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Original Contribution |

Clinical Outcome and Phenotypic Expression in LAMP2 Cardiomyopathy FREE

Barry J. Maron, MD; William C. Roberts, MD; Michael Arad, MD; Tammy S. Haas, RN; Paolo Spirito, MD; Gregory B. Wright, MD; Adrian K. Almquist, MD; Jeanne M. Baffa, MD; J. Philip Saul, MD; Carolyn Y. Ho, MD; Jonathan Seidman, PhD; Christine E. Seidman, MD
[+] Author Affiliations

Author Affiliations: Hypertrophic Cardiomyopathy Center of the Minneapolis Heart Institute Foundation, Minneapolis, Minnesota (Drs Maron and Almquist and Ms Haas); Baylor Cardiovascular Research Institute, Dallas, Texas (Dr Roberts); Heart Institute and Heart Failure Service, Sheba Medical Center, Tal Hashomer, Israel (Dr Arad); Division of Cardiology, Ospedelaiero Ospedali Galliera, Genoa, Italy (Dr Spirito); Children's Heart Clinic, Minneapolis (Dr Wright); Nemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, Delaware (Dr Baffa); Department of Pediatrics, Medical University of South Carolina, Charleston (Dr Saul); Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts (Dr Ho); and Department of Genetics, Harvard Medical School, Boston (Drs J. Seidman and C. E. Seidman).


JAMA. 2009;301(12):1253-1259. doi:10.1001/jama.2009.371.
Text Size: A A A
Published online

Context Mutations in X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease) produce a cardiomyopathy in young patients that clinically mimics severe hypertrophic cardiomyopathy (HCM) due to sarcomere protein mutations. However, the natural history and phenotypic expression of this newly recognized disease is incompletely resolved and its identification may have important clinical implications.

Objectives To determine the clinical consequences, outcome, and phenotypic expression of LAMP2 cardiomyopathy associated with diagnostic and management strategies.

Design, Setting, and Patients Clinical course and outcome were assessed prospectively in 7 young patients (6 boys) with defined LAMP2 mutations from the time of diagnosis (age 7-17 years; median, 14 years) to October 2008. Phenotypic expression of this disease was assessed both clinically and at autopsy.

Main Outcome Measures Progressive heart failure, cardiac death, and transplant.

Results Over a mean (SD) follow-up of 8.6 (2.6) years, and by age 14 to 24 years, the study patients developed left ventricular systolic dysfunction (mean [SD] ejection fraction, 25% [7%]) and cavity enlargement, as well as particularly adverse clinical consequences, including progressive refractory heart failure and death (n = 4), sudden death (n = 1), aborted cardiac arrest (n = 1), or heart transplantation (n = 1). Left ventricular hypertrophy was particularly marked (maximum thickness, 29-65 mm; mean [SD], 44 [15] mm), including 2 patients with massive ventricular septal thickness of 60 mm and 65 mm at ages 23 and 14 years, respectively. In 6 patients, a ventricular pre-excitation pattern at study entry was associated with markedly increased voltages of R-wave or S-wave (15-145 mm; mean [SD], 69 [39] mm), and deeply inverted T-waves. Autopsy findings included a combination of histopathologic features that were consistent with a lysosomal storage disease (ie, clusters of vacuolated myocytes) but also typical of HCM due to sarcomere protein mutations (ie, myocyte disarray, small vessel disease, myocardial scarring).

Conclusions LAMP2 cardiomyopathy is a profound disease process characterized by progressive clinical deterioration leading rapidly to cardiac death in young patients (<25 years). These observations underscore the importance of timely molecular diagnosis for predicting prognosis and early consideration of heart transplantation.

Figures in this Article

Metabolic myocardial storage diseases that mimic the clinical and phenotypic expression of hypertrophic cardiomyopathy (HCM) have recently been reported in young patients,1 including those diseases due to mutations in the X-linked lysosome-associated membrane protein gene (LAMP2; OMIM 309060; Danon disease).17 The morphologic expression and the clinical course experienced by patients with this newly identified cardiomyopathy27 are incompletely resolved. Therefore, it is informative to report our experience with an assessment of the natural history associated with LAMP2 cardiomyopathy.

