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a Department of Pediatric Cardiology, Heart Institute of Japan
b Department of Pediatrics
c Department of Pathology
d Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS AND RESULTS. We evaluated left ventricular function using M-mode and Doppler echocardiography in 34 patients with Fukuyama-type congenital muscular dystrophy. The age ranged from 6 months to 30 years (median: 6 years). A total of 64 recordings were analyzed. Left ventricular dimensions and parameters of systolic function measured included left ventricular end-diastolic dimension, left ventricular fractional shortening, left ventricular wall thickness, and the mean velocity of circumferential fiber shortening and end-systolic wall stress relationship. Left ventricular end-diastolic dimension z score >2 was observed in 2 patients (6%). Left ventricular fractional shortening <0.28 and/or reduced mean velocity of circumferential fiber shortening in the mean velocity of circumferential fiber shortening-end-systolic wall stress relationship were observed in 16 patients (47%). A significant correlation between age and left ventricular fractional shortening was observed, and left ventricular fractional shortening decreased with age. Of 12 patients >15 years of age, 10 (83%) showed decreased left ventricular systolic function. Left ventricular fractional shortening was normal in most patients <10 years of age, and it was reduced in most patients >15 years of age. Five patients died of heart failure or respiratory problems, and a histologic examination confirmed the presence of myocardial fibrosis. No patients showed increased left ventricular wall thickness or a conduction abnormality on electrocardiograms.
CONCLUSION. Cardiac involvement exists in patients with Fukuyama-type congenital muscular dystrophy and becomes evident in older children in the second decade. A cardiac evaluation, including echocardiograms and subsequent follow-up, is important, especially in patients >10 years of age.
Key Words: muscles • heart failure • echocardiography • cardiomyopathy
Abbreviations: FCMD—Fukuyama-type congenital muscular dystrophy • ECG—electrocardiography • LV—left ventricular • LVEDD—left ventricular end-diastolic dimension • LVFS—left ventricular fractional shortening • LVWth—left ventricular wall thickness • mVcf—mean velocity of circumferential fiber shortening • ESWS—end-systolic wall stress • ACE—angiotensin-converting enzyme
Fukuyama-type congenital muscular dystrophy (FCMD), which was first reported by Fukuyama et al1 in 1960, is the second most common type of muscular dystrophy in Japan.2 The prevalence of FCMD in Japan is 6.9–11.9 per 100000 births.1,2 It is an autosomal recessive disorder characterized by weakness of facial and limb muscles and general hypotonia in infancy.2 The maximal level of motor function is usually unassisted sitting or sliding on the buttocks. Mental retardation is usually severe with intelligence quotient scores between 30 and 50.2,3
Recently, mutation of the fukutin gene on chromosome 9q31 was found to be responsible for FCMD.4,5 Genotyping with the polymorphic microsatellite markers D9S2105-D9S2170-D9S2171-D9S2107, which are situated in an 
200-kb critical region of chromosome 9q31, demonstrated a founder haplotype in >80% of FCMD chromosomes.4–7 Furthermore, a 3-kb retrotransposal insertion into the 3' noncoding region in the FCMD gene on chromosome 9q31 is always observed in chromosomes that carry the founder haplotype. It is estimated that 1 of 90 normal Japanese people is a carrier of the founder haplotype.2 In FCMD, 80% of patients are homozygous for the ancestral founder haplotype, and 20% are heterozygous. In patients with ancestral homozygotes, the insertion into the 3' untranslated region may render fukutin messenger RNA unstable and result in reduced production of fukutin.5 In patients with ancestral heterozygotes, the founder haplotype is associated with a noninsertion mutation, such as a point mutation of the fukutin gene. The precise function of fukutin has not been clarified; however, it may function as a glycosyltransferase, and an abnormality in this gene may alter glycosylation of 
-dystroglycan, an extracellular membrane protein, disrupting the basement membrane and transmembranous molecular linkage of muscle fibers.8–10
Hayashi et al11 showed a deficiency of -dystroglycan in the cardiac muscle, as well as in the skeletal muscle in patients with FCMD. Therefore, it is conceivable that cardiac muscle, as well as skeletal muscle, is involved in FCMD. However, there has been no systematic investigation regarding cardiac involvement in patients with FCMD. The purpose of the present study was to evaluate cardiac involvement in patients with FCMD.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Skeletal Muscle System
Severity of the involvement of the skeletal muscle was classified as follows, according to the patients' maximum motor abilities: mild indicated patients who could stand with or without support (9 patients); moderate, patients who could sit (16 patients); and severe, patients who could not sit (9 patients).
