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Cardiac Dysrhythmias, Cardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B

Cardiac Dysrhythmias, Cardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss... J Korean Med Sci 2005; 20: 283-90 Copyright � The Korean Academy ISSN 1011-8934 of Medical Sciences Cardiac Dysrhythmias, Cardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B ,¶ Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy Jong-Seo Hong* , Chang-Seok Ki , � � Jong-Won Kim , Yeon-Lim Suh , type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyo- June Soo Kim*, Kyung Kee Baek*, pathy, slowly progressive skeletal myopathy and contractures of the neck, elbows Byoung Joon Kim , Kyoung Ju Ahn , and ankles. The causative mutation is either in the emerin gene (X-linked recessive Duk-Kyung Kim* EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of Department of Internal Medicine*, Department of Clinical Pathology , Department of Diagnostic cervical flexion and contractures of both elbows and ankles. Sinus arrest with junc- � � Pathology , Department of Neurology , Samsung tional escape beats was noted. He was diagnosed as X-linked recessive EDMD Medical Center, Sungkyunkwan University School of (MIM 310300). A 28-yr-old female showed severe wasting and weakness of hume- Medicine, Seoul; Department of Internal Medicine , Han-il General Hospital, Seoul, Korea roperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was ¶ Current address: Department of Internal Medicine, diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had Han-il General Hospital, Seoul, Korea contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed Received : 27 July 2004 atrial tachycardia with high grade AV block. She was diagnosed as autosomal domi- Accepted : 15 November 2004 nant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing Address for correspondence Duk-Kyung Kim, M.D. sudden death necessitating pacemaker implantation. Cardiologists should know Department of Internal Medicine, Samsung Medical about these unusual genetic diseases with conduction defects, especially in young Center, Sungkyunkwan University School of Medicine, adults. 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel : +82.2-3410-3419, Fax : +82.2-3410-3849 Key Words : Muscular Dystrophies; Cardiomyopathies; emerin; Lamins; Heart Conduction System E-mail : [email protected] INTRODUCTION tinguishable features (7). In these three disorders, cardiac dysrhythmias including Emerin and lamins are members of the intermediate fila- AV block, bradycardia, atrial fibrillation, and characteristic ment protein family, and they are major components of the atrial standstill often lead to syncope and sudden cardiac death. nuclear envelope. Mutations in the emerin gene cause X- Therefore, early diagnosis and implantation of a pacemaker linked recessive (XR) Emery-Dreifuss muscular dystrophy are life saving. Here, we report three cases of EDMD, EDMD2, (1, 2) (EDMD: MIM 310300). and LGMD1B diagnosed by clinical findings and genetic Mutations in the lamin A/C (LMNA) gene, encoding lamins analyses. These three patients are the first cases of EDMD, A and C by alternative splicing, have been found to cause at EDMD2 and LGMD1B, respectively, reported in Korea. least four different kinds of genetic disorders; autosomal dom- inant (AD) Emery-Dreifuss muscular dystrophy (3) (EDMD2: MIM 181350); limb-girdle muscular dystrophy type 1B (4) MATERIALS AND METHODS (LGMD1B; MIM 159001); dilated cardiomyopathy type 1A (5) (CMD1A; MIM 115200); and familial partial lipodystro- Three patients were examined at regular intervals over a phy (6) (FPLD; MIM 151660). period of three to five years by at least one of the authors. The Among these genetic disorders, three disorders, XR EDMD, diagnosis of these patients was made on the basis of clinical AD EDMD2 and LGMD1B, present with both cardiac and symptoms, family histories, physical as well as neurological skeletal manifestations, which include cardiac dysrhythmias, examinations, cardiologic investigations including 12-lead late-onset cardiomyopathy, slowly progressive skeletal myopa- electrocardiography (ECG), ambulatory ECG monitoring, thy and contractures of the neck, elbows, and ankles. In par- electrophysiologic study and echocardiography, electromyo- ticular, XR EDMD and AD EDMD2 share clinically undis- graphy (EMG), laboratory studies of muscle enzymes, and 283 J.-S. Hong, C.-S. Ki, J.-W. Kim, et al. muscle biopsy. Information on deceased family members as Case 1 (XR EDMD: MIM 310300) well as on other family members who were suspected to be affected was obtained from probands. Genetic analyses were A 14-yr-old boy presented with a gait disturbance. At age performed to identify mutations in the LMNA and emerin 1, contractures of the Achilles tendon were noted and con- genes. The genetic analysis of mutations in the lamin gene tractures of the elbows were observed at age 9. On physical (EDMD2, LGMD1B) has been reported previously (8), and examination, the patient showed contractures of both ankles, parts of clinical findings of case 1 and 2 were described else- elbow joints and limitation of neck flexion (Fig. 1A). He also where (9, 10). showed a mild waddling and toe gait. He had weakness of the proximal upper limbs. Both proximal and distal weakness was present in the lower limbs. No deep tendon reflexes could RESULTS be elicited at both ankles and elbow joints. A family history revealed that his maternal uncle had abnormal clinical features Clinical and pathologic findings of three patients are shown similar to those of the patient (Fig. 2A). in Table 1. Cardiac findings are summarized in Table 2. Serum creatine kinase (CK) activity was 481 IU/L (refer- ence interval; 24-204 IU/L). Serum lactate dehydrogenase (LDH) level was 659 IU/L (reference interval; 240-480 IU/L). Table 1. Clinical and pathological