The most current clinical status of 7 previously identified patients with LAMP2 mutations1 was reexamined as of October 2008. Two-dimensional and Doppler echocardiographic studies were performed according to standard methodology with commercially available instruments. As previously described in detail,1,8 sequence analyses of genes that encode 8 sarcomere proteins (β cardiac myosin heavy chain, cardiac myosin-binding protein C, cardiac troponin T, cardiac troponin I, cardiac actin, essential myosin light chain, regulatory myosin light chain, and α-tropomyosin), PRKAG2 (γ subunit of the adenosine monophosphate–activated protein kinase), GLA (α galactosidase), GAA (acid α-1,4-glucosidase), and LAMP2 (lysosome-associated membrane protein 2) were performed in each proband. Only a LAMP2 mutation was found in the probands, which was confirmed by restriction enzyme digestion.8 Tissue sections of left ventricular (LV) myocardium were obtained from formalin-fixed hearts, embedded in paraffin, sectioned at 6-μm thickness, and stained with hematoxylin-eosin and Masson trichrome. All participating centers received approval from their institutional review boards.

Clinical Profile

Clinical, demographic, and outcome data were assembled for the 7 affected proband study patients and are summarized in the Table. At cardiac diagnosis, the 1 female and 6 male patients were 7 to 17 years old (median, 14 years). Clinical recognition in 6 patients occurred by virtue of heart murmur, family screening, and findings on routine electrocardiogram (ECG) or by symptoms (chest pain or syncope) and, in 1 patient, by atrial fibrillation. All patients had predominant or isolated cardiac manifestations without mental retardation or the neurological or musculoskeletal deficits associated with Danon disease.27

Table Graphic Jump LocationTable. Clinical, Demographic, and Pathologic Findings in 7 Patients With LAMP2 Cardiomyopathya

On ECG at diagnosis, 6 patients had ventricular preexcitation patterns with short PR interval (Figure 1). Most patients also showed markedly increased standard lead voltages, precordial lead voltages, or both, with maximum R-wave or S-wave amplitude of 15 to 145 mm (mean [SD], 69 [39] mm), and usually with deep negative T-waves (Figure 1) (Table).

Place holder to copy figure label and caption
Figure 1. 12-Lead Electrocardiogram in LAMP2 Cardiomyopathy (Patient 2)
Graphic Jump Location

Tracing recorded at full standard from a 16-year-old patient showing striking standard and precordial lead voltages, T-wave inversion, and Wolff-Parkinson-White pattern.

Clinical Course

At cardiac diagnosis, all patients were classified in New York Heart Association (NYHA) functional class I. During the subsequent mean (SD) time of 8.6 (2.6) years, each of the 7 patients experienced serious adverse clinical consequences by 14 to 24 years of age (mean, 21 years). Four patients died of acute or progressive heart failure, and 1 patient underwent heart transplantation. Clinical deterioration was often rapid, with the time interval from clinical stability with little or no symptoms and preserved systolic function to end-stage heart failure as brief as 6 months. Two other patients experienced sudden unexpected major arrhythmic events: 1 patient died suddenly (age 14 years) from ventricular fibrillation refractory to implantable cardioverter-defibrillator (ICD) therapy (Figure 2), and 1 patient received an appropriate defibrillator shock for rapid ventricular tachycardia at age 18 years.10

Place holder to copy figure label and caption
Figure 2. Intracardiac Ventricular Electrocardiogram in a Patient With LAMP2 Cardiomyopathy (Patient 1)
Graphic Jump Location

The implantable cardioverter-defibrillator (ICD) elicited a defibrillation shock, which failed to interrupt ventricular fibrillation (280/min). This event was repeated 5 times until ICD capacity was extinguished and death occurred.

