The Rare360 Editorial Team
- Feb 2
- 6 min read

Navigating the Complexity of Danon Disease

A brown teddy bear sitting with a sthethoscope.

Danon disease is a rare multisystem disorder with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Danon disease is one of about 50 different lysosomal storage disorders (LSD) in which genetic variations disrupt the normal activity of lysosomes in human cells. Lysosomes are crucial cellular components in human cells and contain specific proteins known as enzymes that are responsible for breaking down and recycling molecules like fats and sugars. In individuals with a lysosomal storage disorder, the deficiency or insufficient quantities of these enzymes hinder the cells’ ability to function properly.

Specifically, Danon disease results from a mutation or deletion of the LAMP2 gene located on the X chromosome, containing the instructions for the production of an enzyme called lysosomal-associated membrane protein-2 (LAMP-2). There are over 160 different variants in the LAMP2 gene identified to date that can cause Danon disease. Variants that lead to a complete absence of the LAMP2 protein have been shown to be most detrimental. Mutations in the LAMP2 gene impair this process, leading to an abnormal accumulation of material that eventually leads to the development of Danon disease.

It can be either inherited from a parent with the condition or a spontaneous mutation (‘de novo’). Danon disease is not usually evident at birth unless blood tests are done in a suspected case (i.e., a son born to a mother known to have the disease). Typically, males are more severely affected by this condition and develop symptoms at a younger age. Males have only one X chromosome — if they have the LAMP2 mutation or deletion on that chromosome, they may make insufficient amounts of the LAMP2 protein or, in some cases, none at all. Females, on the other hand, have two X chromosomes. If they have a mutation or deletion in one chromosome, the other may still produce enough LAMP2 protein to compensate for the defect. As a result, female patients present with greater variability of disease, ranging from having no signs or symptoms to being severely affected. On average, affected males live to the age of 19, while affected females live to an average age of 34.

Males vs. Females: Navigating the Varying Symptom Landscape of Danon Disease

Danon disease exhibits varying symptoms in males and females, typically manifesting in childhood for most affected males and in early adulthood for most affected females. Here are some common symptoms for both genders:

Males

Hypertrophic Cardiomyopathy: Most affected men experience thickening of the heart muscle (hypertrophic cardiomyopathy), making it challenging for the heart to pump blood. Others may have dilated cardiomyopathy, a condition weakening and enlarging the heart, hindering efficient blood pumping. Some with hypertrophic cardiomyopathy may later develop dilated cardiomyopathy.
Severe Heart Disease: Cardiomyopathy can be severe, often progressing to heart failure. This may be complicated by atrial fibrillation and embolic strokes, resulting in severe neurological disability and potential death without a heart transplant. Patients may also experience Wolff-Parkinson-White (WPW) Syndrome (heart arrhythmia).
Learning Issues or Intellectual Disability: In males, intellectual disability is generally mild, allowing them to typically engage in activities such as reading, maintaining employment, and living independently.
Muscle Weakness: Severe muscle weakness impacting endurance and walking ability.
Visual Disturbances: Some may encounter visual impairment, colour vision disturbances and/or retinal pigment abnormalities.
Lung and Liver Involvement: Liver and lung complications can occur due to skeletal myopathy, resulting in elevated liver enzymes and weakness in the respiratory muscles.
Laboratory Findings: Elevated creatine kinase (~5-fold increase); elevated asparate aminotransferase (AST) (~7-fold increase); and elevated alanine aminotransferase (ALT) (~6-fold increase).

Females:

Late Onset of Symptoms: Symptoms often appear later, with many females not displaying obvious signs until late adolescence or adulthood.
Mild Learning Problems: Learning problems and intellectual disability are typically absent or very mild.
Subtle Muscle Weakness: Muscle weakness is often absent or subtle, with some experiencing fatigue during exercise.
Delayed Cardiomyopathy: Cardiomyopathy is often absent in childhood, developing in adulthood for some women.
Visual Disturbances: Some females may also have visual disturbances and/or retinal pigment abnormalities.
Laboratory Findings: Normal or mildly increased creatine kinase, AST and ALT

Several affected individuals may also present with gastrointestinal disease, breathing problems, or fatigue. Due to the similarities in symptoms, Danon disease is occasionally misdiagnosed as other forms of heart disease or muscular dystrophies, such as Pompe disease.

Learn More Research is being conducted in order to gain a better understanding as to how danon disease impacts people's lives. If you or a loved one is suspected to have or has been diagnosed with danon disease, you have the opportunity to include your perspectives, insights and experiences (P.I.E.) by subscribing to the Rare360 P.I.E. Program.

