Emery-Dreifuss muscular dystrophy is a rare cause of dilated cardiomyopathy in children (approximately 0.2% of cases). Reference Towbin, Lowe and Colan1 It is a neuromuscular disease with three main features: musculoskeletal weakness and wasting, joint contractures, and cardiac disease. Muscle weakness can appear in early childhood (age <15 years); however, muscle wasting progresses slowly. Cardiac involvement usually becomes evident in the second or third decade of life and predominantly manifests as atrial cardiomyopathy (conduction disturbance, atrial standstill, and atrial arrhythmia); furthermore, it is occasionally accompanied by left ventricular systolic dysfunction. Reference Wang and Peng2 We report the case of an 8-year-old girl with Emery-Dreifuss muscular dystrophy, who was diagnosed with acute heart failure without skeletal muscle symptoms.
Case
An 8-year-old girl with a normal family history, normal psychomotor development, and no significant past medical history was referred to our hospital because of nausea, cough, and generalised body swelling. At presentation, her characteristics were as follows: temperature, 36.4°C; pulse rate, 110 beats/min; respiratory rate, 30 cycles/min; and blood pressure, 90/70 mmHg. She had a gallop rhythm, a grade 3/6 parasystolic murmur at the cardiac apex, bibasal crepitation, and hepatomegaly. Chest radiography showed cardiac enlargement (cardio-thoracic ratio, 60%). Echocardiography showed reduced left ventricular systolic function (left ventricular ejection, 25%) with marked ventricular dilation and severe mitral regurgitation. Her laboratory data showed that the troponin T and brain natriuretic peptide levels were 104.4 (upper limit: 26.2 pg/mL) and 2431 pg/mL (upper limit: 18.4 pg/mL), respectively. Cardiac catheterisation on hospitalisation day 9 showed no abnormalities in coronary artery blood flow, and myocardial biopsy showed no evidence of fibrosis other than a mild infiltration by inflammatory cells, which was diagnosed as acute myocarditis. She initiated catecholamine administration for heart failure, but her cardiac contractility and mitral regurgitation were not improved; thus, she was referred to our hospital.
On admission, the patient was stable. Her height was 123 cm (-0.8 SD) and her weight was 17.2 kg (-3.3 SD). A chest radiograph showed mild cardiac enlargement, and a 12-lead electrocardiogram showed reduced amplitude of the P wave and mildly prolonged PR interval, but not atrial or ventricular tachycardia (Fig 1). Holter electrocardiogram showed no arrhythmias. Laboratory data showed mildly increased creatinine kinase (338 U/L) and creatinine kinase-MB levels (26 U/L). Echocardiography showed diffusely decreased cardiac contractility (left ventricular ejection fraction, 40%) and severe mitral regurgitation. Despite heart failure management, cardiac function was not improved; therefore, she underwent mitral valvuloplasty for functional mitral regurgitation. The patient’s condition initially improved and the brain natriuretic peptide levels decreased to 375 pg/mL, but later deteriorated, and she was repeatedly admitted and discharged. Because of the lack of improvement in the course of acute myocarditis, myocardial biopsy was repeated, but there was no fibrosis of the myocardium. Cardiac MRI findings showed delayed enhancement in the ventricular septum to the posterior inferior wall.
Figure 1. Twelve-lead electrocardiography shows reduced amplitude of the Pwave and a mildly prolonged PR interval.
Neurological examination due to prolonged hyperCKemia revealed posterior neck joint contracture and proximal muscle weakness (deltoid manual muscle test; MMT 4-/4-, biceps MMT 4/4). We suspected that the patient may have had a form of skeletal muscle disease, but the dystrophin multiplex-ligation-dependent probe amplification test results and the skeletal muscle MRI findings were normal. Skeletal muscle biopsy showed no abnormal findings, and immunostaining was normal. Genetic testing using next-generation sequencing revealed a mutation in the LMNA gene (c.182T>C:p. Leu6Pro) (Fig 2). We confirmed that the mutation was a de novo mutation, which was not observed in either parent, and she was diagnosed with Emery-Dreifuss muscular dystrophy caused by an LMNA mutation, consistent with the clinical history. She was listed for heart transplantation, as it was difficult to manage her condition with medical treatment alone. Informed consent was obtained from the patient’s parents for publication of this case report.
