T. Prax 1; E. Ehler 1; L. Ungermann 2; I. Štětkářová 3
Authors place of work:
Department of Neurology, Faculty of Health Studies, University of Pardubice and Pardubice Regional Hospital, Czech Republic
1; Radiodiagnostic Department of the Pardubice Regional Hospital, Czech Republic
2; Department of Neurology, Third Faculty of Medicine, Královské Vinohrady University Hospital, Prague, Czech Republic
Published in the journal:
Cesk Slov Neurol N 2021; 84(5): 491-492
Heart problems in individuals with Emery-Dreifuss muscular dystrophy (EDMD) are caused by a number of related complications. Cardiac complications are manifested by arrhythmias, atrio-ventricular (AV) conduction blockages, congestive heart failure, and sudden death. Atrial arrhythmias (extrasystoles, atrial fibrillation or flutter, atrial arrest), and less frequently ventricular arrhythmias, are characteristic cardiac problems. Cardiac involvement does not manifest until the age of 20 and develops independently of changes in the neuromuscular system . Patients report palpitations, presyncope and syncope, poor tolerance to stress, and dyspnea. Due to cardiac involvement, patients should be examined in detail using electrocardiography (ECG), Holter ECG monitoring, echocardiography, and invasive electrophysiological examination. Specific treatments for cardiac manifestations are antiarrhythmic therapy, cardioverter implantation (ICD), and pharmacological and non-pharmacological treatments of cardiac failure. ICD implantation has been shown to significantly reduce the risk of sudden death from ventricular fibrillation. In the terminal stages of cardiac failure, a heart transplant is performed. Anticoagulant therapy is indicated for the prevention of thromboembolic stroke in patients with reduced left ventricular function and in those with atrial arrhythmia .
In this case report, we present a 47-year-old woman with cardiomyopathy in EDMD (with minor clinical expressions on the skeletal muscle) due to a mutation in the LMNA (lamin A) gene, who developed an acute extensive ischemic stroke in the internal carotid artery. The patient was being prepared for cardioverter implantation and permanent anticoagulant medication when acute embolization of stroke occurred.
Over 2 years ago, a 47-year-old woman underwent recurrent symptomatology from the right parietal area of the brain with complete correction. She also had an apicolateral acute transmural myocardial infarction. She was subsequently examined for rheumatology, but rheumatic disease was not detected. Due to suspicion of the patient having a genetic origin of cardiomyopathy with arrhythmias, next generation sequencing was performed with the finding of a mutation in the LMNA gene and EDMD was determined. At that time, only a slight shortening of the m. triceps surae tendons, biceps brachii tendons, uncertain pelvic fixation and subjective small fluctuating dizziness were evident in the neurological finding. The patient’s family history included a cousin with cardiac disease who was implanted with a pacemaker for arrhythmias followed shortly thereafter by a cardioverter. The mother had a pacemaker and died during heart surgery due to a valve defect at the age of 62. The brother died unexpectedly at the age of 35 while cycling, which was retrospectively assessed as the result of a cardiac problem.
Our patient has undergone two myocardial infarctions (non-ST elevation myocardial infarction; NSTEMI) and now has a permanent grade I AV block, Wenckebach-type intermittent AV block symptomatic, paroxysmal atrial fibrillation, and transient polymorphic ventricular tachycardia (documented by implantable loop recorder [ILR]). According to the echocardiography, the patient had an ejection-fraction (EF) of 50%. The MRI of the heart (9/19) indicated a borderline size of the left ventricle, post-ischemic scar apically, and non-specific opacification of the middle layer of the inferoseptal myocardium basally. The causal mutation NM_170707.4(LMNA): c.999_1003dup (p.Arg335Profs*147) in the LMNA gene was found using high-throughput sequencing analysis. This variant was not yet described in any publication or genetic databases. It was evaluated in VarSome software (Lausanne, Switzerland) , which utilizes further prediction programs and assesses variants according to the recommendation of the American Society for Genetics and Genomics. This variant is evaluated as a pathogenic variant within this program – it fulfilled criteria PVS1, PM1, PM2, PP3. No other mutations were found.