findings EMG revealed abnormal spontaneous activities, short dura- XR EDMD AD EDMD2 AD LGMD1B tion low amplitude motor units and short duration polypha- Variables (Case 1) (Case 2) (Case 3) sic motor unit potentials (MUP) and early recruitment pat- terns on volition, suggesting myogenic disorder. Sex Male Female Female Age at examination (yr) 14 28 41 Echocardiographic findings showed normal LV systolic func- Age at onset of muscular 1 3 15 tion and dilated right atrium and right ventricle. ECG showed symptoms (yr) sinus arrest with junctional escape rhythm (Fig. 3A). Ambu- Wasting or weakness latory ECG monitoring revealed episodes of atrial fibrillation Upper girdle Yes Yes Yes with complete AV block and junctional escape rhythm (Fig. Arm No Yes Yes 4A). Asystole up to 4 sec was observed. In an electrophysio- Forearm-hand No Yes No logic study, no electrical signal was noted in the upper right Pelvic girdle Yes Yes Yes Thigh Yes Yes Yes atrium (Fig. 5). Junctional escape beats were noted. A VVI Leg Yes Yes Yes type permanent pacemaker was implanted. Contractures Genetic analysis revealed a mutation in exon 2 of the emerin Neck Yes Yes No gene by deletion of the C nucleotide at position 397 of the Elbows Yes Yes No genomic DNA sequence. Ankles Yes Yes Yes Tendon reflexes Absent Absent Absent CK (24-204 IU/L) 481 195 55 Case 2 (AD EDMD2: MIM 181350) LDH (240-480 IU/L) 659 664 618 EMG Myopathic Myopathic Myopathic A 28-yr-old female presented to the cardiology department Muscle biopsy Myopathic Myopathic Myopathic complaining of intermittent dizziness and palpitation. Exam- ination showed marked wasting and weakness of the shoulder CK, creatine kinase; LDH, lactate dehydrogenase; EMG, electromyo- graphy. girdle, proximal arm, and the proximal and distal leg mus- Table 2. Cardiac findings XR EDMD AD EDMD2 AD LGMD1B Variables (Case 1) (Case 2) (Case 3) Age at detection of cardiac symptoms (yr) 14 28 39 First symptoms Palpitation, Exertional dyspnea Palpitation, Dizziness Syncope, Exertional dyspnea Stroke -- + Conduction system disease Atrial standstill I, II AV-block Atrial standstill Features of rhythm Junctional rhythm Sinus rhythm Junctional rhythm Permanent pacemaker + + + Increased end diastolic diameters RV, RA - LV, LA, RA Left ventricular ejection fraction (%) 60 63 40 Diastolic dysfunction - + - Myocardial hypertrophy -- - AV, atrioventricular; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B 285 A B Fig. 1. Photographs of each patient. (A) XR EDMD patient (case 1) showing flexion contractures of both elbows and Achilles tendons. (B) AD EDMD2 patient (case 2) showing marked muscular atrophy of upper and lower extremities with flexion contractures of both elbows and Achilles tendons. The patient keeps her heel off the floor with equinus deformities of the feet. (C) LGMD1B patient (case 3) shows peroneal dystrophy with Achilles tendon contractures. Equinus deformity of the right foot is more severe than the left one. cles. She developed progressive muscle wasting of the lower are marked variations in fiber size associated with atrophic extremities and difficulty in walking during her teens. She also or hypertrophic myofibers, fiber splitting and an increase of presented with marked limitation of cervical flexion, contrac- internal nuclei. Fiber necrosis and infiltration of inflamma- ture of the both elbows limiting arm extension, and contrac- tory cells were not present. ture of the Achilles tendon causing equinus deformities of Echocardiography showed normal LV cavity size and nor- the feet (Fig. 1B). The deep tendon reflexes of the lower legs mal LV systolic function, but restrictive physiology was noted. were absent. Her elder sister died of unknown causes at 28 yr ECG showed sinus pause and first degree AV block (Fig. 3B). of age with similar clinical features (Fig. 2B). Slow non-sustained atrial tachycardia at a rate of 120 beats/ Serum CK level was 195 IU/L and serum LDH level was min with high grade AV block was noted by ambulatory ECG 664 IU/L. EMG revealed increased insertional activities, short monitoring (Fig. 4B). A VVI type permanent pacemaker was duration polyphasic MUP, and an early recruitment or dec- implanted due to risk of sudden death associated with high reased interference pattern, suggesting a chronic myogenic degree AV block. disorder. Biopsy of the left gastrocnemius muscle revealed Genetic analysis showed a G to A transition in exon 4 region findings compatible with muscular dystrophy (Fig. 6A). Myo- of the lamin A/C (LMNA) gene (c.746G>A: R249Q). fibers are reduced and replaced by fibroadipose tissues. There J.-S. Hong, C.-S. Ki, J.-W. Kim, et al. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II I V1 II V2 III V3 aVR V4 aVL V5 aVF V6 I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II Fig. 2. Pedigrees of the families with XR EDMD (A), AD EDMD2 (B) and LGMD1B (C). Squares indicate male family members, circles female family members and symbols with a slash mark deceased Fig. 3. 12-lead ECG of EDMD (A), AD EDMD2 (B) and LGMD1B family members. Open symbols indicate unaffected family mem- (C). (A) The ECG shows sinus arrest with junctional escape rhythm bers, filled symbols indicate the presence of neuromuscular and at a heart rate of 40 beats per minute. (B) The ECG shows left axis cardiac symptoms, and shaded symbols indicate family members deviation, left anterior hemiblock, first-degree atrioventricular block, who are or were probably affected. Arrows represent proband. B and sinus pause. (C) The ECG shows atrial fibrillation with ST-T and C from reference 8. changes. Case 3 (AD LGMD1B: MIM 159001) eter, scattered small-angulated myofibers and fatty ingrowth A 41-yr-old female presented with ankle contractures start- (Fig. 6B). There was marked atrophy of type 1 fibers with a ing in her early teens. The contractures were more severe on predominance of type 