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Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy
Brain & Development xxx (2017) xxx–xxx www.elsevier.com/locate/braindev
Original article
Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy Tetsushi Yamamoto a,1, Mariko Taniguchi-Ikeda b,⇑,1, Hiroyuki Awano b, Masaaki Matsumoto b, Tomoko Lee c, Risa Harada d, Takamitsu Imanishi a, Nobuhide Hayashi a, Yoshitada Sakai d, Ichiro Morioka b, Yasuhiro Takeshima c, Kazumoto Iijima b, Jun Saegusa a, Tatsushi Toda e a
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan c Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan d Division of Rehabilitation, Kobe University Graduate School of Medicine, Kobe, Japan e Department of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan b
Received 13 March 2017; received in revised form 12 May 2017; accepted 12 May 2017
Abstract Background: One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited. Aim: To compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD). Methods: We compared cardiac involvement between 30 patients with FCMD and 181 patients with DMD using echocardiography and serum biomarkers. All patients were receiving regular checkups at Kobe University Hospital. We used single regression analysis to compare echocardiographic parameters, age, and serum biomarkers. Results: Almost all clinical and echocardiographic parameters were lower in patients with FCMD than DMD. The brain natriuretic peptide concentration in patients with FCMD showed no correlation with age or left ventricular ejection fraction (r = 0.231, p = 0.22 and r = 0.058, p = 0.76, respectively). A log-rank test revealed that the risk of left ventricular systolic dysfunction was lower in patients with FCMD than DMD (p = 0.046, hazard ratio = 0.348). Conclusion: The clinical progression of cardiac dysfunction is significantly milder in patients with FCMD than DMD, while skeletal muscle involvement is significantly worse in patients with FCMD. These data suggest that the pathophysiological findings of FCMD can be explained by less severe cardiac dysfunction in FCMD than DMD. Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Fukuyama congenital muscular dystrophy; Natural history; Cardiac dysfunction; Duchenne muscular dystrophy; Echocardiography
1. Introduction ⇑ Corresponding author at: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Fax: +81 78 382 6099. E-mail address: [email protected] (M. Taniguchi-Ikeda). 1 These authors contributed equally to this work.
Fukuyama congenital muscular dystrophy (FCMD; MIM253800) and Duchenne muscular dystrophy (DMD; MIM310200) are two types of childhood-onset muscular dystrophy. FCMD is an autosomal recessive,
http://dx.doi.org/10.1016/j.braindev.2017.05.008 0387-7604/Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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severe muscular dystrophy associated with an anomaly of the brain [1,2]. It is the second most common childhood muscular dystrophy in Japanese populations, with an incidence of 3/100,000. One of 88 Japanese people is predicted to be a heterozygous carrier for FCMD [1,3]. Patients with FCMD have been recognized almost exclusively in Japan, but several populations outside of Japan, such as in China and Korea, have been recently reported [4]. Mutation of the fukutin gene on chromosome 9q31 has been shown to be responsible for FCMD [3,5,6]. FCMD has also been shown to be the first human disease resulting from the ancestral insertion of a SINE-VNTR-Alu (SVA) retrotransposal element into a causative gene. This insertion originated in an ancestor of Japanese ethnicity 100 generations ago [7,8]. FCMD was recently reported as a splicing disease [9]. FCMD is also known as alpha-dystroglycanopathy, indicating a deficiency in the glycosylation of O-mannose-type glycan [10]. The glycosylation of alpha-dystroglycan is severely reduced in the skeletal muscle of patients with FCMD. The fukutin gene has recently been described as an enzyme that catalyzes cytidine 50 -diphosphate (CDP)-ribitol [11]. Clinically, functional disabilities are more serious in patients with FCMD than in those with DMD; typically, the maximum motor function achievements consist only of unassisted sitting or sliding on the buttocks, and 90% of patients never gain walking ability [2]. However, although patients with DMD manifest clinical signs such as Gower’s sign at around 3 years of age, they usually gain walking ability. Almost all patients with DMD develop cardiomyopathy with left ventricular (LV) dilatation. Therefore, we previously emphasized the importance of the prediction of cardiac involvement in patients with DMD at an early stage [12–14]. Furthermore, the myocardial pathology of FCMD was extensively investigated in a review by Fukuyama et al. [2]. The authors found that little had been reported on cardiac abnormalities in patients with FCMD because previous studies identified almost normal cardiac muscle during autopsy of patients with FCMD. Myocardial fibrosis and a low heart weight were also described in several reports [2]. However, other authors have speculated that LV systolic dysfunction in FCMD is similar to that in DMD [15], although the genotypical variation and motor capacities of patients with FCMD were not fully characterized in that study. Ishigaki [16] reported in a review that LV function decreases after the age of 15 years in patients with FCMD. In the present report, cardiac dysfunction of patients with FCMD at our hospital was investigated by assessment of LV function and some serum biomarkers. Comparative studies between patients with FCMD and those with DMD in our institution were also analyzed.
