Cardiomyopathy of limb-girdle muscular dystrophy

Ihnb-girdle musculardystrophyis usuallyan ~~~[osorn~~~ rccessivc conditionwith onset in the 2nd decade of life. Wcaknc~ tends to begin in either the pelvic or the shoulder girdle muscleswith subsequent involvementof both arcas. The rate of ~~~~ss~~~varies and after 2 decades from time of onsrt, disabilityis 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-girdlemusctthr 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 subsequentlydzvchqed limb-girdlemusculardystrophy.We report 311three sisters with limb-girdlemuscular dystrophy, all of whomhad ~~~nt~d cardiomyopathybefore 30 years of age.

From aheT&ion of Cardiolqy. St. Vincent Hospital,Worcc,rter.W11\9a:hwlts: tb.qwfments of Medicine. Neurologyand Fediatria,. University -f tiassachusetts Schoolof Medicine. Worcester,Massachusetts; #Dcpartmcm of Gxtrol~, Brwn University.Providence.Rhode Island; $Divisionsof Neurp RrfKl andCad-&o&+, Btigharn andWomen’sHaspital and Departmentsof ‘atim& and Medicine, Harvard Medical School,Boston,Massachusetts. Manwzript =&ed February t&1993; revisedmanuscript receivedMay 23. 5% acceptedJune 3,1994. : Dr. David H. Spodick,Divisionof Cardiology, 2. Vincent Hospital,Worcester,Massachusetts 01604. >l!XM by the AmericanCollege 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~cm ular dyst~o~bywas diag nosed at age 13years because o ogressive~~oxirn~lmuscle weaknessbeginningat age 4 and ahnorma~findingson 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 historyof 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 diffuseand in the midaxillaryline, a fourth heart sound gallopwasaudibleand there was a grade 316apical holosystolicmurmur that radiated to the axilla.There was no abdominalorganomegalyor pedal edema, Neurologicexaminationdisclosedintact mentation and cranial nerves. Muscles were thin throughout with mild shoulder girdle weaknessand severe pelvifemoralweakness.Distal arm and leg muscles were relatively spared without evidence of pseudohypertrophy.Deep tendon reflexeswere absent except for trace activityat the triceps. Creatine kinasewas 274 IU/hter. The chest roentgenogram showednormalfindings.The electrocardiogram(ECG) revealed a wanderingatrial pacemakerwith repolarizationabnormalities in the inferolateralleads (Fig. 1A). Echocardiographydisclosed 07351097/94/$7.00

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lipre IL.Delve-lead e~eetrcpcardbgrams.A, Patient 1.Wandering atrial pacemaker with repolarization abnormalities in the inferolateral leads. B, Pat&H 2. Left ventricular hypertrophy by Sokolow-Lyon, Cornell and R wave in lead V, > Wwave in lead V, criteria. C, Patient 3. Left ventricular hypertrophy by SokolowLyon criteria.

leftverrtriculardilationwithdiffusehypokinesia.The left atrium, rightatrium and right ventriclewere not dilated.There wasmild mitral regurgitationby color flow Doppler mapping,with an otherwisenormalmitralvalve(Fig.24. Byradionuclideventriculography,ejection fraction was 32%. Endomyocardialbiopsy revealedmesothelialcellswith no myocardialcells. Patient 2. A40-year old womanwho had had a diagnosisof limb-girdlemuscular dystrophy since age 15 was evaluated because her two siblings (Patients 1 and 3) had both limbgirdle muscular dystrophy and cardiomyopathy. The least affectedof 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 historyof alcohol abuse. Blood pressure was 130/80 mm Hg and heart rate at rest was 100beats/min;there wasno jugular venousdistension.She

had a diffusecardiac apical impulse,laterallydisplaced,and a grade 2/6 holosysrolicmurmur at the left sternal border and apex. Neurologicexamination disclosedmoderate pelvifemoral muscleweakness. Creatine kinase was 384 IUliter. An ECG revealed sinus rhythm with left ventricular hypertrophy by several criteria without “strain”T waves (Fig. IS). On echocardiographythe left ventriclewas diffuselyhypokineticand dilated. Left atrial, right atria1 and right ventricular dimensions were normal. There was mild mitral regurgitationbut no evidence of other abnormalvalve flows(Fig. 2B), Ejection fraction was 27% by radionuclideventrirulography. atient 3. A 43-yearold woman,oldest of the three siblings with limb-girdlemuscular dystrophy.wasevaluatedbecauseof decreasingleft ventricularfunctionrequiringrepeated hospital admissions.Proximalmuscle weaknessbegan at age 18years

