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 310300 ) . mutations in the lamin a / c ( lmna ) gene , encoding lamins a and c by alternative splicing , have been found to cause at least four different kinds of genetic disorders ; autosomal dominant ( ad ) emery - dreifuss muscular dystrophy ( 3 ) ( edmd2 : mim 181350 ) ; limb - girdle muscular dystrophy type 1b ( 4 ) ( lgmd1b ; mim 159001 ) ; dilated cardiomyopathy type 1a ( 5 ) ( cmd1a ; mim 115200 ) ; and familial partial lipodystrophy ( 6 ) ( fpld ; mim 151660 ) . among these genetic disorders , three disorders , xr edmd , ad edmd2 and lgmd1b , 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 ad edmd2 share clinically undistinguishable features ( 7 ) . in these three disorders , cardiac dysrhythmias including av block , bradycardia , atrial fibrillation , and characteristic atrial standstill often lead to syncope and sudden cardiac death . therefore , we report three cases of edmd , edmd2 , and lgmd1b diagnosed by clinical findings and genetic analyses . these three patients are the first cases of edmd , edmd2 and lgmd1b , respectively , reported in korea . 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 ( ecg ) , ambulatory ecg monitoring , electrophysiologic study and echocardiography , electromyography ( emg ) , laboratory studies of muscle enzymes , and muscle biopsy . information on deceased family members as well as on other family members who were suspected to be affected was obtained from probands . the genetic analysis of mutations in the lamin gene ( edmd2 , lgmd1b ) has been reported previously ( 8) , and parts of clinical findings of case 1 and 2 were described elsewhere ( 9 , 10 ) . cardiac findings are summarized in table 2 . a 14-yr - old boy presented with a gait disturbance . at age 1 , contractures of the achilles 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 . a family history revealed that his maternal uncle had abnormal clinical features similar to those of the patient ( fig . serum creatine kinase ( ck ) activity was 481 iu / l ( reference interval ; 24 - 204 iu / l ) . serum lactate dehydrogenase ( ldh ) level was 659 iu / l ( reference interval ; 240 - 480 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 . ambulatory ecg monitoring revealed episodes of atrial fibrillation with complete av block and junctional escape rhythm ( fig . genetic analysis revealed a mutation in exon 2 of the emerin gene by deletion of the c nucleotide at position 397 of the genomic dna sequence . a 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 muscles . 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 achilles tendon causing equinus deformities of the feet ( fig . her elder sister died of unknown causes at 28 yr of age with similar clinical features ( fig . emg revealed increased insertional activities , short duration polyphasic mup , and an early recruitment or decreased interference pattern , suggesting a chronic myogenic disorder . myofibers are reduced and replaced by fibroadipose tissues . there 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 echocardiography showed normal lv cavity size and normal lv systolic function , but restrictive physiology was noted . 3b ) . slow non - sustained atrial tachycardia at a rate of 120 beats / min with high grade av block was noted by ambulatory ecg monitoring ( fig . a vvi type permanent pacemaker was implanted due to risk of sudden death associated with high degree av block . genetic analysis showed a g to a transition in exon 4 region of the lamin a / c ( lmna ) gene ( c.746g > a : r249q ) . a 41-yr - old female presented with ankle contractures starting in her early teens . the contractures were more severe on the right side ( fig . she had gait disturbance and difficulty climbing stairs due to ankle contractures as well as proximal leg weakness . a neurological evaluation revealed limbgirdle muscle weakness , particularly in the proximal arms and thighs . the deep tendon reflexes of both ankle joints were absent . at age 39 , she experienced loss of consciousness for 30 min . two elder sisters died at 20 and 38 yr of age , due to heart problems . emg revealed low amplitude short duration polyphasic mup on volition and decreased interference patterns , compatible with chronic myogenic disorder . a 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 . there was marked atrophy of type 1 fibers with a predominance of type 2 fibers ( fig . the ejection fraction of the left ventricle was 40% and end diastolic diameter of the left ventricle was 58 mm . serial checks of ecg revealed progression of abnormalities from sinus bradycardia , first - degree av block , to episodes of paroxysmal atrial tachycardia . her final ecg ( fig . 