Neurology International 2018; volume 10:7468

Risk stratification in provide a mechanical stabilization of the and Emery nucleus and act as a scaffold for nuclear fac- Correspondence: Abdallah Fayssoil, Raymond tors. In 1999, Bonne et al.6 reported the first Poincaré Hospital, APHP, 104 Boulevard Dreifuss muscular dystrophy LMNA mutation in a group of patients Raymond Poincaré, 92380 Garches, France. with autosomal dominant EDMD. LMNA E-mail: [email protected] Abdallah Fayssoil mutation was found to be present in 8% of patients with . A Key words: LMNA, emerin, , CHU Raymond Poincaré et Université subset of clinical parameters has been arrhythmia, sudden death. Versailles Saint Quentin en Yvelines, shown to be predictive for LMNA muta- Contributions: the authors contributed equally. Garches, France tions in dilated cardiomyopathy: supraven- tricular arrhythmia, conduction defects, Conflict of interest: the authors declare no presence of failure and potential conflict of interest. Abstract moderate cardiomyopathy. In patients with lamins A/C mutation, Funding: none. Laminopathies are genetic disorders cardiac involvement may include atrio-ven- due to gene mutation encoding for tricular conduction and sinus node disor- Received for publication: 26 October 2017. of the . Patients are at risk ders. Conduction system disease seems to Revision received: 28 November 2017. of conduction defect, arrhythmia, sudden appear earlier, reaching 18% in patients <10 Accepted for publication: 2 December 2017. death and heart failure. The authors summa- years whereas cardiomyopathy seems to This work is licensed under a Creative rize predictive factors for cardiac events occur later, reaching 60% in older patients Commons Attribution NonCommercial 4.0 reported in the literature in this group of dis- 7 (>50 years). Other cardiac phenotypes License (CC BY-NC 4.0). ease. have been reported to be associated with LMNA mutations. 4% of patients with ary- ©Copyright A. Fayssoil, 2018 thmogenic right ventricular cardiomyopa- Licensee PAGEPress, Italy thy and without desmosomal gene muta- Neurology International 2018; 10:7468 Introduction tions carried LMNA mutations.8 Apical left onlydoi:10.4081/ni.2018.7468 ventricular aneurysm associated with ven- Laminopathies are genetic disorders tricular rhythm impairment has been report- due to gene mutation encoding for proteins ed in two members of family carrying decade. Bradycardia, complete atrio-ven- of the nuclear envelope that include emerin LMNA mutations.9 In a recentuse study, tricular block, atrial paralysis can occur in and lamins. Emery Dreifuss muscular dys- LMNA, TTN and MYBPC3 were EDMD as well as supraventricular and ven- trophy (EDMD) is a neuromuscular disor- 7 found to be the most prevalent genes dis- tricular arrhythmia. Sudden cardiac death der, reported in 1966 by Emery and ease associated with left ventricular non- (SCD) may be the initial manifestation of Dreifuss,1 characterized by peripheral 14 compaction.10 disease. skeletal muscular weakness, joint contrac- tures and cardiac conduction disorders.2 Clinical spectrum is large in laminopathy, ranging from skeletal muscle failure to Emery Dreifuss muscular dystrophy Risk stratification heart disease. Heart involvement is crucial to search since cardiolaminopathy affects Emery Dreifuss muscular dystrophy is Patients with EDMD and laminopathies prognosis, due to risk of conduction defect, the most known muscular dystrophy among are at risk of SCD. Ventricular arrhythmia laminopathies. We distinguish: and sudden death may occur despite pace- ventricular arrhythmia and heart failure. 7 Predictive factors for significant cardiac i. An X linked form related to mutation in maker implantation. The risk for ventricu- events are essential to know in clinical prac- EMD gene. In 1994, Bione et al.11 iden- lar arrhythmia was reported to reach 18% in a study that included 269 LMNA mutation tice. tified the gene. The EMD gene is locat- ed on Xq28 and encodes carriers (median follow up 43 months).15 In Non-commercialemerin, a of the inner nuclear a study that included 122 LMNA mutation membrane. Emerin is involved in gene carriers (follow up 7 years), the cumulative Laminopathies expression regulation, chromatin archi- atrio-ventricular (AV) block events were tecture and cell signaling. 57±5%, atrial arrhythmia 63±5% and ven- Laminopathies are due to LMNA muta- ii. Au autosomal dominant form related to tricular arrhythmia 34±5%.16 In the study tions, leading to a wide spectrum of dis- mutation in LMNA gene6 by Meune et al.,17 42% of patients with eases that may include dilated cardiomy- iii. An autosomal recessive form which LMNA mutation carrying an implantable opathy with conduction defect,3 neuropathy, seems to be rare12 cardioverter-defibrillator (ICD) received limb girdle muscular dystrophy type IB iv. Recently, FHL1 dysregulation has been appropriate shock in relation with arrhyth- (LGMD1B),4 congenial form of muscular reported to be associated with EDMD13 mia. Prophylactic implantation of an dystrophy,5 EDMD, lipodystrophy type Heart involvement includes arrhythmia, implantable cardioverter defibrillator (ICD) Dunnigan, mandibulo-acral dysplasia and conduction defects and dilated cardiomy- need to be considered and discussed in Hutchinson-Gilford progeria syndrome. opathy. Heart disease is characterized by LMNA mutations patient’s with conduction LMNA gene is located on chromosome progressive replacement of myocardium by system disorders. 1q21 and encodes lamins A and C that are adipose and fibrosis tissue that begins in Some parameters merged from the liter- A-type lamins. Lamines A and C are nuclear atria and affects progressively atrio-ventric- ature for risk stratification. In the study by intermediate filaments proteins, forming a ular node and ventricles. Symptoms may Pasotti et al.,18 the following parameters meshwork (the ) within the occur early, with conduction defects and were found to be predictive factors for heart inner nuclear membrane. Lamines A and C cardiac disease become usual in the third failure or death: NYHA III or IV, conduc-