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c~~a~dio~~a~s.A, Patient 1. The di netic, dilated left ventricle is associatedwith no right atria1and right ventricular Dimensions. ventriculardilationwith large E point septal separation.

adually; at age 36 she was confined to a and pr wheelchair.Her two daughters, aged 6 and 10 years, respectively,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&Omm Hg. Carotid pulse volumeswere 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 examinationwere ~urem~rkabl~.Neurologicexaminationdisclosed severe pelvifcmoral and mild shoulder girdle muscle weaknesswithout 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 echocardiogramdisclosed a dilated, diffuselyhypokinetic 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 vascularresistancewas 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 symptomswhile awaiting heart transplantation. scle biopsy.A muscle biopsy of the left quadrice ed in Patient 1. Light microscopic examinat paraffin-embeddedsections (stained with hematoxylin-eosin) and frozen sections(stained with hemato trichrome,periodicacid-!&M + diastase, 1)variationin the sizeof the muscle fiberswith internalization of the sarcolemmalnuclei (Fig. 3); 2) an increasein endomysial connective tissue; 3) scattered fioers showing loss of cross-

the sarcoplasm, enlargement of sarcolemma! nuclei and prominent 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 phosphatase reaction showed increased enzyme activity within macrophages. Immunofluorescence examination for dystrophin (antiserum courtesy of Dr. E. M. Kunkel, Children’s ospita! edicaP Center, oston) showed no difference between the character and distr~b~t~oflof the ~mmu~o~uorescence 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 examination showed a few abnormal fibers characterized by disorganization of the myofibr~!!ararchitecture with randomly distributed 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).

‘Wellestablished cardiac iIlvo!vemeflt in limb-gir lar dystrophy has thus far been confined to dist cardiac rhythm and conduction (2). However, two othrl patients 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 cardiomyopathy (3,7). This series. In the siblings described herein (Fig. 4), limbmuscular 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 conclusivehistologic proof, the other evidence implies that cardiac muscle was involved by the dystrophic process.

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MASCARENHAS ET AL. CARDIOMYOPATHY OF LIMB-GIRDLE

I

Recombiiant Fraction 0 o.O5

0

Marker D13S175

-LY

-0.46

DlJS221 D138115

-a -a

-0.46 -0.46

0.1 -0.23 -0.23 -0.23

0.15

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MUSCULAR DYSTROPHY

0.3

-0.12 -0.12

0.2 -0.06

-0.01

-0.06

-0.01

-0.12

-0.06

-0.01

ar

his gp(1ttp

trophyand ~~iomyo~thy su a rare ~ut~~~ recessive musculardystrophythat to our knowledgehas not The molecule-defect in this variantis be one that involvescardiacmuscleto monly seen in most patients with limb-girdlemusculardystrophy,althoughthe autosomalrecessive form of limbgirdle musculardystrophyand Marfan syndrome havebeen localizedto a smallregionof chromosome1Sq(12). The extendedfamilyof these sistersis too small to generate useful linkage analysis. Various chromosomal locations for limb-girdlemuscular 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

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.

er possiblechromosomal the locationof dystrophin-relatedprotein (16), of ACIN2, an alpha-actiningene expressed onlyin skeletaland cardiacmuscle(17).However,unlesssimilar linkageanalysiiof this familycannotbe all siie. The differentialdiagnosisof dilated ~~iorn~~thy is extensive (18) and includes a number of neuromuscular disorders. Well established entities are Xlinked muscular dystrophy, Friedreich’sataxia, amyotrophic chorea with acanthocytosis,familialcentronuclear myopathy, Xugelberg-Welandersyndrome and nemalme myopathy. In addition, the findings descriid in this report indicate that limb-girdlemuscular dystrophy may be yet another cause of dilated cardiomyopathy.

1. Bradley WG. The limb girdle syndromes. Handbook of Clinical Neurology. New York: Elsevier, 19~~:43~69. 2. Walton JN. Clinical aspectsof 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 HlnmTenet 1992~50:1%11-7. 12. Donlon T, ~~a~c~~rn S. Reporlon tile genetic ConsFitution o~cbromosome IS. Cytogenet Cell Genet 1991;§83624-42. muscular e&man JS, Richard I, Hillaire et al. A gene for ~~mb~g~rdie 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 analysiswit net t993;30:3&-7.

15. Ben Otbmane $ Ben Pericak-Vance MA, et al. Linkage of Tunisian autosomal 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. BeggsAH, 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.