childhood-onset autosomal-dominant limb-girdle muscular dystrophy with cardiac conduction block

ABSTRACT: We report childhood-onset autosomal-dominant limb-girdlemuscular dystrophy (LGMD) in a Chinese family with complete atrioventricu-lar conduction block in the adult members. Six patients, including 5 menand 1 woman with an age of onset from 3 to 7 years, were affected.The grandfather had exercise intolerance since childhood and completeheart block with pace-maker placement at age 52. Three siblings hadproximal muscle weakness and/or wasting since age 5 and heart blockin their 40s. Two grandsons at the ages 7 and 3 showed exerciseintolerance, and proximal muscle weakness and wasting. Sinus bradycardiawas present in the elder grandson. Muscle enzymes were elevated in 3,particularly in childhood. Muscle biopsies from the proband showed myo-pathic changes with fatty degeneration, whorled fibers, and rimmed vacu-oles. In adult patients, muscle magnetic resonance imaging scans disclosedatrophic changes and fatty degeneration in the gluteal, quadriceps, adduc-tors, hamstrings, gastrocnemius, and soleus muscles, while in child pro-bands the early atrophic changes were seen in the gluteal and hamstringsmuscles. We conclude that this distinct family is characterized by childhood-onset autosomal-dominant LGMD with heart block and that prevention ofsudden death in these patients is important. 1997 John Wiley & Sons,Inc. Muscle Nerve, 20, 286–292, 1997.Key words: limb-girdle muscular dystrophy; autosomal dominant; atrioven-tricular block; muscle magnetic resonance imaging

CHILDHOOD-ONSETAUTOSOMAL-DOMINANT LIMB-GIRDLEMUSCULAR DYSTROPHY WITHCARDIAC CONDUCTION BLOCK

WAN FANG, MD,1 CHIN-CHANG HUANG, MD,1* NAI-SHIN CHU, MD, PhD,1

CHI-JEN CHEN, MD,2 CHIN-SONG LU, MD,1 and CHUN-CHIEH WANG, MD3

1 Department of Neurology, Chang Gung Memorial Hospital, 199, Tung Hwa NorthRoad, Taipei, Taiwan, R.O.C.2 Department of Radiology, Chang Gung Medical College and Memorial Hospital,Taipei, Taiwan3 Department of Cardiology, Chang Gung Medical College and Memorial Hospital,Taipei, Taiwan

Received 17 April 1996; accepted 15 September 1996

Limb-girdle muscular dystrophy (LGMD) was first involvement with cardiomyopathy, arrhythmia, oratrioventricular block in LGMD is not usually pres-defined as a nosological entity and characterized byent.3,13,16,19,28,36,37 Recently, we encountered a Chinesemuscle weakness and wasting in limb-girdle areas.38

family with autosomal-dominant inheritance, early-After an exclusion of spinal muscular atrophy (SMA),onset limb-girdle muscular dystrophy, and heartdystrophinopathies, inflammatory, metabolic andblock in adulthood. We report the clinical manifesta-congenital myopathies, LGMD still remains a heter-tions and the studies on electrophysiology, muscleogenous group of muscle disorders.31 The inheri-magnetic resonance imaging (MRI), and histopathol-tance pattern in LGMD is usually autosomal recessiveogy in this family.or sporadic.25 Autosomal-dominant inheritance is rel-

atively uncommon.1,2,4,7–9,13,14,16,18,21–24,27–30,32,33,35 and usu- REPORT OF CASESally with an adult onset.2,7,8,9,13,14,16,21,28–30,32,33,37 Cardiac Figure 1 shows a three-generation pedigree of this

family without a history of consanguinity.The patient II-3, a 42-year-old man, had difficul-*Correspondence to: Dr. Chin-Chang Huang

ties running and jumping since the age of 5. He hadCCC 0148-639X/97/030286-07 1997 John Wiley & Sons, Inc. proximal leg weakness and could not climb up stairs

