Ihnb-girdle muscular dystrophy is usually an ~~~[osorn~~~ rcces- sivc condition with onset in the 2nd decade of life. Wcaknc~ tends to begin in either the pelvic or the shoulder girdle muscles with subsequent involvement of both arcas. The rate of ~~~~ss~~~ varies and after 2 decades from time of onsrt, disability is often severe (1). The exact ~~evn~~nc~ of cardiac in~l~rn~n~ in this condition has not been reported, but the

pears to be rare and is usually related to distutinces of rb~thm or conduction (2). The few reports of

re in limb-girdle musctthr dystrophy (3.4) do not atory evahtion of left ventricular function. Re-

mtly, ~w~birnn et al. (5) reported an belated case of apparent diluted cardiomyopathy in a patient who subse- quently dzvchqed limb-girdle muscular dystrophy. We report 311 three sisters with limb-girdle muscular dystrophy, all of whom had ~~~nt~d cardiomyopathy before 30 years of age.

From ahe T&ion of Cardiolqy. St. Vincent Hospital, Worcc,rter.W11\9a- :hwlts: tb.qwfments of Medicine. Neurology and Fediatria,. University -f tiassachusetts School of Medicine. Worcester, Massachusetts; #Dcpartmcm of Gxtrol~, Brwn University. Providence. Rhode Island; $Divisions of Neurp RrfKl and Cad-&o&+, Btigharn and Women’s Haspital and Departments of ‘atim& and Medicine, Harvard Medical School, Boston, Massachusetts.

Manwzript =&ed February t&1993; revised manuscript received May 23. 5% accepted June 3,1994.

: Dr. David H. Spodick, Division of Cardiology, 2. Vincent Hospital, Worcester, Massachusetts 01604.

>l!XM by the American College of Cardiology

ent 1. A 36year ald woman was rcferrcd because of a Sy” murmur. She reported shortness of breath rchevcd by bronchodilators. limb-g~rd~c m ular dyst~o~by was diag nosed at age 13 years because o ogressive ~~oxirn~l muscle weakness beginning at age 4 and ahnorma~ findings on muscle biopsy. Both parents were in good health and were not consanguineous. By age 29 she was confined to a wheelchair. At age 36 a repeat muscle biopsy specimen was obtained. There was no history of alcohol abuse or hypertension.

flood pressure was lOtI/ mm Hg, and heart rate at rest was 100 beats/min. There was no jugular venous distension. The prccordial apical impulse was diffuse and in the midaxil- lary line, a fourth heart sound gallop was audible and there was a grade 316 apical holosystolic murmur that radiated to the axilla. There was no abdominal organomegaly or pedal edema, Neurologic examination disclosed intact mentation and cranial nerves. Muscles were thin throughout with mild shoulder girdle weakness and severe pelvifemoral weakness. Distal arm and leg muscles were relatively spared without evidence of pseudohypertrophy. Deep tendon reflexes were absent except for trace activity at the triceps.

Creatine kinase was 274 IU/hter. The chest roentgenogram showed normal findings. The electrocardiogram (ECG) revealed a wandering atrial pacemaker with repolarization abnormalities in the inferolateral leads (Fig. 1A). Echocardiography disclosed

07351097/94/$7.00

JACC Vol. 24. No. 5 Novemhes 1, 199% 1328-33

lipre IL. Delve-lead e~eetrcpcardb- grams. A, Patient 1. Wandering atrial pacemaker with repolarization ab- normalities in the inferolateral leads. B, Pat&H 2. Left ventricular hyper- trophy by Sokolow-Lyon, Cornell and R wave in lead V, > W wave in lead V, criteria. C, Patient 3. Left ventricular hypertrophy by Sokolow- Lyon criteria.

left verrtricular dilation with diffuse hypokinesia. The left atrium, right atrium and right ventricle were not dilated. There was mild mitral regurgitation by color flow Doppler mapping, with an otherwise normal mitral valve (Fig. 24. By radionuclide ventricu- lography, ejection fraction was 32%. Endomyocardial biopsy revealed mesothelial cells with no myocardial cells.

