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Cardiac dysfunction with Becker muscular dystrophy
Cardiomyopathy
Cardiac dysfunction with Becker muscular dystrophy Miho Saito, MD, H i s a o m i Kawai, MD, M a s a s h i Akaike, MD, K a t s u h i t o Adachi, MD, Yoshihiko Nishida, MD, a n d Shiro Saito, MD Tokushima, Japan
Cardiac function was examined in 21 patients with Becker muscular dystrophy (BMD) and compared with 43 patients with Duchenne muscular dystrophy (DMD) and 37 healthy control subjects. Electrocardiography showed myocardial damage was most frequently found in the lateral wall, compatible with autopsy findings. The ratio of the preejection period tothe ejection time was higher in patients with BMD (0.37 ± 0.07, mean ± SD) than in patients with DMD (0.28 ± 0,05) and healthy controls (0.23 ± 0.04). Left ventricular dimension and mitral annular size at end diastole in patients with BMD increased to 52.3 ± 7.7 mm and 28.8 ± 5.3 mm with age, respectively. In patients with cardiac failure and BMD, mitral regurgitation was observed at a rate of 66.7%. No definite relation between the deleted locus of the dystrophin gene and cardiac failure was found. Because motor dysfunction progresses more slowly in BMD than in DMD, a prolonged work load on the morbid myocardium may lead to dilated cardiomyopathy with mitral regurgitation. (Am Heart J 1996;132:642-7.)
Becker m u s c u l a r d y s t r o p h y (BMD) a n d D u c h e n n e m u s c u l a r d y s t r o p h y (DMD) are h e r e d i t a r y degenerative m u s c u l a r disorders c a u s e d b y m u t a t i o n s of t h e d y s t r o p h i n gene. 1 The r e l a t i v e l y m i l d m u s c l e w e a k n e s s a n d b e t t e r prognosis in B M D t h a n in D M D a r e e x p l a i n e d b y the " r e a d i n g f r a m e " theory. 2 H o w e v e r , w h y cardiac failure is a m o r e c o m m o n cause of d e a t h in p a t i e n t s w i t h BMD is not known; 3-9 r e s p i r a t o r y failure is t h e m o s t c o m m o n cause of d e a t h of DMD. I n this study, to clarify t h e m e c h a n i s m of cardiac dysfunction in p a t i e n t s w i t h BMD, we c o m p a r e d cardiac function in p a t i e n t s w i t h B M D w i t h t h a t in
From the First Department of Internal Medicine, School of Medicine, The University of Tokushima, and the Department of Internal Medicine, National Sanatorium of Tokushima Hospital. Supported in part by Research Grant for Nervous and Mental Disorders from the Ministry of Health and Welfare, Japan. Received for publication June 26, 1995; accepted Jan. 5, 1996. Reprint requests: Hisaomi Kawai, MD, First Department of Internal Medicine, School of Medicine, The University of Tokushima, 3-8-15 Kuramotocho, Tokushima 770, Japan. Copyright © 1996 bY Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/lf'/3654
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p a t i e n t s w i t h D M D b y electrocardiography, m e c h a n o c a r d i o g r a p h y , a n d echocardiography. METHODS
Twenty-one patients with BMD aged 3 to 63 years (mean 40 years) were studied (Table I). Motor disability of the lower limbs ranged from a score of 1 to 7 according to the grading system proposed by Swinyard et al. 1° The diagnosis of BMD was made on the basis of clinical features, such as muscle weakness and predominant atrophy of the pelvic girdle and proximal muscles of the extremities, hypertrophy of the calves, milder progression than in DMD, and ambulatory defects after 15 years of age, in addition to dystrophic change of skeletal muscles. 11 Furthermore, the patients showed at least two of the following criteria: (1) a deletion in the dystrophin gene analyzed by Southern blotting 12 or the polymerase chain reaction, ~3, 24 (2) patchy staining of dystrophin on muscle cell membranes, determined immunocytochemically, 15 (3) an abnormal dystrophin size, determined by immunoblotting, 16 and (4) a mother demonstrated to be a gene carrier. As controls, 43 patients with DMD aged 4 to 26 years (mean 16.2 years) were also studied. Their grade of motor dysfunction ranged from I to 8, scored by the grading systern previously mentioned, s° The diagnosis of DMD was made on the basis of characteristic clinical features, dystrophic changes of the skeletal muscle, and two of the following criteria: (1) a deletion in the dystrophin gene, (2) negative immunostaining for dystrophin in the muscle, and (3) a definite genetic carrier or a mother with elevated serum creatine kinase activity. As healthy controls, 20 men aged 15 to 60 years (mean 33.3 years) and 17 boys aged 5 to 14 years (mean 9.2 years) were also studied. Cardiac failure was defined by recent clinical symptoms and features, such as palpitation, dyspnea, facial or pretibial edema, gallop rhythm of heart sounds, cardiomegaly, and a butterfly shadow on the chest radiograph. Cardiac involvement was also studied by electrocardiography, mechanocardiography, echocardiography, and, in some cases, by postmortem examination. The electrocardiographic findings were separated into three groups on R-wave or Q-wave pattern as follows: (1) a prominent R wave in lead V1, (2) a decreased R wave or prominent Q wave in leads I, aVL, and V6, and (3) a prominent Q wave
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Table I. Clinical characteristics of patients with BMD
Age Age at Patient (yr) onset 1 2 3 4 5* 6 7 8* 9 10 11 12 13 14 15"
3 13 15 16 25 35 35 36 37 43 43 61 43 62 50
16
17 18" 19 20 21"
Affected persons in family
3 10 10 5 10 22 17 15 23 10 10 14 17 17 10
---Grandfather Uncle Uncle Uncle Brother Brother -Brother -Brother Cousin Brother
51
15
--
51 52 57 59 63
23 12 15 5 30
-Nephew Nephew Cousin --
Grade of Dystrophic disability change Deleted exon Carriers in lower Cardiac in skeletal of dystrophin in family limbs failure muscle gene I III I I II 1V III II II V IV VI VI V II VI
0 0 0 0 0 + 0 + + 0 0 0 0 0 0
+ + + + + + + Fibrosis + + + + + + +
+
IIl
+
+
47-48
+ + + +
II VI VI IV VI
+ + 0 0 +
+ + + + +
10-16 ND 45-48 45,47,48 45,47,48
+ + + +
+
4,8 47-53 ND 45-48 ND 13 ND 45-53 45,48,51 45,47,48,49 45-53 45,47 3,4 45,47 3,4
Dystrophin staining by immunohistochemistry Patchy Patchy Patchy Patchy Patchy
Abnormal dystrophin by Western blotting +
+ + +
Patchy Patchy
-p
Patchy Patchy Patchy Patchy
+
Patchy Patchy Patchy Patchy
+
+
+
+ -p
Patients 5, 7, and 16 were members of the same family. *Died. ND, Not detected; +, present or positive; 0, absent or negative; --, no available information.
