Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.0
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: LAMP2
• Condition: Danon disease
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• LAMP2 ⇔ 0010281 (danon disease): Moderate Actionability

Actionability Rationale

Most experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: LAMP2 ⇔ 0010281 (OMIM:300257)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Danon-related morbidity and mortality from arrhythmias and heart failure / Evaluation by specialists to guide surveillance and treatment including consideration for implantable device or heart transplant	2	3N	2N	1	8NN

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Danon disease is currently considered to be ultra-rare (2:100,000). The observed prevalence may be rising due to increased detection from wider availability of LAMP2 testing included in clinical genetic cardiomyopathy gene testing panels. Among individuals with hypertrophic cardiomyopathy (HCM, which has an overall prevalence of ~1:500 persons) the prevalence of those with a pathogenic variant in LAMP2 has been reported as 1-4%. [1, 2, 3]

Clinical Features

Danon disease is an autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that presents classically in males with the clinical triad of cardiomyopathy, skeletal myopathy, and intellectual disability. Other less prevalent symptoms may include ophthalmologic, hepatic, and pulmonary disease. Danon cardiomyopathy typically manifests a hypertrophic phenotype in males, which can be extreme. Concentric left-ventricular hypertrophy (LVH) may evolve into a dilated phenotype. Females may present with a dilated or hypertrophic phenotype. Both atrial and ventricular arrhythmias are seen. Electrical conduction abnormalities are also common in males and are variably seen in females. Pre-excitation with a pattern mimicking Wolf-Parkinson-White (WPW) syndrome is the most common electrocardiogram (ECG) finding. Skeletal myopathy in males manifests as progressive proximal muscle weakness of the shoulders, neck, and legs. Muscle weakness is usually mild to asymptomatic in females. Neurocognitive problems are typically mild and may include developmental delay, attention deficit disorder, and intellectual disability. Males with Danon disease are typically able to learn to read, hold jobs, enter relationships, and usually live independently. Learning and cognitive problems are less frequent in females. Eye-related problems can present as choriocapillary ocular atrophy, lens changes, myopia, abnormal visual fields, progressive visual impairment, and maculopathy. Retinal involvement has been reported in males including a near-complete and diffuse loss of pigment in the retinal pigment epithelium, central scotoma, color vision disturbances, and cone rod dystrophy. In females retinal involvement may include peripheral pigmentary retinopathy and a peppered and granular retinal pigment epithelium appearance. Hepatomegaly has been reported in males. [1, 2, 3, 4, 5, 6]

Natural History

Birth and perinatal histories are usually unremarkable. Skeletal muscle weakness may lead to delayed acquisition of motor milestones. Males are typically affected earlier and more severely than females. Males usually present with the classic triad of clinical features which includes childhood onset LVH that is rapidly progressive and often requires heart transplantation. The earliest reported onset of symptoms was at 4 months in a male individual who presented with hypotonia and cardiac failure. Females generally present later in childhood or early adulthood and often with isolated cardiac symptoms. Muscle weakness is seldom debilitating, and patients usually retain the ability to walk as adults. Skeletal muscle weakness is typically not progressive in females. The extent and severity of cardiomyopathy is the major prognostic factor and cardiac transplantation may be inevitable for most males in the second and third decades. Up to 29% of females receive cardiac transplantation. In a review of individuals with Danon disease totaling 518 individuals (272 males and 246 females), the mean age of onset ranged from 12-17 years for males and 26-38 years for females. Mean age at ICD implantation was 23 years (range 9-61) for males and 32 years (range 9-54) for females. Mean age at heart transplantation ranged from 14-23 years for males and 32-42 years for females. Mean age at death ranged from 19-23 years (range 7-47) for males and 37-40 years (range 14-76) for females. Most individuals with Danon disease will experience symptomatic heart failure, making it one of the most severe and penetrant genetic cardiomyopathies. [1, 2, 3, 7]

2. How effective are interventions for preventing harm?

Patient Management

Published guidelines are largely based on expert opinion and extrapolation from HCM guidelines. All LAMP2 variant carriers should undergo baseline multisystem evaluation to assess for the presence of any symptoms or signs of disease. Evaluation of genotype-positive, phenotype-negative individuals should start during infancy (first year of life). (Tier 2) [3]