286 Autosomal-Dominant LGMD with Heart Block MUSCLE & NERVE June 1997

FIGURE 1. Three-generation pedigree of limb-girdle muscular dystrophy and familial heart block indicating an autosomal-dominantinheritance.

and arise from chairs without assistance. Progressive with whorled fibers. Some atrophic fibers showedvacuoles with irregular margin surrounded by a rimarm muscle wasting was found at the age of 15. Seven

years later, he was unable to hold heavy objects. At of granular materials (Fig. 2). Fiber type grouping,group atrophy, and infiltration of inflammatory cellsthe age of 32, second-degree atrioventricular (AV)

block with a ventricular rate of 72 beats per minute were not seen. Periodic acid-Schiff (PAS) stain wasnegative.(bpm) was noted. In 1988, at age 35, neurological

evaluation revealed limb-girdle muscle wasting, par- Evaluation in 1995 revealed muscle weakness in-volving shoulder and pelvic girdles, and proximalticularly over proximal arms and thighs, with normal

mental function, cranial nerve, sensory, and cerebel- arms and legs, particularly hamstrings and bicepsmuscles. Tendon reflexes were hypoactive or absent.lar examinations. Biochemistry showed normal cre-

atine phosphokinase (CPK: 84 m/L; normal: 15–130 There was neither percussion myotonia, con-tractures, nor rigid spine. Muscle enzyme of CPK wasm/L) and mildly elevated lactate dehydrogenase

(LDH: 149 m/L; normal: 47–140 m/L) levels. Nerve elevated (162 m/L). MRI scans of muscles over thelower legs disclosed atrophy and fatty degenerationconduction velocity (NCV) studies were normal but

electromyography (EMG) showed short-duration in the gluteal, quadriceps, adductors, hamstrings, gas-trocnemius, and soleus muscles. The rectus femoris,and small-amplitude polyphasic motor unit poten-

tials over the biceps, vastus medialis, orbicularis oris, sartorius, left gracilis, anterior, and lateral compart-ments of the lower legs and the lateral head of the leftand gluteus maximus muscles. Spontaneous activities

such as fibrillation potentials were absent. Muscle gastrocnemius muscles were relatively spared (Fig. 3).Electrocardiogram (EKG) still showed atrial fibrilla-biopsy demonstrated variation in fiber size with

round atrophic and some hypertrophic fibers and tion and complete AV block.The patient I-1, the father of the proband II-3,increased amount of internal nuclei.

In 1994, Holter monitor study revealed atrial fi- died at age 53 years. He had exercise intolerance anddifficulty running since childhood, but could walk,brillation with complete AV block. The average ven-

tricular rate was 33 bpm and the minimum was 30 arise from a chair, and climb up stairs without sup-port. He had a history of heart block with slow ventric-bpm. The patient refused to have a permanent pace-

maker implant. Echocardiogram revealed a normal ular rate. He received a pacemaker at age 52, butsudden death occurred 1 year later.ventricular size in 1989 but a dilatation of the left

ventricle with an adequate left ventricular perfor- The patient II-2, a 45-year-old woman, the sisterof the proband II-3, developed clumsiness in run-mance in 1991 and 1994. A follow-up muscle biopsy

from the right vastus lateralis muscle showed in- ning and jumping since the age of 5. Poor perfor-mance at gymnastics was noted when attending thecreased internal nuclei, fiber splitting, atrophic and

hypertrophic fibers, fibrosis, and fatty degeneration junior high school. Difficulty in standing from a

Autosomal-Dominant LGMD with Heart Block MUSCLE & NERVE June 1997 287

FIGURE 2. Muscle biopsy from the right vastus lateralis muscle in patient II-3 revealed increased internal nuclei, variation in fiber sizeswith hypertrophic and atrophic fibers, increased endomysial fibrosis, fatty degeneration (arrowhead) of muscle fiber (A, hematoxylin andeosin stain, 3100), whorled fibers (arrows) (B, hematoxylin and eosin stain, 3100; C, modified Gomori-trichrome stain, 3200), rimmedvacuole (arrowhead) in an atrophic fiber (C), and fiber splitting (arrow) with internal migrated nucleus in a hypertrophic fiber (D, modifiedGomori-trichrome stain, 3200).

