Danon’s Disease - Causes, Symptoms, Diagnosis, and Treatment

What Is Danon's Disease?

Danon's disease is a hereditary disorder characterized by cardiomyopathy (wasting of the heart muscle), skeletal muscle myopathy (deterioration of the muscles used for movement), and intellectual disability. The incidence of the disease is very rare and is inherited in an X-linked dominant pattern. This type of inheritance tends to develop more severely in males than females, and the symptoms are seen at a very young age than in older adults.

A cell is made up of many compartments known as lysosomes. Lysosomes within the cell use the enzymes to break large molecules into smaller ones for the cells to use them. Danon's disease is a type of lysosomal storage disorder (X-linked lysosomal and glycogen storage disorder) that occurs due to a defect in the lysosomal cell membrane. This defect is caused due to the mutations in the LAMP2gene, and the treatment aims to address the symptoms present in each individual.

Danon's disease is also addressed with various other names, and they are:

1. Vacuolar cardiomyopathy and myopathy X-linked.

2. X-linked vacuolar cardiomyopathy and myopathy.

3. Antopol disease.

4. Pseudo glycogenosis 2.

5. Glycogen storage disease limited to the heart.

6. Glycogen storage cardiomyopathy.

7. Glycogen storage disease type 2b.

8. Lysosomal glycogen storage disease without acid maltase deficiency.

9. GSD2B.

What Are the Causes of Danon’s Disease?

Mutation in the LAMP2 gene is the exact cause of Danon's disease. The LAMP2 gene acts as an instructor for making a protein known as lysosomal-associated membrane-2 protein. This protein is found in the cell membrane called lysosomes. Lysosomes are compartments within the cells that help digest and recycle the cellular materials. However, the exact role of LAMP-2 protein is unclear.

1. Some studies say that the LAMP-2 protein helps transport digestive enzymes or cellular materials into the lysosome. This transportation requires cellular structures such as autophagic vacuoles or autophagosomes.

2. The LAMP-2 protein is then involved in the fusion of autophagic vacuoles and lysosomes.

Variations or mutations in the LAMP2 gene results in very little or no LAMP-2 protein. It causes the impairment of transporting cellular material into the lysosome. In addition, the fusion between the lysosome and autophagic vacuoles occurs very slowly, leading to the accumulation of autophagic vacuoles. This is the reason why people with Danon's disease have a large number of autophagic vacuoles in their muscle cells. This accumulation may lead to the breakdown of the muscle cells, causing muscle weakness.

What Are the Symptoms of Danon’s Disease?

The symptoms of Danon's disease vary based on severity and gender. In males, the signs and symptoms develop earlier, and they are more severely affected by this condition than in females. This is because Danon's disease is inherited in an X-linked dominant trait. The LAMP2 gene associated with this disorder is present in the X chromosome (one of the two sex chromosomes). Females have two X chromosomes, and a mutation in one of the two X chromosomes in each cell causes the disorder. Males have only one X chromosome, and a mutation in the only one X chromosome in each cell causes the condition. A characteristic feature of this X-linked inheritance is that the X-linked traits cannot be passed to their sons by their fathers.

Males:

The clinical manifestations seen in males are:

1. The onset of heart disease and muscle weakness in childhood or adolescence.

2. Difficulty in learning or intellectual disabilities can be present.

3. Severe muscle weakness affects the ability to walk.

4. Cardiomyopathy (weakness of heart muscle) can be severe, leading to a need for medications. It progresses to heart failure, which is complicated by embolic strokes with severe neurological disability and atrial fibrillation. This can lead to death if a heart transplant is not performed.

5. Fluttering in the chest (palpitations), an abnormal heartbeat or chest pain occurs.

6. Cardiac conduction abnormalities (electrical signals that control the heartbeat) can occur. The common conduction abnormality with Danon's disease is Wolff-Parkinson-white syndrome, which is common in both genders.

7. Problems with the eye, such as visual disturbances, and retinal pigment abnormalities, occur.

8. Danon's disease is unfamiliar to most physicians as it is rare. Mostly, it can be mistaken for other forms of muscular dystrophies and heart disease.

Females:

The clinical symptoms of Danon's disease are less severe in females, and they are:

1. The onset of symptoms will not be obvious in females until late adolescence or even adulthood.

2. Females will not have learning problems or intellectual disabilities, and they are completely absent.

3. Muscle weakness could be gentle, or there will be an absence of muscle weakness. Only a very few females exhaust themselves with exercise.

4. Heart muscle weakness develops in adulthood and can be associated with embolic strokes and atrial fibrillation.

5. In females, symptoms progress more slowly than in males.

6. Danon's disease is unfamiliar to most physicians, and due to the milder symptoms in females, it is more difficult for physicians to diagnose females with Danon's disease.

How Is Danon's Disease Diagnosed?

It is often difficult to diagnose genetic or rare diseases. It is important for a doctor to look at the patient's symptoms, medical history, physical examination, and laboratory test results to diagnose properly. Danon's disease can be diagnosed by performing genetic testing of the LAMP2 gene. It is considered to be the gold-standard diagnosis and is performed in specialized genetic laboratories. In addition, testing resources such as the genetic testing registry (GTR) and Orphanet provide information regarding the genetic tests and the list of international laboratories that offer diagnostic testing for Danon's disease. The doctor might also recommend screening the newborns for lysosomal storage diseases to avoid serious complications.

How Is Danon's Disease Treated?

The treatment aims to address the symptoms, and it might require a team of specialists.

1. The first-line treatment of Danon's disease is medications for heart disease. Careful monitoring of heart disease is needed because it is often associated with rapid progressive cardiomyopathy and sudden death. When there are signs of progressive heart failure, aggressive interventions such as implantable cardioverter-defibrillators and early intervention with heart transplantation might be recommended.

2. Continuous physical therapy helps to maintain muscle strength and flexibility. In addition, regular assessment of muscle strength is needed.

3. Appropriate educational interventions should be received for people with intellectual disabilities, and enrollment in rehabilitation centers for psychological, educational, and social support is mandatory.

Conclusion:

Danon's disease is a rare disorder caused by LAMP2 mutations. Rare disorders are often difficult to interpret by doctors, but early intervention is needed to prevent future complications and sudden death. Treatment will be based on the presenting symptoms such as cardiomyopathy, ocular disease, skeletal myopathy, etc. The overall major goals of the treatment are to slow down heart failure and muscle loss, prevent loss of cognition, and eliminate arrhythmias.