Danon Disease

Article Author:
Ryan D'Souza
Article Editor:
Luke Law
Updated:
7/22/2019 9:50:12 AM
PubMed Link:
Danon Disease

Introduction

Danon disease is a rare X-linked dominant genetic disorder that manifests with the clinical triad of cardiomyopathy, skeletal myopathy, and intellectual disability.[1] It is caused by genetic mutations in the lysosome-associated membrane 2 (LAMP2) gene, with most mutations leading to an absence of LAMP2 protein.[2] Most published data on this disease is abstracted from case reports, limited observational studies, and expert opinion.

Etiology

The primary cause of Danon disease is a genetic mutation in the LAMP2 gene. There are currently over 160 different mutations that researchers have identified in the literature through observational studies, case reports, and databases.[1] The most detrimental mutations are considered to be those leading to a complete absence of the LAMP2 protein. Partial LAMP2 mutation may be an association with less severe clinical symptoms.

Epidemiology

While the prevalence of Danon disease is unknown, it is thought to affect any ethnic group.[3] A pediatric study on hypertrophic cardiomyopathy identified 4% of its patients as having Danon disease.[4] Another observational study diagnosed Danon disease in 17% of patients with both thickened left ventricular walls and electrocardiogram evidence of pre-excitation.[5]

Pathophysiology

There are three isoforms of LAMP2 protein, including LAMP-2A, LAMP-2B, and LAMP-2C. The LAMP-2 protein is in the lysosomal compartment. The cytoplasmic tail of the LAMP-2A isoform serves as a receptor for the uptake of proteins for lysosomal degradation. This process is known as autophagy.[6] The role of each specific LAMP-2 isoform is unclear, although it merits noting that LAMP-2A has ubiquitous expression while LAMP-2B is present in a higher proportion in cardiac tissue, skeletal muscle, and the brain.[7] However, the vast majority of LAMP2 genetic mutations affect all three protein isoforms, leading to Danon disease.

Histopathology

The absence or reduction of LAMP2 protein leads to disruption of intracytoplasmic trafficking with an accumulation of autophagic material and glycogen in cardiac muscle and skeletal muscle cells.[2]

History and Physical

Generally, males show signs at a younger age, including muscle weakness and possibly delayed motor skills. Larger muscle groups are typically affected, including the back, shoulder, neck, and upper legs.[1] This condition may manifest as difficulty with arm raise, getting up from a chair, or walking up a flight of stairs. Fatigue, dyspnea, and lower extremity edema may be a manifestation of progressive cardiomyopathy. Males more often present with hypertrophic cardiomyopathy (90%), while females may manifest equally with either hypertrophic cardiomyopathy or dilated cardiomyopathy. Sudden cardiac death from cardiac disease occurs more frequently in males in their second and third decades of life.[8]

Other clinical manifestations may be harder to diagnose. Liver and lung involvement may be a component of skeletal myopathy leading to liver enzyme increase and respiratory muscle weakness. Visual problems due to the loss of retinal pigment may also affect Danon disease patients.[9]

The role of cognitive issues and psychiatric disease in Danon disease is still unclear. Intellectual disability is typically mild in males as they are still usually able to read, hold jobs, and live independently.[1] A recent observational study exploring cognitive deficits and psychiatric comorbidities in Danon disease revealed that 9 of 12 participants had a normal IQ score, while only one patient had an intellectual disability.[10] However, this study also showed that 69% of participants met criteria for a psychiatric disorder, primarily mood and anxiety disorder, which underscores the need for psychiatric assessment.

