enzymatiques de la chaîne respiratoire mitochondriale dans les myocardiopathies de l'enfant. Etude prospective de 34 cas par biopsies endomyocardiques [in French]. Arch Mal Coeur Vaiss. 1992;85:541-546. 469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.