2 fibers (Fig. 6C, D). the right side (Fig. 1C). She had gait disturbance and diffi- Echocardiographic findings showed dilated cardiomyopa- culty climbing stairs due to ankle contractures as well as prox- thy. The ejection fraction of the left ventricle was 40% and imal leg weakness. A neurological evaluation revealed limb- end diastolic diameter of the left ventricle was 58 mm. Seri- girdle muscle weakness, particularly in the proximal arms al checks of ECG revealed progression of abnormalities from and thighs. The deep tendon reflexes of both ankle joints were sinus bradycardia, first-degree AV block, to episodes of parox- absent. At age 39, she experienced loss of consciousness for ysmal atrial tachycardia. Her final ECG (Fig. 3C) and ambu- 30 min. One year later, transient right hemiparesis developed. latory ECG monitoring showed atrial tachycardia and high Two elder sisters died at 20 and 38 yr of age, due to heart grade (3:1, 4:1) AV block (Fig. 4C). A VVI type permanent problems. Another sister had a clinical picture similar to that pacemaker was implanted. of the patient (Fig. 2C). This patient has a G to T transversion in exon 6 region of Serum CK level was 55 IU/L and serum LDH level was LMNA gene (c.1130G>T: R377L). 618 IU/L. EMG revealed low amplitude short duration poly- phasic MUP on volition and decreased interference patterns, compatible with chronic myogenic disorder. A muscle biopsy DISCUSSION from the quadriceps muscle showed an increase in the num- ber of internal nuclei, mild variation in the muscle fiber diam- The disorders manifested with both cardiac involvement Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B 287 N NN N N 50 mm/s 500 ms 1-I 2-aVF 25 mm/sec 10 mm/mv 3-V1 4-V5 5-hRA dist 25 mm/sec 10 mm/mv 5-hRA prox Bradycardia 22-Dec-2000 12:42:42 41 BPM 7-HIS dist 9-HIS prox NN NN 25 mm/sec 16-STIN 1 10 mm/mv 25 mm/sec Fig. 5. Findings of electrophysiologic study in a patient with XR 10 mm/mv N-N Pause 3220 ms 29-Oct-1999 05:11:58 43 BPM EDMD (case 1). Electrophysiologic study shows no electrical sig- nal in the right upper atrium. Junctional escape beats are noted. N NN N 25 mm/sec 20 mm/mv emerin in immunofluorescent staining of skeletal and cardiac muscles from EDMD patients was observed (2). The lamin A/C (LMNA) gene encodes two proteins of the nuclear lamina, 25 mm/sec 20 mm/mv lamins A (664 amino acids) and C (572 amino acids) produced by alternative splicing (5). Like emerin, lamins A and C are N-N Pause 2060 ms 30-Dec-1999 02:50:12 39 BPM components of the nuclear envelope but are located in the Fig. 4. Findings of ambulatory ECG monitorings of EDMD (A), AD lamina, a multicentric structure associated with the nucleo- EDMD2 (B) and LGMD1B (C). (A) Atrial fibrillation with complete plasmic surface of the inner nuclear membrane. According AV block and junctional escape rhythm. (B) Slow nonsustained to Hutchinson et al. (12), the nuclear membrane damage and atrial tachycardia at a rate of 120 beats per minute with high grade lamina fragility could develop into physical cell disruption AV block. (C) Atrial tachycardia and high grade (3:1, 4:1) AV block leading to myocyte death and tissue damage. In cardiac mus- with the longest R-R interval of 2.06 sec. cle, the loss of individual mononucleated myocytes is cumu- and skeletal muscular dystrophy can be categorized into two lative and eventually leads to atrioventricular block and heart groups. The first group is characterized by muscular dystro- failure when the number of affected myocytes is sufficient to phy with predominant cardiomyopathy, which includes Du- cause the phenotype. Therefore, the extension of myocyte chenne or Becker’s muscular dystrophy. The second group is damage in nodal versus left ventricular myocardium could characterized by muscular dystrophy with predominant car- partly explain the earlier occurrence of atrioventricular block diac conduction disturbances, which includes EDMD and than left ventricular dysfunction (13). LGMD1B. Both EDMD and LGMD1B are caused by the The classical phenotype of EDMD is characterized by the mutations of nuclear envelope proteins, i.e. emerin and lamin, clinical triad of early contractures of the Achilles tendons, respectively. EDMD consists of two diseases, XR emerin gene elbows and postcervical muscles and slowly progressive mus- mutation (EDMD) and AD lamin gene mutation (EDMD2). cle wasting and weakness with a distinctive humeroperoneal Even though they are caused by mutations of different genes, distribution in the early stages of the disease, cardiomyopa- they show very similar clinical features. LGMD1B is an allelic thy with life threatening conduction defects (14). LGMD1B variant of the lamin gene mutation, which has an overlapping is characterized by a slowly progressive weakness of the proxi- phenotype with EDMD (4). mal muscles, mild joint contractures, age-related atrioventric- It is not well-known why defects of nuclear envelope pro- ular cardiac conduction disturbances and dilated cardiomy- teins show cardiac and skeletal myopathy and involvement opathy (15). Phenotypes of LGMD1B overlap with EDMD. of conduction systems in the heart. Emerin is localized at the Although the clinical feature of muscle involvement in both inner nuclear membrane in various tissues by its transmem- XR EDMD and AD EDMD2 are quite similar, the pattern brane domain at the C-terminus (1). Amino acid sequence of muscular involvement in AD EDMD2 is extremely vari- similarities and cellular location suggested that emerin is a able. In XR EDMD, the first symptoms are generally con- member of nuclear lamina-associated protein (LAP) family. tractures, weakness and difficulty in running in patients with Cartegni et al. (11) proposed a general role for emerin in mem- AD EDMD2 and are usually presented between 3 and 6 yr brane anchorage to the cytoskeleton. In heart, its specific local- of age, and the contractures generally appeared afterwards. ization to desmosomes and fasciae adherentes of the interca- Some AD EDMD2 patients lose ambulation, unlike patients lated discs could account for the characteristic conduction with XR EDMD in whom loss of ambulation is very rare. defects described in patients with EDMD. A deficiency of Therefore, muscle weakness and disease course tend to be more J.