All 7 patients developed marked LV systolic dysfunction (ejection fraction, 20%-35%; mean [SD], 25% [7%]), associated with LV cavity dilatation in 4 patients and enlargement in 2 other patients over the follow-up period (Table).1 All 7 patients had received ICDs, which ultimately failed to terminate lethal ventricular tachyarrhythmias in 5.

Phenotype

Echocardiography. The most recent echocardiographic studies obtained in these patients demonstrated diffuse and marked LV hypertrophy in each. Maximum wall thickness (usually of ventricular septum) was 29 to 65 mm (mean [SD], 44 [15] mm), including 2 patients with particularly massive septal thickening of 60 mm and 65 mm at age 23 and 14 years, respectively (Table, patients 1 and 2). Left ventricular end-diastolic cavity dimension was documented to have dilated or enlarged over the follow-up period. Left ventricular outflow obstruction due to mitral valve systolic anterior motion was present at rest in 2 patients (gradient, 65 mm Hg).

Autopsy. Postmortem examination of 2 hearts showed massive cardiac hypertrophy; heart weights were 1265 g and 1425 g with asymmetric LV wall thickening (Figure 3). Patient 1 showed, in addition, substantial myocyte disarray, abnormal intramural coronary arteries (with thickened walls and narrowed lumen), and replacement fibrosis including subepicardial distribution (Figure 3).

Place holder to copy figure label and caption
Figure 3. Pathology of LAMP2 Cardiomyopathy (Patient 1)
Graphic Jump Location

From a 14-year-old boy with sudden death. A, At autopsy, massive asymmetric left ventricular (LV) hypertrophy. Ventricular septal thickness is 65 mm (heart weight, 1425 g), exceeding all hearts reported to date; LV cavity is small. B, Area of LV wall demarcated by white rectangle in A, showing subepicardial necrosis and scarring (arrowheads). C, Disorganized LV architecture. Adjacent cardiac muscle cells (myocytes), or groups of cells, are arranged at perpendicular or oblique angles (Masson trichrome, original magnification ×100). D, High-power photomicrograph showing an abnormal intramural coronary artery with thickened wall and narrowed lumen (periodic acid–Schiff).

Notably, both patients showed prominent clusters of numerous myocytes with distinctive and extensive cytosolic vacuolation (Figure 4) and inclusions of amorphous granular material in some cells within areas of scarring.

Place holder to copy figure label and caption
Figure 4. Left Ventricular Histopathology in LAMP2 Cardiomyopathy (Patient 2)
Graphic Jump Location

From the same patient shown in Figure 1, with findings consistent with a lysosomal storage disease. A, Small focal scars (stained blue) surrounded by viable myocardium (Masson trichrome, original magnification ×40). B, Similar area of myocardium shows subepicardial distribution of scarring and vacuolated myocytes (Masson trichrome, original magnification ×40). C, Clusters of myocytes with vacuolated sarcoplasm (stained red) embedded in an area of scar (stained blue, Masson trichrome, original magnification ×100). D, High-power photomicrograph showing a large empty myocyte surrounded by smaller vesicles in an area of replacement fibrosis (Masson trichrome).

The clinical course of these 7 patients with LAMP2 mutations provides important insights regarding molecular diagnosis as well as the natural history, pathophysiology, and clinical implications of this recently recognized genetic cardiomyopathy.17LAMP2 mutations cause a particularly profound and accelerated cardiac disease process characterized by clinical deterioration and early death, perhaps representing one of the most lethal cardiomyopathies in young and usually male patients. Such an outcome occurred in the patients in our study despite application of the most contemporary treatment strategies, including the ICD,10 which failed to convert ventricular tachyarrhythmias to normal rhythm in 5 patients.