squatting position appeared in the following years. high-degree AV block. The average ventricular ratewas 56 bpm and the minimum only 24 bpm. Echocar-Heart disease was found at the age of 28. Progressive

deterioration of muscle weakness forced her to hold diogram showed dilatation of the left atrium withnormal left ventricular size and adequate left ventric-a handrail to climb up stairs. Dizziness was frequent

since age 37. EKG showed a first-degree AV block ular performance.The patient II-4, a 40-year-old man, the youngerwith a ventricular rate of 60 bpm. Neurological

evaluation at age 45 revealed muscle weakness, par- brother of the proband II-3, could not run a longdistance since elementary school. Difficulty standingticularly involving the hamstrings, biceps, and glu-

teus medius muscles. There was neither facial, bul- up from a squatting position developed insidiously.Proximal muscle wasting of the upper and lower ex-bar, nor extraocular muscle involvement. Knee and

ankle jerks were absent. Myotonia, contracture, and tremities and dyspnea in exercise and climbing upstairs were noted during senior high school. Spinalrigid spines were not seen. Muscle enzymes were nor-

mal (CPK: 94 m/L, LDH: 41 m/L). EMG over the rigidity or myotonia was absent. Although slow ven-tricular rate about 40 bpm was noted in his 40s, thereleft anterior tibialis, vastus medialis, biceps, and or-

bicularis oris muscles showed polyphasic motor unit was neither paroxysmal nocturnal dyspnea, legedema, nor syncopal episodes.potentials with short duration and small amplitude.

Muscle MRI scan over the lower legs disclosed muscle The patient III-5, a 13-year-old boy, the son of thepatient II-2, first noticed exercise intolerance andatrophy and fatty degeneration similar to those of

patient II-3, except for sparing of bilateral gracilis difficulties jumping and running at the age of 7.However, he still could stand up from squatting orand the lateral head of gastrocnemius muscles. EKG

and Holter monitor study revealed atrial flutter with sitting positions and climb up stairs. Evaluation at


particularly the hamstrings muscles. Knee and anklejerks were absent. An elevation of serum CPK (962m/L) and LDH (2763 m/L) levels was found. Musclebiopsy showed a variation in fiber sizes and scatteredatrophic fibers. At age 6, muscle enzymes were stillmarkedly elevated (CPK: 1216 m/L; LDH: 239 m/L).MRI of the lower legs revealed atrophy and fatty de-generation in the proximal muscles, particularly thegluteus minimus, adductors, and hamstring muscles.EKG showed normal cardiac rhythm. Chest X-ray andechocardiogram were normal.

Table 1 summarizes the clinical and laboratorydata of these 6 affected patients. Table 2 summarizesthe muscle MRI findings of 4 affected patients.

DISCUSSION

The patients in this family have a dystrophic myopa-thy with the following characteristics: (1) onset ofmuscle weakness in early childhood and the symp-toms usually limited to the limb-gridle muscles withsparing of the facial, extraocular, and bulbar muscles;(2) flexor muscles were usually more severely in-volved than extensor muscles and without con-

FIGURE 3. MRI of lower legs in the patient II-3. Transaxial SE tracture; (3) marked or moderate elevation of CPK400/10 images through pelvis (A), and upper (B) and middle (C) in childhood, but normal or only slight elevation inthigh show atrophy and symmetric fatty replacement of ham- adulthood; (4) usually late-onset cardiac conductionstrings, quadriceps, adductors, and gluteus medius and minimus

defect and arrhythmia; and (5) autosomal-dominantmuscles (arrowhead), and asymmetric involvement of right gracilisinheritance. Other causes of muscular dystrophiesmuscle with sparing of bilateral rectus femoris and sartorius mus-

cles (arrows). These features suggest myopathic changes. In were excluded, including Duchenne muscular dystro-addition, the size of the left-sided gracilis muscle is increased, phy, facioscapulohumeral (FSH) dystrophy, distalindicating a hypertrophy (B and C). Transaxial SE 416/11 images myopathy, and myotonic dystrophy.through upper (D) and lower (E) calf show asymmetric fatty re-

