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J Korean Med Sci 2005; 20: ISS opyright The Korean cademy of Medical Sciences ardiac Dysrhythmias, ardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss Muscular Dystrophy
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J Korean Med Sci 2005; 20: ISS opyright The Korean cademy of Medical Sciences ardiac Dysrhythmias, ardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1 Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1 (LGMD1) are characterized by cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows and ankles. The causative mutation is either in the emerin gene (X-linked recessive EDMD) or lamin / gene (autosomal dominant EDMD2 or LGMD1). We report three cases of EDMD, EDMD2 and LGMD1. 14-yr-old boy showed limitation of cervical flexion and contractures of both elbows and ankles. Sinus arrest with junctional escape beats was noted. He was diagnosed as X-linked recessive EDMD (MIM ). 28-yr-old female showed severe wasting and weakness of humeroperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of V block were noted. She was diagnosed as autosomal dominant EDMD2 (MIM ). 41-yr-old female had contractures of both ankles and limb-girdle type muscular dystrophy. EG revealed atrial tachycardia with high grade V block. She was diagnosed as autosomal dominant LGMD1 (MIM ). ardiac dysrhythmias in EDMD and LGMD1 include V block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing sudden death necessitating pacemaker implantation. ardiologists should know about these unusual genetic diseases with conduction defects, especially in young adults. Key Words : Muscular Dystrophies; ardiomyopathies; emerin; Lamins; Heart onduction System Jong-Seo Hong*,, hang-seok Ki, Jong-Won Kim, Yeon-Lim Suh, June Soo Kim*, Kyung Kee aek*, young Joon Kim, Kyoung Ju hn, Duk-Kyung Kim* Department of Internal Medicine*, Department of linical Pathology, Department of Diagnostic Pathology, Department of eurology, Samsung Medical enter, Sungkyunkwan University School of Medicine, Seoul; Department of Internal Medicine, Han-il General Hospital, Seoul, Korea urrent address: Department of Internal Medicine, Han-il General Hospital, Seoul, Korea Received : 27 July 2004 ccepted : 15 ovember 2004 ddress for correspondence Duk-Kyung Kim, M.D. Department of Internal Medicine, Samsung Medical enter, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul , Korea Tel : , Fax : ITRODUTIO Emerin and lamins are members of the intermediate filament protein family, and they are major components of the nuclear envelope. Mutations in the emerin gene cause X- linked recessive (XR) Emery-Dreifuss muscular dystrophy (1, 2) (EDMD: MIM ). Mutations in the lamin / (LM) gene, encoding lamins and by alternative splicing, have been found to cause at least four different kinds of genetic disorders; autosomal dominant (D) Emery-Dreifuss muscular dystrophy (3) (EDMD2: MIM ); limb-girdle muscular dystrophy type 1 (4) (LGMD1; MIM ); dilated cardiomyopathy type 1 (5) (MD1; MIM ); and familial partial lipodystrophy (6) (FPLD; MIM ). mong these genetic disorders, three disorders, XR EDMD, D EDMD2 and LGMD1, present with both cardiac and skeletal manifestations, which include cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows, and ankles. In particular, XR EDMD and D EDMD2 share clinically undistinguishable features (7). In these three disorders, cardiac dysrhythmias including V block, bradycardia, atrial fibrillation, and characteristic atrial standstill often lead to syncope and sudden cardiac death. Therefore, early diagnosis and implantation of a pacemaker are life saving. Here, we report three cases of EDMD, EDMD2, and LGMD1 diagnosed by clinical findings and genetic analyses. These three patients are the first cases of EDMD, EDMD2 and LGMD1, respectively, reported in Korea. MTERILS D METHODS Three patients were examined at regular intervals over a period of three to five years by at least one of the authors. The diagnosis of these patients was made on the basis of clinical symptoms, family histories, physical as well as neurological examinations, cardiologic investigations including 12-lead electrocardiography (EG), ambulatory EG monitoring, electrophysiologic study and echocardiography, electromyography (EMG), laboratory studies of muscle enzymes, and 283 284 J.-S. Hong,.-S. Ki, J.