Continuing Education Activity

Danon disease is a rare X-linked dominant genetic disorder that manifests with the clinical triad of cardiomyopathy, skeletal myopathy, and intellectual disability. It is caused by genetic mutations in the lysosome-associated membrane 2 (LAMP2) gene, with most mutations leading to an absence of LAMP2 protein. Most published data on this disease is abstracted from case reports, limited observational studies, and expert opinion. This activity describes the evaluation and management of Danon disease and highlights the role of an interprofessional team approach in managing and improving care for patients with this condition.

Objectives:

• Identify the etiology of Danon disease.
• Describe the evaluation of Danon disease.
• Review the treatment and management options available for Danon disease.
• Describe interprofessional team strategies for improving care coordination and communication to manage Danon disease and improve outcomes.

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 patients with Danon disease. [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 the 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 the 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 patients with Danon disease. 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 patients with Danon disease 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 patients with Danon disease 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 patients with Danon disease 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 patients with Danon disease. 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 patients with Danon disease 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 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 assist 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 5]