Limb-girdle muscular dystrophy with autosomal-placement of posterior compartment. Note relative sparing of lat-dominant inheritance is relatively rare but well docu-eral head of left gastrocnemius muscle (arrow). Coronal SE 400/

19 image through middle thigh (F) confirms fatty degeneration mented.1,2,4,7,9,13,14,16,18,21–24,27–30,32,33,35,37 Review of theof the gluteus medius (arrowhead) and adductor muscles. Note literature revealed 17 families with late-onset auto-relative sparing of left gracilis muscle (arrow). Coronal SE 400/ somal-dominant LGMD.2,7,9,13,14,16,21,28–30,32,33,37 In 1976,19 image through middle calf (G) suggests fatty degeneration of

Bethlem and Van Wijngaarden4 described three fam-gastrocnemius and soleus muscles.ilies with autosomal-dominant LGMD which wascharacterized by childhood onset, and contractureover the ankle, elbow, and interphalangeal joints.the age of 13 revealed muscle weakness and wasting

over bilateral biceps muscles. The size of proximal Furthermore, cardiac involvement was usually ab-sent,18,22,24,27,35 except for 1 patient who had asym-upper limbs was smaller than that of forearms. Bra-

chioradialis, and knee and ankle jerks were absent metrical septal hypertrophy but without EKGabnormalities.10 Our family is different from those ofor hypoactive. Serum CPK was elevated (306 m/L),

while LDH was normal (77 m/L). MRI over the upper Bethlem myopathy, especially in absence of con-tracture, vacuoles in muscles, and AV block.and lower limbs revealed moderate atrophy over bi-

lateral biceps muscles and mild fatty degeneration Whorled fibers have been reported in congenitalmyopathy11 and are considered to be the conse-over the gluteal muscles. EKG showed sinus brady-

cardia with a ventricular rate of 50 bpm. quence of a disorganized intermyofibrillar network.39

They are usually present with slowly progressive limbThe patient III-6, a 6-year-old boy, the son of theproband II-3, had a normal early development but girdle dystrophy.11,34,39 Rimmed vacuoles have been

found in various muscle diseases, including ocularhad frequent falling since the age of 3. He had diffi-culty climbing up stairs since then. Evaluation at age myopathy, oculopharyngeal muscular dystrophy, dis-

tal myopathy, inclusion body myositis (IBM), and4 revealed proximal muscle weakness of the legs,


Table 1. Clinical and laboratory summary of 6 patients with autosomal-dominant LGMD and heart block.

Patient

II-2 II-3 II-4 III-5 III-6I-1

Age (years)/sex 53D/M 45/F 42/M 40/M 13/M 6/MAge at onset (years) NA 5 5 5 7 3Exercise intolerance 1 1 1 1 1 1

Difficulties inRunning 1 1 1 1 1 1

Climbing 2 1 1 2 2 1

Standing from squatting 2 1 1 1 2 1

Muscle weaknessProximal arm 2 1 1 2 1 2

Proximal leg 2 1 1 1 2 1

Muscle wastingProximal arm 2 2 1 1 1 2

Proximal leg 2 2 1 1 2 2

Hyporeflexia or areflexiaIn UE NA 2 1 NA 1 2

In LE NA 1 1 NA 1 1

Conduction block 1 1 1 1 2 2

Serum CPK (m/L) NA 94 162* NA 306* 1216*Serum LDH (m/L) NA 41 53 NA 77 239*EMG NA My My NA NA NAMuscle biopsy NA NA My NA NA My