Of note, females typically manifest with symptoms during middle adulthood with symptoms of heart disease. Skeletal myopathy and intellectual disability may not be present in females with Danon disease.[1]

Evaluation

Muscle biopsy reveals normal acid maltase levels, which differentiated Danon disease from a very similar genetic disorder, Pompe disease. Immunohistochemistry reveals LAMP2 protein deficiency and autophagic vacuole accumulation when observed under electron microscopy.[2][11] Genetic testing may reveal LAMP2 gene mutation. Serological studies may show elevated serum creatine kinase levels about two to three times normal and increased liver function tests.[12]

Electrocardiogram may reveal Wolff-Parkinson-White (WPW) syndrome (pre-excitation syndrome). Echocardiogram and cardiac magnetic resonance imaging may help characterize the degree of cardiac fibrosis, which may be a predictor of future arrhythmogenic events.[13]

Finally, a formal neuropsychological examination may reveal an intellectual disability. Retinal examination may show changes in retinal pigment.[14]

Treatment / Management

There are no currently established guidelines for the diagnosis or management of Danon disease patients. However, a thorough cardiac workup is warranted in newly diagnosed patients and consists of an electrocardiogram, echocardiography, serum brain natriuretic peptide levels, and 24-Holter monitoring. Implantable cardioverter-defibrillator may be necessary for Danon disease patients who have moderate to severe cardiomyopathy, experience symptomatic arrhythmias, and have a family history of premature sudden cardiac death.[13] Cardiac ablation may offer temporary treatment for arrhythmias, although the diffuse and rapidly progressing fibrosis in Danon disease may be refractory to multiple ablation procedures.[5][15] Ultimately, early consideration for cardiac transplantation should be given, particularly in young males who experience rapid progression of hypertrophic cardiomyopathy and risk for sudden cardiac death.[1]

Standard physical therapy and light exercise may be beneficial in preserving muscle strength and flexibility. Recommendations also include that a formal, comprehensive neuropsychological exam may be useful to diagnose neurocognitive problems. A baseline eye examination with a retinal specialist with follow-up based on initial findings is also a suggested diagnostic procedure. Given the X-linked inheritance pattern, genetic counseling is prudent to educate affected families and discuss reproductive risks.[1]

Differential Diagnosis

Other diagnoses that should be considered when evaluating a patient for Danon disease include Pompe disease (autosomal dominant), x-linked myopathy with excessive autophagy (x-linked recessive), x-linked congenital autophagic vacuolar myopathy (x-linked recessive), infantile autophagic vacuolar myopathy (x-linked recessive), and “glycogen storage disease of the heart, lethal congenital” (autosomal recessive).[1] Acquired diseases may also mimic Danon disease, including chloroquine-induced myopathy.[16] However, an x-linked dominant inheritance pattern in conjunction with hypertrophic cardiomyopathy in young males, skeletal myopathy, intellectual disability, supportive diagnostic studies of normal acid maltase levels on muscle biopsy, and immunohistochemistry with LAMP2 protein deficiency strongly suggests Danon disease.

Pertinent Studies and Ongoing Trials

The most extensive observational study comprised 82 total Danon disease patients from 36 different families.[8] This study revealed that 100% of males are affected with intellectual disability, 88% of males are affected by hypertrophic cardiomyopathy, and 80% of males present with skeletal myopathy. Affected males were unlikely to live until age 25 without cardiac transplantation. In affected females, the study reported cognitive deficits in 47%, skeletal myopathy in 50%, and cardiomyopathy in 61% (with an approximately equal prevalence of dilated and hypertrophic cardiomyopathy).

A recent nationwide questionnaire study was carried out in Japan on 39 total Danon disease patients from 20 different families (39 male, 22 female).[17] In this study, 20 patients died from either cardiac failure or sudden cardiac death. WPW syndrome was evident in a high proportion of included patients (54% of males and 22% of females). Interestingly, de novo mutations were present in half of the probands.