-W. Kim, et al. muscle biopsy. Information on deceased family members as well as on other family members who were suspected to be affected was obtained from probands. Genetic analyses were performed to identify mutations in the LM and emerin genes. The genetic analysis of mutations in the lamin gene (EDMD2, LGMD1) has been reported previously (8), and parts of clinical findings of case 1 and 2 were described elsewhere (9, 10). RESULTS linical and pathologic findings of three patients are shown in Table 1. ardiac findings are summarized in Table 2. Table 1. linical and pathological findings Variables XR EDMD (ase 1) D EDMD2 (ase 2) D LGMD1 (ase 3) Sex Male Female Female ge at examination (yr) ge at onset of muscular symptoms (yr) Wasting or weakness Upper girdle Yes Yes Yes rm o Yes Yes Forearm-hand o Yes o Pelvic girdle Yes Yes Yes Thigh Yes Yes Yes Leg Yes Yes Yes ontractures eck Yes Yes o Elbows Yes Yes o nkles Yes Yes Yes Tendon reflexes bsent bsent bsent K ( IU/L) LDH ( IU/L) EMG Myopathic Myopathic Myopathic Muscle biopsy Myopathic Myopathic Myopathic K, creatine kinase; LDH, lactate dehydrogenase; EMG, electromyography. ase 1 (XR EDMD: MIM ) 14-yr-old boy presented with a gait disturbance. t age 1, contractures of the chilles tendon were noted and contractures of the elbows were observed at age 9. On physical examination, the patient showed contractures of both ankles, elbow joints and limitation of neck flexion (Fig. 1). He also showed a mild waddling and toe gait. He had weakness of the proximal upper limbs. oth proximal and distal weakness was present in the lower limbs. o deep tendon reflexes could be elicited at both ankles and elbow joints. family history revealed that his maternal uncle had abnormal clinical features similar to those of the patient (Fig. 2). Serum creatine kinase (K) activity was 481 IU/L (reference interval; IU/L). Serum lactate dehydrogenase (LDH) level was 659 IU/L (reference interval; IU/L). EMG revealed abnormal spontaneous activities, short duration low amplitude motor units and short duration polyphasic motor unit potentials (MUP) and early recruitment patterns on volition, suggesting myogenic disorder. Echocardiographic findings showed normal LV systolic function and dilated right atrium and right ventricle. EG showed sinus arrest with junctional escape rhythm (Fig. 3). mbulatory EG monitoring revealed episodes of atrial fibrillation with complete V block and junctional escape rhythm (Fig. 4). systole up to 4 sec was observed. In an electrophysiologic study, no electrical signal was noted in the upper right atrium (Fig. 5). Junctional escape beats were noted. VVI type permanent pacemaker was implanted. Genetic analysis revealed a mutation in exon 2 of the emerin gene by deletion of the nucleotide at position 397 of the genomic D sequence. ase 2 (D EDMD2: MIM ) 28-yr-old female presented to the cardiology department complaining of intermittent dizziness and palpitation. Examination showed marked wasting and weakness of the shoulder girdle, proximal arm, and the proximal and distal leg mus- Table 2. ardiac findings Variables XR EDMD (ase 1) D EDMD2 (ase 2) D LGMD1 (ase 3) ge at detection of cardiac symptoms (yr) First symptoms Palpitation, Exertional dyspnea Palpitation, Dizziness Syncope, Exertional dyspnea Stroke onduction system disease trial standstill I, V-block trial standstill Features of rhythm Junctional rhythm Sinus rhythm Junctional rhythm Permanent pacemaker Increased end diastolic diameters RV, R - LV, L, R Left ventricular ejection fraction (%) Diastolic dysfunction Myocardial hypertrophy V, atrioventricular; L, left atrium; LV, left ventricle; R, right atrium; RV, right ventricle. Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type cles. She developed progressive muscle wasting of the lower extremities and difficulty in walking during her teens. She also presented with marked limitation of cervical flexion, contracture of the both elbows limiting arm extension, and contracture of the chilles tendon causing equinus deformities of the feet (Fig. 1). The deep tendon reflexes of the lower legs were absent. Her elder sister died of unknown causes at 28 yr of age with similar clinical features (Fig. 2). Serum K level was 195 IU/L and serum LDH level was 664 IU/L. EMG revealed increased insertional activities, short duration polyphasic MUP, and an early recruitment or decreased interference pattern, suggesting a chronic myogenic disorder. iopsy of the left gastrocnemius muscle revealed findings compatible with muscular dystrophy (Fig. 6). Myofibers are reduced and replaced by fibroadipose tissues. There Fig. 1. Photographs of each patient. () XR EDMD patient (case 1) showing flexion contractures of both elbows and chilles tendons. () D EDMD2 patient (case 2) showing marked muscular atrophy of upper and lower extremities with flexion contractures of both elbows and chilles tendons. The patient keeps her heel off the floor with equinus deformities of the feet. () LGMD1 patient (case 3) shows peroneal dystrophy with chilles tendon contractures. Equinus deformity of the right foot is more severe than the left one. are marked variations in fiber size associated with atrophic or hypertrophic myofibers, fiber splitting and an increase of internal nuclei. Fiber necrosis and infiltration of inflammatory cells were not present. Echocardiography showed normal LV cavity size and normal LV systolic function, but restrictive physiology was noted. EG showed sinus pause and first degree V block (Fig. 3). Slow non-sustained atrial tachycardia at a rate of 120 beats/ min with high grade V block was noted by ambulatory EG monitoring (Fig. 4). VVI type permanent pacemaker was implanted due to risk of sudden death associated with high degree V block. Genetic analysis showed a G to transition in exon 4 region of the lamin / (LM) gene (c.746g : R249Q). 