Cardiac Evaluation
Cardiac evaluation included physical evaluation, chest radiograph, electrocardiography (ECG), and echocardiography. Echocardiographic evaluation of left ventricular (LV) function was performed using M-mode, two-dimensional, and Doppler echocardiography. Echocardiograms were recorded and analyzed according to a method described previously.12 The LV dimensions and parameters of systolic function analyzed included LV end-diastolic dimension (LVEDD), fractional shortening (LVFS), and septal and posterior wall thickness (LVWth). LVEDD and LVWth were expressed as z scores. Normal value and SD for the LDEDD and LVWth relative to body surface area were derived from our institutional normal database. Z scores >2 and LVFS <0.28 were considered to be abnormal. The relationship between mean velocity of circumferential fiber shortening (mVcf) and LV end-systolic wall stress (ESWS) was also analyzed, and an mVcf <2 SD was considered to be reduced.13 Regional wall motion abnormality of the LV was evaluated using the short axis view. Parameters of LV diastolic function analyzed included peak early and late inflow velocity (E and A, respectively) and the E/A ratio.14
A total of 64 echocardiographic recordings were analyzed. Of 34 patients, 9 patients had only 1 echocardiogram, and 25 patients had >2 echocardiographic examinations. Ages at the time of the follow-up echocardiographic examination ranged from 18 months to 31 years (median: 12 years). The interval between each echocardiographic examination ranged from 12 months to 11 years (median: 4 years). The present study was primarily designed to evaluate the natural course of LV function in patients with FCMD. Therefore, the data used in the present study were basically those obtained before starting heart-failure therapy. However, in 5 patients with reduced LV systolic function, heart-failure therapy using ß-blockers and/or inhibitors of angiotensin-converting enzyme (ACE) was started, and the response to therapy was assessed by analyzing serial echocardiographic changes in LV systolic function.
Statistical Analysis
Values were expressed as mean ± SD. Analysis of variance was performed to evaluate 3 groups of patients, and, where significance was found, the Student-Newman-Keuls posthoc procedure was applied to determine differences between the specific mean values. Linear regression analysis was used to assess the correlation between age of patients and LV dimensions or shortening fraction. A P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Echocardiography revealed that LVEDD was abnormally increased in 1 (3%) patient, and LVFS was decreased in 9 (18%) patients at the time of the first cardiac evaluation. The mVcf-ESWS relationship was analyzed in 21 patients and showed decreased mVcf in 2 patients. LV septal and posterior wall thickness was measured in 28 patients, and none of them showed increased LV wall thickness. No patients showed regional wall motion abnormality of the LV or abnormality of the diastolic function of the LV. During follow-up, 1 additional patient showed an increase in the LVEDD z score to >2, 8 showed a decrease in LVFS to <0.28, and 2 showed a reduced mVcf in the mVcf-ESWS relationship curve. Thus, among 34 patients, abnormally increased LVEDD was observed in 2 (6%) patients and decreased LV systolic function (decreased LVFS and/or mVcf) in 16 (47%) patients. A significant correlation between age and LVFS was observed, and LVFS decreased with age (Fig 1). LVFS was normal in most patients <10 years of age, and it was reduced in most patients >15 years of age. Z scores of LVEDD did not change significantly with age. There was a tendency for mVcf to be reduced in the mVcf-ESWS relationship curve in patients with LVFS <0.28. Of 12 patients who were >15 years of age during follow-up, 10 (83%) showed decreased LV systolic function (decreased LVFS and/or mVcf). Heart rate at the time of echocardiographic examination was similar in the patients with and without cardiac involvement.
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Because there was no patient who was >15 years of age in the group with severe skeletal muscle involvement, LVFS was compared between the 3 groups with mild, moderate, and severe skeletal muscle involvement in patients <15 years of age. LVFS was not significantly different in the 3 groups (0.27 ± 0.07 in 4 patients with mild skeletal muscle involvement, 0.30 ± 0.07 in 15 patients with moderate skeletal muscle involvement, and 0.30 ± 0.07 in 9 patients with severe skeletal muscle involvement).