2. Materials and methods 2.1. Study population The study group comprised 30 consecutive patients with FCMD and 160 age-matched consecutive patients with DMD who had been receiving regular outpatient physical checkups at the Department of Pediatrics of Kobe University Hospital from August 2007 to May 2016. The diagnosis of FCMD and DMD was confirmed by genetic analysis in all patients. All patients with FCMD had an SVA mutation in one allele. The heterozygous mutations in patients with FCMD included a nonsense mutation in exon 3 [17] in two patients and a deep intronic splicing mutation in intron 5 [18] in three patients. The remaining patient had a compound heterozygous splicing mutation in exon 9 (unpublished data). The genetic backgrounds of patients with DMD, were as follows: deletion mutation (88/160, 55%), nonsense mutation (34/160, 21%), small insertion/ deletion mutation (20/160, 13%), duplication mutation (12/160, 8%), splice site mutation (4/160, 3%), and other mutations (2/160, 1%). Other mutations included chromosomal rearrangement and unknown mutations. Motor function was assessed by an orthopedic doctor specialized in rehabilitation. All patients with FCMD who were found to have asynergy by cardiac echocardiography underwent treatment with a cardioprotective agent. This study was approved by the local ethics committee of Kobe University (Clinical research number 1653), and written informed consent was obtained from all patients and their families after they had been provided with a full explanation of the procedures to be undertaken. 2.2. Serum and echocardiographic examinations Serum laboratory tests such as measurement of the brain natriuretic peptide (BNP), creatine kinase, and aldolase concentrations were performed in both patients with DMD and FCMD. A commercially available echocardiographic system (Aplio XG; Toshiba Medical Systems, Tochigi, Japan) was used for all echocardiographic studies. Digital routine grayscale twodimensional cine loops from three consecutive beats were obtained from the parasternal long-axis, mid-LV short-axis, and standard apical views. The parasternal long-axis view was used to obtain the LV end-diastolic dimension, LV end-systolic dimension, left atrial dimension, intraventricular septal thickness, LV posterior wall thickness, and aortic root dimension. The LV ejection fraction (LVEF) was assessed using the modified Simpson method. All chamber sizes were divided by the body surface area (index). Pulsed-wave Doppler-derived transmitral velocities were obtained from the apical
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
T. Yamamoto et al. / Brain & Development xxx (2017) xxx–xxx
four-chamber view to assess diastolic function. The early diastolic (E) and atrial (A) wave velocities, the E/A ratio, and the E-wave deceleration time were measured using pulsed-wave Doppler [19]. 2.3. Assessment of cardiac involvement in FCMD; genetic background versus motor function The correlation of the cardiac involvement in patients with FCMD and their genetic background or motor function score [2] was analyzed. The motor function score was analyzed with respect to both present motor function and maximum motor development.
Table 1 Motor function of patients with FCMD [2]. Score
Level of motor function
No. of patients present/maximum
0 1
Unable to keep the neck erect Able to keep the neck erect, unable to maintain a sitting position Maintain a sitting position without support Turn around while maintaining a sitting position Able to crawl on the knees Able to stand or to crawl on all fours Able to walk on a flat surface with support Able to walk on a flat surface unsupported Able to ascend a staircase
7/1 7/5
2 3 4 5 6 7
2.4. Echocardiographic findings of FCMD versus DMD We also compared cardiac involvement between patients with FCMD and DMD patients by echocardiography. Cardiac involvement was defined as an LVEF of <53% [19]. 2.5. Statistical analysis All data are presented as mean ± standard deviation. The Mann–Whitney U test was used to compare the two muscular dystrophy groups. Single regression analysis was used to evaluate the correlations between parameters. Proportional differences were evaluated using Fisher’s exact test. Two correlation lines were compared using analysis of covariance. Receiver operating characteristic (ROC) curve analysis was used to detect the cut-off value for motor function and cardiac involvement. Kaplan–Meier survival estimation was applied for the LV systolic dysfunction of the entire patient cohort. A log-rank test and the Cox proportional hazards model were used for comparisons of FCMD and DMD. For all analyses, p values of <0.05 were considered statistically significant. All analyses were performed using the commercially available R software, version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). 3. Results 3.1. Genetic distributions and motor function scores of patients with FCMD Thirty consecutive patients with FCMD were enrolled in the present study. Six patients (20%) had compound heterozygous mutations (all patients had an SVA mutation in one allele) in fukutin, and the remaining 24 (80%) had homozygous SVA insertions. Four patients (13%) were ambulatory and 26 (87%) were not ambulatory at the time of the examinations (Table 1).
3
8
7/11 0/2 5/5 0/1 2/2 1/1 1/1
3.2. Baseline and comparisons of serum and echocardiographic parameters In total, 160 patients with DMD (856 recordings) and 30 patients with FCMD (62 recordings) underwent serum and echocardiographic examinations. The clinical and echocardiographic characteristics of the two groups are listed in Table 2. Almost all clinical parameters, such as body weight, body surface area, and serum biomarker concentrations, were lower in patients with FCMD than DMD. Likewise, almost all echocardiographic parameters were lower in patients with FCMD than DMD with the exception of the LVEF, heart rate, and atrial wave. Blood pressure was not significantly different between the two groups. Single regression analysis demonstrated a relationship between clinical parameters and age (Fig. 1A–D) and between echocardiographic parameters and age (Fig. 2A–C). Regression lines showed a significant difference in both groups. Interestingly, the BNP concentration in patients with FCMD showed no correlation with age or LVEF (r = 0.231, p = 0.22 and r = 0.058, p = 0.76, respectively) (Fig. 2D). 3.3. Relationship of cardiac involvement Three patients with FCMD who carried homozygous SVA insertions developed cardiac dysfunction. Cardiac dysfunction had no genotypic or phenotypic correlation between patients with heterozygous mutations and homozygous SVA insertions (p = 0.99). The ROC curve revealed that the cut-off score for the current motor function with cardiac involvement was <2 points (Fig. 3A). Cardiac involvement was present in 2 (14%) of 14 patients with a score of <2 points and in 1 (6%) of 16 patients with a score of >2 points. We further determined that the cut-off score for the peak motor function with cardiac involvement was <3 points (Fig. 3B). Cardiac involvement was present in 2 (13%)
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Table 2 Clinical and echocardiographic characteristics of patients. FCMD n = 62
DMD n = 856
p value
Age (years) Height (cm) Weight (kg) Body surface area (m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Creatine Kinase (IU/l) Aldolase (IU/l) Brain natriuretic peptide (pg/ml)
