Cardioembolic stroke related to limb-girdle muscular dystrophy 1B
© Chen et al.; licensee BioMed Central Ltd. 2013
Received: 28 September 2012
Accepted: 18 December 2012
Published: 29 January 2013
Cardioembolic stroke is an under-recognized complication in patients with limb-girdle muscular dystrophy 1B. Here we present a young stroke patient who had a novel lamin A/C gene (LMNA) mutation.
This is a 39-year-old man who had slowly progressive proximal muscle weakness and cardiac arrhythmia since adolescent and a family history of similar manifestation. He sustained acute ischemic stroke in the left middle cerebral artery territory. Intravenous recombinant tissue plasminogen activator therapy was given with significant neurological improvement. Additionally, genetic sequencing of the LMNA gene of the patient identified a mutation in c.513+1 G>A that resulted in a splicing aberration.
We suggested that LMNA gene related myopathies should be considered in young stroke patients with long-standing myopathic features.
KeywordsNeuromuscular disorder Limb-girdle muscular dystrophy Emery-Dreifuss muscular dystrophy Cardioembolic stroke Thrombolytic therapy Cardiac arrhythmia
Limb-girdle muscular dystrophy 1B (LGMD1B) is an autosomal dominant muscular dystrophy caused by a lamin A/C gene (LMNA) mutation, and is characterized by slowly progressive proximal weakness with few contractures and age-related cardiac arrhythmias. The LMNA gene is located on chromosome 1q21.1–21.2 and comprises 12 exons consisting of a 25 KB coding region of the gene [1, 2]. The LMNA gene encodes lamins A and C, which are components of the nuclear envelope but are located in the lamina, a multimeric structure associated with the nucleoplasmic surface of the inner nuclear membrane. Lamins are structurally homologous with other intermediate filaments, and are expressed in a wide range of tissues, including adult heart and skeletal muscle .
List of important diseases caused by mutations of the LMNA gene
Disease (and its acronym)
Striatal muscle involvement
Emery-Dreifuss muscular dystrophy (AD-EDMD)
Limb-girdle muscular dystrophy 1B (LGMD-1B)
Dilated cardiomyopathy and conduction-system disease (DCM-CD)
Charcot-Marie-Tooth disease type 2B1 (CMT-2B1)
Partial lipodystrophy syndrome
Familial partial lipodystrophy, Dunnigan type (FPLD2)
Mandibuloacral dysplasia I (MAD1)
Hutchinson–Gilford progeria syndrome (HGPS)
Atypical Werner’s syndrome (AWRN)
Here we present a case of a young stroke patient with long lasting myopathic features which prompted the detection of a novel LMNA mutation. Intravenous administration of recombinant tissue plasminogen activator (rt-PA) successfully improved his initial severe neurological disability.
The patient was a 39-year-old man, who was the first of 2 siblings. His mother had a history of slowly progressive proximal muscle weakness, received pacemaker implantation for slow heart rate at the age of 40 years, and died from sudden cardiac arrest at the age of 50. His younger brother also had similar proximal lower limbs weakness; however he committed suicide at age 31 years. For our index patient, toe-walking and frequent falls were first noted at the age of around 5 years. In his adolescence, he developed proximal leg weakness with Gowers’ sign (i.e., with hip girdle weakness, the patient arises from a stooped or a squatting position by using his hands to “climb up the legs”). Around age 30 years, atrial fibrillation (AF) was found, and he was prescribed with aspirin and an angiotensin-converting enzymes inhibitor. In addition, mild ankle contractures were noted. An electromyographic study revealed myopathic changes, consisting of muscle potentials of small amplitudes and polyphasic waves of short duration, in biceps brachii and rectus femoris. His baseline creatine kinase level was around 200 IU/L (reference range, <190 IU/L for a male). At age 36 years, he complained of chest tightness, and electrocardiography showed AF with slow ventricular rate, right bundle branch block, and transient ventricular tachycardia. Pacemaker implantation (VVI pacemaker, i.e., ventricular pacing, ventricular sensing, pacemaker inhibited) was done at that time.