286 J.-S. Hong,.-S. Ki, J.-W. Kim, et al. I avr V1 V4 avl V2 V5 I avf V3 V6 I V1 V2 I V3 avr V4 avl V5 avf V6 I avr V1 V4 avl V2 V5 I avf V3 V6 Fig. 2. Pedigrees of the families with XR EDMD (), D EDMD2 () and LGMD1 (). Squares indicate male family members, circles female family members and symbols with a slash mark deceased family members. Open symbols indicate unaffected family members, filled symbols indicate the presence of neuromuscular and cardiac symptoms, and shaded symbols indicate family members who are or were probably affected. rrows represent proband. and from reference 8. ase 3 (D LGMD1: MIM ) Fig lead EG of EDMD (), D EDMD2 () and LGMD1 (). () The EG shows sinus arrest with junctional escape rhythm at a heart rate of 40 beats per minute. () The EG shows left axis deviation, left anterior hemiblock, first-degree atrioventricular block, and sinus pause. () The EG shows atrial fibrillation with ST-T changes. 41-yr-old female presented with ankle contractures starting in her early teens. The contractures were more severe on the right side (Fig. 1). She had gait disturbance and difficulty climbing stairs due to ankle contractures as well as proximal leg weakness. neurological evaluation revealed limbgirdle muscle weakness, particularly in the proximal arms and thighs. The deep tendon reflexes of both ankle joints were absent. t age 39, she experienced loss of consciousness for 30 min. One year later, transient right hemiparesis developed. Two elder sisters died at 20 and 38 yr of age, due to heart problems. nother sister had a clinical picture similar to that of the patient (Fig. 2). Serum K level was 55 IU/L and serum LDH level was 618 IU/L. EMG revealed low amplitude short duration polyphasic MUP on volition and decreased interference patterns, compatible with chronic myogenic disorder. muscle biopsy from the quadriceps muscle showed an increase in the number of internal nuclei, mild variation in the muscle fiber diameter, scattered small-angulated myofibers and fatty ingrowth (Fig. 6). There was marked atrophy of type 1 fibers with a predominance of type 2 fibers (Fig. 6, D). Echocardiographic findings showed dilated cardiomyopathy. The ejection fraction of the left ventricle was 40% and end diastolic diameter of the left ventricle was 58 mm. Serial checks of EG revealed progression of abnormalities from sinus bradycardia, first-degree V block, to episodes of paroxysmal atrial tachycardia. Her final EG (Fig. 3) and ambulatory EG monitoring showed atrial tachycardia and high grade (3:1, 4:1) V block (Fig. 4). VVI type permanent pacemaker was implanted. This patient has a G to T transversion in exon 6 region of LM gene (c.1130g t: R377L). DISUSSIO The disorders manifested with both cardiac involvement Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type I 50 mm/s 500 ms 1 10 mm/mv 2-aVF 3-V1 4-V mm/mv radycardia 22-Dec :42:42 41 PM 5-hR dist 5-hR prox 7-HIS dist 1 10 mm/mv 2 10 mm/mv - Pause 3220 ms 1 20 mm/mv 2 20 mm/mv - Pause 2060 ms 29-Oct :11:58 30-Dec :50:12 Fig. 4. Findings of ambulatory EG monitorings of EDMD (), D EDMD2 () and LGMD1 (). () trial fibrillation with complete V block and junctional escape rhythm. () Slow nonsustained atrial tachycardia at a rate of 120 beats per minute with high grade V block. () trial tachycardia and high grade (3:1, 4:1) V block with the longest R-R interval of 2.06 sec. and skeletal muscular dystrophy can be categorized into two groups. The first group is characterized by muscular dystrophy with predominant cardiomyopathy, which includes Duchenne or ecker s muscular dystrophy. The second group is characterized by muscular dystrophy with predominant cardiac conduction disturbances, which includes EDMD and LGMD1. oth EDMD and LGMD1 are caused by the mutations of nuclear envelope proteins, i.e. emerin and lamin, respectively. EDMD consists of two diseases, XR emerin gene mutation (EDMD) and D lamin gene mutation (EDMD2). Even though they are caused by mutations of different genes, they show very similar clinical features. LGMD1 is an allelic variant of the lamin gene mutation, which has an overlapping phenotype with EDMD (4). It is not well-known why defects of nuclear envelope proteins show cardiac and skeletal myopathy and involvement of conduction systems in the heart. Emerin is localized at the inner nuclear membrane in various tissues by its transmembrane domain at the -terminus (1). mino acid sequence similarities and cellular location suggested that emerin is a member of nuclear lamina-associated protein (LP) family. artegni et al. (11) proposed a general role for emerin in membrane anchorage to the cytoskeleton. In heart, its specific localization to desmosomes and fasciae adherentes of the intercalated discs could account for the characteristic conduction defects described in patients with EDMD. deficiency of 43 PM 39 PM 9-HIS prox 16-STI 1 Fig. 5. Findings of electrophysiologic study in a patient with XR EDMD (case 1). Electrophysiologic study shows no electrical signal in the right upper atrium. Junctional escape beats are noted. emerin in immunofluorescent staining of skeletal and cardiac muscles from EDMD patients was observed (2). The lamin / (LM) gene encodes two proteins of the nuclear lamina, lamins (664 amino acids) and (572 amino acids) produced by alternative splicing (5). Like emerin, lamins and are components of the nuclear envelope but are located in the lamina, a multicentric structure associated with the nucleoplasmic surface of the inner nuclear membrane. ccording to Hutchinson et al. (12), the nuclear membrane damage and lamina fragility could develop into physical cell disruption leading to myocyte death and tissue damage. In cardiac muscle, the loss of individual mononucleated myocytes is cumulative and eventually leads to atrioventricular block and heart failure when the number of affected myocytes is sufficient to cause the phenotype. Therefore, the extension of myocyte damage in nodal versus left ventricular myocardium could partly explain the earlier occurrence of atrioventricular block than left ventricular dysfunction (13). The classical phenotype of EDMD is characterized by the clinical triad of early contractures of the chilles tendons, elbows and postcervical muscles and slowly progressive muscle wasting and weakness with a distinctive humeroperoneal distribution in the early stages of the disease, cardiomyopathy with life threatening conduction defects (14). LGMD1 is characterized by a slowly progressive weakness of the proximal muscles, mild joint contractures, age-related atrioventricular cardiac conduction disturbances and dilated cardiomyopathy (15). Phenotypes of LGMD1 overlap with EDMD. lthough the clinical feature of muscle involvement in both XR EDMD and D EDMD2 are quite similar, the pattern of muscular involvement in D EDMD2 is extremely variable. In XR EDMD, the first symptoms are generally contractures, weakness and difficulty in running in patients with D EDMD2 and are usually presented between 3 and 6 yr of age, and the contractures generally appeared afterwards. Some D EDMD2 patients lose ambulation, unlike patients with XR EDMD in whom loss of ambulation is very rare. Therefore, muscle weakness and disease course tend to be more 288 J.-S. Hong,.-S. Ki, J.-W. Kim, et al. D Fig. 6. The histopathologic findings of skeletal muscle biopsy specimen in D EDMD2 () and LGMD1 (-D) patient. () 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). () Variation in myofiber size, frequent internal nuclei and fatty ingrowth are noted in hematoxylin and eosin stain ( 200). () TPase ph 4.6 stain reveals atrophy of type 1 fibers (dark brown stain, 200). (D) TPase ph 9.4 stain reveals a predominance of type 2 fibers (brown stain, 100). severe in D EDMD2 than XR EDMD (7). In LGMD1, symmetrical weakness starts in the proximal lower limb muscles, and gradually the upper limb muscles also become affected. Early contractures of the spine were absent, and contractures of the elbows and the chilles tendons were either minimal or late, distinguishing this disorder from EDMD (15). The findings of muscular involvement in our cases are compatible with the above description. In the XR EDMD patient (case 1), contractures of the chilles tendon and the elbows were prominent without evident muscle wasting. However, D EDMD2 (case 2) showed severe muscle wasting, difficulty in walking and joint contractures. In LGMD1 (case 3), the predominant feature is a weakness of hip girdle muscle and shoulder girdle muscles. nkle contractures started later and milder compared with cases of EDMD. ardiac involvement in EDMD may occur at any age or may even be present at every onset, while on the other hand, neuromuscular symptoms precede cardiological symptoms Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type in nearly all patients with LGMD1 (15). The cardiac conduction defect is the most serious and life threatening clinical manifestation of the disease and is considered to be a hallmark of cardiomyopathy of EDMD. EG in the early findings shows sinus bradycardia, small P-wave and prolonged P-R interval. ccording to the progress of disease, EG shows atrial fibrillation or flutter, complete V block with idioventricular rhythm and atrial paralysis (atrial standstill) (14). The documentation of the absence of electrical atrial activity and inability to pace the atria by electrocardiogram and electrophysi
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