Discussion

Danon disease was first identified in two males with myopathy, cardiomyopathy, and mental retardation in 1981 as “lysosomal glycogen storage disease with normal acid maltase activity,” also called Glycogen Storage Disease Type 2b. ^{Reference Danon, Oh and DiMauro1} It was later discovered that it is caused by the LAMP-2 mutation, which results in a lack of lysosome-associated membrane protein that is associated in intracellular waste and senescent organelle autophagy. ^{Reference Cenacchi, Papa, Pegoraro, Marozzo, Fanin and Angelini2} Accumulation of intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal muscle and myocardial cells constitutes the basic pathophysiology of the disease. The LAMP-2 mutation has been found in 4%–6% of children with hypertrophic cardiomyopathies. ^{Reference Cenacchi, Papa, Pegoraro, Marozzo, Fanin and Angelini2,Reference Hayashi, Tanimoto and Hirayama-Yamada3}

Danon disease is a multisystemic disease with a classic triad of cardiomyopathy, myopathy, and mental retardation. There may also be involvement of the eyes, liver, and, in rare cases, the lungs. Symptoms in males occur in early childhood and in adolescence and young adulthood in females. ^{Reference Boucek, Jirikowic and Taylor4} While the earliest symptom onset age reported in the literature was 4 months, the age at diagnosis range from 0 to 65 years. ^{Reference Bertini, Donati and Broda5,Reference Lotan, Salazar-Mendiguchía and Mogensen6} While our first case was asymptomatic, second case was found to be symptomatic for the first time when she was 16 years old.

Almost all patients have cardiac involvement and present with fatigue, chest pain, palpitations, or syncope. While hypertrophic cardiomyopathy is seen in 96% of males, dilated cardiomyopathy can be seen in 27%–29% of females. ^{Reference Brambatti, Caspi and Maolo7} Biventricular hypertrophic cardiomyopathy was evident in our cases. In addition, as a result of diffuse hypertrophy, fibrosis and scar tissue formation, many types of arrhythmias can be seen, such as conduction disorders, accessory pathways, and atrial and ventricular arrhythmias. Wolff-Parkinson-White (WPW) pattern and pre-excitation due to fasciculoventricular pathways are seen in 33%–69% of male patients and 27%–43% of females. ^{Reference Lotan, Salazar-Mendiguchía and Mogensen6,Reference Jhaveri, Herber, Zahka, Boyle, Saarel and Aziz8} In our cases, Wolff-Parkinson-White pattern was also evident on electrocardiogram, and in our second case, ventricular tachycardia attacks were also present. Skeletal myopathy manifests as proximal muscle weakness, myalgia, and limited exercise tolerance. The creatinine kinase elevation seen in most patients was also present in our cases.

Danon disease should be considered in every patient with hypertrophic cardiomyopathy, skeletal myopathy, and neurocognitive findings. Electrocardiography, liver transaminase, serum creatinine kinase, lactate dehydrogenase, brain natriuretic peptide, and troponin levels should be examined in cases of clinical suspicion. Arrhythmias should be screened with 24-hour rhythm Holter monitoring in the presence of normal electrocardiography results. Electromyography supports the diagnosis of myopathy. Echocardiography is the gold standard for the diagnosis of hypertrophic or dilated cardiomyopathy. The use of cardiac MRI is increasing in the evaluation of myocardial scarring, oedema, and fibrosis. ^{Reference Rigolli, Kahn, Brambatti, Contijoch and Adler9} Definitive diagnosis can be made by mutation analysis for LAMP-2 gene.

The major goals of treatment are to alleviate heart failure, prevent sudden death, and avoid neurological impairment. Diuretic and calcium channel blockers that have the potential to cause hypovolemia should be avoided, and competitive sports and heavy exercise should be forbidden. The American Heart Association recommends implantable cardioverter defibrillator implantation for patients with a history of cardiac arrest, sustained ventricular tachycardia, or ventricular fibrillation. ^{Reference Ommen, Mital and Burke10} Implantable cardioverter defibrillator implantation was recommended to our female patient, but her family did not approve. Despite all these approaches, heart failure is progressive and death is inevitable if cardiac transplantation is not performed. Genetic counselling is recommended for all families in Danon disease. Studies on autophagy-modifying agents and gene therapy are still ongoing.