Prognosis

Prognosis primarily depends on the severity of cardiomyopathy. The need for cardiac transplantation is typically inevitable for most males by the second and third decades.[8] A study by Boucek and colleagues reported that the average age of first symptom, heart transplant, and death are 12.1, 17.9, and 19.0 years in male patients, and 27.9, 33.7, and 34.6 years in female patients.[8]

Complications

Arrhythmias are very common, noted in 53% of patients.[8] Sudden cardiac death likely from ventricular arrhythmias is a significant cause of death in Danon disease patients. In one high-profile series, sudden cardiac death occurred in 2 of 9 patients (29%).[18]

Deterrence and Patient Education

Given the X-linked dominant inheritance pattern, genetic counseling should be offered to Danon disease patients and their extended families. Due to the implementation of early heart transplant, men are more capable of fathering children, and thus, the inheritance risks for LAMP2 mutations to future offspring should be conveyed. Specifically, mothers affected with Danon disease will pass on the risk of the disease to half of their sons and daughters. Fathers affected with Danon disease will pass on the risk of the disease to all of their daughters and none of their sons. Genetic counseling is optimal at centers with experience in cardiomyopathy genetic counseling.[19]

Enhancing Healthcare Team Outcomes

There are no current, ongoing clinical trials in Danon disease, and evidential basis is primarily from retrospective observational data and expert opinion. Danon disease patient care is optimal with a collaborative team approach consisting of a primary care provider, cardiologist, geneticist, neurologist, ophthalmologist, and a physical medicine and rehabilitation physician.[1][20]

Because of the limited life expectancy, extensive counseling with the patient and family is highly recommended. A mental health nurse should provide counseling to the patient, given the poor prognosis.

Those with impaired intellectual functioning may require social workers, psychotherapists, and home care workers to ensure that there is no diminution of quality of life. A home care nurse should follow up on the patient and communicate with the team if medical issues arise.

Genetic counseling should be a strong recommendation to the family. The decision to allow participation in exercise requires good judgment as it can worsen the muscular dystrophy.  It is vital that clinicians not undertake aggressive invasive treatments because of the poor prognosis; the key is to cause less harm to the patient,

Given the rapid progression of cardiac disease, particularly in affected male patients, regular cardiology appointments are warranted and often input from the Advanced Heart Failure, Heart Transplant, and Clinical Cardiac Electrophysiology services.[1][20]

Interprofessional healthcare team management is the best approach, to include the physician team (including specialists) collaborating on a treatment plan. Nursing will always have a seat at the table by assisting with monitoring and coordinating between other providers. Often specialty trained nurses in genetics manage follow-up and must coordinate care with the clinical team. Physical therapy, mental health, and genetic counseling are all important aspects of managing cases of Danon disease. Each of these specialties must communicate their findings and activities to the rest of the team, so optimal interprofessional management drives improved outcomes. [Level V]