in leads II, III, and a V F . 17 The electrocardiographic findings in patients with BMD were compared with those in patients with DMD. Mechanocardiographic and echocardiographic examinations were performed in 18 patients with BMD. The ratio of the preejection period to the ejection time (PEP:ET) was calculated to evaluate left ventricular systolic function as the PEP:ET ratio = (Q = 2 - LVET)/ET (Q = 2 interval from the onset of QRS complex to the aortic second heart sound; LVET, left ventricular ejection time), is and the correlation between the PEP:ET ratios and motor disability grades and between the ratios and ages were examined. The left ventricular end-diastolic dimension (LVDd) and the mitral annular size at end diastole were measured by echocardiography, and correlations of these values with age were also examined. Mitral valve prolapse was diagnosed by the presence of dislocation Ofthe mitral leaflet toward the left atrial side in the area of coaptation on two-dimensional echocardiography. 19 Mitral regurgitation was detected by Doppler color-flow imaging, and its grade was assessed with the grading scale of Miyatake et al. 2° These examinations were also done in patients with DMD and the healthy controls. Patients with BMD were divided into two groups, those with and without cardiac failure, and the frequencies of mitral regurgitation in the two groups were compared. Statistics. Statistical analysis of the data was performed by Student's t test or chi-square test. Normal values for PEP:ET ratio, LVDd, and mitral annular size were ex-
pressed as the range from 10% to 90% in healthy men and healthy boys.
RESULTS Electrocardiographic
findings. I n p a t i e n t s w i t h BMD, a d e c r e a s e d R w a v e or p r o m i n e n t Q w a v e in leads in I, aVL, a n d V6 w e r e m o s t f r e q u e n t l y found (89.5%), followed b y a p r o m i n e n t R w a v e in lead V1 (47.4%) a n d a p r o m i n e n t Q w a v e in leads II, III, a n d a V F (36.8%). I n p a t i e n t s w i t h DMD, a p r o m i n e n t R w a v e in lead V1 w a s m o s t f r e q u e n t l y found (88.3%), followed b y a d e c r e a s e d R w a v e or p r o m i n e n t Q w a v e in leads in I, aVL, a n d VG (73.2%) a n d a p r o m i n e n t Q w a v e in l e a d s II, III, a n d a V F (37.2%) (Fig. 1). PEP:ET ratio. T h e P E P : E T ratio w a s significantly h i g h e r (p < 0.01) in p a t i e n t s w i t h B M D (0.37 _+ 0.07, m e a n _+ SD) t h a n in p a t i e n t s w i t h D M D (0.28 _+ 0.05), h e a l t h y m e n (0.23 +__0.04), a n d h e a l t h y boys (0.23 _+ 0.05) (Fig. 2). N o r m a l v a l u e s r a n g e d f r o m 0.18 to 0.28 in h e a l t h y m e n a n d f r o m 0.17 to 0.29 in h e a l t h y boys. T h e P E P : E T ratio a n d t h e degree of m o t o r disability of t h e lower l i m b s in p a t i e n t s w i t h B M D w e r e not significantly correlated. D e s p i t e mild m o t o r dysfunction of g r a d e s 2 to 4, the P E P : E T ratios in p a t i e n t s w i t h B M D i n c r e a s e d to 0.30 to 0.50, which w e r e m o r e t h a n in p a t i e n t s w i t h D M D w i t h compa-
644
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Fig. 2. PEP:ET ratios. PEP:ET ratio was significantly higher in patients with BMD ( b l a c k s q u a r e s , n = 18) than in patients with DMD ( s t a r s , n = 41), healthy men ( w h i t e s q u a r e s , n = 20), and healthy boys ( w h i t e s q u a r e s , n = 17). **p < 0.01.
rable or more severe motor dysfunction (Fig. 3). The PEP:ET ratio and age in patients with BMD did significantly positively correlate (r = 0.481, p < 0.05), but did not in patients with DMD or healthy controls (Fig. 4, A). LVDd and mitral annular size. LVDd was significantly larger in patients with BMD (52.3 _+ 7.7 ram) than in patients with DMD (42.2 +_ 7.5 mm), healthy men (41.8 +_ 7.3 mm), and healthy boys (40.0 +_ 5.7
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Fig. 3. Relation between PEP:ET ratio and grade of motor dysfunction in lower limbs: PEP:ET ratios were higher in patients with BMD than in patients with DMD. S q u a r e s , BMD; s t a r s , D M D ; p o u n d s i g n , patient with BMD and cardiac failure.
