Severe Dilated Cardiomyopathy in a Patient With Myotonic Dystrophy Type 2 and Homozygous Repeat Expansion in ZNF9

Cardiomyopathy is a well-recognized association in skeletal myopathies such as Duchenne, Becker, and Emery-Dreifuss muscular dystrophy, sarcoglycanopathies, glycogenosis disorders, mitochondrial myopathies, and myotonic dystrophy type 1 and 2.1 Myotonic dystrophy type 2 (DM2), also known as proximal myotonic myopathy, is an autosomal-dominant disorder characterized by myotonia (90%) and muscle dysfunction (82%).2 Other less common clinical manifestations include posterior subcapsular cataracts, insulin-insensitive diabetes mellitus type 2, testicular failure, and a variety of cardiac abnormalities including supraventricular tachycardia, atrial fibrillation, ventricular ectopy, and heart failure.3 Dilated cardiomyopathy and noncompaction cardiomyopathy have been reported in DM2 as well.4,5 Expansion of the CCTG within a complex repeat motif, (TG)n(TCTG)n(CCTG)n, in the first intron of the gene zinc finger protein 9 ZNF9 (CNBP) causes DM2. The normal allele size of the complex repeat is between 104 bp and 176 bp. RNA transcribed from the expanded allele results in toxic effects within the cell. Specifically in DM1, RNA containing the abnormal repeat interacts with RNA-binding proteins that then lead to downstream effects that can disrupt regulation of alternative splicing, mRNA translation, or mRNA stability.6 A 65-year-old patient presented with a 4-year history of worsening exercise intolerance. She was only able to walk for 5 minutes before developing dyspnea, chest discomfort, and angina. In addition, she noted difficultly in rising from the floor or a low chair without assistance and had occasional diplopia, mild dysphagia, and skeletal muscle weakness. Her medical history was significant for cataracts and multiple cardiac procedures. She was diagnosed with multivessel coronary artery disease and underwent coronary artery bypass surgery 4 years prior to presentation. She had progressive symptoms compatible with heart failure and underwent mitral and tricuspid valve repairs for regurgitant valve disease a year later. At that time, she also had removal of a papillary fibroelastoma from the aortic valve. She continued to have symptoms of chest fullness, shortness of breath, and fatigue. She underwent coronary angiography and had percutaneous stenting 1 year prior to this admission. After each intervention she had only temporary relief of her symptoms with subsequent recurrence. As well, she developed atrial fibrillation and New York Heart Association class III heart failure. She was referred to our institution for additional management. Her medications included oral digoxin 0.125 mg daily, metoprolol 12.5 mg daily, lisinopril 10 mg daily, furosemide 40 mg daily, isosorbide mononitrate 30 mg daily, rosuvastatin 2.5 mg daily, aspirin 81 mg daily, and warfarin 2.5 mg daily. She was treated with milrinone, which was discontinued due to lack of clinical benefit. The patient’s family history was notable for a brother who died at age 33 after a heart transplant for cardiomyopathy and a sister who died at 42 after her second mitral valve replacement for what was thought to be rheumatic heart disease (Figure 1). A sister also underwent ablation for an irregular heartbeat. Her two other brothers are alive; the oldest had a myocardial infarction in his 60s, and the other brother had a coronary stent in his 60s. Her father died in his 50s from an unknown cancer and her mother died at the age of 85 after hip surgery. Both of her children and all her nieces and nephews are alive and clinically asymptomatic. Pedigree from a myotonic dystrophy type 2 (DM2) family with the proband indicated by an arrow. The numbers below the pedigree symbols represent repeat length in the 4 individuals who were genetically tested. Aside from the proband, the other genetically tested individuals with a single DM2 repeat expansion are asymptomatic for neuromuscular or cardiac symptoms. The proband had muscle weakness, cataracts, and dilated cardiomyopathy. On initial physical examination, she was a thin woman with frontal balding. Her cardiac examination was significant for jugular venous distention noted to the jaw line. She had an irregularly, irregular heart beat with an S3 gallop and a left ventricular heave. Bibasilar rales were heard to the mid-chest. She had 3+ pitting edema to the thighs bilaterally. Her neurologic examination showed mild weakness in the deltoids, biceps, finger extensors, finger flexors, and iliopsoas muscles. Reflexes were hypoactive and grip myotonia was present. Surface electrocardiography results showed atrial fibrillation with a right bundle branch block, left anterior fascicular block, and a prolonged QTc of 497 ms. Transthoracic echocardiography showed a mildly dilated left ventricle with severely reduced left and right ventricular function and biatrial dilation with an ejection fraction of 20% to 25%. Right and left heart catheterization demonstrated patent grafts with elevated filling pressures (right atrial pressure of 18 mm Hg, right ventricular pressure of 51/13 mm Hg, pulmonary artery pressure of 50/23 mm Hg with a mean of 32 mm Hg, and pulmonary capillary wedge pressure of 20 mm Hg). Her pulmonary artery saturation was 38% with a cardiac output of 2.4 L/min by Fick and a cardiac index of 1.5 L/min/m2 (Figure 2). (A) Surface electrocardiography showing atrial fibrillation, right bundle branch block, left anterior fascicular block, and a prolonged QTc of 497 ms. (B) Transthoracic echocardiography in the apical 4-chamber and parasternal