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.
A 19-year-old man, previously in good health, was hospitalized for intermittent heart palpitations. There was no family history of cardiomyopathy, arrhythmia, or sudden cardiac death. His sister had died of cirrhosis at age 12 years, but the exact cause of this cirrhosis was unknown. A physical examination showed that this patient was hemodynamically stable. An electrocardiogram (ECG) showed Wolff–Parkinson–White (WPW) syndrome with paroxysmal wide QRS tachycardia (Fig. A and B). An echocardiogram revealed left ventricular wall thickening, suspected hypertrophic non-obstructive cardiomyopathy, and myocardial amyloidosis with an initial septal thickness of 17 mm and a left ventricular wall thickness of 13 mm (Fig. A and B). Pertinent laboratory test results (Table ) included elevated serum concentrations of myo-inositol (667.5 ng/mL, normal < 107 ng/mL), cardiac troponin (CTnI; 0.187 ng/mL, normal < 0.05 ng/mL), creatine kinase-MB (5.40 ng/mL, normal < 4.3 ng/mL), aspartate aminotransferase (262.5 U/L, normal 15–40 U/L), and alanine aminotransferase (136.1 U/L, normal 9.0–50 U/L). During the process of radiofrequency ablation, the patient repeatedly showed atrioventricular block (AVB; Fig. C). However, after 3 radiofrequency ablation procedures, his WPW disappeared, but he continued to show second degree AVB (Fig. D).\nTwo years after radiofrequency ablation, the patient was again hospitalized for palpitations and dizziness. On physical examination, his apical beat was diffuse, his cardiac boundaries were enlarged to the left, and systolic murmurs were heard in the auscultation areas of his bicuspid and tricuspid valves. ECG indicated atrial flutter, WPW, and third-degree AVB (Fig. E and F). An echocardiogram showed that myocardial densification was incomplete, his left atrium and ventricle were enlarged, his left ventricular beat was diffusely weakened, and his systolic function was reduced. His mitral and tricuspid valves showed regurgitation and thickening of the interventricular septum, with a left ventricular diastolic diameter of 68 mm, a left ventricular wall thickness of 9 mm, a septal thickness of 12 mm, and an ejection fraction of 46% (Fig. C and D). Furthermore, cardiovascular magnetic resonance imaging (CMRI) indicated suspected amyloidosis of the cardiac muscle (Fig. ). His laboratory test results had deteriorated since his previous admission, with his serum myo-inositol, creatine kinase-MB, aspartate aminotransferase, and alanine aminotransferase concentrations being higher than before, and his brain natriuretic peptide concentration being elevated (824.0 pg/mL, normal < 100 pg/mL) (Table ). Amyloid cardiomyopathy was excluded by performing relevant laboratory tests and pathological diagnosis of the adipose tissue attached to the walls. Hyperplasia was observed in the fibrous tissue of the dermis, along with widening of the subcutaneous fat lobule space and positive Congo red staining (Fig. ). These results did not support a diagnosis of amyloid cardiomyopathy (Table ), and the transthyretin (TTR) gene was negative. A cardiac resynchronization therapy pacemaker was implanted to relieve the patient's clinical symptoms. Fifteen days later, he returned to our hospital because of a skin infection at the pacemaker implantation site and was given a permanent replacement pacemaker.\nOne month later, the patient was again hospitalized at our institution because of repeated aggravation of heart failure and the appearance of symptoms of restlessness and confusion. No abnormality was found on computed tomography of the head. No improvement was observed after symptomatic treatment, and he died of cardiac arrest.\nSubsequent genetic testing revealed that this patient was hemizygous for a previously unreported deletion mutation (p.Gly221Ilefs∗19) in the LAMP2 gene, confirming the diagnosis of Danon disease (Fig. ). A myocardial biopsy was not performed.