10 ± 6 120 ± 25 20 ± 9 0.82 ± 0.26 100 ± 16 63 ± 11 107 ± 18 2638 ± 2151 20 ± 14 7.7 ± 6.2
11 ± 3 140 ± 18 37 ± 15 1.17 ± 0.29 103 ± 12 61 ± 9 91 ± 13 5339 ± 4746 37 ± 33 18.8 ± 58.3
0.21 <0.001 <0.001 <0.001 0.20 0.19 <0.001 <0.001 <0.001 <0.001
Echocardiographic parameters Left ventricular end-diastolic dimension (mm) Left ventricular end-diastolic dimension index (mm/m2) Left ventricular end-systolic dimension (mm) Left ventricular end-systolic dimension index (mm/m2) % Fractional shortening (%) Ejection fraction (%) Left atrial dimension (mm) Left atrial dimension index (mm/m2) Intra ventricular septal thickness (mm) Intra ventricular septal thickness index (mm/m2) Left ventricular posterior wall thickness (mm) Left ventricular posterior wall thickness index (mm/m2) Aortic root dimension (mm) Aortic root dimension index (mm/m2) Early diastolic wave velocity (cm/s) Atrial wave velocity (cm/s) Early diastolic and atrial wave velocities ratio Early diastolic-wave deceleration time (msec) Inferior vena cava at expiration (mm)
34 ± 6 44.1 ± 9 23 ± 6 29.2 ± 5.6 33.1 ± 6 60.3 ± 7.1 19 ± 4 25.6 ± 8.8 6±1 7.8 ± 1.7 6±1 7.5 ± 2 19 ± 3 24.9 ± 5.1 87 ± 17 52 ± 14 1.8 ± 0.4 136 ± 21 8±3
42 ± 8 37.4 ± 7.7 30 ± 10 26 ± 6.6 30.6 ± 9.5 58.0 ± 12.2 25 ± 5 22.1 ± 6.4 7±1 6.5 ± 1.6 7±1 6.5 ± 1.4 22 ± 3 19.6 ± 4 95 ± 17 44 ± 12 2.3 ± 0.7 156 ± 29 10 ± 3
<0.001 <0.001 <0.001 <0.001 0.003 0.024 0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.062 <0.001 <0.001 <0.001 <0.001 <0.001
of 16 patients with a score of <2 points and in 1 (9%) of 11 patients with a score of >3 points. Fisher’s exact test revealed no distinct correlation between either the present or peak motor score or cardiac involvement (p = 0.57 and p = 0.99, respectively). The overall survival rate was calculated using a Kaplan–Meier survival curve in 30 patients with FCMD. The cardiac involvement-free rate did not decline to 50% at the age of 25 years in patients with FCMD. A log-rank test revealed a significant difference between the FCMD and DMD groups (p = 0.046) (Fig. 4). Patients with FCMD had a lower risk of LV systolic dysfunction than did patients with DMD (hazard ratio = 0.348). 4. Discussion The main outcome of our study was the identification of a natural history of cardiac dysfunction in patients with FCMD as revealed by Kaplan–Meier survival analysis. To the best of our knowledge, this is the first report of the comparison of serum biomarkers and cardiac parameters between patients with FCMD and DMD. The lower rate of LVEF observed in the present study is consistent with previous reports [15], and the
progression of cardiac dysfunction in patients with FCMD appeared to be significantly slower than in patients with DMD. A possible reason for this observation is that the LV systolic dysfunction rates differed between the two dystrophies. Physiological functional disabilities are generally more severe in patients with FCMD than DMD. Therefore, the afterload recovery in patients with FCMD was lower than that in patients with DMD. Indeed, Murakami et al. [20] described patients with mild cardiomyopathy [classified as Cardiomyopathy: Familial dilated (CMD 1X) and caused by compound heterozygous mutations in fukutin] who retained the ability to walk. A lower cardiac load arising from severely limited motor function likely contributed to the mild progression of cardiac involvement in patients with FCMD. In a past study, some patients developed severe cardiac dysfunction before the age of 15 years [15]. In the present study, no patients showed severe cardiac dysfunction. This difference might have been due to sample size limitations. However, cardioprotective agents such as beta-blockers and angiotensin-converting enzyme inhibitors have recently become widely used for patients with cardiomyopathy, and these agents
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Fig. 1. Relationship between age and clinical data in patients with FCMD and DMD. Solid line and open triangle, patients with FCMD. Broken line and broken open circle, patients with DMD. (A) Scatter graph showing the relationship between age and height in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (B) Scatter graph showing the relationship between age and weight in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (C) Scatter graph showing the relationship between age and creatine kinase concentration in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (D) Scatter graph showing the relationship between age and BNP concentration in patients with FCMD and DMD. No correlation is observed in patients with FCMD.
might have been effective for FCMD in the patient enrolled in our study. 4.1. Comparison of serum and echocardiographic parameters A further novel finding in this study is that no correlation was observed between the BNP concentration and LVEF in patients with FCMD. The reason for the lack of this relationship is not fully understood. BNP is secreted from the left atrium. Patients with FCMD and DMD have low BNP concentrations because their motor limitations require them to stay mainly in the supine position; hence, the left atrial dimension is not usually enlarged. In patients with severe cardiomyopathy, however, the BNP concentration is elevated because high atrial pressure is needed to increase the preload and maintain cardiac output. In a previous study, however, the BNP concentration was not elevated in patients with
DMD who had significant LVEF dysfunction [21]. In the present study, the LVEF was preserved in patients with FCMD compared with patients with DMD. Therefore, the LVEF might not be expected to correlate with the BNP concentration in patients with FCMD. Mutations in the dystrophin protein, a structural protein implicated in DMD, result in mechanical stress that directly affects muscle integrity and wasting upon the turnover of regenerated muscle fibers, leading to endstage cardiac dysfunction. FCMD, however, is caused by deficient alpha-dystroglycan glycosylation. The activity of the O-glycosylation enzyme on cardiac muscle remains largely unknown. In mice, glycosylation is less severely affected in cardiac muscle than in skeletal muscle [22]. Although further studies are needed, our findings suggest that glycosylation in the cardiac muscle of patients with FCMD is less severely affected than that in the skeletal muscle because the cardiac function of patients with FCMD in this study had no distinct
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Fig. 2. Relationship between cardiac function and age in patients with FCMD and DMD. Solid line and open triangle, patients with FCMD. Broken line and broken open circle, patients with DMD. (A) Scatter graph showing the relationship between age and left ventricular end-diastolic dimension in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (B) Scatter graph showing the relationship between age and left ventricular end-systolic dimension in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (C) Scatter graph showing the relationship between age and left ventricular ejection fraction in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (D) Scatter graph showing the relationship between left ventricular ejection fraction and BNP concentration in patients with FCMD and DMD. The BNP concentrations (Y-axis) are displayed logarithmically. A significant difference is shown between the two correlation lines (p < 0.001). No correlation is seen in patients with FCMD.
