Danon disease is an X-linked dominant cause of debilitating cardioskeletal myopathy and is a lysosomal storage disorder.
Although considered rare, the exact incidence is unknown .
Danon disease is characterized by the triad of :
- the most prominent clinical feature, and may be an isolated feature
- generally a hypertrophic cardiomyopathy, which can be massive, is seen, however, a dilated cardiomyopathy may be appreciated in affected females or in end-stage disease in affected patients from either gender
- progression to congestive heart failure, usually with preserved ejection fraction (HFpEF), is inevitable
- most patients also develop arrhythmias, especially Wolff-Parkinson-White syndrome
- skeletal myopathy
- mild progressive proximal muscle weakness
- serum creatine kinase levels are usually also elevated
- intellectual disability
- usually mild in severity
Given the inheritance pattern, males are more severely affected, with symptoms manifesting in childhood or adolescence . Affected females generally have a late-onset clinical presentation .
Danon disease is X-linked dominant and is caused by mutations in the LAMP2 gene, which normally encodes for the lysosome-associated membrane protein-2 (LAMP-2) . The exact function of LAMP-2 is yet to be determined, however, a prominent theory suggests that it has a role in aiding fusing autophagic vacuoles with the lysosome, which in turn allows for the transport of cellular materials into lysosomes .
Deficiencies of LAMP-2, therefore, are thought to result in a slowing of this fusion process and a subsequent accumulation of autophagic vacuoles (proven microscopically) , especially in skeletal and cardiac muscle, which may have a role in the development of the clinically observed myopathies .
Most patients exhibit findings in-keeping with massive (or 'mammoth') concentric hypertrophic cardiomyopathy (see article for general discussion of echocardiographic features) . Left ventricular thickness may be as high as 65 mm, the largest ever reported in medical literature , often with a normal ejection fraction . However, as aforementioned, echocardiographic features more in-keeping with a dilated cardiomyopathy (see article for general discussion) may be appreciated in affected females or in end-stage disease in either affected patients from either gender .
Cardiac MRI (CMR) is able to more precisely characterize the concentric hypertrophic cardiomyopathy (see article for general discussion of CMR features), and resultant changes to cardiac hemodynamics, caused by Danon disease . Late gadolinium enhancement, often indicative of fibrosis, is nearly always seen in affected patients, most commonly involving the lateral wall but also the anterior and posterior walls, in a subendocardial, intramyocardial or transmural distribution . The degree of fibrosis is important because when severe, has been suggested to be an indication for an implantable cardioverter defibrillator to prevent sudden cardiac death from arrhythmogenic events .
Treatment and prognosis
The mainstay of treatment is cardiac transplantation . While awaiting transplantation, treatment should be enacted for congestive cardiac failure, including consideration of an implantable cardioverter defibrillator to prevent sudden cardiac death, especially in patients with a high degree of fibrosis shown on cardiac MRI . In patients with concurrent arrhythmias, cardiac ablation should also be considered . Patients usually do not require treatment for myopathy.
Prognosis is very poor without cardiac transplantation, with males usually surviving until their early twenties, and females their early thirties . Studies describing the follow-up of patients with cardiac transplantation are rare, however, it is thought that long-term survival can occur .
History and etymology
The disease is named after Moris J Danon, an American neurologist, who described the disease initially as 'lysosomal glycogen storage disease with normal acid maltase' with his colleagues in 1981 . The condition has since been shown to not be a glycogen storage disease, and thus the original name should not be used.