Diagnostic Pathways for Danon Disease

Danon disease, being a rare condition, might not be readily identified by all healthcare providers. A diagnosis often involves a review of medical history and symptoms, a physical exam, and various tests. Doctors may order the following tests to diagnose Danon disease:

Genetic Testing: The gold standard for diagnosis is genetic testing of the LAMP2 gene, available in specialized laboratories. Possible genetic testing includes single-gene testing, multigene panel, exome sequencing, and genome sequencing. Most genetic variants associated with Danon disease predict reduced levels or the absence of the LAMP2 protein. While the sensitivity of LAMP2 genetic testing is not precisely known, its non-invasive nature makes it the predominant diagnostic method.
Muscle Biopsy: A muscle biopsy is performed to examine cells, which involves removal of a small tissue sample for microscopic analysis. Skeletal muscle biopsy is conducted in certain males to determine the cause of muscle weakness. If the biopsy reveals glycogen buildup and/or empty spaces in the muscle cells, Danon disease becomes a likely consideration. A heart biopsy may also be considered.
Other Supportive Labs
- Electrocardiogram (ECG) to check for Wolff-Parkinson-White (WPW) syndrome.
- Imaging techniques like echocardiogram and cardiac magnetic resonance to access the degree of cardiac fibrosis, serving as a predictor for potential arrhythmogenic events.
- A formal neuropsychological examination to uncover any intellectual disability.
- Electroretinogram while retinal examination may reveal changes in retinal pigment.

Treatment Realities: Coping with Symptoms of Danon Disease

Currently, there are no approved treatments to reverse the effects of Danon disease. The approach to managing Danon disease primarily concentrates on treating symptoms, especially those related to heart disease. A team of specialists, including Cardiologists, Geneticists, Physical Therapists, Neurologists, Genetic Counselors, Education Specialists, and Rehabilitation Physicians, may be involved in the treatment plan.

Here are some strategies for managing Danon disease:

Medication: Heart failure medications may be used to manage cardiac symptoms. However, these are not effective in the long term.
Surgery: In severe cases, a heart transplant may be considered.
Physical Therapy: Targeted exercises can help strengthen weakened muscles.
Educational Support: This can address learning disabilities that may be present.
Implantable Cardioverter-Defibrillator: This device, which is connected to the heart, can correct irregular heart rhythms.
Monitoring: Regular check-ups are essential to monitor disease progression and adjust treatment plans accordingly.

A table showing the recommended regular check-ups for individuals with Danon Disease with the following concerns and clinical evaluations: Cardiac, Electrocardiography, Echocardiography, Cardiac MRI, Ambulatory arrhythmia monitoring, Neuromuscular, Clinical assessment for neurologic changes and strength (including 6-min walking test), Neurocognitive, Monitor developmental progress & educational needs, Formal developmental assessments, Psychiatric/Behavioural assessment for anxiety, attention, & aggressive behaviour, exam by ophthalmologist for evidence of cone-rod dystrophy: best corrected visual acuity, color vision testing, visual field testing, and Assess family need for social work support (e.g., respite care, home nursing, other local resources) & care coordination. — Recommended Surveillance for Individuals with Danon Disease

It's crucial to emphasize that the management of Danon disease should be personalized and supervised by healthcare professionals familiar with the disease. Additionally, while these management strategies can help control symptoms and enhance quality of life, they do not constitute a cure for the disease.

Conclusion

In conclusion, Danon Disease presents a complex landscape, with its intricate web of symptoms affecting various systems in the body. The identification of over 160 mutations in the LAMP2 gene underscores the genetic diversity of this condition. Yet, despite significant strides, Danon disease is not well understood, highlighting the pressing need for continued research to unravel its intricacies and enhance both diagnostic capabilities and treatment modalities.

The variability in life expectancy among individuals with Danon disease accentuates the importance of personalized care. The severity of symptoms and the management of complications play pivotal roles in shaping outcomes. In instances of severe cardiac involvement leading to heart failure, life expectancy can be significantly impacted. However, the prospect of improved outcomes and potentially extended life expectancy exists with early diagnosis, meticulous medical care, and interventions like heart transplantation. Patients must work closely with healthcare professionals to develop a personalized treatment plan and monitor their condition regularly.

Looking ahead, the landscape of Danon Disease research holds promise. Exploring the biochemical intricacies of the LAMP2 gene is a key avenue, offering potential insights that could shape future therapeutic approaches. The prospect of protein replacement therapy, successfully employed in other conditions with missing proteins, stands as a beacon of hope. Ongoing gene therapy clinical trials underscore the commitment to translating research findings into tangible advancements, offering renewed hope for individuals grappling with Danon disease.

As the scientific community delves deeper into the complexities of Danon Disease, the collaborative efforts of researchers, healthcare providers, and patients remain essential. Through sustained dedication to understanding, diagnosis, and treatment, we aspire to illuminate the path toward a brighter, more hopeful future for those affected by Danon Disease.