mm) (p < 0.01). Normal ranges were from 32.5 to 51.5 mm in healthy men and from 32.7 to 47.3 mm in healthy boys. The mitral annular size was significantly larger in patients with BMD (28.8 _+ 5.3 ram) than in patients with DMD (21.4 +_ 5.3 ram), healthy men (22.7 _ 2.9 ram), and healthy boys (18.3 +_ 3.8 ram) (p < 0.01). Normal values ranged from 19.0 to 26.4 mm in healthy men and from 13.4 to 23.2 mm in healthy boys. Left ventricular end-diastolic dimension and age (r = 0.524, p < 0.05) significantly positively correlated (Fig. 4, B), as did mitral annular size and age (r = 0.512,p < 0.05) in patients with BMD (Fig. 4, C) but not in the control groups. Mitral regurgitation in patients with BMD. The frequencY of mitral regurgitation was significantly higher (p < 0.05) in patients with BMD (5 of 18; 27.8%) t h a n in patients with DMD (4 of 43; 9.3%). Furthermore, mitral regurgitation was significantly higher in patients with BMD and cardiac failure (4 of 6; 66.7%) t h a n in those without cardiac failure (1 of 12; 8.3%). The severity of mitral regurgitation was grade 4 in I patient, grade 3 in 2 patients, and grade I in the other 2 patients; in patients with DMD severity was grade 3 in I patient, grade 2 in 2 patients, and grade 1 in 1 patient. The average left ventricular end-diastolic dimension and mitral annular size in patients with BMD and mitral regurgitation were increased to 59.4 mm and 34.6 mm, respectively. The mitral regurgitation jet was perpendicularly directed to the leaflet in two patients with BMD and posteriorly in the other three patients with mitral valve prolapse. In four patients with DMD and mitral re-
Volume 132, Number 3 American Heart Journal
gurgitation, the mean mitral annular size was slightly increased to 29.9 mm, and only one had remarkable annular dilatation; the mitral regurgitation jet was posteriorly directed because of mitral valve prolapse in all. Pathologic findings in autopsied BMD hearts. Patients 16 and 13 were autopsied. Patient 16 died from respiratory and cardiac failure. The heart weighed 330 gm, and the atria and ventricles were markedly dilated bilaterally. Patient 13 died from respiratory failure. His heart weighed 260 gm but was not dilated. In patient 16, microscopic examination revealed extensive areas of fatty replacement and fibrosis in the subepicardial muscle and middle zones of the myocardium, particularly in the left ventricular lateral wall. In patient 13, marked fibrosis was relatively localized to the posterior and lateral myocardium.
0.6-
DISCUSSION
Dysfunctional dystrophin is present in the myocardium and skeletal muscles in patients with BMD. 21 Therefore one might expect milder myocardial damage in patients with BMD t h a n in patients with DMD, who lack dystrophin in the skeletal and cardiac muscle. However, cardiac dysfunction is a more frequent cause of death in patients with BMD t h a n in patients with DMD. 39 The mechanism of cardiac dysfunction in patients with BMD is still unknown. Before the discovery of dystrophin and its gene, definite diagnosis of DMD and BMD was difficult because of their clinical similarlity to limb-girdle muscular dystrophy or female gene carrier of the Duchenne type. In our study, all the patients were diagnosed on the basis of dystrophin or dystrophin gene abnormalities in addition to clinical findings. Only one previous report exists on cardiac function in a large number of patients with BMD definitely diagnosed by immunohistochemical, immunoblotting, and gene analysis of dystrophin. 9 We found t h a t a prominent R wave in lead V1, suggesting the posterior wall damage, was most frequently present on electrocardiographic findings in
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from exons 45 to 53 was found in 4 of the patients with BMD, from exons 10 to 16 in 1 patient, and in exon 13 in 1. Among the patients without cardiac failure, deletion of exons 45 to 53 was found in 8 patients, of exons 3 and 4 in 2 patients, and of exons 4 to 8 in I patient (Table I). Thus deletions in the "hot spot" of the dystrophin gene were observed in 66.7% (4 of 6) of the patients with BMD and cardiac failure and in 72.7% (8 of 11) of those without cardiac failure.
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Fig. 4. Relation of age with PEP:ET ratio, (A), LVDd (B), and mitral annual size (C): PEP:ET Ratio and age significantly positively correlated in patients with BMD (r = 0.481, p < 0.05). LVDd was significantly larger in patients with BMD than in control subjects and became larger with age (r = 0.524, p < 0.05). Mitral annular size and age significantlypositively correlated in patients with BMD (r = 0.512, p < 0.01). Control groups showed no such correlations. Black squares, BMD; stars, DMD; white squares, normal controls; pound signs, patient with BMD and cardiac failure. Regression lines show the relationship for patients with BMD. Vertical bars on right sides of each figure show normal ranges in healthy boys (a) and healthy adult men (b).
patients with DMD, as reported by another study. 17 Cziner and Levin22 proposed t h a t dystrophin was required to physically reinforce the sarcolemma against axial stress, and t h a t forces directed along the major axis of the left ventricle were greater to the posterior wall t h a n to other parts of the myocardium, where the fibers are directed longitudinally. Therefore they considered t h a t initial myocardial involvement in patients with DMD occurs in the posterior
646
September 1996 American Heart Journal
Saito et al.