The clinical presentation of LAMP2 cardiomyopathy mimics severe HCM caused by mutations in genes encoding cardiac sarcomere proteins,1,2 as both are associated with marked LV hypertrophy. However, even though LAMP2 cardiomyopathy is a phenocopy of HCM, it represents a fundamentally different pathologic process that results from a defect in lysosome function. In 2005, we reported genetic diagnoses in the present 7 patients with LAMP2 mutations,1 and in the ensuing and relatively brief 3-year period, prospectively recognized that these patients had all experienced adverse and lethal disease consequences. Specifically, each patient evolved into an end-stage phase characterized by LV systolic dysfunction with enlarging cavity size11 and experienced severe outcome—sudden death, heart failure death, heart transplantation, or an appropriate ICD intervention triggered by rapid ventricular tachyarrhythmia10—at age 14 to 24 years. Of note, the patients presented here with LAMP2 cardiomyopathy demonstrated a clinical profile dominated by cardiac manifestations, largely without overt evidence of the multisystem and extracardiac abnormalities (eg, mental retardation, hepatic involvement, and overt skeletal myopathy) reported in other patients with Danon disease.27 These observations underscore the heterogeneous clinical expression of LAMP2 mutations.

Reliably predicting future adverse clinical events in HCM by genetic testing for sarcomeric mutations has proved challenging.9,12,13 In contrast, genetic identification of LAMP2 cardiomyopathy is highly informative of prognosis. Although the clinical outcome in the relatively small cohort of patients in this study was uniformly adverse, we recognize that LAMP2 mutations exhibit heterogeneity in disease expression and clinical course,14 particularly between male and female individuals.2,3 Indeed, 7 female LAMP2 obligate carriers (age range, 19-51 years) in 2 of the families remain asymptomatic and at present have not developed LV hypertrophy or systolic dysfunction, underscoring the striking differences in clinical phenotypes and outcomes between female carriers and affected male patients with LAMP2 mutations.2,4,5,7 However, LAMP2 cardiomyopathy can emerge in female patients (Table, patient 3), presumably because of unfortunate X-inactivation of the nonmutated chromosome.

The early experience with the distinctive natural history and prognosis of patients with LAMP2 mutations establishes the importance of molecular diagnosis and underscores the utility of genetic testing. In this regard, a high index of suspicion should be raised for LAMP2 cardiomyopathy (and genetic testing) in young patients demonstrating massive LV hypertrophy and distinctive ECGs with greatly increased voltages and Wolff-Parkinson-White pattern. These observations also raise legitimate consideration for early intervention with heart transplantation4,15 as a treatment for LAMP2 cardiomyopathy (probably when LV systolic dysfunction intervenes) despite the possibility of extracardiac organ involvement in this disease.3,4

The observations from this study also provide insight into the phenotypic and pathologic expression of LAMP2 cardiomyopathy. Despite youthful age, most of the patients in this report with this metabolic storage disease showed particularly massive LV hypertrophy, and 2 patients had the most substantial hypertrophy reported in humans.1618 Histopathology of the hypertrophied LV showed a hybrid architecture with features of traditional HCM due to sarcomere protein mutations (ie, myocyte disarray, intramural small vessel disease, and myocardial scarring including subepicardial distribution)17,1921 but also distinctive evidence of lysosomal dysfunction for which clusters of numerous vacuolated and vesicle-like myocytes were embedded in areas of replacement fibrosis. The material contents of these myocytes could not be defined on the available postmortem tissue. However, a murine model of LAMP2 cardiomyopathy has demonstrated the accumulation of nonspecific, partially degraded biologic material (presumably lysosomal cellular debris) in large vacuoles indicative of impaired autophagy and associated with only a modest elevation in cardiac glycogen.22

In conclusion, LAMP2 cardiomyopathy in young patients appears to be a lethal genetic disease. The clinical resemblance of LAMP2 to sarcomeric HCM underscores the necessity and power of timely genetic testing in young patients with substantial LV hypertrophy, for the early molecular identification of this myocardial storage disease characterized by adverse clinical course.

Corresponding Author: Barry J. Maron, MD, Minneapolis Heart Institute Foundation, 920 E 28th St, Ste 620, Minneapolis, MN 55407 (hcm.maron@mhif.org).