[Neurology International 2018; 10:7468] [page 1] Editorial tion system disorder, clinical manifestation on. Cell Mol Life Sci 2006;63:2702-9 al. Clinical genetics and outcome of lef of LMNA deficiency, left ventricular ejec- 3. Fatkin D, MacRae C, Sasaki T, et al. ventricular non-compaction cardiomy- tion fraction (LVEF) <35%, left ventricular Missense mutations in opathy. Eur Heart J 2017 Oct 6. end diastolic volume >180 mL and history the rod domain of the lamin A/C gene as 11. Bione S, Maestrini E, Rivella S, et al. of competitive sport. In multivariate analy- causes of dilated cardiomyopathy Identification of a novel X-linked sis, NYHA III or IV and history of compet- and conduction-system disease. N Engl gene responsible for Emery- itive sport were predictive factors for con- J Med 1999;341:1715-24. Dreifuss muscular dystrophy. Nat Genet gestive heart failure or SCD or death.18 In 4. Muchir A, Bonne G, van der Kooi AJ, et 1994;8:323-7. the study by Van Rijsingen et al.,15 risk fac- al. Identification of mutations in 12. Di Barletta RM, Ricci E, Galluzzi G, et tors for ventricular arrhythmia were: male the gene encoding lamins A/C in auto- al. Different mutations in the LMNA gender, non-sustained ventricular tachycar- somal dominant limb girdle muscular gene cause autosomal dominant and dia, LVEF<45% and non-missense muta- dystrophy with atrioventricular conduc- autosomal recessive Emery-Dreifuss tion. Recently, Kumar et al.16 reported the tion disturbances (LGMD1B). Hum Mo muscular dystrophy. Am J Hum Genet following parameters as predictive factors Genet 2000;9:1453-9. 2000;66:1407-12. for cardiac events: male gender, 5.Quijano-Roy S, Mbieleu B, 13. Tiffin HR, Jenkins ZA, Gray MJ, et al. LVEF≤50% and non-missense mutations. Bönnemann CG, et al. De novo LMNA Dysregulation of FHL1 spliceforms due mutations cause a new form of congen- to an indel mutation produces ital muscular dystrophy. Ann Neurol an Emery-Dreifuss muscular dystrophy 2008;64:177-86. plus phenotype. Neurogenetics Conclusions 6. Bonne G, Di Barletta MR, Varnous S, et 2013;14:113-21 al. Mutations in 14. Finsterer J, Stöllberger C, Maeztu C. Patients with EDMD and laminopathies the gene encoding lamin A/C cause Sudden cardiac death in neuromuscular are at risk for cardiac morbidity ad mortali- autosomal dominant Emery-Dreifuss disorders. Int J Cardiol 2016;203:508- ty due to rhythmic events and dilated car- muscular dystrophy. Nat Genet 15. diomyopathy. Risk stratification relies on 1999;21:285-8. 15. van Rijsingen IA, Arbustini E, Elliott genetic, electrocardiogram (EKG), EKG only 7. van Berlo JH, de Voogt WG, van der PM, et al. Risk factors for malignant Holter findings as well as LVEF value and Kooi AJ, et al. Meta-analysis of clinical ventricular arrhythmias in lamin a/c exercise testing. Cardiac magnetic reso- characteristics of 299 carriers of LMNA mutation carriers a European cohort nance imaging and electrophysiological gene mutations: do lamin A/C muta- study. J Am Coll Cardiol 2012;59:493- studies may provide additional prognostic tions portend a high risk of suddenuse 500. value and require more future research in death? J Mol Med (Berl) 2005;83:79- 16. Kumar S, Baldinger SH, Gandjbakhch this field. 83. E, et al. Long-Term Arrhythmic and 8. Quarta G, Syrris P, Ashworth M, et al. Nonarrhythmic Outcomes of Lamin Mutations in the Lamin A/C gene A/C Mutation Carriers. J Am Coll mimic arrhythmogenic right ventricular Cardiol 2016;68:2299-307. References cardiomyopathy. Eur Heart J 2012;33: 17. Meune C, Van Berlo JH, Anselme F, et 1128-36. al. Primary prevention of sudden death 1. Emery AE, Dreifuss FE. Unusual type 9. Forissier JF, Bonne G, Bouchier C, et in patients with lamin A/C gene muta- of benign x-linked muscular dystrophy. al. Apical left ventricular aneurysm tions. N Engl J Med 2006;354:209-10. J Neurol Neurosurg Psychiatry without atrio-ventricular block due to 18. Pasotti M, Klersy C, Pilotto A, et al. 1966;29:338-42 a lamin A/C gene mutation. Eur J Heart Long-term outcome and risk stratifica- 2. Ellis JA. Emery-Dreifuss muscular dys- Fail 2003;5:821-5. tion in dilated cardiolaminopathies. J trophy at the nuclear envelope: 10 years 10. Sedaghat-Hamedani F, Haas J, Zhu Fet Am Coll Cardiol 2008;52:1250-60. Non-commercial

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