wall. In contrast, in patients with BMD, a decreased R wave or prominent Q wave in leads I, aVL, and V6, . suggesting the lateral wall damage, was most frequent, followed by a prominent R wave in lead V1. In :an autopsied case after death caused by cardiorespiratory failure, myocardial damage was marked in the lateral wall, corresponding to electrocardiographic findings before death. These results indicate that myocardial damage does not progress in the same way in patients with BMD as in patients with DMD. In patients with BMD, the PEP:ET ratio was increased at low grades of motor dysfunction and was significantly higher than that in patients with DMD with similar motor dysfunction. This finding indicates that cardiac dysfunction in patients with BMD progresses from an early stage of disability. The PEP:ET ratio, the left ventricular dimension, and mitral annular size increased with age, suggesting that a persistent work load on the impaired myocardium over a long period may result in systolic dysfunction, dilatation of the left ventricle, and subsequent cardiac failure. Mitral regurgitation was frequently observed in patients with BMD and cardiac failure, suggesting that regurgitation could progress to cardiac failure. The regurgitation jet was perpendicularly directed to the leaflet or posteriorly. Therefore the main cause of mitral regurgitation in patients with BMD is considered to be insufficiency of mitral valve coaptation because of annular enlargement and malalignment of the mitral complex resulting from ventricular dilatation. Howev~er, mitral regurgitation in DMD could be explained by mitral valve prolapse because of myocardial asynergy and insufficiency of posterior papillary muscle. In fact, only one of our DMD patients with mitral regurgitation had marked a n n u l a r dilatation. Recently, Muntoni et al. 23 reported X-linked dilated cardiomyopathy with a dystrophin gene deletion. They proposed that the brain promotor of the dystrophin gene induced high levels of transcription in skeletal muscle but not in the heart, so patients lacking this promotor gene manifested cardiomyopathy despite the absence of muscle weakness. Yoshida et al. 24 speculated that a deletion around exon 1 of the dystrophin gene may severely and selectively affect the expression and the function of cardiac dystrophin. Cardiac dysfunction was also reported in clinically typical patients with BMD with deletion of the dystrophin gene involving exons 48, 25 45 through 53, 26 47, 24 and 48 and 49, 9 suggesting relations between these regions of the gene and expression or function of myocardial dystrophin. However, in this study, we could not confirm the relation
between the deleted locus of the dystrophin gene and cardiac dysfunction. In this study we found that patients with BMD frequently showed dilated cardiomyopathy and mitral regurgitation from annular dilatation and mitral valve prolapse. The high frequency of cardiac failure in patients with BMD is probably caused by longterm work load on the impaired myocardium because motor dysfunction progresses more slowly in p a tients with BMD than in patients with DMD. Therefore patients with BMD without cardiac failure will probably have cardiac failure at a later age. Careful observation of the cardiac state and timely treatment of cardiac dysfunction are needed for patients with BMD, regardless of whether they have cardiac failure at first examination. We t h a n k Professor K. Hizawa, F i r s t D e p a r t m e n t of Pathology, School of Medicine, T h e U n i v e r s i t y of T o k u s h i m a , for pathologic e x a m i n a t i o n of a u t o p s i e d B M D cases.
REFERENCES
1. Kunkel LM, Hejtm ancik JF, Caskey CTh. Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature 1986;322:73-7. 2. Monaco AP, Bertelson CJ, Liechti-Gallati SI Moser H, Kunkel LM. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 1988;2:90-5. 3. Vrints C, Mercelis R, Vanagt E, Snoeck J, Martin JJ. Manifestations of Becket-type muscular dystrophy. Acta Cardiologica 1983;38:479-86. 4. Yazawa M, Ikeda S, Owa M, Haruta S, Yanagisawa N, Tanaka E, et al. A family of Becker's progressive muscular dystrophy with severe cardiomyopathy. Eur Neurol 1987;27:13-9. 5. Yoshida t~ Takeda S, Haruta S, Shoji S, Ko~zumi H. Two brothers of probable Becker's type muscular dystrophy presenting exertional myalgia and myocardial involvement. Neuro Med 1988;29:599-606. 6. Lazzeroai E, Favaro L, Botti G. Dilated cardiomyopathy with regional myocardial hypoperfusion in Becker's muscular dystrophy. Int J Cardiol 1989;22:126-9. 7. Casazza F, Brambilla G, Salvato A, Morandi L, Gronda E, Bonacina Z. Cardiac transplantation in Becker muscular dystrophy. J Neuro11988; 235:496~8. 8. Donofrio PD, Challa VR, Hackshaw BT, Millis SA, Cordell R. Cardiac transplantation in a patient with muscular dystrophy and cardiomyopathy. Arch Neurol 1989;46:705-7. 9. Melacini T, Fanin M, Danieli GA, Fasoli G, Villanova C, Angelini C, et al. Cardiac involvement in Becker muscular dystrophy. J Am Coll Cardiol 1993;22:1927-34. 10. Swinyard C, Deaver G, Greenspan L. Gradients of functional ability of importance in rehabilitation of patients with progressive muscular and neuromuscular diseases. Arch Phys Med 1957;38:574-9. 11. Miyoshi K, Kawai H, Iwasa M, Kusaka K, Nishino H. Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy: seventeen cases in eight families including an autopsied case. Brain 1986;109:31-54. 12. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 1987;50:509-17. 13. Chamberlain JS, Gibbs RA, Ranier JE, Nguyen PN, Caskey CT. Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification. Nucleic Acids Res 1988;16:11141-56. '14. Beggs AH, Koenig M, Boyce FM, Kunkel LM. Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction. Hum Genet 1990;86:45-8.
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15. Arahata K, Ishiura S, Ishiguro T, Tsukahara T, Suhara Y, Eguchi C, et al. Immunostaining of skeletal and cardiac muscle surface merebrahe with antibody against Duchenne muscular dystrophy peptide. Nature 1988;333:861-3. 16. Hoffman EP, Fischbeck KH, Brown RH, Johnson M, Medori R, Loike JD, et al. Characterization of dystrophin in muscle-biopsy specimens from patients With Duchenne's or Becker's muscular dystrophy. N Engl J Med 1988;318:1363-8. 17. Perloff JK, Roberts WC, Leon AC, O'Doherty D. The distinctive electrocardiogram of Duchenne's progressive muscular dystrophy: An electrocardiographic-pathologic correlative study. Am J Med 1967; 42:179-88. 18. Lewis RP, Rittgers SE, Forester WF, Boudoulas H. A critical review of the systolic time intervals. Circulation 1977;56:146-58. 19. Nagata S, Nimura Y, Sakakibara H, Beppu S, Park YD, Kawazoe K, et al. Mitral valve lesion associated with secundum atrial septal defect. Analysis by real time two dimensional echocardiography. Br Heart J 1983;49:51-8. 20. Miyatake K, Izumi S, Okamoto M, Kinoshita N, Asonuma H, Nakagawa H, et al. Semiquantitative grading of severity of mitral regurgitation by real time two-dimensional doppler flow imaging technique. J Am Coll Cardiol 1986;7:82-8.