D, age at death; M, male; F, female; NA, not available; 1, positive; 2, negative; UE, upper extremities; LE, lower extremities; CPK, creatinephosphokinase; LDH, lactate dehydrogenase; My, myopathic change; EMG, electromyography.*Abnormal data.

autosomal-dominant LGMD.7,8,13,14,21,29 The pattern of were relatively spared except for mild involvementof the flexor hallucis and digitorum longus musclesmuscle weakness in our patients was different from

patients with ocular myopathy, oculopharyngeal mus- in adult patients. The mild involvement of the gas-trocnemius and sparing of the soleus muscles in childcular dystrophy, and distal myopathy. The lack of

inflammatory cells seemed to rule out inclusion body patient III-6 and severe fatty degeneration of thesemuscles in adult patients II-2 and II-3 may demon-myositis. The negative PAS stain may exclude glyco-

gen storage disease. The autosomal-dominant inheri- strate the evolution of muscle fatty degenerationfrom the limb-girdle muscles to distal muscles. Wast-tance is also different from that of Duchenne/Becker

muscular dystrophy. ing of the gastrocnemius muscles, particularly themedial head, did not occur in LGMD particularlyMuscle MRI confirmed fatty degeneration in the

gluteal, adductor, hamstrings, and quadriceps mus- when the duration was less than 20 years.34

Cardiac involvement has been well documentedcles, and further revealed widespread lesions in clini-cally unaffected gastrocnemius and soleus muscles in in various muscular dystrophies.3,5,10,12,13,16,19,28,36,37 In

Duchenne muscular dystrophy, cardiomyopathies oradult patients II-2 and II-3. The severity of MRIchanges did not consistently correlate with the de- conduction abnormalities are common.12 Conduc-

tion disturbances are also frequently noted in myo-gree of weakness. In the pelvis, the gluteus mediusand minimus muscles were more severely involved tonic dystrophy,17 Emery–Dreifuss muscular dystro-

phy,5 and Kearns–Sayre syndrome.20 In LGMD,than the gluteus maximus muscle. In the thigh, thesartorius, gracilis, and rectus femoris muscles were cardiac involvement has been considered relatively

rare,3,10,13,16,19,28,36,37 but cardiomyopathy,12,13,16,19,36,37 con-relatively spared. Asymmetric involvement of rightgracilis muscle was noted in patient II-3. The relative duction defects,3,19 complete AV block,11,13,21,37 atrial

fibrillation,28 ventricular tachycardia,19 and mitral re-sparing of rectus femoris muscle may add additionalevidence of selective involvement in quadriceps mus- gurgitation19 have been reported. Among them, car-

diac presentations usually developed several yearscles as previously described in the recessive or spo-radic LGMD.34 The thigh adductors were much after muscular symptoms, with the exception of two

pedigrees in which cardiomyopathies and conduc-weaker than the abductors, and such selective weak-ness was regarded to be characteristic in LGMD.34 In tion block preceded the appearance of muscle

weakness.13,19the lower legs, the anterior and lateral compartments


Table 2. Muscle MRI findings in 4 patients with autosomal-dominant LGMD and heart block.

