An eight-year-old Hispanic boy presented with persistent palpitations. Past medical history included asthma, myopia, hypothyroidism, and speech delay. Family history was unremarkable for muscular dystrophies, cardiomyopathy, arrhythmias, or sudden cardiac death. On physical examination, he was hemodynamically stable. A grade 3/6 pansystolic murmur along the left lower sternal border was appreciated. Interestingly, no skeletal muscle disease was appreciated as the patient had 5/5 strength present bilaterally in upper and lower extremities.\nPertinent labs () included elevated brain natriuretic peptide (average 5228 ± 3660 pg/mL; normal <100 pg/mL), elevated creatine kinase (average 649 ± 105 U/L; normal 94–499 U/L), elevated AST (average 363 ± 44 U/L; normal 10–40 U/L), and elevated ALT (average 225 ± 47 U/L; normal 7–56 U/L) levels. No troponin levels were reported. Electrocardiogram (ECG) showed a Wolf-Parkinson-White (WPW) with a left bundle branch block pattern, and peaked QRS complexes consistent with hypertrophic cardiomyopathy (). Echocardiogram revealed hypertrophic cardiomyopathy (HCM) with initial septal thickness of 26 mm.
A 46-year-old man was referred to our cardiology office in 2014. He stated that he had a history of heart problems and denied any other medical problems. He also denied any familial history of mental retardation, disorders of musculoskeletal development, cardiac disease, or sudden death.\nOn a review of the records obtained from his former physician’s office, we noted that he had experienced a pre-syncopal episode in 2005. At that time, an electrocardiogram (EKG) had shown a high degree atrioventricular block, and a transthoracic echocardiogram (TTE) revealed an ejection fraction (EF) of 65%, with an intraventricular septum thickness of 3 cm. Doppler interrogation of the left ventricle outflow tract demonstrated a peak velocity of 1.4 m/sec (normal < 1.7 m/sec). He had been diagnosed with hypertrophic cardiomyopathy (HCM) while a cardiac catheterization revealed nonobstructive coronary arteries. Subsequently, he had undergone the placement of an implantable cardiac defibrillator (ICD) in 2006, as there was a significant risk of sudden cardiac death in a setting of HCM and a high degree atrioventricular block.\nHe continued to follow up with a cardiologist and serial follow-up TTEs were performed. One notable feature was septal thickness, reduced to 1.6-1.9 cm in 2010 and the EF reduced to 69% in 2010 and 45%-50% in 2011. Thus, disease progression in this patient involved the thinning of the walls and transition to a dilated cardiomyopathy.\nThe patient was lost to follow-up for a few years after 2011. In 2014, he finally presented to our office. After a review of all the records, we considered the possibility of a genetic disease. Genetic testing for hypertrophic cardiomyopathy involved sequencing nine sarcomeric genes and three metabolic genes. The sarcomeric genes tested involved the synthesis of the following proteins – beta-myosin heavy chain, myosin-binding protein C, troponin T, troponin I, troponin C, alpha-tropomyosin, regulatory myosin light chain 2, essential myosin light chain 3, and cardiac actin. The metabolic genes tested were Anderson-Fabry disease (GLA), Danon disease (LAMP-2), and familial Wolff-Parkinson-White syndrome (PRKAG2).\nGenetic testing revealed a substitution of thymine to cytosine at position 52 (NM_002294.2, NM_013995.2(LAMP2):c.52T>C) in exon 1 of the LAMP-2 gene, resulting in a Cys18Arg mutation. A mosaic pattern was not seen. Our search led to the discovery of no other identifiable etiology of this patient’s cardiac pathology besides this genetic mutation. We thus believe that this genetic variation is in fact pathogenic.\nSubsequently, the patient was informed that his cardiac condition had been traced to a genetic mutation. Since DD also involves skeletal myopathy and neurocognitive derangements, the patient was referred to a neurologist for a formal assessment of these conditions. His creatinine kinase was 404 (normal range: 30-200 U/L), but no neuromuscular abnormalities were detected on electromyographic testing. Furthermore, no cognitive defect was detected. The patient was also advised to have his family members genetically and phenotypically tested. His two children had normal results. The patient is not in touch with his parents and siblings, and, hence, they were not tested. Hence, it is unclear whether the patient has a de novo mutation or an inherited disorder. However, given the absence of any reports of a familial disease similar to that of the patient, it is quite likely that this is a de novo mutation.\nIn 2016, he developed exertional dyspnea during daily activities. The EKG revealed a 100% paced rhythm and the TTE showed a significantly dilated left ventricle (LVEDD of 6.6 cm, septal thickness of 1.3 cm) with an EF of 25% (Figure ). His symptoms fell in the New York Heart Association Class 2 of congestive heart failure, guideline-directed medical therapy, including carvedilol, lisinopril, and spironolactone, were initiated. Cardiac resynchronization therapy was recommended, but the patient declined it. His symptoms have gradually improved with medical treatment and, later, lisinopril was switched to sacubitril/valsartan. Patients with Danon disease are generally referred for evaluation for heart transplantation soon after diagnosis. However, since our patient’s disease progression is much less severe and he has responded to medical therapy, we have opted to hold off on the transplantation process.