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21. Anan R, Higuchi I, Ichinari K, Kubota K, Kisanuki A, Arima S, et al. Myocardial patchy staining of dystrophinin Becker's muscular dystrophy associated with cardiomyopathy. Am Heart J 1992;123:1088-9. 22. Cziner DG, Levin RI. The cardiomyopathy of Duchenne's muscular dystrophy and the function ofdystrophin. Med Hypotheses 1993;40:16973. 23. Muntoni F, Cau M, Ganau A, Congiu R, Arvedi G, Mateddu A, et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Eng J Med 1993; 329:921-5. 24. Yoshida K, Ikeda S, Nakamura A, Kagoshima M, Takeda S, Shoji S, et al. Molecular analysis of the Duchenne muscular dystrophy gene in patients with Becker muscular dystrophy presenting with dilated cardiomyopathy. Muscle Nerve 1993;16:1161-6. 2 5 . Gold R, Kress W, Meurers B, Meng G, Reichmann H, M~ller CR. Brief communication: Becket muscular dystrophy: detection of unusual disease courses by combined approach to dystrophin analysis. Muscle Nerve 1992;15:214-8. 26. Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, et al. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 1991;49:54-67.
Cardiac dysfunction with Becker muscular dystrophy Miho Saito, MD, H i s a o m i Kawai, MD, M a s a s h i Akaike, MD, K a t s u h i t o Adachi, MD, Yoshihiko Nishida, MD, a n d Shiro Saito, MD Tokushima, Japan
Cardiac function was examined in 21 patients with Becker muscular dystrophy (BMD) and compared with 43 patients with Duchenne muscular dystrophy (DMD) and 37 healthy control subjects. Electrocardiography showed myocardial damage was most frequently found in the lateral wall, compatible with autopsy findings. The ratio of the preejection period tothe ejection time was higher in patients with BMD (0.37 ± 0.07, mean ± SD) than in patients with DMD (0.28 ± 0,05) and healthy controls (0.23 ± 0.04). Left ventricular dimension and mitral annular size at end diastole in patients with BMD increased to 52.3 ± 7.7 mm and 28.8 ± 5.3 mm with age, respectively. In patients with cardiac failure and BMD, mitral regurgitation was observed at a rate of 66.7%. No definite relation between the deleted locus of the dystrophin gene and cardiac failure was found. Because motor dysfunction progresses more slowly in BMD than in DMD, a prolonged work load on the morbid myocardium may lead to dilated cardiomyopathy with mitral regurgitation. (Am Heart J 1996;132:642-7.)
Becker m u s c u l a r d y s t r o p h y (BMD) a n d D u c h e n n e m u s c u l a r d y s t r o p h y (DMD) are h e r e d i t a r y degenerative m u s c u l a r disorders c a u s e d b y m u t a t i o n s of t h e d y s t r o p h i n gene. 1 The r e l a t i v e l y m i l d m u s c l e w e a k n e s s a n d b e t t e r prognosis in B M D t h a n in D M D a r e e x p l a i n e d b y the " r e a d i n g f r a m e " theory. 2 H o w e v e r , w h y cardiac failure is a m o r e c o m m o n cause of d e a t h in p a t i e n t s w i t h BMD is not known; 3-9 r e s p i r a t o r y failure is t h e m o s t c o m m o n cause of d e a t h of DMD. I n this study, to clarify t h e m e c h a n i s m of cardiac dysfunction in p a t i e n t s w i t h BMD, we c o m p a r e d cardiac function in p a t i e n t s w i t h B M D w i t h t h a t in
From the First Department of Internal Medicine, School of Medicine, The University of Tokushima, and the Department of Internal Medicine, National Sanatorium of Tokushima Hospital. Supported in part by Research Grant for Nervous and Mental Disorders from the Ministry of Health and Welfare, Japan. Received for publication June 26, 1995; accepted Jan. 5, 1996. Reprint requests: Hisaomi Kawai, MD, First Department of Internal Medicine, School of Medicine, The University of Tokushima, 3-8-15 Kuramotocho, Tokushima 770, Japan. Copyright © 1996 bY Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/lf'/3654
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p a t i e n t s w i t h D M D b y electrocardiography, m e c h a n o c a r d i o g r a p h y , a n d echocardiography. METHODS
Twenty-one patients with BMD aged 3 to 63 years (mean 40 years) were studied (Table I). Motor disability of the lower limbs ranged from a score of 1 to 7 according to the grading system proposed by Swinyard et al. 1° The diagnosis of BMD was made on the basis of clinical features, such as muscle weakness and predominant atrophy of the pelvic girdle and proximal muscles of the extremities, hypertrophy of the calves, milder progression than in DMD, and ambulatory defects after 15 years of age, in addition to dystrophic change of skeletal muscles. 11 Furthermore, the patients showed at least two of the following criteria: (1) a deletion in the dystrophin gene analyzed by Southern blotting 12 or the polymerase chain reaction, ~3, 24 (2) patchy staining of dystrophin on muscle cell membranes, determined immunocytochemically, 15 (3) an abnormal dystrophin size, determined by immunoblotting, 16 and (4) a mother demonstrated to be a gene carrier. As controls, 43 patients with DMD aged 4 to 26 years (mean 16.2 years) were also studied. Their grade of motor dysfunction ranged from I to 8, scored by the grading systern previously mentioned, s° The diagnosis of DMD was made on the basis of characteristic clinical features, dystrophic changes of the skeletal muscle, and two of the following criteria: (1) a deletion in the dystrophin gene, (2) negative immunostaining for dystrophin in the muscle, and (3) a definite genetic carrier or a mother with elevated serum creatine kinase activity. As healthy controls, 20 men aged 15 to 60 years (mean 33.3 years) and 17 boys aged 5 to 14 years (mean 9.2 years) were also studied. Cardiac failure was defined by recent clinical symptoms and features, such as palpitation, dyspnea, facial or pretibial edema, gallop rhythm of heart sounds, cardiomegaly, and a butterfly shadow on the chest radiograph. Cardiac involvement was also studied by electrocardiography, mechanocardiography, echocardiography, and, in some cases, by postmortem examination. The electrocardiographic findings were separated into three groups on R-wave or Q-wave pattern as follows: (1) a prominent R wave in lead V1, (2) a decreased R wave or prominent Q wave in leads I, aVL, and V6, and (3) a prominent Q wave