Newly diagnosed individuals may be best served by a team approach that includes a primary care physician in conjunction with specialties including cardiology, genetics, neurology, neuromuscular disease, pulmonology, ophthalmology, rehabilitation medicine, and physical therapy. Genetic counseling should be offered to families so that they are knowledgeable about the inheritance pattern, reproductive risks, and technologies available to those who wish to pursue further testing before, during, and after pregnancy. Follow-up care should be tailored to individuals’ needs and clinical status. (Tier 2) [1, 3, 5]

Cardiology evaluations are critical given the nature of the expected cardiac progression; early input from both advanced heart failure and transplant and clinical cardiac electrophysiology sub-specialties will be beneficial. Newly diagnosed individuals should typically be studied by ECG and echocardiography, along with measurements of serum natriuretic peptide (BNP) levels and consideration for 24-hour Holter or event monitoring. Cardiac magnetic resonance (cMRI) can be considered in place of echocardiography to assess the extent of fibrotic changes and patterns of hypertrophy that may predict higher risks of arrhythmogenic events. Exercise testing with the use of treadmill ergometry or cardiopulmonary exercise testing is useful for risk stratification and to provide guidance about physical activity. (Tier 2) [1, 3, 5]

Implantable cardioverter-defibrillator (ICD) therapy should be strongly considered in individuals with symptomatic arrhythmias, moderate to severe hypertrophy, substantial fibrosis burden on cMRI imaging, unexplained syncope, and/or family history of premature sudden death. A subcutaneous device should be considered in young individuals who do not require pacing. For the treatment of heart disease, clinical signs and symptoms should guide the use of medications for congestive heart failure and arrhythmias, such as diuretics and antiarrhythmics, with beta blockers as first-line therapies. Additional therapies to attenuate cardiac remodeling (i.e., renin-angiotensin-aldosterone system inhibition) should be considered. (Tier 2) [1, 3, 6]

A European multicenter registry reported 30 males and 35 females with pathogenic variants in LAMP2. A total of 38 (67%) received an implantable device: permanent pacemaker, ICD, or cardiac resynchronization therapy (CRT) with an ICD. The most common (21 of 29) indication for ICD/CRT implantation was primary prevention. Appropriate ICD/CRT with an ICD intervention for sustained ventricular arrhythmia was reported in 6 patients (equal between males and females), 4 of whom were implanted for primary prevention. Of the 38 with an implantable device, 14 (37%) died at ages ranging from 14 to 69 years. The cause of death was heart failure in 9, heart failure and ventricular tachycardia in 1 (age 26), and sudden cardiac death in 1 (age 47). Another study reported outcomes in 7 individuals (6 male) with genetically confirmed Danon disease who were followed prospectively. At the time of diagnosis, the individuals were 7 to 15 years old (mean 12). On ECG at diagnosis, 6 had ventricular pre-excitation patterns with short PR interval. All 7 had ICD placement. Four males died of acute and/or progressive heart failure. One male died suddenly (age 12) from ventricular fibrillation refractory to ICD therapy. The female received appropriate defibrillator shock for rapid ventricular tachycardia at age 18 and was alive at last follow-up at age 22. One male received a transplant and was alive at last follow-up at age 23. (Tier 5) [8, 9]

Prompt consideration is recommended for cardiac transplantation in individuals with progressive symptoms or significant decrease in left ventricular ejection fraction, since this is the only intervention that modifies disease course. Steroid-sparing immunosuppressive agents should be considered to mitigate the risk of myopathy. Post-transplantation survival in patients with Danon disease appears to be similar to that in patients with other cardiomyopathies. In a multicenter cohort of individuals with Danon disease who underwent cardiac transplantation (n=38; 19 males and 19 females), median follow-up time after transplantation for the entire cohort was 4.4 years (range 1.5–12.8 years). The median age at transplant for the cohort was 20.2 years (15.8–27.9 years), with no difference in age between males and females. There were 2 deaths (1 female and 1 male) and 2 retransplants (1 female and 1 male) in the entire cohort. There was no difference in actuarial graft survival between males and females and the estimated graft survival was 87.1% (95%CI: 63.6%–95.9%) at 5 years. (Tier 2) [1, 3, 6]

