LIVING WITH DANON DISEASE: SYMPTOMS, DIAGNOSIS, TREATMENT, AND PROGNOSIS
Danon disease is an X-linked dominant genetic disorder affecting multiple organ systems. It affects both skeletal and heart muscles. Cardiomyopathy, intellectual disabilities, and skeletal muscle weakness are found in people with this rare disease.
Danon disease was first described by Moris Danon in the 1980s. The condition can vary in symptoms and severity. Danon disease prevalence is less than 1 in a million people.
What is Danon Disease?
Danon disease is grouped under lysosomal storage disorders (LSD). With these types of storage disorders, toxins build up in the body due to molecules not being broken down properly in the cells.
The onset of symptoms happens at an earlier age in males than in females. Males, on average, first show signs of the genetic condition at about age 12 or 13. With Danon disease in females, the first signs are evident in early adulthood at about age 28. In general, women show symptoms about 15 years after men.
The disease involves skeletal myopathy but also affects the heart and can, therefore, be life-threatening.
What Causes Danon Disease?
The cause of Danon disease is a mutation in the LAMP2 gene on the X chromosome. Because it is an X-linked disorder, males are more severely affected than females since they only have a single X chromosome, while females have two.
The Genetic Basis of Danon Disease
To understand the genetic basis of the disease, we need to learn about the genes involved in lysosome function. A lysosome is an organelle. An organelle is a membrane-bound structure inside a cell that has a specific function. You can think of an organelle as a little organ enclosed by a covering called a membrane.
The lysosome is a sac containing enzymes that digest material. Another important organelle is an autophagic vacuole. Autophagy means “self-eating,” and a vacuole is a sac, so autophagic vacuoles are sacs in which substances are digested. Lysosomes combine with autophagic vacuoles to form a sac containing digestive enzymes. This process of combining requires special proteins found on the covering (membrane) of the lysosome. These are known as lysosome-associated membrane proteins.
LAMP2 is a gene that provides the information to make these lysosome-associated membrane proteins, which allow a lysosome to fuse with an autophagic vacuole. Danon disease affects the lysosomes of cells because of a gene mutation. The LAMP2 mutation causes problems with how lysosomes function since it alters the proteins on the membrane. As a result, vacuoles containing glycogen build up instead of fusing with the lysosomes. In Danon disease, these glycogen-containing vacuoles accumulate in skeletal and cardiac muscles.
Danon Disease Symptoms
There are various symptoms that can be present in a person with Danon disease since the condition affects more than one organ system.
- Cardiomyopathy:
- Hypertrophic cardiomyopathy, i.e., thickening of the heart muscle, is the most common cardiac manifestation of Danon disease and is common in males with the disorder.
- Dilated cardiomyopathy (enlargement of the heart chambers) can also occur in people with hypertrophic cardiomyopathy. This condition is more common in females with Danon disease.
- Arrhythmias (irregular heart rhythms) are common and can be life-threatening. Several kinds of arrhythmia have been found in patients with Danon disease. Wolff–Parkinson–White (WPW) syndrome is one of the most common conduction abnormalities seen in patients. Wolff Parkinson white pattern in Danon disease (preexcitation) is when there is an extra pathway along which the electrical signals of the heart pass. This conduction abnormality pattern is evident on an ECG. This can result in sudden cardiac arrest, which may be fatal.
- Heart failure may develop in people with Danon disease, and in severe cases, cardiac transplantation may be necessary.
- Skeletal Muscle Weakness:
- Progressive muscle weakness of the legs, shoulders, and neck, often starting in childhood, is part of the phenotypic expression of Danon disease. A skeletal muscle biopsy will show the presence of vacuoles containing glycogen, indicating muscle disease.
- Individuals with Danon disease often face difficulty with gross motor skills (running, jumping). There can be a delay in motor skill development (especially in males) because of muscle weakness.
- Exercise intolerance is a symptom sometimes seen in people with Danon disease.
- Patients may feel pain and cramps in the muscles because of the accumulated glycogen.
- Intellectual Disability and Psychiatric Problems:
- Individuals may experience intellectual disability to varying degrees, from mild to severe. Learning difficulties may present in children with the condition.
- Psychiatric issues. Patients may have psychiatric issues, such as a mood disorder or anxiety. Some behavioral issues have been noted in children with the condition.
- Speech delays. Language ability, including speech, may be delayed in children with Danon disease.
- Other Possible Features:
- Retinal disease (pigmentary retinopathy) may be present, which can cause vision problems. Blurred vision and floaters may be evident. Vision issues affect 69% of males with Danon disease.