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Table I. Clinical characteristics of patients with BMD
Age Age at Patient (yr) onset 1 2 3 4 5* 6 7 8* 9 10 11 12 13 14 15"
3 13 15 16 25 35 35 36 37 43 43 61 43 62 50
16
17 18" 19 20 21"
Affected persons in family
3 10 10 5 10 22 17 15 23 10 10 14 17 17 10
---Grandfather Uncle Uncle Uncle Brother Brother -Brother -Brother Cousin Brother
51
15
--
51 52 57 59 63
23 12 15 5 30
-Nephew Nephew Cousin --
Grade of Dystrophic disability change Deleted exon Carriers in lower Cardiac in skeletal of dystrophin in family limbs failure muscle gene I III I I II 1V III II II V IV VI VI V II VI
0 0 0 0 0 + 0 + + 0 0 0 0 0 0
+ + + + + + + Fibrosis + + + + + + +
+
IIl
+
+
47-48
+ + + +
II VI VI IV VI
+ + 0 0 +
+ + + + +
10-16 ND 45-48 45,47,48 45,47,48
+ + + +
+
4,8 47-53 ND 45-48 ND 13 ND 45-53 45,48,51 45,47,48,49 45-53 45,47 3,4 45,47 3,4
Dystrophin staining by immunohistochemistry Patchy Patchy Patchy Patchy Patchy
Abnormal dystrophin by Western blotting +
+ + +
Patchy Patchy
-p
Patchy Patchy Patchy Patchy
+
Patchy Patchy Patchy Patchy
+
+
+
+ -p
Patients 5, 7, and 16 were members of the same family. *Died. ND, Not detected; +, present or positive; 0, absent or negative; --, no available information.
in leads II, III, and a V F . 17 The electrocardiographic findings in patients with BMD were compared with those in patients with DMD. Mechanocardiographic and echocardiographic examinations were performed in 18 patients with BMD. The ratio of the preejection period to the ejection time (PEP:ET) was calculated to evaluate left ventricular systolic function as the PEP:ET ratio = (Q = 2 - LVET)/ET (Q = 2 interval from the onset of QRS complex to the aortic second heart sound; LVET, left ventricular ejection time), is and the correlation between the PEP:ET ratios and motor disability grades and between the ratios and ages were examined. The left ventricular end-diastolic dimension (LVDd) and the mitral annular size at end diastole were measured by echocardiography, and correlations of these values with age were also examined. Mitral valve prolapse was diagnosed by the presence of dislocation Ofthe mitral leaflet toward the left atrial side in the area of coaptation on two-dimensional echocardiography. 19 Mitral regurgitation was detected by Doppler color-flow imaging, and its grade was assessed with the grading scale of Miyatake et al. 2° These examinations were also done in patients with DMD and the healthy controls. Patients with BMD were divided into two groups, those with and without cardiac failure, and the frequencies of mitral regurgitation in the two groups were compared. Statistics. Statistical analysis of the data was performed by Student's t test or chi-square test. Normal values for PEP:ET ratio, LVDd, and mitral annular size were ex-
pressed as the range from 10% to 90% in healthy men and healthy boys.
RESULTS Electrocardiographic
findings. I n p a t i e n t s w i t h BMD, a d e c r e a s e d R w a v e or p r o m i n e n t Q w a v e in leads in I, aVL, a n d V6 w e r e m o s t f r e q u e n t l y found (89.5%), followed b y a p r o m i n e n t R w a v e in lead V1 (47.4%) a n d a p r o m i n e n t Q w a v e in leads II, III, a n d a V F (36.8%). I n p a t i e n t s w i t h DMD, a p r o m i n e n t R w a v e in lead V1 w a s m o s t f r e q u e n t l y found (88.3%), followed b y a d e c r e a s e d R w a v e or p r o m i n e n t Q w a v e in leads in I, aVL, a n d VG (73.2%) a n d a p r o m i n e n t Q w a v e in l e a d s II, III, a n d a V F (37.2%) (Fig. 1). PEP:ET ratio. T h e P E P : E T ratio w a s significantly h i g h e r (p < 0.01) in p a t i e n t s w i t h B M D (0.37 _+ 0.07, m e a n _+ SD) t h a n in p a t i e n t s w i t h D M D (0.28 _+ 0.05), h e a l t h y m e n (0.23 +__0.04), a n d h e a l t h y boys (0.23 _+ 0.05) (Fig. 2). N o r m a l v a l u e s r a n g e d f r o m 0.18 to 0.28 in h e a l t h y m e n a n d f r o m 0.17 to 0.29 in h e a l t h y boys. T h e P E P : E T ratio a n d t h e degree of m o t o r disability of t h e lower l i m b s in p a t i e n t s w i t h B M D w e r e not significantly correlated. D e s p i t e mild m o t o r dysfunction of g r a d e s 2 to 4, the P E P : E T ratios in p a t i e n t s w i t h B M D i n c r e a s e d to 0.30 to 0.50, which w e r e m o r e t h a n in p a t i e n t s w i t h D M D w i t h compa-
644
September i996 American Heart Journal
Saito et al.
100"
n=17
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20"
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n=7
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Fig. 1. Electrocardiographic findings. A, Decreased R wave or prominent Q wave in leads I, aVL, and V6; B, prominent R wave in lead V]; C, prominent Q wave in leads II, III, and aVF. Decreased R wave or prominent Q wave in leads I, aVL, and Vs were most frequent in patients with BMD.