A European multicenter registry reported 30 males and 35 females with pathogenic variants in LAMP2. Eight males and eight females (27%) underwent heart transplantation or received a left ventricular assist device (LVAD). Five of the 8 heart transplant/LVAD male recipients (62%) died within 1 year from the procedure. Causes of death included heart failure, rejection, stroke, and a non-Danon-related death. No death was reported among females receiving a heart transplant during a mean follow-up of 10.6 years (range, 4-17). (Tier 5) [9]

A large review of 56 females and 90 males with genetically confirmed Danon disease reported that a total of 29 patients received a heart transplant, including one individual bridged with an LVAD. Complications after transplant were only described in males, two of which required re-transplant because of the allograft rejection, and four developed profound muscle weakness, with two of them requiring reinstitution of mechanical ventilatory support because of respiratory failure. (Tier 5) [10]

A formal neuromuscular evaluation is recommended at initial evaluation. Physicians should aim to prevent progressive loss of muscle strength and flexibility in individuals with Danon disease through standard physical therapy and light exercise. Assessment of muscle strength, particularly the proximal muscles of the shoulder, neck, and legs, should be performed during scheduled physical examination visits. (Tier 2) [1, 3]

A comprehensive neuropsychological exam is recommended to assess neurocognitive problems. Intellectual difficulties should be anticipated and identified for early intervention. Enrollment in a rehabilitation center for educational, psychological, and social support is suggested. (Tier 2) [1, 3]

A baseline exam with a retinal specialist is recommended with prospective ophthalmologic examinations based on initial findings. (Tier 2) [1, 3]

Liver function tests are recommended, including alanine transaminase, aspartate transaminase, and lactate dehydrogenase. (Tier 2) [3]

Surveillance

Yearly multidisciplinary follow-up visits are recommended to begin in the first year of life in males, whereas females can start annual follow-up visits around the age of 6 years. Echocardiography is recommended at least every 1-2 years (more frequent as cardiac structural changes and symptoms progress). ECG and BNP/troponin/creatine kinase levels at least annually. Cardiac MRI imaging might be helpful in identifying mild phenotypes and should be used upon clinical suspicion or when adequate echocardiographic images are not attainable. Ambulatory 24-hour Holter monitoring (at least yearly, or every 6 months if the left atrium is dilated) or consideration of an implantable loop recorder is recommended based on the high incidence of atrial fibrillation and advanced atrioventricular block. Cardiac evaluations every three to six months, including consideration of transplant evaluation, may be appropriate in patients with evidence of significant cardiac involvement. Cardiac MRI imaging should be repeated every 2-3 years to monitor progression of fibrosis. (Tier 2) [1, 3]

Extracardiac surveillance recommendations include:
•Blood tests for liver function should occur annually
•Neuromuscular clinical assessment should occur annually if symptomatic, otherwise every 3-4 years
•Development/neuropsychological evaluations if new manifestations appear
•Exam by an ophthalmologist is recommended every 3-5 years or as needed based on concerns. (Tier 2) [1, 3]

Circumstances to Avoid

Dehydration and over-diuresis should be avoided. (Tier 2) [1]

Avoidance of smoking, excess alcohol consumption, and substance abuse may delay disease progression. Stimuli-activating autophagy such as strenuous physical activity and diet therapy should be decreased due to the risk of enhancing disease progression in a LAMP-2-deficient heart. Strenuous physical activity and competitive sports also increase the risk of stress-provoked arrhythmia in those without an ICD and the risk of arrhythmic storm in those with an ICD. Cardiotoxic medications and stimulants should also be avoided. (Tier 2) [3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked
The estimated de novo rate for this condition is high (≤40%), reflecting its malignant nature and negative effect on reproduction. Cases of germline mosaicism have also been described. [1, 3, 4]

Prevalence of Genetic Variants

Approximately 95% of individuals with Danon disease have a detectable pathogenic variant on sequence analysis. Another ~5% have a pathogenic variant detectable by gene-targeted deletion/duplication analysis. (Tier 3) [2, 3]

Penetrance

The penetrance in Danon disease is age related and has not been well studied in the literature. Given the severity of the cardiac phenotype, the penetrance is estimated as high or nearly complete in males by the second decade. Females appear to also have a high cardiac penetrance that is later in onset compared to males. (Tier 4) [2]