-S. Hong, C.-S. Ki, J.-W. Kim, et al. A B C D Fig. 6. The histopathologic findings of skeletal muscle biopsy specimen in AD EDMD2 (A) and LGMD1B (B-D) patient. (A) Myofibers are reduced in number and replaced by fibroadipose tissues. There are atrophic or hypertrophic myofibers, internalization of sarcolemmal nuclei and fiber splitting (hematoxylin and eosin stain, ×200). (B) Variation in myofiber size, frequent internal nuclei and fatty ingrowth are noted in hematoxylin and eosin stain (×200). (C) ATPase pH 4.6 stain reveals atrophy of type 1 fibers (dark brown stain, ×200). (D) ATPase pH 9.4 stain reveals a predominance of type 2 fibers (brown stain, ×100). severe in AD EDMD2 than XR EDMD (7). In LGMD1B, were prominent without evident muscle wasting. However, symmetrical weakness starts in the proximal lower limb mus- AD EDMD2 (case 2) showed severe muscle wasting, difficulty cles, and gradually the upper limb muscles also become affect- in walking and joint contractures. In LGMD1B (case 3), the ed. Early contractures of the spine were absent, and contrac- predominant feature is a weakness of hip girdle muscle and tures of the elbows and the Achilles tendons were either min- shoulder girdle muscles. Ankle contractures started later and imal or late, distinguishing this disorder from EDMD (15). milder compared with cases of EDMD. The findings of muscular involvement in our cases are com- Cardiac involvement in EDMD may occur at any age or patible with the above description. In the XR EDMD patient may even be present at every onset, while on the other hand, (case 1), contractures of the Achilles tendon and the elbows neuromuscular symptoms precede cardiological symptoms Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B in nearly all patients with LGMD1B (15). ed cardiomyopathy. Vohanka et al. (20) reported that screen- The cardiac conduction defect is the most serious and life ing for mutations in the XR EDMD gene was performed threatening clinical manifestation of the disease and is con- among 450 patients affected with severe heart rhythm defects sidered to be a hallmark of cardiomyopathy of EDMD. ECG and/or dilated cardiomyopathy, and XR EDMD was found in the early findings shows sinus bradycardia, small P-wave among ten patients. Therefore, investigators should be con- and prolonged P-R interval. According to the progress of dis- cerned about the genetic association of severe cardiac involve- ease, ECG shows atrial fibrillation or flutter, complete AV ment even in patients without muscular symptoms. block with idioventricular rhythm and atrial paralysis (atrial In conclusion, EDMD and LGMD1B are characterized by standstill) (14). The documentation of the absence of electri- slowly progressive skeletal myopathy and contractures of neck, cal atrial activity and inability to pace the atria by electrocar- elbows and ankles, cardiac dysrhythmia, and late-onset car- diogram and electrophysiological study in a patient with atrial diomyopathy. Cardiac dysrhythmias in EDMD and LGMD1B paralysis, is recognized as a pathognomonic finding of EDMD include AV block, bradycardia, atrial fibrillation, sinus arrest (16). The normal myocardium is progressively replaced by and characteristic atrial standstill, causing syncope and sudden fibroadipose tissue (17), which results in atrial paralysis by cardiac death necessitating pacemaker implantation. Because loss of atrial contractility and heart failure by atrial and ven- these patients are commonly undiagnosed, cardiologists should tricular dilatation. Carriers are also at risk of cardiac arrhyth- be aware of these unusual genetic diseases as causes of conduc- mias and sudden death (17). Patients with LGMD1B show tion defects, especially in young adults. similar cardiological abnormalities to those of EDMD. They include conduction disturbances and dysrythmias, present- ing as an AV block, atrial fibrillation with high degree AV ACKNOWLEDGMENTS block and junctional escape rhythm, bradycardia, atrial stand- still and syncopal attacks. AV conduction disturbances in- We are deeply indebted to Dr. Manfred Wehnert (Institute creased with age in LGMD1B patients and became more of Human Genetics, Ernst-Moritz-Arndt University Greif- severe (15). The potential complications of the cardiac pathol- swald, Germany) for genetic analysis of mutation in the emerin ogy in EDMD and LGMD1B include syncope, cerebral and gene. pulmonary emboli, congestive heart failure, cor pulmonale, and sudden cardiac death, which may occur in the early twen- ties (18). REFERENCES In our study, the manifestations of cardiac involvement were similar to those of reported cases. Atrial standstill was 1. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, To- noted in patients with EDMD and LGMD1B. The patient niolo D. Identification of a novel X-linked gene responsible for Emery- with LGMD1B had a history of syncope and cerebral throm- Dreifuss muscular dystrophy. Nat Genet 1994; 8: 323-7. boembolism. The patient with LGMD1B showed findings 2. Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, Haya- of dilated cardiomyopathy. However, in patients with EDMD, shi YK, Tsukahara T, Arahata K. 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Cardiac Dysrhythmias, Cardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B

Hong, Jong-Seo; Ki, Chang-Seok; Kim, Jong-Won; Suh, Yeon-Lim; Kim, June Soo; Baek, Kyung Kee; Kim, Byoung Joon; Ahn, Kyoung Ju; Kim, Duk-Kyung
Journal of Korean Medical Science , Volume 20 (2) – Apr 30, 2005