Author Contributions: Dr Maron had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Maron.

Acquisition of data: Maron, Roberts, Arad, Haas, Spirito, Wright, Almquist, Baffa, Saul, C. E. Seidman.

Analysis and interpretation of data: Maron, Ho, J. Seidman, C. E. Seidman.

Drafting of the manuscript: Maron, Haas, Ho, J. Seidman, C. E. Seidman.

Critical revision of the manuscript for important intellectual content: Maron, Roberts, Arad, Spirito, Wright, Almquist, Baffa, Saul, Ho, C. E. Seidman.

Obtained funding: C. E. Seidman.

Administrative, technical, or material support: Maron, Haas, Wright, Baffa, Saul, Ho.

Study supervision: Maron, Spirito.

Financial Disclosures: None reported.

Funding/Support: This study was supported in part by grants from the Howard Hughes Medical Institute and National Institutes of Health.

Role of the Sponsor: The funding agencies had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Arad M, Maron BJ, Gorham JM,  et al.  Glycogen storage disease presenting as hypertrophic cardiomyopathy.  N Engl J Med. 2005;352(4):362-372
PubMed   |  Link to Article
Yang Z, McMahon CJ, Smith LR,  et al.  Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children.  Circulation. 2005;112(11):1612-1617
PubMed   |  Link to Article
Charron P, Villard E, Sébillon P,  et al.  Danon's disease as a cause of hypertrophic cardiomyopathy: a systemic survey.  Heart. 2004;90(8):842-846
PubMed   |  Link to Article
Sugie K, Yamamoto A, Murayama K,  et al.  Clinicopathological features of genetically confirmed Danon disease.  Neurology. 2002;58(12):1773-1778
PubMed   |  Link to Article
Taylor MR, Ku L, Slavov D,  et al; Familial Cardiomyopathy Registry.  Danon disease presenting with dilated cardiomyopathy and a complex phenotype.  J Hum Genet. 2007;52(10):830-835
PubMed   |  Link to Article
Nishino I, Fu J, Tanji K,  et al.  Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).  Nature. 2000;406(6798):906-910
PubMed   |  Link to Article
Fanin M, Nascimbeni AC, Fulizio L, Spinazzi M, Melacini P, Angelini C. Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon's disease.  Am J Pathol. 2006;168(4):1309-1320
PubMed   |  Link to Article
Niimura H, Bachinski LL, Sangwatanaroj S,  et al.  Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.  N Engl J Med. 1998;338(18):1248-1257
PubMed   |  Link to Article
Ackerman MJ, Van Driest SL, Ommen SR,  et al.  Prevalence and age dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective.  J Am Coll Cardiol. 2002;39(12):2042-2048
PubMed   |  Link to Article
Maron BJ, Spirito P, Shen W-K,  et al.  Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy.  JAMA. 2007;298(4):405-412
PubMed   |  Link to Article
Harris KM, Spirito P, Maron MS,  et al.  Prevalence, clinical profile and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy.  Circulation. 2006;114(3):216-225
PubMed   |  Link to Article
Van Driest SL, Ackerman MJ, Ommen SR,  et al.  Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.  Circulation. 2002;106(24):3085-3090
PubMed   |  Link to Article
Maron BJ, McKenna WJ, Danielson GK,  et al; Task Force on Clinical Expert Consensus Documents, American College of Cardiology; Committee for Practice Guidelines, European Society of Cardiology.  American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.  J Am Coll Cardiol. 2003;42(9):1687-1713
PubMed   |  Link to Article
Bertini E, Donati MA, Broda P,  et al.  Phenotypic heterogeneity in two unrelated Danon patients associated with the LAMP-2 gene mutation.  Neuropediatrics. 2005;36(5):309-313
PubMed   |  Link to Article
Echaniz-Laguna A, Mohr M, Epailly E,  et al.  Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease.  Muscle Nerve. 2006;33(3):393-397
PubMed   |  Link to Article
Maron BJ, Gross BW, Stark SI. Images in cardiovascular medicine: extreme left ventricular hypertrophy.  Circulation. 1995;92(9):2748
PubMed   |  Link to Article
Roberts CS, Roberts WC. Morphologic features. In: Zipes DP, Rowlands DJ, eds. Progress in Cardiology. Philadelphia, PA: Lea & Febinger; 1989;2:3-32
Roberts WC, Podolak MJ. The king of hearts: analysis of 23 patients with hearts weighing 1,000 grams or more.  Am J Cardiol. 1985;55(4):485-494
PubMed   |  Link to Article
Varnava AM, Elliott PM, Mahon N, Davies MJ, McKenna WJ. Relation between myocyte disarray and outcomes in hypertrophic cardiomyopathy.  Am J Cardiol. 2001;88(3):275-279
PubMed   |  Link to Article
Maron BJ, Roberts WC. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy.  Circulation. 1979;59(4):689-706
PubMed   |  Link to Article
Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy.  J Am Coll Cardiol. 1986;8(3):545-557
PubMed   |  Link to Article
Tanaka Y, Guhde G, Suter A,  et al.  Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice.  Nature. 2000;406(6798):902-906
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. 12-Lead Electrocardiogram in LAMP2 Cardiomyopathy (Patient 2)
Graphic Jump Location