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Fig. 2. PEP:ET ratios. PEP:ET ratio was significantly higher in patients with BMD ( b l a c k s q u a r e s , n = 18) than in patients with DMD ( s t a r s , n = 41), healthy men ( w h i t e s q u a r e s , n = 20), and healthy boys ( w h i t e s q u a r e s , n = 17). **p < 0.01.
rable or more severe motor dysfunction (Fig. 3). The PEP:ET ratio and age in patients with BMD did significantly positively correlate (r = 0.481, p < 0.05), but did not in patients with DMD or healthy controls (Fig. 4, A). LVDd and mitral annular size. LVDd was significantly larger in patients with BMD (52.3 _+ 7.7 ram) than in patients with DMD (42.2 +_ 7.5 mm), healthy men (41.8 +_ 7.3 mm), and healthy boys (40.0 +_ 5.7
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Fig. 3. Relation between PEP:ET ratio and grade of motor dysfunction in lower limbs: PEP:ET ratios were higher in patients with BMD than in patients with DMD. S q u a r e s , BMD; s t a r s , D M D ; p o u n d s i g n , patient with BMD and cardiac failure.
mm) (p < 0.01). Normal ranges were from 32.5 to 51.5 mm in healthy men and from 32.7 to 47.3 mm in healthy boys. The mitral annular size was significantly larger in patients with BMD (28.8 _+ 5.3 ram) than in patients with DMD (21.4 +_ 5.3 ram), healthy men (22.7 _ 2.9 ram), and healthy boys (18.3 +_ 3.8 ram) (p < 0.01). Normal values ranged from 19.0 to 26.4 mm in healthy men and from 13.4 to 23.2 mm in healthy boys. Left ventricular end-diastolic dimension and age (r = 0.524, p < 0.05) significantly positively correlated (Fig. 4, B), as did mitral annular size and age (r = 0.512,p < 0.05) in patients with BMD (Fig. 4, C) but not in the control groups. Mitral regurgitation in patients with BMD. The frequencY of mitral regurgitation was significantly higher (p < 0.05) in patients with BMD (5 of 18; 27.8%) t h a n in patients with DMD (4 of 43; 9.3%). Furthermore, mitral regurgitation was significantly higher in patients with BMD and cardiac failure (4 of 6; 66.7%) t h a n in those without cardiac failure (1 of 12; 8.3%). The severity of mitral regurgitation was grade 4 in I patient, grade 3 in 2 patients, and grade I in the other 2 patients; in patients with DMD severity was grade 3 in I patient, grade 2 in 2 patients, and grade 1 in 1 patient. The average left ventricular end-diastolic dimension and mitral annular size in patients with BMD and mitral regurgitation were increased to 59.4 mm and 34.6 mm, respectively. The mitral regurgitation jet was perpendicularly directed to the leaflet in two patients with BMD and posteriorly in the other three patients with mitral valve prolapse. In four patients with DMD and mitral re-
Volume 132, Number 3 American Heart Journal
gurgitation, the mean mitral annular size was slightly increased to 29.9 mm, and only one had remarkable annular dilatation; the mitral regurgitation jet was posteriorly directed because of mitral valve prolapse in all. Pathologic findings in autopsied BMD hearts. Patients 16 and 13 were autopsied. Patient 16 died from respiratory and cardiac failure. The heart weighed 330 gm, and the atria and ventricles were markedly dilated bilaterally. Patient 13 died from respiratory failure. His heart weighed 260 gm but was not dilated. In patient 16, microscopic examination revealed extensive areas of fatty replacement and fibrosis in the subepicardial muscle and middle zones of the myocardium, particularly in the left ventricular lateral wall. In patient 13, marked fibrosis was relatively localized to the posterior and lateral myocardium.
0.6-
DISCUSSION
Dysfunctional dystrophin is present in the myocardium and skeletal muscles in patients with BMD. 21 Therefore one might expect milder myocardial damage in patients with BMD t h a n in patients with DMD, who lack dystrophin in the skeletal and cardiac muscle. However, cardiac dysfunction is a more frequent cause of death in patients with BMD t h a n in patients with DMD. 39 The mechanism of cardiac dysfunction in patients with BMD is still unknown. Before the discovery of dystrophin and its gene, definite diagnosis of DMD and BMD was difficult because of their clinical similarlity to limb-girdle muscular dystrophy or female gene carrier of the Duchenne type. In our study, all the patients were diagnosed on the basis of dystrophin or dystrophin gene abnormalities in addition to clinical findings. Only one previous report exists on cardiac function in a large number of patients with BMD definitely diagnosed by immunohistochemical, immunoblotting, and gene analysis of dystrophin. 9 We found t h a t a prominent R wave in lead V1, suggesting the posterior wall damage, was most frequently present on electrocardiographic findings in
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from exons 45 to 53 was found in 4 of the patients with BMD, from exons 10 to 16 in 1 patient, and in exon 13 in 1. Among the patients without cardiac failure, deletion of exons 45 to 53 was found in 8 patients, of exons 3 and 4 in 2 patients, and of exons 4 to 8 in I patient (Table I). Thus deletions in the "hot spot" of the dystrophin gene were observed in 66.7% (4 of 6) of the patients with BMD and cardiac failure and in 72.7% (8 of 11) of those without cardiac failure.
645
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Fig. 4. Relation of age with PEP:ET ratio, (A), LVDd (B), and mitral annual size (C): PEP:ET Ratio and age significantly positively correlated in patients with BMD (r = 0.481, p < 0.05). LVDd was significantly larger in patients with BMD than in control subjects and became larger with age (r = 0.524, p < 0.05). Mitral annular size and age significantlypositively correlated in patients with BMD (r = 0.512, p < 0.01). Control groups showed no such correlations. Black squares, BMD; stars, DMD; white squares, normal controls; pound signs, patient with BMD and cardiac failure. Regression lines show the relationship for patients with BMD. Vertical bars on right sides of each figure show normal ranges in healthy boys (a) and healthy adult men (b).
patients with DMD, as reported by another study. 17 Cziner and Levin22 proposed t h a t dystrophin was required to physically reinforce the sarcolemma against axial stress, and t h a t forces directed along the major axis of the left ventricle were greater to the posterior wall t h a n to other parts of the myocardium, where the fibers are directed longitudinally. Therefore they considered t h a t initial myocardial involvement in patients with DMD occurs in the posterior
646
September 1996 American Heart Journal
Saito et al.