II-2 II-3 III-5 III-6

Patient R L R L R L R L

Age/sex 45/F 42/M 13/M 6/MIllipsoas muscles 2 2 2 2 2 2 2 2

Gluteal muscleGluteal maximus 1 1 1p11 1p11 6 6 6 6

Gluteal medius 111 111 111 111 1 1 1 1

Gluteal minimus 111 111 111 111 1 1 11 11

Thigh musclesQuadriceps

Rectus femoris 2 2 2 2 2 2 6 6

Vastus lateralis 11 11 11 11 2 2 1 1

Vastus intermedius 1p11 11 1 1 2 2 1 1

Vastus medialis 11 11 11 11 2 2 1 1

AdductorsProximal 1 1 2 2 2 2 6 6

Distal 111 111 111 111 2 2 11 11

Hamstrings 111 111 111 111 2 2 11 11

Sartorius 2 2 2 2 2 2 6 6

Gracilis 2 2 111 2 2 2 6 6

Lower leg musclesAnterior tibialis 2 2 2 2 2 2 2 2

Extensor H&D longus 6 6 2 2 2 2 2 2

Posterior tibialis 6 6 2 2 2 2 2 2

Flexor H&D longus 1 1 1 6 2 2 2 2

Peroneus 6 6 2 2 2 2 2 2

GastrocnemiusMedial head 111 111 111 111 2 2 1 1

Lateral head 1 6 111 6 2 2 2 2

Soleus 11 111 111 111 2 2 2 2

Upper limb musclesBiceps NA NA NA NA * * NA NATriceps NA NA NA NA 2 2 NA NA

H&D, hallucis and digitorum; F, female; M, male; NA, not available; R, right; L, left; 2, absent; 6, equivocal fatty degeneration; 1, mild fattydegeneration; 11, moderate fatty degeneration; 111, marked fatty degeneration.*Moderate atrophy.

Graber et al.15 described a family with an evolution autosomal-dominant limb-girdle muscular dystrophywith cardiac involvement.37 In that study, 35 patientsof the hereditary conduction and cardiac muscle dis-

order in which sinus bradycardia and premature in three families had weakness of the proximal lowerlimbs from age 4–38 years. Cardiac conduction ab-atrial contraction developed in the 2nd decade and

then were followed by AV block with atrial fibrillation normalities, such as AV block and bradycardia, mightlead to syncope or sudden death, necessitating pace-or flutter in the 3–4th decade, and then congestive

heart failure in the 5–6th decades. However, there maker implantation. In nearly all patients, muscularinvolvement preceded cardiological involvement.was no skeletal muscle involvement. The association

of autosomal-dominant LGMD with familial heart The clinical manifestations of their patients werequite similar to those of ours.block has been reported only twice previously.13,37

Fitzpatrick et al.13 described an Italian family with an In conclusion, we describe a distinct three-genera-tion family with childhood-onset autosomal-domi-autosomal-dominant restrictive cardiomyopathy in

childhood or the 3–4th decades. Bundle branch nant LGMD and familial heart block in adults. Recentadvances in linkage analysis have linked one kindredblock might occur and lead to a complete AV block.

Fibrosis in the conducting system accounts for the of late-onset autosomal-dominant LGMD to chromo-some 5q,33 Bethlem myopathy to 21q,18 and progres-development of heart block. However, most patients

had restrictive cardiomyopathy and only 4 individuals sive familial heart block to 19q.6 We consider thatfurther molecular genetic studies in this Chinese fam-developed a progressive skeletal myopathy in the

4–5th decades. Recently another study reported an ily should be performed to elucidate the genetic het-


19. Kawashima S, Ueno M, Kondo T, Yamamoto J, Iwasaki T:erogeneity of autosomal-dominant LGMD with famil-Marked cardiac involvement in limb-girdle muscular dystro-ial heart block. phy. Am J Med Sci 1990;299:411–414.

20. Leveille AS, Newell FW: Autosomal dominant Kearns-Sayresyndrome. Ophthalmology 1980;87:99–108.We express our appreciation to Ms. Lily Lee and Dr. S.K. Lin for

21. Marconi G, Pizzi A, Arimondi CG, Vannelli B: Limb girdletechnical assistance and to Ms. Chien-Zu Tsui for typing the manu-muscular dystrophy with autosomal dominant inheritance.script.Acta Neurol Scand 1991;83:234–238.

22. Merlini L, Morandi L, Granata C, Ballestrazzi A: Bethlemmyopathy: early onset benign autosomal dominant myopathy

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childhood-onset autosomal-dominant limb-girdle muscular dystrophy with cardiac conduction block

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