This study is the first attempt to evaluate the prevalence of Danon’s disease among a large population of patients with a previous diagnosis of HCM. The findings may therefore have implications for the diagnosis strategy of such patients. We found a mutation in two index patients. The prevalence in the total HCM population is 1% of all index cases (two of 197), or 3% of index cases without mutations in sarcomeric genes (two of 73) or 4% of index cases in the molecular analysis (two of 50). Interestingly, the frequency was closely related to the associated phenotype. Danon’s disease was responsible for half of the index cases (two of four) of HCM in patients who evolved towards clinical skeletal myopathy. In addition, Wolff-Parkinson-White syndrome was present in one and second degree atrioventricular block in both of these patients. In contrast, no mutation was found in isolated HCM (fig 1), in subgroups with HCM and Wolff-Parkinson-White syndrome (without skeletal myopathy), or in HCM and isolated CK increase.
A diagnostic strategy may be proposed to improve identification of patients with Danon’s disease, based on our results (in the specific context of patients with a previous diagnosis of HCM) and on results from previous studies (through the description of the clinical features of patients with Danon’s disease).8,9
As a first step, all patients with idiopathic HCM should be considered, whatever the familial context, except when it is a familial form with a male to male transmission (which excludes X linked disease). All of these patients should benefit from careful clinical and biological evaluation, including clinical muscular testing and determination of serum CK concentration, to search for additional features of Danon’s disease. Interestingly, in previous studies skeletal myopathy was mild in most cases (85%) but all male patients had increased serum CK concentration.9
Wolff-Parkinson-White syndrome was present in 35%, mild mental retardation was observed in 70%, and most patients had HCM and low ejection fraction.9
Women were less severely affected, with later onset cardiomyopathy. As a second step, and on the basis of our results, we propose that Danon’s disease can be reasonably excluded when HCM is isolated (without associated abnormalities). In contrast, in the presence of unusual clinical associations (especially HCM and clinical skeletal myopathy), the diagnosis of Danon’s disease should be discussed further. Other hereditary cardiac diseases should also be discussed (such as mitochondrial myopathy, glycogen storage disorders, and PRKAG2 gene related disease) because of overlapping clinical features (especially skeletal muscle disease and Wolff-Parkinson-White syndrome). As a third step, direct molecular screening of the LAMP2 gene should be performed to confirm or exclude Danon’s disease. An alternative would be to take a skeletal muscular biopsy to search for vacuolar myopathy, and if it is present, to analyse the biopsy immunohistochemically with specific LAMP2 antibodies. However, molecular genetic screening is less invasive, possibly more efficient or sensitive (if mutations do not lead to a stop codon and the absence of the protein), and remains the criterion of reference in women (where the protein may be present because of one normal X chromosome).
To distinguish HCM from Danon’s disease may be important, as the pathophysiology, clinical evolution, prognosis, mode of inheritance, and therefore genetic counselling are very different. Firstly, the natural history of Danon’s disease seems to be characterised in male patients by an early onset and a very poor prognosis. This was the case in our two patients with heart failure and death at 22 and 25 years. In the largest population studied so far (20 male patients), the mean age at onset was less than 20 years in all cases and all patients except one died before 30 years.9
Deaths were related to left ventricular dysfunction and congestive heart failure or sudden death. This is in contrast with the natural history of HCM, where cardiac death is evaluated to be about 1–2% a year and only 10% evolve towards heart failure.10,11
Secondly, and contrary to HCM, the clinical spectrum of Danon’s disease is broad with additional cardiac or non-cardiac features. Until now, ophthalmic abnormality has not been regarded as a manifestation of Danon’s disease. However, we suggest that it may be, as it was observed in one of our patients (patient 2 and his family) as well as in a previously published case.12
Overall, this specific spectrum and evolution justifies a specific medical follow up. Thirdly, there is no specific treatment for Danon’s disease. Management with inotrope negative or chronotrope negative agents, used for HCM, should be used with caution in Danon’s disease because of the frequent evolution towards systolic left ventricular dysfunction and atrioventricular block. Fourthly, Danon’s disease is an X linked dominant disorder and this inheritance may be difficult to recognise. As mothers of patients may be clinically healthy and because de novo mutations are possible (reported by Arad et al6
and present in our patient 1), some patients present as “sporadic” cases without a familial context. In contrast, when mothers of patients are clinically affected, the mode of inheritance may mimic the autosomal mode. Only male to male transmission allows the recognition of autosomal dominant inheritance and excludes X linked inheritance. These difficulties underline the usefulness of an accurate cardiac and molecular diagnosis. The information and genetic counselling subsequently given to patients and their relatives will obviously be different for HCM13
and Danon’s disease, especially as regards the risk of transmission. The discussion about prenatal diagnosis is also different since the severity of the disease appears obvious in all patients with Danon’s disease, whereas the prognosis is more variable and quite good for most patients with HCM related to sarcomeric genes.
In conclusion, physicians must be aware of Danon’s disease, which may mimic HCM but results in a very different clinical evolution, prognosis, mode of inheritance, and subsequently different genetic counselling. A careful clinical evaluation for this disease should therefore be considered for all patients with idiopathic HCM, especially for male patients with a diagnosis at less than 30 years but also for women with later onset. The presence of unusual clinical associations should subsequently lead to molecular screening to confirm or rule out the disease.