Discussion and conclusions
Mutations in the LMNA gene cause a variety of human disease with numerous different phenotypes [4–6]. The skeletal muscle phenotypes of AD-EDMD and LGMD1B overlap. Both diseases are inherited in an autosomal dominant fashion and express as slowly progressive proximal limb weakness. AD-EDMD has more prominent muscle wasting in humero-peroneal distribution, early contractures of the elbow flexors, Achilles tendons and rigid cervical spine, and has lethal cardiac arrhythmia that requires pacemaker insertion. The cardiac involvement of AD-EDMD may occur at any age or even as an isolated presentation without detectable skeletal muscle manifestation . On the other hand, LGMD1B has typical girdle weakness, absent or minimal contractures, and has age-related severity of atrioventricular conduction disturbances. The neuromuscular symptomatology almost always precedes cardiological involvement in LGMD1B . Therefore, our patient should be classified as having LGMD1B based on less contractures and age-related cardiac conduction disturbance.
Ischemic stroke of cardioembolic origin is a relatively rare but severe complication among patients of myopathy and cardiac arrhythmia. In a literature review, the prevalence of AF or atrial flutter in patients with primary myopathies was estimated as 15% . The most frequently reported myopathies that are associated with arrhythmia included myotonic dystrophy, EDMD, dystrophinopathies, and limb girdle muscular dystrophies. The stroke rate in patients with myopathy and AF/atrial flutter was around 6.5%, and most of them received oral anticoagulant for secondary stroke prevention .
Comparison of patients with LMNA gene mutation and stroke
Age of stroke
Arrhythmia during all follow-up
Pacemaker insertion and age
Mutation of LMNA gene
Onishi et al., 2002 
AF, AVB, VPC
p.Ser303Pro (c.907 T>C)
Boriani et al., 2003 
AF, AFL, AVB
p.Arg386Lys (c.1157 G>A)
57 and 70
AF, AVB, SAB
p.Arg527Pro (c.1580 G>C)
43 and 44
p.Arg377Leu (c.1130 G>T)
Liang et al., 2007 
VPC, VT, VF
p.Trp520Gly (c.1558 T>G)
Redondo-Vergé et al., 2011 
Aphasia, right hemiparesis
p.Arg89Leu (c.266 G>T)
Tanaka et al., 2012 
Dysarthria, left hemiparesis
Aphasia, right hemiplegia
AF, RBBB, AVB
c.IVS2+1 G>A (c.513+1 G>A)
To date, more than 300 mutations have been reported in LMNA gene (based on an on-line database: http://www.UMD.be/LMNA/). A novel mutation in c.513+1 G>A was identified from our index patient. Although the mutation does not affect the coding region, its position is in the splice donor site of intron 2. We speculate this splicing donor site mutation may be associated with abnormal splicing process. One German pedigree was reported to have a synonymous codon change of LMNA gene in c.513 G>A, resulting in a so-called “neutral” mutation of Lys171Lys, which leads to abnormal splicing of intron 2 and possibly causes LGMD1B . In addition, another family of LGMD1B had a mutation in the splice donor site of intron 9 (IVS9+5 G>C), which also leads to abnormal splicing of LMNA mRNA . Therefore, our case probably had a disease-causing mutation in the intron, which leads to abnormal splicing of LMNA gene and mutant lamin production.
In conclusion, we presented a LGMD1B patient with proven LMNA gene mutation who suffered from disabling cardioembolic stroke, and was treated effectively with intravenous thrombolytic therapy. When a suspected cardioembolic stroke occurring at a relatively young age is associated with long-standing myopathic features, LMNA gene related disorders should be considered.
Written informed consent was obtained from the patient and his wife for publication of this Case report, any accompanying images, and the included family information. A copy of the written consent is available for review by the Series Editor of this journal.