Patient 2. A40-year old woman who had had a diagnosis of limb-girdle muscular dystrophy since age 15 was evaluated because her two siblings (Patients 1 and 3) had both limb- girdle muscular dystrophy and cardiomyopathy. The least affected of the three sisters, she could walk around her home with assistance but required a wheelchair for ambulation elsewhere. Her 5-year old daughter was well. There was no history of alcohol abuse.

Blood pressure was 130/80 mm Hg and heart rate at rest was 100 beats/min; there was no jugular venous distension. She

had a diffuse cardiac apical impulse, laterally displaced, and a grade 2/6 holosysrolic murmur at the left sternal border and apex. Neurologic examination disclosed moderate pelvifemo- ral muscle weakness.

Creatine kinase was 384 IUliter. An ECG revealed sinus rhythm with left ventricular hypertrophy by several criteria without “strain” T waves (Fig. IS). On echocardiography the left ventricle was diffusely hypokinetic and dilated. Left atrial, right atria1 and right ventricular dimensions were normal. There was mild mitral regurgitation but no evidence of other abnormal valve flows (Fig. 2B), Ejection fraction was 27% by radionuclide ventrirulography.

atient 3. A 43-year old woman, oldest of the three siblings with limb-girdle muscular dystrophy. was evaluated because of decreasing left ventricular function requiring repeated hospital admissions. Proximal muscle weakness began at age 18 years

1330 MASCARENHAS ET AL. CARDIOMYOPATHY OF LIMB-GIRDLE MUSCULAR DYSTROPHY

JACC Vol. 24. No. 5 November 1, 199k1328-33

c~~a~dio~~a~s. A, Patient 1. The di netic, dilated left ventricle is associated with no right atria1 and right ventricular Dimensions. ventricular dilation with large E point septal separation.

and pr adually; at age 36 she was confined to a wheelchair. Her two daughters, aged 6 and 10 years, respec- tively, were both well. There was no history of hypertension or alcohol abu.se. She had obvious muscle weakness and tachycardia at rest (105 beatslmin); blood pressure was 110&O mm Hg. Carotid pulse volumes were diminished. There were minimal jugular venous distension and mild central cyanosis. She had a diffuse precordial impulse with a loud fourth &sound gallop but no murmurs. Results of abdominal examination were ~urem~rkabl~. Neurologic examination dis- closed severe pelvifcmoral and mild shoulder girdle muscle weakness without evidence of pseudohypertrophy.

Creatine kinase was 236 IWiter. An ECG revealed sinus rhythm with left ventricular hypertrophy by several criteria (Fig. 16). A chest roentgenogram showed cardiomegaly. An echocardiogram disclosed a dilated, diffusely hypokinetic left

ventricle (Fig. 2C). On cardiac catheterization, pulmonary capillary wedge pressure was 24 mm Hg, decreasing to 17 mm Hg with intravenous nitroprusside. The pulmonary vascular resistance was 259 dynes-cm-s-’ at rest, decreasing to 46 dynescms-’ after intravenous nitroprusside. Coronary angiography revealed normal coronary arteries. She died 4 years after the onset of her cardiac symptoms while awaiting heart transplantation.

scle biopsy. A muscle biopsy of the left quadrice ed in Patient 1. Light microscopic examinat

paraffin-embedded sections (stained with hematoxylin-eosin) and frozen sections (stained with hemato trichrome, periodic acid-!&M + diastase, 1) variation in the size of the muscle fibers with internalization of the sarcolemmal nuclei (Fig. 3); 2) an increase in endomysial connective tissue; 3) scattered fioers showing loss of cross-

the sarcoplasm, enlargement of sarcolemma! nuclei and prom- inent nucleoli).

ica! reactions on frozen secrions showed no variation in the t~or~~a~ checkerbaIrd pattern of type 1 and 2 fibers (n~coti~am~de~ade~i~ dinucleotide, reduced form, adenosine tripbosp!~tase 9.4, 4.6, 4.3). The acid phos- phatase reaction showed increased enzyme activity within macrophages. Immunofluorescence examination for dystro- phin (antiserum courtesy of Dr. E. M. Kunkel, Children’s

ospita! edicaP Center, oston) showed no difference be- tween the character and distr~b~t~ofl of the ~mmu~o~uores- cence on the surfaces of the muscle fibers and those of normal human adult muscle. Tissue pre d in plastic for l-pm thick to!~~di~e b!~e-stained sections for uhrastructural exami- nation showed a few abnormal fibers characterized by disor- ganization of the myofibr~!!ar architecture with randomly dis- tributed sarcomeres. Dystrophin assay (courtesy of Dr. F. J. Krolikowski, Genica Pharmaceutical corporation, Worcester) showed normal dystrophin levels.