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Pubmed Central
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Copyright © 2005 The Korean Academy of Medical Sciences
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1011-8934
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1598-6357
DOI
10.3346/jkms.2005.20.2.283
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J Korean Med Sci 2005; 20: 283-90 Copyright � The Korean Academy ISSN 1011-8934 of Medical Sciences Cardiac Dysrhythmias, Cardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B ,¶ Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy Jong-Seo Hong* , Chang-Seok Ki , � � Jong-Won Kim , Yeon-Lim Suh , type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyo- June Soo Kim*, Kyung Kee Baek*, pathy, slowly progressive skeletal myopathy and contractures of the neck, elbows Byoung Joon Kim , Kyoung Ju Ahn , and ankles. The causative mutation is either in the emerin gene (X-linked recessive Duk-Kyung Kim* EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of Department of Internal Medicine*, Department of Clinical Pathology , Department of Diagnostic cervical flexion and contractures of both elbows and ankles. Sinus arrest with junc- � � Pathology , Department of Neurology , Samsung tional escape beats was noted. He was diagnosed as X-linked recessive EDMD Medical Center, Sungkyunkwan University School of (MIM 310300). A 28-yr-old female showed severe wasting and weakness of hume- Medicine, Seoul; Department of Internal Medicine , Han-il General Hospital, Seoul, Korea roperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was ¶ Current address: Department of Internal Medicine, diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had Han-il General Hospital, Seoul, Korea contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed Received : 27 July 2004 atrial tachycardia with high grade AV block. She was diagnosed as autosomal domi- Accepted : 15 November 2004 nant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing Address for correspondence Duk-Kyung Kim, M.D. sudden death necessitating pacemaker implantation. Cardiologists should know Department of Internal Medicine, Samsung Medical about these unusual genetic diseases with conduction defects, especially in young Center, Sungkyunkwan University School of Medicine, adults. 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel : +82.2-3410-3419, Fax : +82.2-3410-3849 Key Words : Muscular Dystrophies; Cardiomyopathies; emerin; Lamins; Heart Conduction System E-mail : [email protected] INTRODUCTION tinguishable features (7). In these three disorders, cardiac dysrhythmias including Emerin and lamins are members of the intermediate fila- AV block, bradycardia, atrial fibrillation, and characteristic ment protein family, and they are major components of the atrial standstill often lead to syncope and sudden cardiac death. nuclear envelope. Mutations in the emerin gene cause X- Therefore, early diagnosis and implantation of a pacemaker linked recessive (XR) Emery-Dreifuss muscular dystrophy are life saving. Here, we report three cases of EDMD, EDMD2, (1, 2) (EDMD: MIM 310300). and LGMD1B diagnosed by clinical findings and genetic Mutations in the lamin A/C (LMNA) gene, encoding lamins analyses. These three patients are the first cases of EDMD, A and C by alternative splicing, have been found to cause at EDMD2 and LGMD1B, respectively, reported in Korea. least four different kinds of genetic disorders; autosomal dom- inant (AD) Emery-Dreifuss muscular dystrophy (3) (EDMD2: MIM 181350); limb-girdle muscular dystrophy type 1B (4) MATERIALS AND METHODS (LGMD1B; MIM 159001); dilated cardiomyopathy type 1A (5) (CMD1A; MIM 115200); and familial partial lipodystro- Three patients were examined at regular intervals over a phy (6) (FPLD; MIM 151660). period of three to five years by at least one of the authors. The Among these genetic disorders, three disorders, XR EDMD, diagnosis of these patients was made on the basis of clinical AD EDMD2 and LGMD1B, present with both cardiac and symptoms, family histories, physical as well as neurological skeletal manifestations, which include cardiac dysrhythmias, examinations, cardiologic investigations including 12-lead late-onset cardiomyopathy, slowly progressive skeletal myopa- electrocardiography (ECG), ambulatory ECG monitoring, thy and contractures of the neck, elbows, and ankles. In par- electrophysiologic study and echocardiography, electromyo- ticular, XR EDMD and AD EDMD2 share clinically undis- graphy (EMG), laboratory studies of muscle enzymes, and 283 J.-S. Hong, C.-S. Ki, J.-W. Kim, et al. muscle biopsy. Information on deceased family members as Case 1 (XR EDMD: MIM 310300) well as on other family members who were suspected to be affected was obtained from probands. Genetic analyses were A 14-yr-old boy presented with a gait disturbance. At age performed to identify mutations in the LMNA and emerin 1, contractures of the Achilles tendon were noted and con- genes. The genetic analysis of mutations in the lamin gene tractures of the elbows were observed at age 9. On physical (EDMD2, LGMD1B) has been reported previously (8), and examination, the patient showed contractures of both ankles, parts of clinical findings of case 1 and 2 were described else- elbow joints and limitation of neck flexion (Fig. 1A). He also where (9, 10). showed a mild waddling and toe gait. He had weakness of the proximal upper limbs. Both proximal and distal weakness was present in the lower limbs. No deep tendon reflexes could RESULTS be elicited at both ankles and elbow joints. A family history revealed that his maternal uncle had abnormal clinical features Clinical and pathologic findings of three patients are shown similar to those of the patient (Fig. 2A). in Table 1. Cardiac findings are summarized in Table 2. Serum creatine