A phenocopy of sarcomeric hypertrophic cardiomyopathy: LAMP2 cardiomyopathy (Danon disease) from China.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease characterized by otherwise unexplained left ventricular (LV) hypertrophy, and caused by a multitude of mutations in genes encoding proteins of the cardiac sarcomere. 3 Notably, HCM is heterogeneous in terms of phenotypic expression, clinical presentation and course, as well as management strategies, i.e. with severe disease consequences in some patients but a benign course and normal life expectancy in many others. Recently, there has been increasing recognition that other uncommon inherited diseases may mimic the phenotypic and clinical features of sarcomeric HCM, but are caused by distinctly different gene mutations. –7 These conditions include most prominently Fabry disease (X-linked a-galactosidase deficiency with glycosphingolipid deposition), PRKAG2 (regulatory subunit of adenosine monophosphate-activated protein kinase), and LAMP2 (a lysosomal storage disease, also known as Danon disease) (Figure 1). –7 LAMP2 cardiomyopathy is an X-linked primary deficiency in lyosome-associated membrane protein-2 caused by several ‘private’ (i.e. reported in only a single patient or family) radical mutations in the LAMP2 gene, including frameshifts, splicing sites, deletions, and insertions. 7 Although apparently rare, the geographic distribution of LAMP2 mutations is wide, i.e. reported from the USA, Italy, Australia, Sweden, the UK, and Japan, 9 and now recognized in China. Most of the current knowledge of LAMP2 is based on case reports and small series, although a registry consisting of 82 patients has been assembled since 2006. This ‘new’ disease is the subject of a report by Cheng and associates from Beijing. These investigators studied 50 consecutive and unselected patients with a concentric pattern of LV hypertrophy (using ventricular septal to posterior wall thickness ratio of ,1.3). After diagnosing and excluding 14 patients with cardiac amyloidosis, genetic testing for mutations in the LAMP2 gene was performed in the remaining 36; unfortunately, the clinical cardiac diagnoses in these latter patients are not specified. Nevertheless, in 3 of these 36 patients with concentric hypertrophy novel LAMP2 frameshift mutations were identified (6% of the overall study cohort). Cheng et al. recognize that the distinction of LAMP2 cardiomyopathy from ‘typical’ sarcomeric HCM is not an academic exercise, but rather a key differential diagnosis that is likely to be unreliable based on clinical criteria alone (Figure 1), and is resolvable only with contemporary genetic testing. Indeed, an accurate and reliable LAMP2 molecular diagnosis is crucial, given that the natural history and complications attributable to these two conditions are very different. LAMP2 is an almost uniformly severe and unfortunate clinical entity (particularly in affected males) characterized by early morbidity and limited life expectancy, with survival beyond 25 years uncommon. The Danon Registry reports the following disease landmarks on average: first symptoms, 12 years; transplant, 18 years; death, without transplant, 19 years. While the three Chinese patients reported here are currently asymptomatic, they are still young (14–16 years old), with the future potential risk of clinical deterioration. Such dire consequences of LAMP2 mutations result from the profound structural abnormalities evident in the histopathology of LV myocardium characterized by extensive replacement scarring, with autophagic and vacuolated myocytes presumably containing degraded lysosomal material (Figure 2). Indeed, and perhaps not unexpectedly, this greatly distorted myocardium has proved refractory to effective and reliable termination of potentially lifethreatening ventricular tachyarrhythmias by implantable cardioverter-defibrillators (ICDs) (Figure 2), as occurred in five of