correlation with the motor function scores. Indeed, patients with FCMD with mild cardiomyopathy [20] show damage to the cardiac muscle, possibly because they have less severe exercise limitations, which could affect the worsening of cardiac function. However, more severe skeletal muscle phenotypes, which are usually seen in patients with compound heterozygous mutations in exon 3 or intron 5 in fukutin, have no influence on the manifestation of cardiomyopathy or treatment with cardioprotective agents. Therefore, although further analysis of larger samples is needed, we suggest that cardiac muscle damage could mainly be caused by exercise or environmental factors, not by genotype-induced cardiac damage itself. FCMD is a splicing disease, and antisense oligonucleotide therapy for skeletal muscle has been expected to represent a future treatment strategy. However, it has been suggested that antisense oligonucleotides do
not accumulate on cardiac muscle cells [23]. Therefore, an alternative therapeutic strategy is necessary for the management of cardiac dysfunction in patients with FCMD. 4.2. Strengths and limitations of this study This study had certain limitations. First, it was a single-center retrospective study; thus, further multicenter studies might be necessary to confirm our findings. Second, possibly because of the sample limitation, we cannot conclude whether patients with higher motor index scores have more severe cardiac dysfunction due to excess cardiac load or, alternatively, whether patients with lower motor index scores have more severe dysfunction due to serious pathological changes affecting the heart muscle. Further multicenter studies with larger samples might be necessary to clarify this issue.
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Fig. 3. Receiver operating characteristic (ROC) curve for motor function score. (A) The ROC curve shows that the cut-off value for motor function and cardiac involvement was <2 points. When the motor function score was used as the single factor with which to evaluate cardiac involvement, the area under the curve, sensitivity, and specificity were 0.61%, 66.7%, and 59.3%, respectively. (B) The ROC curve shows that the cut-off score for peak motor function and cardiac involvement was <3 points. When the peak motor function score was used as the single factor with which to evaluate cardiac involvement, the area under the curve, sensitivity, and specificity were 0.55%, 66.7%, and 40.7%, respectively.
Fig. 4. Comparison of cardiac involvement-free rate between patients with FCMD and DMD. Survival curves were calculated using the Kaplan–Meier method and analyzed by the log-rank test. The solid line indicates patients with FCMD, and the broken line indicates patients with DMD. The log-rank test revealed a significant difference between the two groups (p = 0.046). Patients with FCMD had a lower risk of a decreased LVEF than did patients with DMD (hazard ratio = 0.348). In patients with FCMD, the cardiac dysfunction-free survival rate did not decline to 50% at the age of 25 years.
Another potential limitation was the small cohort of patients. Given that both FCMD and DMD are rare diseases, however, it might prove difficult to enroll adequate numbers of patients in future studies. Further-
more, the cardiac function of patients was evaluated by echocardiography. Cardiovascular magnetic resonance with gadolinium enhancement has been shown to have an advantage over echocardiography in terms of reproducibility. However, because patients with FCMD have moderate to severe intellectual disability, we considered that magnetic resonance imaging in this population would present challenges. However, echocardiographic evaluation of the LVEF is the most widely used method by which to assess LV function in patients with FCMD and DMD. The American Academy of Pediatrics has recommended that echocardiographic assessment represents the optimum method by which to monitor cardiac dysfunction in patients with muscular dystrophy, and that cardiovascular magnetic resonance imaging should be used in patients with poor echocardiographic acoustic windows [24]. Therefore, we used echocardiographic assessment to evaluate cardiac function in this study. 4.3. Clinical implications Although the rate of cardiac dysfunction in patients with FCMD was lower than that in patients with DMD, patients with FCMD showed a decrease in their LVEF with age. However, no significant relationship was observed between cardiac function and the BNP concentration. Therefore, cardiac function should be routinely assessed and using echocardiography in patients with FCMD, with subsequent follow-up. In summary, patients with FCMD had less severe cardiac dysfunction than did patients with DMD.
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Funding sources This work was supported by a Grant-in-Aid for Scientific Research (C) JSPS KAKENHI (Grant No. JP15K09621) and by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and Development (AMED; Grant No. 16822810). Disclosure of conflicts of interest The authors have no financial or personal relations that could pose a conflict of interest. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Acknowledgements We would like to thank all of the patients and their families for their cooperation in this study. We would also like to thank Ms. Asami Kita and Michiko Ujihara for their technical assistance. References [1] Fukuyama Y, Ohsawa M. A genetic study of the Fukuyama type congenital muscular dystrophy. Brain Dev 1984;6:373–90. [2] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type – clinical, genetic and pathological considerations. Brain Dev 1981;3:1–29. [3] Kobayashi K, Nakahori Y, Miyake M, Matsumura K, KondoIida E, Nomura Y, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388–92. [4] Yoshioka M, Kuroki S. Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. Am J Med Genet 1994;53:245–50. [5] Toda T, Segawa M, Nomura Y, Nonaka I, Masuda K, Ishihara T, et al. Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33. Nat Genet 1993;5:283–6. [6] Toda T, Ikegawa S, Okui K, Kondo E, Saito K, Fukuyama Y, et al. Refined mapping of a gene responsible for Fukuyama-type congenital muscular dystrophy: evidence for strong linkage disequilibrium. Am J Hum Genet 1994;55:946–50. [7] Watanabe M, Kobayashi K, Jin F, Park KS, Yamada T, Tokunaga K, et al. Founder SVA retrotransposal insertion in Fukuyama-type congenital muscular dystrophy and its origin in Japanese and Northeast Asian populations. Am J Med Genet A 2005;138:344–8. [8] Colombo R, Bignamini AA, Carobene A, Sasaki J, Tachikawa M, Kobayashi K, et al. Age and origin of the FCMD 30 -untranslatedregion retrotransposal insertion mutation causing Fukuyamatype congenital muscular dystrophy in the Japanese population. Hum Genet 2000;107:559–67.