kinase (CK) activity was 481 IU/L (refer- ence interval; 24-204 IU/L). Serum lactate dehydrogenase (LDH) level was 659 IU/L (reference interval; 240-480 IU/L). Table 1. Clinical and pathological findings EMG revealed abnormal spontaneous activities, short dura- XR EDMD AD EDMD2 AD LGMD1B tion low amplitude motor units and short duration polypha- Variables (Case 1) (Case 2) (Case 3) sic motor unit potentials (MUP) and early recruitment pat- terns on volition, suggesting myogenic disorder. Sex Male Female Female Age at examination (yr) 14 28 41 Echocardiographic findings showed normal LV systolic func- Age at onset of muscular 1 3 15 tion and dilated right atrium and right ventricle. ECG showed symptoms (yr) sinus arrest with junctional escape rhythm (Fig. 3A). Ambu- Wasting or weakness latory ECG monitoring revealed episodes of atrial fibrillation Upper girdle Yes Yes Yes with complete AV block and junctional escape rhythm (Fig. Arm No Yes Yes 4A). Asystole up to 4 sec was observed. In an electrophysio- Forearm-hand No Yes No logic study, no electrical signal was noted in the upper right Pelvic girdle Yes Yes Yes Thigh Yes Yes Yes atrium (Fig. 5). Junctional escape beats were noted. A VVI Leg Yes Yes Yes type permanent pacemaker was implanted. Contractures Genetic analysis revealed a mutation in exon 2 of the emerin Neck Yes Yes No gene by deletion of the C nucleotide at position 397 of the Elbows Yes Yes No genomic DNA sequence. Ankles Yes Yes Yes Tendon reflexes Absent Absent Absent CK (24-204 IU/L) 481 195 55 Case 2 (AD EDMD2: MIM 181350) LDH (240-480 IU/L) 659 664 618 EMG Myopathic Myopathic Myopathic A 28-yr-old female presented to the cardiology department Muscle biopsy Myopathic Myopathic Myopathic complaining of intermittent dizziness and palpitation. Exam- ination showed marked wasting and weakness of the shoulder CK, creatine kinase; LDH, lactate dehydrogenase; EMG, electromyo- graphy. girdle, proximal arm, and the proximal and distal leg mus- Table 2. Cardiac findings XR EDMD AD EDMD2 AD LGMD1B Variables (Case 1) (Case 2) (Case 3) Age at detection of cardiac symptoms (yr) 14 28 39 First symptoms Palpitation, Exertional dyspnea Palpitation, Dizziness Syncope, Exertional dyspnea Stroke -- + Conduction system disease Atrial standstill I, II AV-block Atrial standstill Features of rhythm Junctional rhythm Sinus rhythm Junctional rhythm Permanent pacemaker + + + Increased end diastolic diameters RV, RA - LV, LA, RA Left ventricular ejection fraction (%) 60 63 40 Diastolic dysfunction - + - Myocardial hypertrophy -- - AV, atrioventricular; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B 285 A B Fig. 1. Photographs of each patient. (A) XR EDMD patient (case 1) showing flexion contractures of both elbows and Achilles tendons. (B) AD EDMD2 patient (case 2) showing marked muscular atrophy of upper and lower extremities with flexion contractures of both elbows and Achilles tendons. The patient keeps her heel off the floor with equinus deformities of the feet. (C) LGMD1B patient (case 3) shows peroneal dystrophy with Achilles tendon contractures. Equinus deformity of the right foot is more severe than the left one. cles. She developed progressive muscle wasting of the lower are marked variations in fiber size associated with atrophic extremities and difficulty in walking during her teens. She also or hypertrophic myofibers, fiber splitting and an increase of presented with marked limitation of cervical flexion, contrac- internal nuclei. Fiber necrosis and infiltration of inflamma- ture of the both elbows limiting arm extension, and contrac- tory cells were not present. ture of the Achilles tendon causing equinus deformities of Echocardiography showed normal LV cavity size and nor- the feet (Fig. 1B). The deep tendon reflexes of the lower legs mal LV systolic function, but restrictive physiology was noted. were absent. Her elder sister died of unknown causes at 28 yr ECG showed sinus pause and first degree AV block (Fig. 3B). of age with similar clinical features (Fig. 2B). Slow non-sustained atrial tachycardia at a rate of 120 beats/ Serum CK level was 195 IU/L and serum LDH level was min with high grade AV block was noted by ambulatory ECG 664 IU/L. EMG revealed increased insertional activities, short monitoring (Fig. 4B). A VVI type permanent pacemaker was duration polyphasic MUP, and an early recruitment or dec- implanted due to risk of sudden death associated with high reased interference pattern, suggesting a chronic myogenic degree AV block. disorder. Biopsy of the left gastrocnemius muscle revealed Genetic analysis showed a G to A transition in exon 4 region findings compatible with muscular dystrophy (Fig. 6A). Myo- of the lamin A/C (LMNA) gene (c.746G>A: R249Q). fibers are reduced and replaced by fibroadipose tissues. There J.-S. Hong, C.-S. Ki, J.-W. Kim, et al. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II I V1 II V2 III V3 aVR V4 aVL V5 aVF V6 I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II Fig. 2. Pedigrees of the families with XR EDMD (A), AD EDMD2 (B) and LGMD1B (C). Squares indicate male family members, circles female family members and symbols with a slash mark deceased Fig. 3. 