DNA analysis. Merlzoh. Hood was acquired from the surviving affected siblings (Patients 1 and 2) and the unaffected parents through venepuncture, and DNA was extracted from mononuclear cells. Primer sequences for three chromosome 13q microsatellite markers (D13S175, D13S2211, D13S115) were utilized to ascertain genotype and enable linkage analysis.

Results. The two surviving affected members of the family and their parents were studied by linkage analysis. Both affected members inherited the same paternal allele for all three microsatellite markers but different maternal alleles. The small family size precluded any significant results and these results neither confirm nor refute the notion of linkage to chromosome 13q markers (Table 1).

‘Well established cardiac iIlvo!vemeflt in limb-gir lar dystrophy has thus far been confined to dist cardiac rhythm and conduction (2). However, two othrl pa- tients with dilated cardiomyopathy in putative limb-girdle

ystrophy have been described (5, ejection fraction of 50% and the other with d hypokinesia. Because both were male patie changes characteristic of Duchenne muscular dystrophy, they might in fact have had an X-linked muscular dystrsplly, a disorder frequently associated with a form of dilated cardio- myopathy (3,7).

This series. In the siblings described herein (Fig. 4), limb- muscular dystrophy was diagnosed when the sisters were ir teens, as reported in other patients with limb-girdle

muscular dystrophy (8;. One of the sisters who underwent a muscle biopsy bad normal dystrophin levels. In addition to skeletal muscle involvement there was striking cardiomyopathy in al! three, characterized by left ventricular dilation with involvement of both the septum and the free wail and a significantly decreased ejection fraction. The right atrium and ventricle in two of the three sisters were normal; the increased right ventricular and right atria! dimensions in the third sister may have been due to high left-sided pressures. Mild mitral regurgitation in al! three sisters could be explained by their left ventricular dysfunction as there was no evidence of anatomic mitral valve abnorma!ities. A normal coronary arteriogram in the oldest sibling excluded any ischemic disease and there was no evidence to support an infectious or toxic cause. An attempt was made to study cardiac muscle, but the myocardial biopsy of the

right ventricle revealed only mesotheiia! cells. Although biopsy yie!ded no conclusive histologic proof, the other evidence implies that cardiac muscle was involved by the dystrophic process.

1332 MASCARENHAS ET AL. CARDIOMYOPATHY OF LIMB-GIRDLE MUSCULAR DYSTROPHY

JACC Vol. 24, No. 5 ~wcmber I, 1991:1328-33

Recombiiant Fraction 0

Marker 0 o.O5 0.1 0.15 0.2 0.3

D13S175 -LY -0.46 -0.23 -0.12 -0.06 -0.01

DlJS221 -a -0.46 -0.23 -0.12 -0.06 -0.01

D138115 -a -0.46 -0.23 -0.12 -0.06 -0.01

his gp(1ttp

trophy and ~~iomyo~thy su a rare ~ut~~~ recessive

muscular dystrophy that to our knowledge has not The molecule- defect in this variant is be one that involves cardiac muscle to monly seen in most patients with

limb-girdle muscular dystrophy, although the autosomal recessive form of limbgirdle muscular dystrophy and Marfan syndrome have been localized to a small region of chromosome 1Sq (12).

The extended family of these sisters is too small to generate useful linkage analysis. Various chromosomal locations for limb-girdle muscular dystrophy have been hy some have been established for subtypes of the condition. Chromosome 1Sq has been linked to the condition in two large, inbred families (13) and to a~p~xim~tely one third of

er possible chromosomal the location of dystrophin-related protein (16),

of ACIN2, an alpha-actinin gene expressed only in skeletal and cardiac muscle (17). However, unless similar

linkage analysii of this family cannot be all siie.