Histology
Five patients died during follow-up. All of them had decreased LVFS. Three patients died of respiratory problems at 2, 27, and 31 years of age. The patient who died at 2 years of age had tetralogy of Fallot. LVFS in these patients was 0.23, 0.16, and 0.26, respectively. Two patients died of heart failure at 16 and 17 years of age, and LVFS before death was 0.05 and 0.09, respectively. Autopsy was performed in 4 patients, and in all of the patients a moderate-to-severe degree of multifocal fibrosis was observed throughout the LV wall, especially in the anterior, lateral, and posterior wall (Figs 2 and 3). The degree of fibrosis was more severe in patients who died of heart failure than in those who died of respiratory problems.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The relationship between age and cardiac dysfunction in patients with congenital muscular dystrophy has not been evaluated. The present study showed that LV systolic dysfunction became common in older children >15 years of age (Fig 1). In Duchenne and Becker muscular dystrophy, a similar tendency for cardiac dysfunction to become evident in the second decade has been reported.15–17
Relationship Between Cardiac and Skeletal Muscle Involvement
It has been shown that in FCMD the phenotype of both the skeletal muscle and the central nervous system is more severe in patients with ancestral heterozygotes, which carry the founder mutation on one allele and a noninsertion mutation on the other, than in patients with ancestral homozygotes.7 In the present study, among patients <15 years of age, the severity of cardiac dysfunction in those with heterozygotes was similar to that in patients with homozygotes, indicating that, at least in young children, LV function in patients with heterozygotes is similar to that in patients with homozygotes.
There was no patient >15 years of age in the group with severe skeletal muscle involvement, and in patients <15 years of age, no significant difference in LVFS was seen among the 3 groups with mild, moderate, and severe skeletal muscle involvement, indicating that there is a discrepancy in the involvement of the cardiac and skeletal muscle systems. The discrepancy between cardiac dysfunction and skeletal muscle abnormality is also observed in Duchenne and Becker muscular dystrophy.15–17
In patients with Duchenne and Becker muscular dystrophy, distinctive ECG abnormalities consisting of a tall R wave on V1 and deep but narrow Q waves on leads I, aVL, V5, and V6 have been reported.15–18 In the present study, although deep but narrow Q waves on leads I, aVL, V5, and V6 were not frequent, a tall R wave on V1 with an R/S ratio >1 was observed in 60% of those patients. These findings suggest that ECG findings in FCMD are somewhat similar to that in Duchene and Becker muscular dystrophy.
Although the ECG abnormality was common in FCMD, cardiomegaly on chest radiography was rare. In textbooks of pediatrics, it is written that cardiomegaly and heart failure are prominent in FCMD.24 This statement is not generally true. In the present study, cardiomegaly on the chest radiograph was noted only in 9% of patients. In the present study, heart failure was rare in young children. Heart failure and cardiac dysfunction detected by echocardiography became evident mostly in older children in the second decade.
In Duchenne muscular dystrophy, multifocal degenerative changes of varying severity have been observed.16 In the present study, a moderate-to-severe degree of multifocal fibrosis was observed throughout the LV wall, especially in the anterior, lateral, and posterior wall in patients who had shown severely depressed LV function (Figs 2 and 3). These histologic studies confirmed that cardiac involvement exists in patients with FCMD.
The precise function of fukutin protein has not yet been clarified, but it may function as a glycosyltransferase. An abnormality of fukutin may alter glycosylation of -dystroglycan. -Dystroglycan, an extracellular membrane glycoprotein, is a central component of the dystrophin-glycoprotein complex, and its abnormality may result in disruption of the basement membrane.8 Duchenne and Becker-type muscular dystrophy are caused by dystrophin gene mutation.25 The present study showing that cardiac involvement exists in patients with FCMD is in agreement with the notion that abnormalities in any component of the dystrophin-extracellular glycoprotein complex can cause both cardiac and skeletal muscle degeneration.11,19–22,25
Clinical Implications
The present study suggests that cardiac involvement exists in patients with FCMD and becomes evident in older children in the second decade. Therefore, we suggest that a cardiac evaluation including echocardiograms should be performed by ages 10–12 years in all patients with FCMD with subsequent routine follow-up.
The present study evaluated LV function obtained primarily before the use of antiheart failure agents. Once we recognized the presence of cardiac involvement in patients with FCMD, we decided to treat the patients with ACE inhibitors or a combination of ACE inhibitors and ß-blockers. Jefferies et al25 reported recently that similar pharmacological interventions led to improvement of LV function in patients with Duchenne and Becker muscular dystrophy. The heart-failure therapy used in a small number of patients in the present study was effective in improving cardiac function. However, the long-term effect on cardiac function and the effect on life expectancy remain unknown and should be determined in future studies.
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CONCLUSIONS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Toshio Nakanishi, MD, Department of Pediatric Cardiology, Heart Institute of Japan, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan. E mail: E-mail: pnakanis{at}hij.twmu.ac.jp
The authors have indicated they have no financial relationships relevant to this article to disclose.
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