During the night, about 3 hours after falling asleep, the patient experienced sudden left movement disorder along with marked restlessness. The husband called the emergency service and the patient was admitted to the ICU of the stroke center. We present a 47-year-old woman with cardiomyopathy in EDMD (with minor clinical expressions on the skeletal muscle) due to a mutation in the lamin A gene, who developed an acute extensive ischemic stroke in the internal carotid artery. The patient was being prepared for cardioverter implantation and permanent anticoagulant medication when acute embolization of CMP occurred in the middle cerebral artery. The penumbra was only affected to a small extent; ASPECTS was 3 points. CTA of the cerebral arteries showed closure of the terminal section of the internal carotid artery (ICA) on the right side (segment C7) with a transition to M1 (10 mm) (Fig. 1). The patient was consulted at a comprehensive stroke center that did not recommend intravenous thrombolysis (IVT) or mechanical thrombectomy (catheter-based therapy) for the already significant and extensive ischemic changes in the brain tissue. The finding was evaluated as an emboligenic occlusion of the distal ICA, most likely of cardiac origin. The next day, somnolence, dysarthria and dysphagia were added to left-sided hemiplegia. A follow-up CT of the brain was performed with the finding of expansively behaving tissue softening in the right hemisphere with a midline shift, with a subphalcinic and descending transtentorial herniation (Fig. 2). The patient was transferred to neurosurgery, where an extensive right-sided hemicraniectomy was performed. This was followed by a stay at the Anesthesiology and Resuscitation Department (ARO). After disconnection from complete mechanical ventilation (immediate postoperative), she was transferred to a neurological ICU. Here, the patient's environmental cooperation gradually improved, and passive and active rehabilitation was started. The neurological finding was dominated by significant psychological changes with fluctuations in cooperation, partial neglect syndrome, plegia of the left upper limb and severe paresis of the left lower limb.
There was a significant reduction in cerebral edema on both the follow-up CT and the brain MRI two months after the onset of the disease. The development of postischemic changes in the brain parenchyma were evident (Fig. 3).
EDMD has an incidence of 0.1–0.4 in 100,000 individuals and is characterized by the early development of contractures in the elbows, Achilles tendons and neck extensors. Furthermore, the development of muscle weakness and the development of atrophy in the humeroperoneal distribution is typical . Cardiac involvement develops in more than 90% of patients and manifests itself in various types of conduction blocks and dilated cardiomyopathy.
(Online only) EDMD occurs on the basis of pathogenic mutations in no less than 5 various genes – EDMD and FHL1 encoding emerin, FHL1 for X-linked forms, laminopathies A and C, SYNE1 and SYNE2 encoding nesprins 1 and nesprins 2 .
AD laminopathies are characterized by defects in the nuclear membrane. When compared with emerinopathy, they arise earlier, have more pronounced muscle contractures (cervical, elbow, and ankle flexors), disturbances in heart conduction, and slowly progressing muscle atrophy with weakness in the humeroperoneal distribution. Mutation in the LMNA gene can manifest with a broad clinical spectrum – from EDMD, limb girdle muscle dystrophy to dilated cardiomyopathy [5,6]. Emerin is found to a greater extent in tissues than laminin. In some forms, a lamin defect can lead to the dislocation of emerin, which is then not contained in the nuclear envelope but in the endoplasmic reticulum . Our patient with the AD mutation in the lamin A gene had only a very mild finding in the skeletal muscle (shortening of flexors in the elbows, in the area of the Achilles tendon, and a mild pelvic fixation disorder), and a significant cardiological finding.
In EDMD, dilated and hypokinetic cardiomyopathy is often associated with AV block. XLR FHL-1 associated with EDMD is characterized by a conduction defect with arrhythmias. Mild hypertrophy with systolic dysfunction and restriction, non-dilated ventricles, QTc prolongation, fibrous-fat changes, and scarring of the left ventricular trabeculae are described as variants. Arrhythmias, often of atrial origin, which occur before left ventricular systolic dysfunction, are at the forefront of XLR emerinopathy. One typical manifestation of emerinopathy is atrial standstill, which requires anticoagulant therapy to prevent systemic embolization of the heart. The risk of ventricular arrhythmia in AD laminopathy is high . Depression of left ventricular function may occur in later stages. Only isolated heart failure can occur without muscle weakness and contractures. The risk of sudden cardiac death can be as high as 40% in the absence of any previous cardiac symptoms .