wall. In contrast, in patients with BMD, a decreased R wave or prominent Q wave in leads I, aVL, and V6, . suggesting the lateral wall damage, was most frequent, followed by a prominent R wave in lead V1. In :an autopsied case after death caused by cardiorespiratory failure, myocardial damage was marked in the lateral wall, corresponding to electrocardiographic findings before death. These results indicate that myocardial damage does not progress in the same way in patients with BMD as in patients with DMD. In patients with BMD, the PEP:ET ratio was increased at low grades of motor dysfunction and was significantly higher than that in patients with DMD with similar motor dysfunction. This finding indicates that cardiac dysfunction in patients with BMD progresses from an early stage of disability. The PEP:ET ratio, the left ventricular dimension, and mitral annular size increased with age, suggesting that a persistent work load on the impaired myocardium over a long period may result in systolic dysfunction, dilatation of the left ventricle, and subsequent cardiac failure. Mitral regurgitation was frequently observed in patients with BMD and cardiac failure, suggesting that regurgitation could progress to cardiac failure. The regurgitation jet was perpendicularly directed to the leaflet or posteriorly. Therefore the main cause of mitral regurgitation in patients with BMD is considered to be insufficiency of mitral valve coaptation because of annular enlargement and malalignment of the mitral complex resulting from ventricular dilatation. Howev~er, mitral regurgitation in DMD could be explained by mitral valve prolapse because of myocardial asynergy and insufficiency of posterior papillary muscle. In fact, only one of our DMD patients with mitral regurgitation had marked a n n u l a r dilatation. Recently, Muntoni et al. 23 reported X-linked dilated cardiomyopathy with a dystrophin gene deletion. They proposed that the brain promotor of the dystrophin gene induced high levels of transcription in skeletal muscle but not in the heart, so patients lacking this promotor gene manifested cardiomyopathy despite the absence of muscle weakness. Yoshida et al. 24 speculated that a deletion around exon 1 of the dystrophin gene may severely and selectively affect the expression and the function of cardiac dystrophin. Cardiac dysfunction was also reported in clinically typical patients with BMD with deletion of the dystrophin gene involving exons 48, 25 45 through 53, 26 47, 24 and 48 and 49, 9 suggesting relations between these regions of the gene and expression or function of myocardial dystrophin. However, in this study, we could not confirm the relation
between the deleted locus of the dystrophin gene and cardiac dysfunction. In this study we found that patients with BMD frequently showed dilated cardiomyopathy and mitral regurgitation from annular dilatation and mitral valve prolapse. The high frequency of cardiac failure in patients with BMD is probably caused by longterm work load on the impaired myocardium because motor dysfunction progresses more slowly in p a tients with BMD than in patients with DMD. Therefore patients with BMD without cardiac failure will probably have cardiac failure at a later age. Careful observation of the cardiac state and timely treatment of cardiac dysfunction are needed for patients with BMD, regardless of whether they have cardiac failure at first examination. We t h a n k Professor K. Hizawa, F i r s t D e p a r t m e n t of Pathology, School of Medicine, T h e U n i v e r s i t y of T o k u s h i m a , for pathologic e x a m i n a t i o n of a u t o p s i e d B M D cases.
REFERENCES
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Volume 132, Number 3 American Heart Journal
15. Arahata K, Ishiura S, Ishiguro T, Tsukahara T, Suhara Y, Eguchi C, et al. Immunostaining of skeletal and cardiac muscle surface merebrahe with antibody against Duchenne muscular dystrophy peptide. Nature 1988;333:861-3. 16. Hoffman EP, Fischbeck KH, Brown RH, Johnson M, Medori R, Loike JD, et al. Characterization of dystrophin in muscle-biopsy specimens from patients With Duchenne's or Becker's muscular dystrophy. N Engl J Med 1988;318:1363-8. 17. Perloff JK, Roberts WC, Leon AC, O'Doherty D. The distinctive electrocardiogram of Duchenne's progressive muscular dystrophy: An electrocardiographic-pathologic correlative study. Am J Med 1967; 42:179-88. 18. Lewis RP, Rittgers SE, Forester WF, Boudoulas H. A critical review of the systolic time intervals. Circulation 1977;56:146-58. 19. Nagata S, Nimura Y, Sakakibara H, Beppu S, Park YD, Kawazoe K, et al. Mitral valve lesion associated with secundum atrial septal defect. Analysis by real time two dimensional echocardiography. Br Heart J 1983;49:51-8. 20. Miyatake K, Izumi S, Okamoto M, Kinoshita N, Asonuma H, Nakagawa H, et al. Semiquantitative grading of severity of mitral regurgitation by real time two-dimensional doppler flow imaging technique. J Am Coll Cardiol 1986;7:82-8.
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21. Anan R, Higuchi I, Ichinari K, Kubota K, Kisanuki A, Arima S, et al. Myocardial patchy staining of dystrophinin Becker's muscular dystrophy associated with cardiomyopathy. Am Heart J 1992;123:1088-9. 22. Cziner DG, Levin RI. The cardiomyopathy of Duchenne's muscular dystrophy and the function ofdystrophin. Med Hypotheses 1993;40:16973. 23. Muntoni F, Cau M, Ganau A, Congiu R, Arvedi G, Mateddu A, et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Eng J Med 1993; 329:921-5. 24. Yoshida K, Ikeda S, Nakamura A, Kagoshima M, Takeda S, Shoji S, et al. Molecular analysis of the Duchenne muscular dystrophy gene in patients with Becker muscular dystrophy presenting with dilated cardiomyopathy. Muscle Nerve 1993;16:1161-6. 2 5 . Gold R, Kress W, Meurers B, Meng G, Reichmann H, M~ller CR. Brief communication: Becket muscular dystrophy: detection of unusual disease courses by combined approach to dystrophin analysis. Muscle Nerve 1992;15:214-8. 26. Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, et al. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 1991;49:54-67.