- Some patients with Danon disease have short stature.
- Patients may suffer from various gastrointestinal issues, including an enlarged liver and abnormal levels of liver enzymes.
How is Danon Disease Diagnosed?
There are various tests that can be completed besides a clinical evaluation and medical history. Some of the diagnostic tests for Danon disease are:
- Echocardiogram (heart ultrasound) and electrocardiograms: An ultrasound can give good visuals of the heart, showing the chambers and how blood flows through them. The electrocardiogram shows how electrical impulses pass through the heart; this helps to show any arrhythmias.
- Cardiac MRI: This allows to see how thickened or enlarged the heart muscle is in people with Danon disease.
- Muscle biopsy: A small portion of muscle tissue is removed and evaluated for the presence of glycogen-containing vacuoles.
- Genetic testing (LAMP2 gene analysis): Molecular testing can show evidence of LAMP2 gene variants that are present when a person has Danon disease.
- Ophthalmologic evaluation (eye exam): An ophthalmologist may see a lack of pigment or photoreceptors in the retina of a patient with the condition.
- Liver function tests: These will show high levels of certain enzymes such as aspartate and alanine aminotransferase.
Early diagnosis of Danon disease is crucial because it is progressive. The disorder can be confused with other similar conditions like Pompe disease and infantile autophagic vacuolar myopathy.
Differential Diagnosis
- Danon vs. Pompe disease: Pompe disease is also a rare genetic disorder. While both Danon disease and Pompe disease patients have weak muscles and cardiomyopathy and show elevated creatine kinase levels (mostly in males in the case of Danon disease), Pompe patients do not show neurological signs that are typically seen in patients who have Danon disease.
- Infantile autophagic vacuolar myopathy: Various muscle disorders can be categorized as infantile autophagic vacuolar myopathies, i.e., where autophagic vacuoles are found in muscle tissue. Vacuoles can also occur in Danon disease and Pompe disease. Therefore, to narrow down the diagnosis, further tests are needed, with particular attention to the presence of glycogen in vacuoles.
Danon Disease Treatment and Management
Currently, there is no cure for Danon Disease. A person with the condition is treated by a multidisciplinary team of specialists (cardiologists, neurologists, geneticists, therapists, etc.) to provide comprehensive care, with treatments focusing on managing symptoms and slowing progression. Early intervention is important to help manage symptoms and for monitoring the progression of the disorder.
- Cardiomyopathy Management:
- Medications to manage heart failure and arrhythmias. This may include beta blockers and diuretics. Beta-blockers can help with certain arrhythmias, while diuretics help remove excess fluid. Fluid balance management is important in managing heart failure.
- Implantable cardioverter-defibrillator (ICD) or pacemakers for life-threatening arrhythmias. Subcutaneous ICDs are helpful in LAMP2 cardiomyopathy.
- Ablation therapy may be performed to treat arrhythmias in Danon disease.
- A Holter monitor is a device you can wear that tracks heart activity. It is a useful way to monitor how the heart is beating over a period of time.
- In cases of significant cardiac compromise, heart transplantation may be a viable consideration.
- Skeletal Muscle Weakness Management:
- Physical therapy, aimed at maintaining muscle strength and functional ability.
- Exercise (within tolerance) to promote muscle health.
- Intellectual Disability Management:
- Educational support and individualized learning plans.
- Speech therapy and occupational therapy.
- Social and psychological support and behavioral therapy, if needed.
- Retinal Disease Management:
- Regular eye exams.
- Management of vision problems, including using eyeglasses.
- Genetic Counseling: This can help families understand the inheritance pattern of the disease and the likelihood of passing on the condition to their children. A woman who has the defective LAMP2 gene has a 50% chance of passing it on to her children, but a man with the gene mutation will pass it on to all his female children.
Prognosis
The prognosis of Danon disease can vary significantly depending on factors like disease severity. While average life expectancy has been reported to be around 19 years for men and 34 years for women, individual outcomes can differ.
People with the disease should avoid smoking and alcohol and should aim to maintain a healthy lifestyle.
Research and the Future
Research has focused largely on genetic therapy. Gene therapy, where the abnormal LAMP2 gene is replaced by a normal LAMP-2B gene, shows promise in helping patients improve symptoms, alleviating cardiac signs, and improving the quality of life. Phase 2 trials are now underway.
More research has been conducted using stem cell technology to provide further insight into Danon disease. Research into medication that can be used to help manage the condition is also ongoing.
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