The pathognomonic finding for EDMD is atrial standstill with a lack of atrial response to intracardiac electrical and mechanical stimulation. AD laminopathy is characterized by nuclear membrane defects [2,10].
Our patient had two heart attacks (NSTEMI) and now has a permanent AV block of the first degree, intermittent AV block of the second degree, paroxysmal atrial fibrillation, and transient polymorphic ventricular tachycardia.
Patients with EDMD are at risk of arrhythmias, which can lead to sudden death (ventricular fibrillation). (Online only)Pacemaker implantation has not been shown to reduce the risk of arrhythmias and sudden death, and there have been repeated sudden deaths in patients with pacemaker implants . Only the implantation of a cardioverter has been shown to significantly improve the fate of these patients. Due to atrial arrhythmias and cardiomyopathy with EF reduction (below 45% in EDMD), there is a high probability of intracardiac thrombus formation and subsequent embolizations, especially in the brain. Therefore, anticoagulant therapy is indicated in these patients. (Online only) Elderly patients with EDMD develop cardiomyopathy. In our patient, the cardiologist monitored the occurrence of arrhythmias (ILR-long-term subcutaneous registration) and prepared the patient for cardioverter implantation. The next plan was to use permanent anticoagulant medication. During this period, however, an embolization of the internal carotid artery on the right with severe ischemic CMP occurred. Embolic stroke was clearly diagnosed on the findings in the carotid and arteria cerebri media vessel during the CTA upon admission to neurology. An extensive hemicraniectomy was performed for expansive tissue softening in the middle cerebral artery on the right side. In the following course, there was a significant clinical improvement in psyche and movements. The patient was implanted with a cardioverter and anticoagulant therapy with dabigatran was initiated.
According to the American Heart Association recommendation, early detection of arrhythmias with defibrillator implantation and initiation of anticoagulant therapy in muscular dystrophies is necessary  to prevent the extensive embolization CMP found in our patient. (Online only).
Supported by the PROGRES Q 35 Research projects of Charles University, Prague.
The Editorial Board declares that the manu script met the ICMJE “uniform requirements” for biomedical papers.
Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.
Assoc. Prof. Edvard Ehler, MD, CSc., FEAN
Department of Neurology
Faculty of Health Studies
University of Pardubice
and Pardubice Regional Hospital
532 03 Pardubice
Accepted for review: 4. 11. 2020
Accepted for print: 1. 9. 2021
An extended version of the article is available at csnn.eu.
1. Karpati G, Hilton-Jones D, Bushby K et al. Disorders of voluntary muscles. 8th ed. Cambridge, UK: Cambridge University Press 2010.
2. Faiella W, Bessoudo R. Cardiac manifestation in Emery-Dreifuss muscular dystrophy. CMAJ 2018; 190(3): E1414–E1417. doi: 10.1503/cmaj.180410.
3. Kopanos C, Tsiolkas V, Kouris A et al. VarSome: the human genomic variant search engine. Bioinformatics 2019; 35(11): 1978–1980. doi: 10.1093/bioinformatics/bty897.
4. Granger B, Gueneau L, Drouin-Garraud V et al. Modifier locus of the skeletal muscle involvement in Emery-Dreifuss muscular dystrophy. Hum Genet 2011; 129(2): 149–150. doi: 10.1007/s00439-010-0909-1.
5. Voháňka S, Vlčková E, Bednařík J. Genetika nervosvalových onemocnění. Cesk Slov Neurol N 2019; 82/115(2): 229–235. doi: 10: 14735/amcsnn2019229.
6. Angelini C. LGMD. Identification, description and classification. Acta Myologica 2020; 39(4): 207–217. doi: 10.36185/2532-1900-024.
7. Bakay M, Wang Z, Melcon G et al. Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain 2006; 129(Pt 4): 996–1013. doi: 10.1093/brain/awl023.
8. Arbustini E, Ri Torro A, Giuliani L et al. Cardiac phenotypes in hereditary muscle disorders. J Am Coll Cardiol 2018; 72(20): 2485–2506. doi: 10.1016/j.jacc.2018.08.2182.
9. Bednařík J, Gaillyová R, Kadaňka Z et al. Nemoci kosterního svalstva. Prague: Triton 2001.
10. Mercuri E, Muntoni F. Muscular Dystrophies. Lancet 2013; 381(9869): 845–860. doi: 10.1016/S0140-6736(12)61897-2.