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Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
Original article
Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy Tetsushi Yamamoto a,1, Mariko Taniguchi-Ikeda b,⇑,1, Hiroyuki Awano b, Masaaki Matsumoto b, Tomoko Lee c, Risa Harada d, Takamitsu Imanishi a, Nobuhide Hayashi a, Yoshitada Sakai d, Ichiro Morioka b, Yasuhiro Takeshima c, Kazumoto Iijima b, Jun Saegusa a, Tatsushi Toda e a
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan c Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan d Division of Rehabilitation, Kobe University Graduate School of Medicine, Kobe, Japan e Department of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan b
Received 13 March 2017; received in revised form 12 May 2017; accepted 12 May 2017
Abstract Background: One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited. Aim: To compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD). Methods: We compared cardiac involvement between 30 patients with FCMD and 181 patients with DMD using echocardiography and serum biomarkers. All patients were receiving regular checkups at Kobe University Hospital. We used single regression analysis to compare echocardiographic parameters, age, and serum biomarkers. Results: Almost all clinical and echocardiographic parameters were lower in patients with FCMD than DMD. The brain natriuretic peptide concentration in patients with FCMD showed no correlation with age or left ventricular ejection fraction (r = 0.231, p = 0.22 and r = 0.058, p = 0.76, respectively). A log-rank test revealed that the risk of left ventricular systolic dysfunction was lower in patients with FCMD than DMD (p = 0.046, hazard ratio = 0.348). Conclusion: The clinical progression of cardiac dysfunction is significantly milder in patients with FCMD than DMD, while skeletal muscle involvement is significantly worse in patients with FCMD. These data suggest that the pathophysiological findings of FCMD can be explained by less severe cardiac dysfunction in FCMD than DMD. Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Fukuyama congenital muscular dystrophy; Natural history; Cardiac dysfunction; Duchenne muscular dystrophy; Echocardiography
1. Introduction ⇑ Corresponding author at: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Fax: +81 78 382 6099. E-mail address: [email protected] (M. Taniguchi-Ikeda). 1 These authors contributed equally to this work.
Fukuyama congenital muscular dystrophy (FCMD; MIM253800) and Duchenne muscular dystrophy (DMD; MIM310200) are two types of childhood-onset muscular dystrophy. FCMD is an autosomal recessive,
http://dx.doi.org/10.1016/j.braindev.2017.05.008 0387-7604/Ó 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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severe muscular dystrophy associated with an anomaly of the brain [1,2]. It is the second most common childhood muscular dystrophy in Japanese populations, with an incidence of 3/100,000. One of 88 Japanese people is predicted to be a heterozygous carrier for FCMD [1,3]. Patients with FCMD have been recognized almost exclusively in Japan, but several populations outside of Japan, such as in China and Korea, have been recently reported [4]. Mutation of the fukutin gene on chromosome 9q31 has been shown to be responsible for FCMD [3,5,6]. FCMD has also been shown to be the first human disease resulting from the ancestral insertion of a SINE-VNTR-Alu (SVA) retrotransposal element into a causative gene. This insertion originated in an ancestor of Japanese ethnicity 100 generations ago [7,8]. FCMD was recently reported as a splicing disease [9]. FCMD is also known as alpha-dystroglycanopathy, indicating a deficiency in the glycosylation of O-mannose-type glycan [10]. The glycosylation of alpha-dystroglycan is severely reduced in the skeletal muscle of patients with FCMD. The fukutin gene has recently been described as an enzyme that catalyzes cytidine 50 -diphosphate (CDP)-ribitol [11]. Clinically, functional disabilities are more serious in patients with FCMD than in those with DMD; typically, the maximum motor function achievements consist only of unassisted sitting or sliding on the buttocks, and 90% of patients never gain walking ability [2]. However, although patients with DMD manifest clinical signs such as Gower’s sign at around 3 years of age, they usually gain walking ability. Almost all patients with DMD develop cardiomyopathy with left ventricular (LV) dilatation. Therefore, we previously emphasized the importance of the prediction of cardiac involvement in patients with DMD at an early stage [12–14]. Furthermore, the myocardial pathology of FCMD was extensively investigated in a review by Fukuyama et al. [2]. The authors found that little had been reported on cardiac abnormalities in patients with FCMD because previous studies identified almost normal cardiac muscle during autopsy of patients with FCMD. Myocardial fibrosis and a low heart weight were also described in several reports [2]. However, other authors have speculated that LV systolic dysfunction in FCMD is similar to that in DMD [15], although the genotypical variation and motor capacities of patients with FCMD were not fully characterized in that study. Ishigaki [16] reported in a review that LV function decreases after the age of 15 years in patients with FCMD. In the present report, cardiac dysfunction of patients with FCMD at our hospital was investigated by assessment of LV function and some serum biomarkers. Comparative studies between patients with FCMD and those with DMD in our institution were also analyzed.