Tracing recorded at full standard from a 16-year-old patient showing striking standard and precordial lead voltages, T-wave inversion, and Wolff-Parkinson-White pattern.

Place holder to copy figure label and caption
Figure 2. Intracardiac Ventricular Electrocardiogram in a Patient With LAMP2 Cardiomyopathy (Patient 1)
Graphic Jump Location

The implantable cardioverter-defibrillator (ICD) elicited a defibrillation shock, which failed to interrupt ventricular fibrillation (280/min). This event was repeated 5 times until ICD capacity was extinguished and death occurred.

Place holder to copy figure label and caption
Figure 3. Pathology of LAMP2 Cardiomyopathy (Patient 1)
Graphic Jump Location

From a 14-year-old boy with sudden death. A, At autopsy, massive asymmetric left ventricular (LV) hypertrophy. Ventricular septal thickness is 65 mm (heart weight, 1425 g), exceeding all hearts reported to date; LV cavity is small. B, Area of LV wall demarcated by white rectangle in A, showing subepicardial necrosis and scarring (arrowheads). C, Disorganized LV architecture. Adjacent cardiac muscle cells (myocytes), or groups of cells, are arranged at perpendicular or oblique angles (Masson trichrome, original magnification ×100). D, High-power photomicrograph showing an abnormal intramural coronary artery with thickened wall and narrowed lumen (periodic acid–Schiff).

Place holder to copy figure label and caption
Figure 4. Left Ventricular Histopathology in LAMP2 Cardiomyopathy (Patient 2)
Graphic Jump Location

From the same patient shown in Figure 1, with findings consistent with a lysosomal storage disease. A, Small focal scars (stained blue) surrounded by viable myocardium (Masson trichrome, original magnification ×40). B, Similar area of myocardium shows subepicardial distribution of scarring and vacuolated myocytes (Masson trichrome, original magnification ×40). C, Clusters of myocytes with vacuolated sarcoplasm (stained red) embedded in an area of scar (stained blue, Masson trichrome, original magnification ×100). D, High-power photomicrograph showing a large empty myocyte surrounded by smaller vesicles in an area of replacement fibrosis (Masson trichrome).