References

[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. Circulation. Heart failure. 2014 Sep;     [PubMed PMID: 25228319]
[2] Nishino I,Fu J,Tanji K,Yamada T,Shimojo S,Koori T,Mora M,Riggs JE,Oh SJ,Koga Y,Sue CM,Yamamoto A,Murakami N,Shanske S,Byrne E,Bonilla E,Nonaka I,DiMauro S,Hirano M, Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000 Aug 24;     [PubMed PMID: 10972294]
[3] Nishino I, Autophagic vacuolar myopathy. Seminars in pediatric neurology. 2006 Jun;     [PubMed PMID: 17027858]
[4] Charron P,Villard E,Sébillon P,Laforêt P,Maisonobe T,Duboscq-Bidot L,Romero N,Drouin-Garraud V,Frébourg T,Richard P,Eymard B,Komajda M, Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey. Heart (British Cardiac Society). 2004 Aug;     [PubMed PMID: 15253947]
[5] Arad M,Maron BJ,Gorham JM,Johnson WH Jr,Saul JP,Perez-Atayde AR,Spirito P,Wright GB,Kanter RJ,Seidman CE,Seidman JG, Glycogen storage diseases presenting as hypertrophic cardiomyopathy. The New England journal of medicine. 2005 Jan 27;     [PubMed PMID: 15673802]
[6] Fukuda M, Biogenesis of the lysosomal membrane. Sub-cellular biochemistry. 1994;     [PubMed PMID: 8146882]
[7] Konecki DS,Foetisch K,Zimmer KP,Schlotter M,Lichter-Konecki U, An alternatively spliced form of the human lysosome-associated membrane protein-2 gene is expressed in a tissue-specific manner. Biochemical and biophysical research communications. 1995 Oct 13;     [PubMed PMID: 7488019]
[8] Boucek D,Jirikowic J,Taylor M, Natural history of Danon disease. Genetics in medicine : official journal of the American College of Medical Genetics. 2011 Jun;     [PubMed PMID: 21415759]
[9] Schorderet DF,Cottet S,Lobrinus JA,Borruat FX,Balmer A,Munier FL, Retinopathy in Danon disease. Archives of ophthalmology (Chicago, Ill. : 1960). 2007 Feb;     [PubMed PMID: 17296900]
[10] Yardeni M,Weisman O,Mandel H,Weinberger R,Quarta G,Salazar-Mendiguchía J,Garcia-Pavia P,Lobato-Rodríguez MJ,Simon LF,Dov F,Arad M,Gothelf D, Psychiatric and cognitive characteristics of individuals with Danon disease (LAMP2 gene mutation). American journal of medical genetics. Part A. 2017 Sep;     [PubMed PMID: 28627787]
[11] Balmer C,Ballhausen D,Bosshard NU,Steinmann B,Boltshauser E,Bauersfeld U,Superti-Furga A, Familial X-linked cardiomyopathy (Danon disease): diagnostic confirmation by mutation analysis of the LAMP2gene. European journal of pediatrics. 2005 Aug;     [PubMed PMID: 15889279]
[12] Sugie K,Yamamoto A,Murayama K,Oh SJ,Takahashi M,Mora M,Riggs JE,Colomer J,Iturriaga C,Meloni A,Lamperti C,Saitoh S,Byrne E,DiMauro S,Nonaka I,Hirano M,Nishino I, Clinicopathological features of genetically confirmed Danon disease. Neurology. 2002 Jun 25;     [PubMed PMID: 12084876]
[13] Miani D,Taylor M,Mestroni L,D'Aurizio F,Finato N,Fanin M,Brigido S,Proclemer A, Sudden death associated with danon disease in women. The American journal of cardiology. 2012 Feb 1;     [PubMed PMID: 22074992]
[14] Prall FR,Drack A,Taylor M,Ku L,Olson JL,Gregory D,Mestroni L,Mandava N, Ophthalmic manifestations of Danon disease. Ophthalmology. 2006 Jun;     [PubMed PMID: 16751040]
[15] Yang Z,Funke BH,Cripe LH,Vick GW 3rd,Mancini-Dinardo D,Peña LS,Kanter RJ,Wong B,Westerfield BH,Varela JJ,Fan Y,Towbin JA,Vatta M, LAMP2 microdeletions in patients with Danon disease. Circulation. Cardiovascular genetics. 2010 Apr;     [PubMed PMID: 20173215]
[16] Posada C,García-Cruz A,García-Doval I,Millán BS,Teijeira S, Chloroquine-induced myopathy. Lupus. 2011 Jun;     [PubMed PMID: 21300683]
[17] Sugie K,Komaki H,Eura N,Shiota T,Onoue K,Tsukaguchi H,Minami N,Ogawa M,Kiriyama T,Kataoka H,Saito Y,Nonaka I,Nishino I, A Nationwide Survey on Danon Disease in Japan. International journal of molecular sciences. 2018 Nov 8;     [PubMed PMID: 30413001]
[18] 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 Mar 25;     [PubMed PMID: 19318653]
[19] Hershberger RE,Givertz MM,Ho CY,Judge DP,Kantor PF,McBride KL,Morales A,Taylor MRG,Vatta M,Ware SM, Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline. Journal of cardiac failure. 2018 May;     [PubMed PMID: 29567486]
[20] D'souza RS,Mestroni L,Taylor MRG, Danon disease for the cardiologist: case report and review of the literature. Journal of community hospital internal medicine perspectives. 2017 Mar;     [PubMed PMID: 28638575]