2. Materials and methods 2.1. Study population The study group comprised 30 consecutive patients with FCMD and 160 age-matched consecutive patients with DMD who had been receiving regular outpatient physical checkups at the Department of Pediatrics of Kobe University Hospital from August 2007 to May 2016. The diagnosis of FCMD and DMD was confirmed by genetic analysis in all patients. All patients with FCMD had an SVA mutation in one allele. The heterozygous mutations in patients with FCMD included a nonsense mutation in exon 3 [17] in two patients and a deep intronic splicing mutation in intron 5 [18] in three patients. The remaining patient had a compound heterozygous splicing mutation in exon 9 (unpublished data). The genetic backgrounds of patients with DMD, were as follows: deletion mutation (88/160, 55%), nonsense mutation (34/160, 21%), small insertion/ deletion mutation (20/160, 13%), duplication mutation (12/160, 8%), splice site mutation (4/160, 3%), and other mutations (2/160, 1%). Other mutations included chromosomal rearrangement and unknown mutations. Motor function was assessed by an orthopedic doctor specialized in rehabilitation. All patients with FCMD who were found to have asynergy by cardiac echocardiography underwent treatment with a cardioprotective agent. This study was approved by the local ethics committee of Kobe University (Clinical research number 1653), and written informed consent was obtained from all patients and their families after they had been provided with a full explanation of the procedures to be undertaken. 2.2. Serum and echocardiographic examinations Serum laboratory tests such as measurement of the brain natriuretic peptide (BNP), creatine kinase, and aldolase concentrations were performed in both patients with DMD and FCMD. A commercially available echocardiographic system (Aplio XG; Toshiba Medical Systems, Tochigi, Japan) was used for all echocardiographic studies. Digital routine grayscale twodimensional cine loops from three consecutive beats were obtained from the parasternal long-axis, mid-LV short-axis, and standard apical views. The parasternal long-axis view was used to obtain the LV end-diastolic dimension, LV end-systolic dimension, left atrial dimension, intraventricular septal thickness, LV posterior wall thickness, and aortic root dimension. The LV ejection fraction (LVEF) was assessed using the modified Simpson method. All chamber sizes were divided by the body surface area (index). Pulsed-wave Doppler-derived transmitral velocities were obtained from the apical
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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four-chamber view to assess diastolic function. The early diastolic (E) and atrial (A) wave velocities, the E/A ratio, and the E-wave deceleration time were measured using pulsed-wave Doppler [19]. 2.3. Assessment of cardiac involvement in FCMD; genetic background versus motor function The correlation of the cardiac involvement in patients with FCMD and their genetic background or motor function score [2] was analyzed. The motor function score was analyzed with respect to both present motor function and maximum motor development.
Table 1 Motor function of patients with FCMD [2]. Score
Level of motor function
No. of patients present/maximum
0 1
Unable to keep the neck erect Able to keep the neck erect, unable to maintain a sitting position Maintain a sitting position without support Turn around while maintaining a sitting position Able to crawl on the knees Able to stand or to crawl on all fours Able to walk on a flat surface with support Able to walk on a flat surface unsupported Able to ascend a staircase
7/1 7/5
2 3 4 5 6 7
2.4. Echocardiographic findings of FCMD versus DMD We also compared cardiac involvement between patients with FCMD and DMD patients by echocardiography. Cardiac involvement was defined as an LVEF of <53% [19]. 2.5. Statistical analysis All data are presented as mean ± standard deviation. The Mann–Whitney U test was used to compare the two muscular dystrophy groups. Single regression analysis was used to evaluate the correlations between parameters. Proportional differences were evaluated using Fisher’s exact test. Two correlation lines were compared using analysis of covariance. Receiver operating characteristic (ROC) curve analysis was used to detect the cut-off value for motor function and cardiac involvement. Kaplan–Meier survival estimation was applied for the LV systolic dysfunction of the entire patient cohort. A log-rank test and the Cox proportional hazards model were used for comparisons of FCMD and DMD. For all analyses, p values of <0.05 were considered statistically significant. All analyses were performed using the commercially available R software, version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). 3. Results 3.1. Genetic distributions and motor function scores of patients with FCMD Thirty consecutive patients with FCMD were enrolled in the present study. Six patients (20%) had compound heterozygous mutations (all patients had an SVA mutation in one allele) in fukutin, and the remaining 24 (80%) had homozygous SVA insertions. Four patients (13%) were ambulatory and 26 (87%) were not ambulatory at the time of the examinations (Table 1).