Tables

Table Graphic Jump LocationTable. Clinical, Demographic, and Pathologic Findings in 7 Patients With LAMP2 Cardiomyopathya

References

Arad M, Maron BJ, Gorham JM,  et al.  Glycogen storage disease presenting as hypertrophic cardiomyopathy.  N Engl J Med. 2005;352(4):362-372
PubMed   |  Link to Article
Yang Z, McMahon CJ, Smith LR,  et al.  Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children.  Circulation. 2005;112(11):1612-1617
PubMed   |  Link to Article
Charron P, Villard E, Sébillon P,  et al.  Danon's disease as a cause of hypertrophic cardiomyopathy: a systemic survey.  Heart. 2004;90(8):842-846
PubMed   |  Link to Article
Sugie K, Yamamoto A, Murayama K,  et al.  Clinicopathological features of genetically confirmed Danon disease.  Neurology. 2002;58(12):1773-1778
PubMed   |  Link to Article
Taylor MR, Ku L, Slavov D,  et al; Familial Cardiomyopathy Registry.  Danon disease presenting with dilated cardiomyopathy and a complex phenotype.  J Hum Genet. 2007;52(10):830-835
PubMed   |  Link to Article
Nishino I, Fu J, Tanji K,  et al.  Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).  Nature. 2000;406(6798):906-910
PubMed   |  Link to Article
Fanin M, Nascimbeni AC, Fulizio L, Spinazzi M, Melacini P, Angelini C. Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon's disease.  Am J Pathol. 2006;168(4):1309-1320
PubMed   |  Link to Article
Niimura H, Bachinski LL, Sangwatanaroj S,  et al.  Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.  N Engl J Med. 1998;338(18):1248-1257
PubMed   |  Link to Article
Ackerman MJ, Van Driest SL, Ommen SR,  et al.  Prevalence and age dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective.  J Am Coll Cardiol. 2002;39(12):2042-2048
PubMed   |  Link to Article
Maron BJ, Spirito P, Shen W-K,  et al.  Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy.  JAMA. 2007;298(4):405-412
PubMed   |  Link to Article
Harris KM, Spirito P, Maron MS,  et al.  Prevalence, clinical profile and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy.  Circulation. 2006;114(3):216-225
PubMed   |  Link to Article
Van Driest SL, Ackerman MJ, Ommen SR,  et al.  Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.  Circulation. 2002;106(24):3085-3090
PubMed   |  Link to Article
Maron BJ, McKenna WJ, Danielson GK,  et al; Task Force on Clinical Expert Consensus Documents, American College of Cardiology; Committee for Practice Guidelines, European Society of Cardiology.  American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.  J Am Coll Cardiol. 2003;42(9):1687-1713
PubMed   |  Link to Article
Bertini E, Donati MA, Broda P,  et al.  Phenotypic heterogeneity in two unrelated Danon patients associated with the LAMP-2 gene mutation.  Neuropediatrics. 2005;36(5):309-313
PubMed   |  Link to Article
Echaniz-Laguna A, Mohr M, Epailly E,  et al.  Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease.  Muscle Nerve. 2006;33(3):393-397
PubMed   |  Link to Article
Maron BJ, Gross BW, Stark SI. Images in cardiovascular medicine: extreme left ventricular hypertrophy.  Circulation. 1995;92(9):2748
PubMed   |  Link to Article
Roberts CS, Roberts WC. Morphologic features. In: Zipes DP, Rowlands DJ, eds. Progress in Cardiology. Philadelphia, PA: Lea & Febinger; 1989;2:3-32
Roberts WC, Podolak MJ. The king of hearts: analysis of 23 patients with hearts weighing 1,000 grams or more.  Am J Cardiol. 1985;55(4):485-494
PubMed   |  Link to Article
Varnava AM, Elliott PM, Mahon N, Davies MJ, McKenna WJ. Relation between myocyte disarray and outcomes in hypertrophic cardiomyopathy.  Am J Cardiol. 2001;88(3):275-279
PubMed   |  Link to Article
Maron BJ, Roberts WC. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy.  Circulation. 1979;59(4):689-706
PubMed   |  Link to Article
Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy.  J Am Coll Cardiol. 1986;8(3):545-557
PubMed   |  Link to Article
Tanaka Y, Guhde G, Suter A,  et al.  Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice.  Nature. 2000;406(6798):902-906
PubMed   |  Link to Article
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Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

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