3c ) and ambulatory ecg monitoring showed atrial tachycardia and high grade ( 3:1 , 4:1 ) av block ( fig . this patient has a g to t transversion in exon 6 region of lmna gene ( c.1130g > t : r377l ) . a 14-yr - old boy presented with a gait disturbance . at age 1 , contractures of the achilles 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 . a family history revealed that his maternal uncle had abnormal clinical features similar to those of the patient ( fig . serum creatine kinase ( ck ) activity was 481 iu / l ( reference interval ; 24 - 204 serum lactate dehydrogenase ( ldh ) level was 659 iu / l ( reference interval ; 240 - 480 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 . ambulatory ecg monitoring revealed episodes of atrial fibrillation with complete av block and junctional escape rhythm ( fig . 4a ) . asystole up to 4 sec was observed . in an electrophysiologic study , no electrical signal was noted in the upper right atrium ( fig . 5 ) . genetic analysis revealed a mutation in exon 2 of the emerin gene by deletion of the c nucleotide at position 397 of the genomic dna sequence . a 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 muscles . 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 achilles tendon causing equinus deformities of the feet ( fig . her elder sister died of unknown causes at 28 yr of age with similar clinical features ( fig . emg revealed increased insertional activities , short duration polyphasic mup , and an early recruitment or decreased interference pattern , suggesting a chronic myogenic disorder . there are marked variations in fiber size associated with atrophic or hypertrophic myofibers , fiber splitting and an increase of internal nuclei . echocardiography showed normal lv cavity size and normal lv systolic function , but restrictive physiology was noted . 3b ) . slow non - sustained atrial tachycardia at a rate of 120 beats / min with high grade av block was noted by ambulatory ecg monitoring ( fig . a vvi type permanent pacemaker was implanted due to risk of sudden death associated with high degree av block . genetic analysis showed a g to a transition in exon 4 region of the lamin a / c ( lmna ) gene ( c.746g > a : r249q ) . a 41-yr - old female presented with ankle contractures starting in her early teens . the contractures were more severe on the right side ( fig . 1c ) . she had gait disturbance and difficulty climbing stairs due to ankle contractures as well as proximal leg weakness . a neurological evaluation revealed limbgirdle muscle weakness , particularly in the proximal arms and thighs . the deep tendon reflexes of both ankle joints were absent . at age 39 , she experienced loss of consciousness for 30 min . two elder sisters died at 20 and 38 yr of age , due to heart problems . another sister had a clinical picture similar to that of the patient ( fig . 2c ) . emg revealed low amplitude short duration polyphasic mup on volition and decreased interference patterns , compatible with chronic myogenic disorder . a 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 . there was marked atrophy of type 1 fibers with a predominance of type 2 fibers ( fig . the ejection fraction of the left ventricle was 40% and end diastolic diameter of the left ventricle was 58 mm . serial checks of ecg revealed progression of abnormalities from sinus bradycardia , first - degree av block , to episodes of paroxysmal atrial tachycardia . her final ecg ( fig . 3c ) and ambulatory ecg monitoring showed atrial tachycardia and high grade ( 3:1 , 4:1 ) av block ( fig . this patient has a g to t transversion in exon 6 region of lmna gene ( c.1130g > t : r377l ) . the disorders manifested with both cardiac involvement 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 becker 's muscular dystrophy . the second group is characterized by muscular dystrophy with predominant cardiac conduction disturbances , which includes edmd and lgmd1b . both edmd and lgmd1b 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 ad lamin gene mutation ( edmd2 ) . even though they are caused by mutations of different genes , they show very similar clinical features . lgmd1b 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 c - terminus ( 1 ) . amino acid sequence similarities and cellular location suggested that emerin is a member of nuclear lamina - associated protein ( lap ) family . ( 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 . a deficiency of 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 , lamins a ( 664 amino acids ) and c ( 572 amino acids ) produced by alternative splicing ( 5 ) . like emerin , lamins a and c 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 . according 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 achilles 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 ) . lgmd1b is characterized by a slowly progressive weakness of the proximal muscles , mild joint contractures , age - related atrioventricular cardiac conduction disturbances and dilated cardiomyopathy ( 15 ) . although the clinical feature of muscle involvement in both xr edmd and ad edmd2 are quite similar , the pattern of muscular involvement in ad edmd2 is extremely variable . in xr edmd , the first