3
8
7/11 0/2 5/5 0/1 2/2 1/1 1/1
3.2. Baseline and comparisons of serum and echocardiographic parameters In total, 160 patients with DMD (856 recordings) and 30 patients with FCMD (62 recordings) underwent serum and echocardiographic examinations. The clinical and echocardiographic characteristics of the two groups are listed in Table 2. Almost all clinical parameters, such as body weight, body surface area, and serum biomarker concentrations, were lower in patients with FCMD than DMD. Likewise, almost all echocardiographic parameters were lower in patients with FCMD than DMD with the exception of the LVEF, heart rate, and atrial wave. Blood pressure was not significantly different between the two groups. Single regression analysis demonstrated a relationship between clinical parameters and age (Fig. 1A–D) and between echocardiographic parameters and age (Fig. 2A–C). Regression lines showed a significant difference in both groups. Interestingly, the BNP concentration in patients with FCMD showed no correlation with age or LVEF (r = 0.231, p = 0.22 and r = 0.058, p = 0.76, respectively) (Fig. 2D). 3.3. Relationship of cardiac involvement Three patients with FCMD who carried homozygous SVA insertions developed cardiac dysfunction. Cardiac dysfunction had no genotypic or phenotypic correlation between patients with heterozygous mutations and homozygous SVA insertions (p = 0.99). The ROC curve revealed that the cut-off score for the current motor function with cardiac involvement was <2 points (Fig. 3A). Cardiac involvement was present in 2 (14%) of 14 patients with a score of <2 points and in 1 (6%) of 16 patients with a score of >2 points. We further determined that the cut-off score for the peak motor function with cardiac involvement was <3 points (Fig. 3B). Cardiac involvement was present in 2 (13%)
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Table 2 Clinical and echocardiographic characteristics of patients. FCMD n = 62
DMD n = 856
p value
Age (years) Height (cm) Weight (kg) Body surface area (m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Creatine Kinase (IU/l) Aldolase (IU/l) Brain natriuretic peptide (pg/ml)
10 ± 6 120 ± 25 20 ± 9 0.82 ± 0.26 100 ± 16 63 ± 11 107 ± 18 2638 ± 2151 20 ± 14 7.7 ± 6.2
11 ± 3 140 ± 18 37 ± 15 1.17 ± 0.29 103 ± 12 61 ± 9 91 ± 13 5339 ± 4746 37 ± 33 18.8 ± 58.3
0.21 <0.001 <0.001 <0.001 0.20 0.19 <0.001 <0.001 <0.001 <0.001
Echocardiographic parameters Left ventricular end-diastolic dimension (mm) Left ventricular end-diastolic dimension index (mm/m2) Left ventricular end-systolic dimension (mm) Left ventricular end-systolic dimension index (mm/m2) % Fractional shortening (%) Ejection fraction (%) Left atrial dimension (mm) Left atrial dimension index (mm/m2) Intra ventricular septal thickness (mm) Intra ventricular septal thickness index (mm/m2) Left ventricular posterior wall thickness (mm) Left ventricular posterior wall thickness index (mm/m2) Aortic root dimension (mm) Aortic root dimension index (mm/m2) Early diastolic wave velocity (cm/s) Atrial wave velocity (cm/s) Early diastolic and atrial wave velocities ratio Early diastolic-wave deceleration time (msec) Inferior vena cava at expiration (mm)
34 ± 6 44.1 ± 9 23 ± 6 29.2 ± 5.6 33.1 ± 6 60.3 ± 7.1 19 ± 4 25.6 ± 8.8 6±1 7.8 ± 1.7 6±1 7.5 ± 2 19 ± 3 24.9 ± 5.1 87 ± 17 52 ± 14 1.8 ± 0.4 136 ± 21 8±3
42 ± 8 37.4 ± 7.7 30 ± 10 26 ± 6.6 30.6 ± 9.5 58.0 ± 12.2 25 ± 5 22.1 ± 6.4 7±1 6.5 ± 1.6 7±1 6.5 ± 1.4 22 ± 3 19.6 ± 4 95 ± 17 44 ± 12 2.3 ± 0.7 156 ± 29 10 ± 3
<0.001 <0.001 <0.001 <0.001 0.003 0.024 0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.062 <0.001 <0.001 <0.001 <0.001 <0.001
of 16 patients with a score of <2 points and in 1 (9%) of 11 patients with a score of >3 points. Fisher’s exact test revealed no distinct correlation between either the present or peak motor score or cardiac involvement (p = 0.57 and p = 0.99, respectively). The overall survival rate was calculated using a Kaplan–Meier survival curve in 30 patients with FCMD. The cardiac involvement-free rate did not decline to 50% at the age of 25 years in patients with FCMD. A log-rank test revealed a significant difference between the FCMD and DMD groups (p = 0.046) (Fig. 4). Patients with FCMD had a lower risk of LV systolic dysfunction than did patients with DMD (hazard ratio = 0.348). 4. Discussion The main outcome of our study was the identification of a natural history of cardiac dysfunction in patients with FCMD as revealed by Kaplan–Meier survival analysis. To the best of our knowledge, this is the first report of the comparison of serum biomarkers and cardiac parameters between patients with FCMD and DMD. The lower rate of LVEF observed in the present study is consistent with previous reports [15], and the
progression of cardiac dysfunction in patients with FCMD appeared to be significantly slower than in patients with DMD. A possible reason for this observation is that the LV systolic dysfunction rates differed between the two dystrophies. Physiological functional disabilities are generally more severe in patients with FCMD than DMD. Therefore, the afterload recovery in patients with FCMD was lower than that in patients with DMD. Indeed, Murakami et al. [20] described patients with mild cardiomyopathy [classified as Cardiomyopathy: Familial dilated (CMD 1X) and caused by compound heterozygous mutations in fukutin] who retained the ability to walk. A lower cardiac load arising from severely limited motor function likely contributed to the mild progression of cardiac involvement in patients with FCMD. In a past study, some patients developed severe cardiac dysfunction before the age of 15 years [15]. In the present study, no patients showed severe cardiac dysfunction. This difference might have been due to sample size limitations. However, cardioprotective agents such as beta-blockers and angiotensin-converting enzyme inhibitors have recently become widely used for patients with cardiomyopathy, and these agents
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Fig. 1. Relationship between age and clinical data in patients with FCMD and DMD. Solid line and open triangle, patients with FCMD. Broken line and broken open circle, patients with DMD. (A) Scatter graph showing the relationship between age and height in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (B) Scatter graph showing the relationship between age and weight in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (C) Scatter graph showing the relationship between age and creatine kinase concentration in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (D) Scatter graph showing the relationship between age and BNP concentration in patients with FCMD and DMD. No correlation is observed in patients with FCMD.