One review described five cohorts of individuals with Danon disease (518 individuals total; 272 males and 246 females). Penetrance ranges from the five cohorts are shown below.
Feature/Outcome
Cardiomyopathy, hypertrophic phenotype: Males 84-96% Females 29-71%
Cardiomyopathy, dilated phenotype: Males 4-33% Females 27-71%
Cardiac conduction abnormalities: Males 58-86% Females 57-80%
Pre-excitation mimicking WPW: Males 48-80% Females 22-35%
Myopathy: Males 76-100% Females 5-50%
ICD implantation: Males 6-50% Females 18-38%
Pacemaker: Males 10-30% Females 8-17%
Heart transplant: Males 5-33% Females 5-29%
Cognitive problems: Males 46-100% Females 6-47%
Ocular abnormalities: Males 6-69% Females 5-64% (Tier 5) [7]

Relative Risk

No information on relative risk was found.

Expressivity

Cardiac manifestations are usually the most prominent and severe, whereas skeletal muscle and neurologic phenotypes can vary considerably. Males are typically affected earlier and more severely than females. The phenotypic spectrum in females is broader and more variable. Some females have no discernable clinical features. Skeletal muscle weakness appears to be milder than that of males. (Tier 3) [1, 3]

Cardiomyopathy in females, when present, is less likely to be hypertrophic than in males. In males, a dilated phenotype may develop later as LVH progresses; this does not appear to be the case in females. Intellectual disability is usually mild but can be of variable degree, particularly in females. The large variability in clinical presentation and specific cardiac features in females is presumably because of different patterns of X chromosome inactivation. (Tier 4) [2, 3]

4. What is the Nature of the Intervention?

Nature of Intervention

Identified interventions include both non-invasive (ECG, echocardiography, cardiac MRI) and invasive (possible ICD implantation, and possible heart transplant). The implantation of an ICD involves invasive surgery and device management, potentially starting at a young age. Those who are young will require multiple device replacements during their lifetime. Long-term risks include infection and vascular complications. In pediatric patients, ICD implantation is more challenging, and complications are more frequent due to the increased heart rates and activity of the population. Inappropriate ICD shocks and device complications can be minimized by optimal device programming and appropriate lead selection. In addition, the use of ICD therapy carries a risk for psychological consequences due to the fear of being shocked, particularly among patients who have experienced a shock. In a systematic review that included 4,916 patients with inherited arrhythmia syndromes inappropriate shocks occurred in 20%, device-related complications in 22%, and ICD-related psychological problems in 8.5%. [1, 11, 12, 13, 14, 15]

Complications of heart transplant may include organ rejection, post-transplant myopathy (due to the use of certain immunosuppressive agents), psychiatric issues that may occur in the peri- and postoperative period, and long-term use of prednisone and other immunosuppressive agents. A multicenter study of 38 individuals with Danon disease who underwent heart transplantation (19 males and 19 females) reported one episode of antibody-mediated rejection, and 7 episodes (19%) of acute cellular rejection in the total cohort (6 females and 1 male). Worsening myopathy post-transplant was reported in 4 males but no females. [9, 10, 16]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Danon disease is unfamiliar to many practitioners. Due to extracardiac manifestations being less prevalent and severe, the diagnosis of Danon disease is more challenging in females. Misdiagnoses may occur in the absence of genetic testing. LAMP2 is included in most HCM and dilated cardiomyopathy gene panels. Thus, if Danon disease is not initially suspected the diagnosis may be revealed to clinicians through the results of genetic testing. (Tier 4) [1, 3]

Milder disease often seen in females may delay diagnosis until a later time when their hearts may have already become hypokinetic and/or dilated. (Tier 3) [3]

Diagnosis of Danon disease is uncommon even in cardiomyopathy clinics and may not be familiar to many general cardiologists. Danon disease can be misdiagnosed as sarcomeric HCM, which it mimics in clinical presentation. (Tier 5) [8, 9]

Date of Search: 08.08.2023

Reference List

1. D'souza RS, Levandowski C, Slavov D, Graw SL, Allen LA, Adler E, Mestroni L, Taylor MR. Danon disease: clinical features, evaluation, and management. Circ Heart Fail. (2014) 7(1941-3297):843-9.