The differential diagnosis of dilated ~~iorn~~thy is extensive (18) and includes a number of neuromuscular disorders. Well established entities are X- linked muscular dystrophy, Friedreich’s ataxia, amyotrophic chorea with acanthocytosis, familial centronuclear myopathy, Xugelberg-Welander syndrome and nemalme myopathy. In addition, the findings descriid in this report indicate that limb-girdle muscular dystrophy may be yet another cause of dilated cardiomyopathy.

I

ar

th~flki~~ of the cardiac

disease process, no~iuva nificaut abnormali~, ind early. In contrasts the abnormal in mu

We thank Jane Grieshach for the illustrations.

1. Bradley WG. The limb girdle syndromes. Handbook of Clinical Neurology. New York: Elsevier, 19~~:43~69.

2. Walton JN. Clinical aspects of humau muscular dystrophy. In: Boume OH, Golarz MN, editors. Muscular Dystrophy in Man and Animals. Basek Karger, 1963:264-78.

3. Perloff JK, f&Leon AC Jr, CPDohelly D. The cardiomyopathy of progressive muscular dystrophy. Circulation 1966,33:625-48.

4. Welsh JD, Lynn TN Jr, Haase GR. Cardiac findings in 73 patients with muscular dystrophy. Arch Intern Med 1%112:97-103.

5. Kawashima S, Ueno M, Kondo T, Yamamoto 3, fwasaki T. Marked cardiac involvement in limb-girdle dystrophy. Am J Med Sci 1990,2991411-4.

6. Hoshio A, Kotake H, Saito M, et al. Cardiac involvement in a patient with limb-girdle muscular dystrophy. Heart Lung 1987;16:439-41.

7. Bmoke MH. A Clinician’s View of Neuromuscular Diseases. Baltimore: Williams & Wilkins, 1986~78-81.

8. Norman A. Thomas N, Oakley J, Harper P. Distinction of Becker from limb girdle muscular dystrophy by means of dystrophin cDNA probes. Lancet 1989$X6-8.

9. Walton JN, Nattrass FJ. On the classification, natural history and treatment of the myopathies. Brain 1954;77:169-231.

10. Marconi G, Pii 4 Arimondi CG, Vanelli B. Limb girdle muscular

dystrophy with autosomaJ domiflant inheritance. Acta Neural Stand 1991; 83:234-S.

C. Yamaoka LH, Gilchrist J . et al. C~n~rrnat~o~ of genetic h&erogeneity in limb girdle musfdar dystrophy: linkage of an w&ma1 dominant form to chromosome 5a. Am J Hlnm Tenet 1992~50:1%11-7.

12. Donlon T, ~~a~c~~rn S. Reporl on tile genetic ConsFitution o~cbromosome IS. Cytogenet Cell Genet 1991;§83624-42.

e&man JS, Richard I, Hillaire et al. A gene for ~~mb~g~rdie muscular dystrophy maps to chromosome 15 by linkage. C R Acad Sci IPI 1991;312: 141-s.

, Richard 1, Vainzof ht. eF at. Rvideoce of f genetic heterogeneity in the autosomai recessive dub forms of limb-girdle

followhtg linkage analysis wit net t993;30:3&-7.

15. Ben Otbmane $ Ben Tunisian autosomal

Pericak-Vance MA, et al. Linkage of re uchenne-hkc muscular dystrophy to the

pericentromeric region of chromosome 13q. Nat Genet 199232:315-7. 16. Passes-Buenos MR, Terwiihnger J, Ott J, et d. Linkage an&is of families

recessive limb-girdle muscular dystrophy @_OMD) and 6q the dystrop~~i~-aerated sequence. Am J Med Genet 1991;38:

140-6. 17. Beggs AH, Byers TJ, Knoll J et al. Cloning and characterization of two

human skeletal muscle o-actinin’genes located on chromosomes 1 and 11. iol Chem 1992;267:9281-8.

18. Wenger ML, Abe~mann , Roberts WC. Cardiomyopathy and specihc heart muscle disease. fn: st JW, Schlant RC, Rackley CR, Sonoenblick

, Wenger NK, editors. The Heart. 7th ed. New York: McGraw-Hill, 1990:1278-337.