Figure 2. Sequence analysis of the LMNA gene. A mutation (c.182T>C:p. Leu6Pro) is observed in the proband.
Discussion
We identified two important clinical issues in this study: cardiac complications in patients with Emery-Dreifuss muscular dystrophy can precede neurological symptoms, and muscle and myocardial biopsies can show normal findings even in cases diagnosed with Emery-Dreifuss muscular dystrophy.
First, cardiac complications in patients with Emery-Dreifuss muscular dystrophy can precede neurological symptoms. Cardiac complications usually appear after muscle weakness but can also be early symptoms. Reference Boriani, Gallina and Merlini3 However, in such cases, the symptoms are often related to bradycardia or arrhythmia, Reference Redondo-Vergé, Yaou, Fernández-Recio, Dinca, Richard and Bonne4 and there have been no reports of heart failure being the trigger for diagnosis, as in this case. Generally, the first cardiac complication of Emery-Dreifuss muscular dystrophy is damage to the atrial myocardium and atrioventricular node, which causes atrial standstill and atrial arrhythmias (i.e., atrial fibrillation/flutter and atrioventricular block), and as the disease progresses, damage to the ventricle leads to ventricular arrhythmias and decreased cardiac function. Reference Wang and Peng2 Although there were no subjective symptoms, the patient had joint contracture in the posterior neck, proximal muscle weakness, reduced P-wave amplitude, and mild prolongation of the PR interval on electrocardiography, which were suspected to be features of atrial dysfunction. Particularly, the presence of reduced P-wave amplitude despite atrial enlargement was different from the features of a typical dilated cardiomyopathy. She did not have a slow heart rate, atrial standstill, or advanced atrioventricular block; thus, a pacemaker was not placed.
Second, muscle biopsy and myocardial biopsies can show normal findings even in patients with Emery-Dreifuss muscular dystrophy, as these may not show specific pathological findings. Reference Sewry, Brown and Mercuri5 Myocardial biopsies from the right ventricle have rarely been reported, Reference Sanna, Dello Russo and Toniolo6,Reference Voit, Krogmann and Lenard7 However, pathological myocardial features of Emery-Dreifuss muscular dystrophy at autopsy have been reported, showing fibrosis and replacement of the atrial and ventricular myocardium with adipose tissue. Reference Hara, Nagara, Mawatari, Kondo and Sato8 In our case, muscle biopsy and two myocardial biopsies were performed, but no specific pathological features, such as fibrosis, were observed in either specimen. The reason remains unknown but may be associated with the lack of muscle symptoms and absence of right ventricular dysfunction in the ventricular specimen that was biopsied. The observation of normal findings in the muscle or myocardium does not exclude a diagnosis of Emery-Dreifuss muscular dystrophy. When Emery-Dreifuss muscular dystrophy is suspected, genetic testing is useful for establishing a subtype-specific diagnosis. Reference Sewry, Brown and Mercuri5,Reference Heller, Shih, Kalra and Kang9
As this disease does not cause mental development disorders and the skeletal muscle symptom progression is slow, heart transplantation may be needed. Reference Wu, Gupta and Brown10 This case was also considered a good candidate for heart transplantation as the cardiac symptoms at rest were very mild.
In conclusion, Emery-Dreifuss muscular dystrophy is a mild, slowly progressive, neuromuscular disorder with few subjective symptoms; therefore, cardiac complications, particularly cardiac dysfunction, can be the initial manifestation. Skeletal muscle biopsy and myocardial biopsy may not be diagnostic, and genetic testing should be performed if this disease is suspected.
Acknowledgements
The authors are grateful to Dr Kenji Kurosawa for providing useful discussions.
Funding
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of interest
None.
Ethical standards
Not applicable.
