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 23-year-old man had Danon disease from the age of 12 years, when symptoms began, until 23 years old when he succumbed to his disease. He was first admitted to the Affiliated Hospital of Jining Medical University at 12 years old because of transient loss of consciousness with palpitation. He had suffered from a poor ability of physical activity, mild mental retardation, and learning difficulty. Pansystolic murmur along the left lower sternal border was not observed. Echocardiography showed HCM with a maximum left ventricular end-diastolic diameter (LVEDd) of 45 mm, left ventricular posterior wall (LVPW) thickness of 12 mm, maximum interventricular septal (IVS) thickness of 11 mm, and left ventricular ejection fraction (LVEF) of 60%. Electromyography showed normal muscle strength and deep tendon reflexes. He was diagnosed with Danon disease at 13 years of age in Beijing Union Hospital by genetic testing, which showed that he carried a deletion mutation (c.257_258delCC) in exon 3 of the LAMP-2 gene. An endomyocardial biopsy and electron microscopic examination showed autophagic vacuoles. ECG showed type B Wolff–Parkinson–White (WPW) syndrome, a high voltage in the left ventricle, and an inverted T wave (). He then underwent successful ablation in Beijing Union Hospital. He was asymptomatic for the next 3 years.\nAt the age of 17 years, he had persistent palpitations and visited the hospital. ECG () showed an ectopic rhythm, paroxysmal supraventricular tachycardia, complete left bundle branch block, and high voltage in the left ventricle. He switched to sinus rhythm following treatment with propafenone. However, an ECG () showed ventricular premature contraction. At a physical examination, a heaving apical impulse and a grade 4/6 pansystolic murmur along the left lower sternal border were observed. Follow-up echocardiography indicated that left ventricular hypertrophy of the patient progressively worsened (). MRI was performed and showed LGE in the muscular interventricular septum and the front wall of the left ventricle. However, the liver and bilateral gastrocnemius skeletal muscles were negative for LGE (). This process of cardiac hypertrophy was rapidly advancing at this stage.\nIn the next 4 years, HCM progressed to the dilated phase. The LVEDd increased from 44 to 58 mm, while the IVS decreased from 24 to 19 mm and LVPW decreased from 31 to 17 mm. The LVEF was reduced from 60% to 22% (). At the age of 23 years, an ECG () showed atrial fibrillation. An MRI () showed that gadolinium contrast enhancement was visible in the liver, psoas muscle, and bilateral gastrocnemius muscles. These abnormal findings manifested with the classic triad of cardiomyopathy, skeletal myopathy, and intellectual disability in this patient. He received an automatic implantable cardioverter-defibrillator, even after considering a heart transplant, which he refused, and he finally succumbed to his disease with sudden cardiac arrest. Unfortunately, the patient did not undergo an investigation of his device to identify the trigger for cardiac death.\nDuring the 10-year follow-up, pertinent laboratory examination values, including creatine kinase (CK), creatine kinase isoenzyme (CK-MB), hydroxybutyrate dehydrogenase, alanine aminotransferase (ALT), aspartate aminotransferase, and lactic dehydrogenase levels, were considerably elevated (). Echocardiographic data indicated that HCM had progressed into DCM ().