12-lead ECG of EDMD (A), AD EDMD2 (B) and LGMD1B family members. Open symbols indicate unaffected family mem- (C). (A) The ECG shows sinus arrest with junctional escape rhythm bers, filled symbols indicate the presence of neuromuscular and at a heart rate of 40 beats per minute. (B) The ECG shows left axis cardiac symptoms, and shaded symbols indicate family members deviation, left anterior hemiblock, first-degree atrioventricular block, who are or were probably affected. Arrows represent proband. B and sinus pause. (C) The ECG shows atrial fibrillation with ST-T and C from reference 8. changes. Case 3 (AD LGMD1B: MIM 159001) eter, scattered small-angulated myofibers and fatty ingrowth A 41-yr-old female presented with ankle contractures start- (Fig. 6B). There was marked atrophy of type 1 fibers with a ing in her early teens. The contractures were more severe on predominance of type 2 fibers (Fig. 6C, D). the right side (Fig. 1C). She had gait disturbance and diffi- Echocardiographic findings showed dilated cardiomyopa- culty climbing stairs due to ankle contractures as well as prox- thy. The ejection fraction of the left ventricle was 40% and imal leg weakness. A neurological evaluation revealed limb- end diastolic diameter of the left ventricle was 58 mm. Seri- girdle muscle weakness, particularly in the proximal arms al checks of ECG revealed progression of abnormalities from and thighs. The deep tendon reflexes of both ankle joints were sinus bradycardia, first-degree AV block, to episodes of parox- absent. At age 39, she experienced loss of consciousness for ysmal atrial tachycardia. Her final ECG (Fig. 3C) and ambu- 30 min. One year later, transient right hemiparesis developed. latory ECG monitoring showed atrial tachycardia and high Two elder sisters died at 20 and 38 yr of age, due to heart grade (3:1, 4:1) AV block (Fig. 4C). A VVI type permanent problems. Another sister had a clinical picture similar to that pacemaker was implanted. of the patient (Fig. 2C). This patient has a G to T transversion in exon 6 region of Serum CK level was 55 IU/L and serum LDH level was LMNA gene (c.1130G>T: R377L). 618 IU/L. EMG revealed low amplitude short duration poly- phasic MUP on volition and decreased interference patterns, compatible with chronic myogenic disorder. A muscle biopsy DISCUSSION from the quadriceps muscle showed an increase in the num- ber of internal nuclei, mild variation in the muscle fiber diam- The disorders manifested with both cardiac involvement Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B 287 N NN N N 50 mm/s 500 ms 1-I 2-aVF 25 mm/sec 10 mm/mv 3-V1 4-V5 5-hRA dist 25 mm/sec 10 mm/mv 5-hRA prox Bradycardia 22-Dec-2000 12:42:42 41 BPM 7-HIS dist 9-HIS prox NN NN 25 mm/sec 16-STIN 1 10 mm/mv 25 mm/sec Fig. 5. Findings of electrophysiologic study in a patient with XR 10 mm/mv N-N Pause 3220 ms 29-Oct-1999 05:11:58 43 BPM EDMD (case 1). Electrophysiologic study shows no electrical sig- nal in the right upper atrium. Junctional escape beats are noted. N NN N 25 mm/sec 20 mm/mv emerin in immunofluorescent staining of skeletal and cardiac muscles from EDMD patients was observed (2). The lamin A/C (LMNA) gene encodes two proteins of the nuclear lamina, 25 mm/sec 20 mm/mv lamins A (664 amino acids) and C (572 amino acids) produced by alternative splicing (5). Like emerin, lamins A and C are N-N Pause 2060 ms 30-Dec-1999 02:50:12 39 BPM components of the nuclear envelope but are located in the Fig. 4. Findings of ambulatory ECG monitorings of EDMD (A), AD lamina, a multicentric structure associated with the nucleo- EDMD2 (B) and LGMD1B (C). (A) Atrial fibrillation with complete plasmic surface of the inner nuclear membrane. According AV block and junctional escape rhythm. (B) Slow nonsustained to Hutchinson et al. (12), the nuclear membrane damage and atrial tachycardia at a rate of 120 beats per minute with high grade lamina fragility could develop into physical cell disruption AV block. (C) Atrial tachycardia and high grade (3:1, 4:1) AV block leading to myocyte death and tissue damage. In cardiac mus- with the longest R-R interval of 2.06 sec. cle, the loss of individual mononucleated myocytes is cumu- and skeletal muscular dystrophy can be categorized into two lative and eventually leads to atrioventricular block and heart groups. The first group is characterized by muscular dystro- failure when the number of affected myocytes is sufficient to phy with predominant cardiomyopathy, which includes Du- cause the phenotype. Therefore, the extension of myocyte chenne or Becker’s muscular dystrophy. The second group is damage in nodal versus left ventricular myocardium could characterized by muscular dystrophy with predominant car- partly explain the earlier occurrence of atrioventricular block diac conduction disturbances, which includes EDMD and than left ventricular dysfunction (13). LGMD1B. Both EDMD and LGMD1B are caused by the The classical phenotype of EDMD is characterized by the mutations of nuclear envelope proteins, i.e. emerin and lamin, clinical triad of early contractures of the Achilles tendons, respectively. EDMD consists of two diseases, XR emerin gene elbows and postcervical muscles and slowly progressive mus- mutation (EDMD) and AD lamin gene mutation (EDMD2). cle wasting and weakness with a distinctive humeroperoneal Even though they are caused by mutations of different genes, distribution in the early stages of the disease, cardiomyopa- they show very similar clinical features. LGMD1B is an allelic thy with life threatening conduction defects (14). LGMD1B variant of the lamin gene mutation, which has an overlapping is characterized by a slowly progressive weakness of the proxi- phenotype with EDMD (4). mal muscles, mild joint contractures, age-related atrioventric- It is not well-known why defects of nuclear envelope pro- ular cardiac conduction disturbances and dilated cardiomy- teins show cardiac and skeletal myopathy and involvement opathy (15). Phenotypes of LGMD1B overlap with EDMD. of conduction systems in the heart. Emerin is localized at the Although the clinical feature of muscle involvement in both inner nuclear membrane in various tissues by its transmem- XR EDMD and AD EDMD2 are quite similar, the pattern brane domain at the C-terminus (1). Amino acid sequence of muscular involvement in AD EDMD2 is extremely vari- similarities and cellular location suggested that emerin is a able. In XR EDMD, the first symptoms are generally con- member of nuclear lamina-associated protein (LAP) family. tractures, weakness and difficulty in running in patients with Cartegni et al. (11) proposed a general role for emerin in mem- AD EDMD2 and are usually presented between 3 and 6 yr brane anchorage to the cytoskeleton. In heart, its specific local- of age, and the contractures generally appeared afterwards. ization to desmosomes and fasciae adherentes of the interca- Some AD EDMD2 patients lose ambulation, unlike patients lated discs could account for the characteristic conduction with XR EDMD in whom loss of ambulation is very rare. defects described in patients with EDMD. A deficiency of Therefore, muscle weakness and disease course tend to be more J.