Lamin A/C gene
- LGMD 1B:
Limb-girdle muscular dystrophy 1B
Autosomal dominant Emery-Dreifuss muscular dystrophy
Recombinant tissue plasminogen activator
National Institutes of Health Stroke Scale
Middle cerebral artery
- Lin F, Worman HJ: Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J Biol Chem. 1993, 268: 16321-16326.PubMedGoogle Scholar
- Wydner KL, McNeil JA, Lin F, Worman HJ: Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization. Genomics. 1996, 32: 474-478. 10.1006/geno.1996.0146.PubMedView ArticleGoogle Scholar
- Faktin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, Atherton J, Vidaillet HJ, Spudich S, De Girolami U, Seidman JG, Seidman C, Muntoni F, Müehle G, Johnson W, McDonough B: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med. 1999, 341: 1715-1724. 10.1056/NEJM199912023412302.View ArticleGoogle Scholar
- Boriani G, Gallina M, Merlini L, Bonne G, Toniolo D, Amati S: Clinical relevance of atrial fibrillations/flutter, stroke, pacemaker implant, and heart failure in Emery–Dreifuss muscular dystrophy: a long-term longitudinal study. Stroke. 2003, 34: 901-908. 10.1161/01.STR.0000064322.47667.49.PubMedView ArticleGoogle Scholar
- Benedetti S, Merlini L: Laminopathies: from the heart of the cell to the clinics. Curr Opin Neurol. 2004, 17: 553-560. 10.1097/00019052-200410000-00005.PubMedView ArticleGoogle Scholar
- Woman HJ, Fong LG, Muchir A, Young SG: Laminopathies and the long strange trip from basic cell biology to therapy. J Clin Invest. 2009, 119: 1825-1836. 10.1172/JCI37679.View ArticleGoogle Scholar
- Bonne G, Mercuri E, Muchir A, Urtizberea A, Bécane HM, Recan D, Merlini L, Wehnert M, Boor R, Reuner U, Vorgerd M, Wicklein EM, Eymard B, Duboc D, Penisson-Besnier I, Cuisset JM, Ferrer X, Desguerre I, Lacombe D, Bushby K, Pollitt C, Toniolo D, Fardeau M, Schwartz K, Muntoni F: Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol. 2000, 48: 170-180. 10.1002/1531-8249(200008)48:2<170::AID-ANA6>3.0.CO;2-J.PubMedView ArticleGoogle Scholar
- Zacharias AZ, Wagener ME, Warren ST, Hopkins LC: Emery-Dreifuss muscular dystrophy. Semin Neurol. 1999, 19: 67-79. 10.1055/s-2008-1040827.PubMedView ArticleGoogle Scholar
- van der Kooi AJ, Ledderhof TM, de Voogt WG, Res CJ, Bouwsma G, Troost D, Busch HF, Becker AE, de Visser M: A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement. Ann Neurol. 1996, 39: 636-642. 10.1002/ana.410390513.PubMedView ArticleGoogle Scholar
- Finsterer J, Stöllberger C: Atrial fibrillation/flutter in myopathies. Int J Cardiol. 2008, 128: 304-310. 10.1016/j.ijcard.2007.12.041.PubMedView ArticleGoogle Scholar
- Onishi Y, Higuchi J, Ogawa T, Namekawa A, Hayashi H, Odakura H, Goto K, Hayashi YK: The first Japanese case of autosomal dominant Emery-Dreifuss muscular dystrophy with a novel mutation in the lamin A/C gene. Rinsho Shinkeigaku. 2002, 42: 140-144.PubMedGoogle Scholar
- Liang WC, Yuo CY, Liu CY, Lee CS, Goto K, Hayashi YK, Jong YJ: Novel LMNA mutation in a Taiwanese family with autosomal dominant Emery-Dreifuss muscular dystrophy. J Formos Med Assoc. 2007, 106 (2 Suppl): S27-S31.PubMedView ArticleGoogle Scholar
- Redondo-Vergé L, Yaou RB, Fernández-Recio M, Dinca L, Richard P, Bonne G: Cardioembolic stroke prompting diagnosis of LMNA-associated Emery-Dreifuss muscular dystrophy. Muscle Nerve. 2011, 44: 587-589. 10.1002/mus.22179.PubMedView ArticleGoogle Scholar
- Tanaka K, Uehara T, Sato K, Amano T, Minematsu K, Toyoda K: Successful intravenous rt-PA thrombolysis for a childhood cardioembolic stroke with Emery-Dreifuss muscular dystrophy. Cerebrovasc Dis. 2012, 33: 92-93. 10.1159/000331930.PubMedView ArticleGoogle Scholar
- Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D: Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med. 2006, 354: 209-210.PubMedView ArticleGoogle Scholar
- Todorova A, Halliger-Keller B, Walter MC, Dabauvalle MC, Lochmüller H, Müller CR: A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B. J Med Genet. 2003, 40: e115-10.1136/jmg.40.10.e115.PubMedPubMed CentralView ArticleGoogle Scholar
- Muchir A, Bonne G, van der Kooi AJ, van Meegen M, Baas F, Bolhuis PA, de Visser M, Schwartz K: Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet. 2000, 9: 1453-1459. 10.1093/hmg/9.9.1453.PubMedView ArticleGoogle Scholar
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