2. Taylor MRG, Adler ED. Danon Disease. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. Danon Disease. Gene Reviews. (1993) Website: https://www.ncbi.nlm.nih.gov/pubmed/32134616

3. Hong KN, Eshraghian EA, Arad M, Argirò A, Brambatti M, Bui Q, Caspi O, de Frutos F, Greenberg B, Ho CY, Kaski JP, Olivotto I, Taylor MRG, Yesso A, Garcia-Pavia P, Adler ED. International Consensus on Differential Diagnosis and Management of Patients With Danon Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. (2023) 82(1558-3597):1628-1647.

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. DANON DISEASE. MIM: 300257: 2020 Sep 22. World Wide Web URL: http://omim.org.

5. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies: Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC). European Heart Journal. (2023) Website: https://doi.org/10.1093/eurheartj/ehad194

6. Limongelli G, Adorisio R, Baggio C, Bauce B, Biagini E, Castelletti S, Favilli S, Imazio M, Lioncino M, Merlo M, Monda E, Olivotto I, Parisi V, Pelliccia F, Basso C, Sinagra G, Indolfi C, Autore C, WG on Cardiomyopathies of SIC (Società Italiana di Cardiologia), WG on Cardiomyopathies of SICPed (Società Italiana di Cardiologia Pediatrica). Diagnosis and Management of Rare Cardiomyopathies in Adult and Paediatric Patients. A Position Paper of the Italian Society of Cardiology (SIC) and Italian Society of Paediatric Cardiology (SICP). Int J Cardiol. (2022) 357(1874-1754):55-71.

7. Cenacchi G, Papa V, Pegoraro V, Marozzo R, Fanin M, Angelini C. Review: Danon disease: Review of natural history and recent advances. Neuropathol Appl Neurobiol. (2020) 46(1365-2990):303-322.

8. Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB, Almquist AK, Baffa JM, Saul JP, Ho CY, Seidman J, Seidman CE. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA. (2009) 301(1538-3598):1253-9.

9. Lotan D, Salazar-Mendiguchía J, Mogensen J, Rathore F, Anastasakis A, Kaski J, Garcia-Pavia P, Olivotto I, Charron P, Biagini E, Baban A, Limongelli G, Ashram W, Wasserstrum Y, Galvin J, Zorio E, Iacovoni A, Monserrat L, Spirito P, Iascone M, Arad M, Cooperating Investigators‡. Clinical Profile of Cardiac Involvement in Danon Disease: A Multicenter European Registry. Circ Genom Precis Med. (2020) 13(2574-8300):e003117.

10. Brambatti M, Caspi O, Maolo A, Koshi E, Greenberg B, Taylor MRG, Adler ED. Danon disease: Gender differences in presentation and outcomes. Int J Cardiol. (2019) 286(1874-1754):92-98.

11. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, III, Freedman RA, Gettes LS, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol.. (2013) Website: http://www.ncbi.nlm.nih.gov/pubmed/23265327

12. Olde Nordkamp LR, Postema PG, Knops RE, van Dijk N, Limpens J, Wilde AA, de Groot JR. Implantable cardioverter-defibrillator harm in young patients with inherited arrhythmia syndromes: A systematic review and meta-analysis of inappropriate shocks and complications. Heart Rhythm. (2016) 13(2):443-54.

13. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. (2018) 15(10):e73-e189.

14. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C, Ackerman M, Belhassen B, Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace. (2013) 15(10):1389-406.

15. Brugada J, Blom N, Sarquella-Brugada G, Blomstrom-Lundqvist C, Deanfield J, Janousek J, Abrams D, Bauersfeld U, Brugada R, Drago F, de Groot N, Happonen JM, Hebe J, Yen Ho S, Marijon E, Paul T, Pfammatter JP, Rosenthal E. Pharmacological and non-pharmacological therapy for arrhythmias in the pediatric population: EHRA and AEPC-Arrhythmia Working Group joint consensus statement. Europace. (2013) 15(9):1337-82.

16. Hong KN, Battikha C, John S, Lin A, Bui QM, Brambatti M, Storm G, Boynton K, Medina-Hernandez D, Garcia-Alvarez A, Castel MA, Garcia-Guereta L, Diez Lopez C, Perez-Gomez L, Miani D, Symanski JD, Taylor MR, Garcia-Pavia P, Adler ED. Cardiac Transplantation in Danon Disease. J Card Fail. (2022) 28(1532-8414):664-669.