symptoms are generally contractures , weakness and difficulty in running in patients with ad edmd2 and are usually presented between 3 and 6 yr of age , and the contractures generally appeared afterwards . some ad 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 severe in ad edmd2 than xr edmd ( 7 ) . in lgmd1b , 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 achilles 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 achilles tendon and the elbows were prominent without evident muscle wasting . however , ad edmd2 ( case 2 ) showed severe muscle wasting , difficulty in walking and joint contractures . in lgmd1b ( case 3 ) , cardiac 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 in nearly all patients with lgmd1b ( 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 . ecg in the early findings shows sinus bradycardia , small p - wave and prolonged p - r interval . according to the progress of disease , ecg shows atrial fibrillation or flutter , complete av 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 electrophysiological study in a patient with atrial paralysis , is recognized as a pathognomonic finding of edmd ( 16 ) . the normal myocardium is progressively replaced by fibroadipose tissue ( 17 ) , which results in atrial paralysis by loss of atrial contractility and heart failure by atrial and ventricular dilatation . they include conduction disturbances and dysrythmias , presenting as an av block , atrial fibrillation with high degree av block and junctional escape rhythm , bradycardia , atrial standstill and syncopal attacks . av conduction disturbances increased with age in lgmd1b patients and became more severe ( 15 ) . the potential complications of the cardiac pathology in edmd and lgmd1b include syncope , cerebral and pulmonary emboli , congestive heart failure , cor pulmonale , and sudden cardiac death , which may occur in the early twenties ( 18 ) . in our study , the manifestations of cardiac involvement were similar to those of reported cases . all three patients had severe bradycardia due to either conduction defects , atrial tachycardia with high grade av block , atrial fibrillation , and sinus arrest with junctional escape rhythm . ( 19 ) reviewed 73 cases of xr edmd from six families , and showed that 30 patients died suddenly between the age of 25 and 59 yr . among them , only four patients had minor symptoms with dizziness or syncopal episodes , therefore , they ascertained that sudden death due to edmd was unpredictable in most cases . consequently , a very important aspect of management of edmd and lgmd1b was determined to be the early detection of cardiac conduction defects . all patients were implanted with pacemakers . however , these patients had not been diagnosed before , even though they were consulted to cardiologists for rhythm disturbances in other hospitals . based on the experience of our cases , we propose that screening for mutations in the emerin or lamin gene should be considered in patients with severe conduction defects and/or dilated cardiomyopathy . ( 20 ) reported that screening for mutations in the xr edmd gene was performed among 450 patients affected with severe heart rhythm defects and/or dilated cardiomyopathy , and xr edmd was found among ten patients . therefore , investigators should be concerned about the genetic association of severe cardiac involvement even in patients without muscular symptoms . in conclusion , edmd and lgmd1b are characterized by slowly progressive skeletal myopathy and contractures of neck , elbows and ankles , cardiac dysrhythmia , and late - onset cardiomyopathy . cardiac dysrhythmias in edmd and lgmd1b include av block , bradycardia , atrial fibrillation , sinus arrest and characteristic atrial standstill , causing syncope and sudden cardiac death necessitating pacemaker implantation . because these patients are commonly undiagnosed , cardiologists should be aware of these unusual genetic diseases as causes of conduction defects , especially in young adults .
emery - dreifuss muscular dystrophy ( edmd ) and limb - girdle muscular dystrophy type 1b ( lgmd1b ) 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 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 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 310300 ) . 
 a 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 av block were noted . 
 she was diagnosed as autosomal dominant edmd2 ( mim 181350 ) . a 41-yr - old female had contractures of both ankles and limb - girdle type muscular dystrophy . 
 ecg revealed atrial tachycardia with high grade av block . 
 she was diagnosed as autosomal dominant lgmd1b ( mim 159001 ) . 
 cardiac dysrhythmias in edmd and lgmd1b include av block , bradycardia , atrial tachycardia , atrial fibrillation , and atrial standstill , causing sudden death necessitating pacemaker implantation . 
 cardiologists should know about these unusual genetic diseases with conduction defects , especially in young adults .