-S. Hong, C.-S. Ki, J.-W. Kim, et al. A B C D Fig. 6. The histopathologic findings of skeletal muscle biopsy specimen in AD EDMD2 (A) and LGMD1B (B-D) patient. (A) Myofibers are reduced in number and replaced by fibroadipose tissues. There are atrophic or hypertrophic myofibers, internalization of sarcolemmal nuclei and fiber splitting (hematoxylin and eosin stain, ×200). (B) Variation in myofiber size, frequent internal nuclei and fatty ingrowth are noted in hematoxylin and eosin stain (×200). (C) ATPase pH 4.6 stain reveals atrophy of type 1 fibers (dark brown stain, ×200). (D) ATPase pH 9.4 stain reveals a predominance of type 2 fibers (brown stain, ×100). severe in AD EDMD2 than XR EDMD (7). In LGMD1B, were prominent without evident muscle wasting. However, symmetrical weakness starts in the proximal lower limb mus- AD EDMD2 (case 2) showed severe muscle wasting, difficulty cles, and gradually the upper limb muscles also become affect- in walking and joint contractures. In LGMD1B (case 3), the ed. Early contractures of the spine were absent, and contrac- predominant feature is a weakness of hip girdle muscle and tures of the elbows and the Achilles tendons were either min- shoulder girdle muscles. Ankle contractures started later and imal or late, distinguishing this disorder from EDMD (15). milder compared with cases of EDMD. The findings of muscular involvement in our cases are com- Cardiac involvement in EDMD may occur at any age or patible with the above description. In the XR EDMD patient may even be present at every onset, while on the other hand, (case 1), contractures of the Achilles tendon and the elbows neuromuscular symptoms precede cardiological symptoms Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B in nearly all patients with LGMD1B (15). ed cardiomyopathy. Vohanka et al. (20) reported that screen- The cardiac conduction defect is the most serious and life ing for mutations in the XR EDMD gene was performed threatening clinical manifestation of the disease and is con- among 450 patients affected with severe heart rhythm defects sidered to be a hallmark of cardiomyopathy of EDMD. ECG and/or dilated cardiomyopathy, and XR EDMD was found in the early findings shows sinus bradycardia, small P-wave among ten patients. Therefore, investigators should be con- and prolonged P-R interval. According to the progress of dis- cerned about the genetic association of severe cardiac involve- ease, ECG shows atrial fibrillation or flutter, complete AV ment even in patients without muscular symptoms. block with idioventricular rhythm and atrial paralysis (atrial In conclusion, EDMD and LGMD1B are characterized by standstill) (14). The documentation of the absence of electri- slowly progressive skeletal myopathy and contractures of neck, cal atrial activity and inability to pace the atria by electrocar- elbows and ankles, cardiac dysrhythmia, and late-onset car- diogram and electrophysiological study in a patient with atrial diomyopathy. Cardiac dysrhythmias in EDMD and LGMD1B paralysis, is recognized as a pathognomonic finding of EDMD include AV block, bradycardia, atrial fibrillation, sinus arrest (16). The normal myocardium is progressively replaced by and characteristic atrial standstill, causing syncope and sudden fibroadipose tissue (17), which results in atrial paralysis by cardiac death necessitating pacemaker implantation. Because loss of atrial contractility and heart failure by atrial and ven- these patients are commonly undiagnosed, cardiologists should tricular dilatation. Carriers are also at risk of cardiac arrhyth- be aware of these unusual genetic diseases as causes of conduc- mias and sudden death (17). Patients with LGMD1B show tion defects, especially in young adults. similar cardiological abnormalities to those of EDMD. They include conduction disturbances and dysrythmias, present- ing as an AV block, atrial fibrillation with high degree AV ACKNOWLEDGMENTS block and junctional escape rhythm, bradycardia, atrial stand- still and syncopal attacks. AV conduction disturbances in- We are deeply indebted to Dr. Manfred Wehnert (Institute creased with age in LGMD1B patients and became more of Human Genetics, Ernst-Moritz-Arndt University Greif- severe (15). The potential complications of the cardiac pathol- swald, Germany) for genetic analysis of mutation in the emerin ogy in EDMD and LGMD1B include syncope, cerebral and gene. pulmonary emboli, congestive heart failure, cor pulmonale, and sudden cardiac death, which may occur in the early twen- ties (18). REFERENCES In our study, the manifestations of cardiac involvement were similar to those of reported cases. Atrial standstill was 1. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, To- noted in patients with EDMD and LGMD1B. The patient niolo D. Identification of a novel X-linked gene responsible for Emery- with LGMD1B had a history of syncope and cerebral throm- Dreifuss muscular dystrophy. Nat Genet 1994; 8: 323-7. boembolism. The patient with LGMD1B showed findings 2. Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, Haya- of dilated cardiomyopathy. However, in patients with EDMD, shi YK, Tsukahara T, Arahata K. 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Published: Apr 30, 2005

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