Resident Physician University of calgary Calgary, Alberta, Canada
Case background: The correct classification of cardiomyopathy gene variants has important diagnostic, prognostic, therapeutic and reproductive management implications for the proband and first-degree relatives. We demonstrate the functional significance of a novel hemizygous DMD variant that caused dystrophin-deficient cardiomyopathy.
A 36-year-old male presented to hospital with cardiogenic shock after about three months of progressive dyspnea and pre-syncopal events that were increasing in frequency. Initial echocardiography showed a left ventricular ejection fraction of 10.7% with severe mitral regurgitation, moderate to severe tricuspid regurgitation, and a moderately dilated right ventricle with severe right ventricular dysfunction. Cardiac MRI showed severe biventricular dilation and dysfunction. The patient remained inotrope-dependent and required a HeartMate 3 left ventricular assist device (LVAD) as a bridge to transplant. Genetic testing revealed a hemizygous DMD c.4857_4859del variant of uncertain significance. This variant results in the deletion of 1 amino acid in the DMD protein but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). The functional significance of this variant was unknown at that time.
Of note, on investigation, our patient was also found to have a chronically elevated creatine kinase level with the range being 1340-2199 U/L (normal 30-350U/L). Right heart catheterization (RHC) prior to LVAD, while off of inotropic support with milrinone, showed pulmonary artery pressures (PA) of 59/39 (45) mmHg. Cardiac output of 4.8 litres/minute, and a left ventricular end diastolic pressure (LVEDP) of 33 mmHg. Post-LVAD RHC was normal, with right atrial mean pressure of 4 mmHg, PA 24/10 (15) mmHg, LVEDP of 6 mmHg, cardiac index of 2.64 L/min/m2 by Fick and a pulmonary vascular resistance (PVR) of 1.8 woods units.
About two years post-LVAD implantation, the patient received a heart transplant. We performed dystrophin staining on the explant to determine the functional significance of the DMD variant. Dystrophin staining confirmed the absence of several functional domains localized near the N-terminus, consistent with dystrophin deficiency. Cascade predictive genetic testing identified the familial variant in his two brothers, who also have dystrophin-deficient cardiomyopathy, as well as his mother.
Management Challenges: Management in this case was based on necessity. In order for the patient to come off of inotropic support, he required LVAD implantation as a bridge to cardiac transplant. There are many complications that come from living with an LVAD, and our patient experienced firstly a hemothorax that required bilateral thoracotomy with insertion of bilateral chest tubes. He then developed a driveline infection with methicillin sensitive staphylococcus aureus (MSSA) bacteremia that was acutely treated and then managed with long-term suppressive antibiotics in the form of doxycycline up until the time of transplant.
After transplant, the donor heart had complete sinus node arrest. There were few, unconducted P waves that were initially thought to be due to an atrioventricular block, but were finally deemed to be coming from the remnant recipient sinus node. At about seven days post-transplant, the donor sinus node began functioning normally and until that time, the patient was atrially paced with epicardial pacing.
Despite these complications, our patient has done well post-transplant.
Conclusion: Dystrophin-deficient cardiomyopathy results in progressive heart failure and the risk of sudden cardiac death. We demonstrate the functional significance of a novel hemizygous DMD c.4857_4859del variant to reclassify it as likely pathogenic. This has important diagnostic, prognostic, therapeutic, and reproductive management implications.
For instance, confirmation of diagnosis for the proband may have significant reproductive implications, but will also allow for therapeutic interventions, especially in the cases where gene variants may hold a high risk of adverse outcomes. The adverse outcomes in these cases include advanced heart failure and sudden cardiac death, in which intervention including implantable cardioverter-defibrillators may be warranted.
Similarly, for first-degree relatives who may not yet have an obvious phenotype related to dystrophin-deficient cardiomyopathy, there is now research to support prophylactic therapy in the form of Angiotensin Converting Enzyme Inhibitors for those with Duchenne Muscular Dystrophy leading to reduced heart failure hospitalizations as well as overall survival improvement.
Not only does genetic testing have real implications for our probands and family members clinically, but it is also shown to be cost effective to use cascade genetic testing versus periodical clinical surveillance alone, in asymptomatic relatives of those with dilated cardiomyopathy to conduct clinical surveillance. Cascade testing includes surveillance of confirmed carriers, while being able to exclude risk in non-carriers. This allows for resources to be placed where there is need, alleviating both the anxiety of family members who are deemed to be non-carriers, as well as alleviating an unnecessary long-term screening burden on the healthcare system.