short-axis views showing a mildly dilated left ventricle and dilated atria consistent with restrictive cardiomyopathy with concomitant severely reduced left and right ventricular function with a left ventricular ejection fraction of 20% to 25%. (C) Right atrial pressure tracing showing elevated pulmonary capillary wedge pressure of 18 mm Hg. (D) Chest film showing mildly enlarged cardiac silhouette with small right pleural effusion and generalized haziness. Electromyography testing showed prominent myotonic discharges. Genetic testing for myotonic dystrophy type 1 was normal. Muscle biopsy revealed features of a chronic and active myopathy with the presence of peculiarly atrophic fibers and markedly increased internal nuclei consistent with myotonic dystrophy. At the age of 67, the patient died of heart failure. Dystrophy type 2 genetic testing of the proband (II.2) showed that the patient had a 15,600-bp expansion on one allele of ZNF9 and a 4700-bp expansion on the other allele. Subsequent testing in the family showed that her asymptomatic brother (II.1) had a 3600-bp expansion in one allele. Her daughter (III.1) was found to have a 1300-bp expansion, and her son (III.2) had a 900-bp expansion (Figure 1). Both children were asymptomatic. On echocardiography, the daughter had borderline left ventricular enlargement and the son had borderline left atrial enlargement. While there have been multiple reports of homozygosity in myotonic dystrophy type 1, homozygosity for the CCTG expansion in ZNF9 is extremely rare due to the rarity of DM2, with only one published report from a large consanguineous family.7 In this report, the oldest homozygote had the most severe DM2 phenotype within her family. She had leg weakness starting at age 40, cataracts at 46, diabetes mellitus, ventricular arrhythmia, and dilated cardiomyopathy. Her two homozygous affected sisters had milder symptoms at the time of the report. After comparison with 6 other heterozygous family members, the authors concluded that homozygotes within this family demonstrated a similar clinical course with no significant difference in muscle histology and brain imaging. However, in our family, biallelic expansions appear to demonstrate a more severe phenotype, although we have limited genotypic information on other family members. Presumably both parents were carriers, yet neither demonstrated symptoms of DM, although her father died early in his 50s of cancer. Her brother, who is a proven carrier, has no symptoms of DM2 in his 60s. The deceased brother (II.3) and sister (II.6) may both have been homozygotes like the proband and this hypothesis could explain the early symptoms and severity of disease. Unfortunately, a major limitation of our report is the inability to genotype these deceased individuals. Finally, although young, both of the proband’s children who are carriers have been thoroughly evaluated and are currently disease-free. Dystrophy type 2 is generally thought to be less severe and to have less cardiac involvement than its related disorder myotonic dystrophy type 1. However, it is now becoming recognized that severe cardiomyopathy can occur in DM2 as well.4 Early recognition of cardiac manifestations is important because there are therapies available that can modify the clinical course. Surveillance for individuals with primary myopathies should include an electrocardiogram and echocardiogram. Ambulatory 24-hour Holter monitoring, exercise stress test, single-photon emission computed tomography, cardiac magnetic resonance imaging (MRI), positron emission tomography, coronary angiography, or myocardial biopsy may also be needed to diagnose the condition, particularly if the neurologic diagnosis is not definitive and to further define the phenotypic expression.1 One study has suggested that cardiac MRI/magnetic resonance spectroscopy may be a more sensitive tool for evaluation for cases in which subclinical cardiomyopathy is suspected.8 Atrioventricular and intraventricular conduction delay is common in myotonic dystrophy. Arrhythmias can occur early on or often even before the onset of neuromuscular symptoms and can sometimes lead to sudden cardiac death.9 At the present time, cardiac manifestations are much better studied in myotonic dystrophy 1. Studies in these patients have shown that conduction disease and prolongation of the PR and QTc intervals are associated with a higher risk of sudden cardiac death.10 One DM2 case-control study found that conduction defects were less frequent in DM2 patients when compared with age-matched type 1 patients but that supraventricular arrhythmias had a similar prevalance.11 One study by Schoser and colleagues12 found the frequency of sudden cardiac death before the age of 45 in DM2 patients to be 4 in 297. All 4 patients had dilated cardiomyopathy, and cardiac histopathology demonstrated pathogenic CCUG ribonuclear inclusions in the cardiac myocytes. The efficacy of pacemaker/defibrillator implantation in this population is not well defined. Although an automated implantable cardioverter-defibrillator will prevent sudden death, heart failure, respiratory failure due to diaphragmatic involvement, and skeletal muscle weakness are progressive and fatal. Physicians should be aware of the risk of cardiac complications in DM2 patients, especially in those rare patients with two ZNF9 repeat expansions. Close cardiac monitoring with biannual echocardiograms and electrocardiographs should be considered in all genetically at-risk ZNF9 carriers. Initiation of cardiac medications may slow the progression of disease or attenuate heart failure symptoms.