might have been effective for FCMD in the patient enrolled in our study. 4.1. Comparison of serum and echocardiographic parameters A further novel finding in this study is that no correlation was observed between the BNP concentration and LVEF in patients with FCMD. The reason for the lack of this relationship is not fully understood. BNP is secreted from the left atrium. Patients with FCMD and DMD have low BNP concentrations because their motor limitations require them to stay mainly in the supine position; hence, the left atrial dimension is not usually enlarged. In patients with severe cardiomyopathy, however, the BNP concentration is elevated because high atrial pressure is needed to increase the preload and maintain cardiac output. In a previous study, however, the BNP concentration was not elevated in patients with
DMD who had significant LVEF dysfunction [21]. In the present study, the LVEF was preserved in patients with FCMD compared with patients with DMD. Therefore, the LVEF might not be expected to correlate with the BNP concentration in patients with FCMD. Mutations in the dystrophin protein, a structural protein implicated in DMD, result in mechanical stress that directly affects muscle integrity and wasting upon the turnover of regenerated muscle fibers, leading to endstage cardiac dysfunction. FCMD, however, is caused by deficient alpha-dystroglycan glycosylation. The activity of the O-glycosylation enzyme on cardiac muscle remains largely unknown. In mice, glycosylation is less severely affected in cardiac muscle than in skeletal muscle [22]. Although further studies are needed, our findings suggest that glycosylation in the cardiac muscle of patients with FCMD is less severely affected than that in the skeletal muscle because the cardiac function of patients with FCMD in this study had no distinct
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Fig. 2. Relationship between cardiac function and age in patients with FCMD and DMD. Solid line and open triangle, patients with FCMD. Broken line and broken open circle, patients with DMD. (A) Scatter graph showing the relationship between age and left ventricular end-diastolic dimension in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (B) Scatter graph showing the relationship between age and left ventricular end-systolic dimension in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (C) Scatter graph showing the relationship between age and left ventricular ejection fraction in patients with FCMD and DMD. A significant difference is shown between the two correlation lines (p < 0.001). (D) Scatter graph showing the relationship between left ventricular ejection fraction and BNP concentration in patients with FCMD and DMD. The BNP concentrations (Y-axis) are displayed logarithmically. A significant difference is shown between the two correlation lines (p < 0.001). No correlation is seen in patients with FCMD.
correlation with the motor function scores. Indeed, patients with FCMD with mild cardiomyopathy [20] show damage to the cardiac muscle, possibly because they have less severe exercise limitations, which could affect the worsening of cardiac function. However, more severe skeletal muscle phenotypes, which are usually seen in patients with compound heterozygous mutations in exon 3 or intron 5 in fukutin, have no influence on the manifestation of cardiomyopathy or treatment with cardioprotective agents. Therefore, although further analysis of larger samples is needed, we suggest that cardiac muscle damage could mainly be caused by exercise or environmental factors, not by genotype-induced cardiac damage itself. FCMD is a splicing disease, and antisense oligonucleotide therapy for skeletal muscle has been expected to represent a future treatment strategy. However, it has been suggested that antisense oligonucleotides do
not accumulate on cardiac muscle cells [23]. Therefore, an alternative therapeutic strategy is necessary for the management of cardiac dysfunction in patients with FCMD. 4.2. Strengths and limitations of this study This study had certain limitations. First, it was a single-center retrospective study; thus, further multicenter studies might be necessary to confirm our findings. Second, possibly because of the sample limitation, we cannot conclude whether patients with higher motor index scores have more severe cardiac dysfunction due to excess cardiac load or, alternatively, whether patients with lower motor index scores have more severe dysfunction due to serious pathological changes affecting the heart muscle. Further multicenter studies with larger samples might be necessary to clarify this issue.
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Fig. 3. Receiver operating characteristic (ROC) curve for motor function score. (A) The ROC curve shows that the cut-off value for motor function and cardiac involvement was <2 points. When the motor function score was used as the single factor with which to evaluate cardiac involvement, the area under the curve, sensitivity, and specificity were 0.61%, 66.7%, and 59.3%, respectively. (B) The ROC curve shows that the cut-off score for peak motor function and cardiac involvement was <3 points. When the peak motor function score was used as the single factor with which to evaluate cardiac involvement, the area under the curve, sensitivity, and specificity were 0.55%, 66.7%, and 40.7%, respectively.
Fig. 4. Comparison of cardiac involvement-free rate between patients with FCMD and DMD. Survival curves were calculated using the Kaplan–Meier method and analyzed by the log-rank test. The solid line indicates patients with FCMD, and the broken line indicates patients with DMD. The log-rank test revealed a significant difference between the two groups (p = 0.046). Patients with FCMD had a lower risk of a decreased LVEF than did patients with DMD (hazard ratio = 0.348). In patients with FCMD, the cardiac dysfunction-free survival rate did not decline to 50% at the age of 25 years.
Another potential limitation was the small cohort of patients. Given that both FCMD and DMD are rare diseases, however, it might prove difficult to enroll adequate numbers of patients in future studies. Further-
more, the cardiac function of patients was evaluated by echocardiography. Cardiovascular magnetic resonance with gadolinium enhancement has been shown to have an advantage over echocardiography in terms of reproducibility. However, because patients with FCMD have moderate to severe intellectual disability, we considered that magnetic resonance imaging in this population would present challenges. However, echocardiographic evaluation of the LVEF is the most widely used method by which to assess LV function in patients with FCMD and DMD. The American Academy of Pediatrics has recommended that echocardiographic assessment represents the optimum method by which to monitor cardiac dysfunction in patients with muscular dystrophy, and that cardiovascular magnetic resonance imaging should be used in patients with poor echocardiographic acoustic windows [24]. Therefore, we used echocardiographic assessment to evaluate cardiac function in this study. 4.3. Clinical implications Although the rate of cardiac dysfunction in patients with FCMD was lower than that in patients with DMD, patients with FCMD showed a decrease in their LVEF with age. However, no significant relationship was observed between cardiac function and the BNP concentration. Therefore, cardiac function should be routinely assessed and using echocardiography in patients with FCMD, with subsequent follow-up. In summary, patients with FCMD had less severe cardiac dysfunction than did patients with DMD.
Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008
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Funding sources This work was supported by a Grant-in-Aid for Scientific Research (C) JSPS KAKENHI (Grant No. JP15K09621) and by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and Development (AMED; Grant No. 16822810). Disclosure of conflicts of interest The authors have no financial or personal relations that could pose a conflict of interest. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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Please cite this article in press as: Yamamoto T et al. Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. Brain Dev (2017), http://dx.doi.org/10.1016/j.braindev.2017.05.008