Danon disease

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Danon disease is a condition characterized by weakening of the heart muscle (cardiomyopathy); weakening of the muscles used for movement, called skeletal muscles (myopathy); and intellectual disabilities. People with Danon disease may develop the condition at different ages. Signs and symptoms of this condition appear about 15 years earlier in males than in females. Males first experience health problems in childhood or adolescence; without treatment, these individuals typically live into early adulthood. Females start experiencing health problems in early adulthood and typically survive into mid-adulthood without treatment.

Cardiomyopathy is the most common symptom of Danon disease, and it occurs in all males and in most females. Beginning in childhood, most affected males develop hypertrophic cardiomyopathy, which is a thickening of the heart muscle that may make it harder for the heart to pump blood. Others with Danon disease may have dilated cardiomyopathy, which is a condition that weakens and enlarges the heart, preventing it from pumping blood efficiently. About half of females with Danon disease have hypertrophic cardiomyopathy, and the other half have dilated cardiomyopathy. Rarely, individuals with hypertrophic cardiomyopathy later develop dilated cardiomyopathy. Either type of cardiomyopathy can lead to heart failure and premature death.

Individuals with Danon disease can have other heart-related signs and symptoms, including a sensation of fluttering or pounding in the chest (palpitations), an abnormal heartbeat (arrhythmia), or chest pain. Many affected individuals have abnormalities of the electrical signals that control the heartbeat (conduction abnormalities). Affected individuals often have a specific conduction abnormality known as cardiac preexcitation. The type of cardiac preexcitation most often seen in people with Danon disease is called the Wolff-Parkinson-White syndrome pattern.

Skeletal myopathy occurs in most males with Danon disease and in some affected females. The weakness typically occurs in the muscles of the shoulders, neck, and upper thighs. Many males with Danon disease have elevated levels of an enzyme called creatine kinase in their blood, which often indicates muscle disease.

Most males with Danon disease have mild intellectual disabilities, but this is much less common in affected females.

There can be other signs and symptoms of the condition in addition to the three characteristic features. Several affected individuals have had gastrointestinal disease, breathing problems, or visual abnormalities.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Danon disease is caused by variants (also called mutations) in the LAMP2 gene. The LAMP2 gene provides instructions for making a protein called lysosome-associated membrane glycoprotein 2 (LAMP-2). As its name suggests, this protein is found in the membrane of cellular structures called lysosomes. Lysosomes are compartments in the cell that digest and recycle different types of materials. The LAMP-2 protein helps transport cellular materials or digestive enzymes into the lysosome. Three slightly different versions (isoforms) of the LAMP-2 protein are produced. These isoforms have slightly different functions and are found in different tissues throughout the body. The main isoform is needed to transport materials into lysosomes using a formation of cellular structures called autophagic vacuoles (or autophagosomes). Cellular material is first enclosed in an autophagic vacuole inside the cell. The vacuole then attaches (fuses) to a lysosome to transfer the cellular material into the lysosome. The LAMP-2 protein is involved in the fusion between autophagic vacuoles and lysosomes.

Variants in the LAMP2 gene lead to the production of very little or no functional LAMP-2 protein. Studies have shown that fusion between autophagic vacuoles and lysosomes occurs more slowly in cells without the LAMP-2 protein, which causes autophagic vacuoles to accumulate in these cells. Accumulation of these vacuoles in the heart likely causes heart muscle cells to expand and eventually die, leading to the enlarged and weakened heart common in people with Danon disease. Similarly, in skeletal muscle cells, this accumulation likely leads to the breakdown of the muscle cells, causing muscle weakness. The cause of the other signs and symptoms of Danon disease is unclear, but it is likely related to the accumulation of vacuoles in other affected tissues.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome) a variant in the only copy of the gene in each cell is sufficient to cause the condition. In females (who have two copies of the X chromosome) one altered copy of the gene can cause the condition, although the features may be less severe than in people with both copies altered. Some people with only one altered copy of the gene may have no signs or symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Danon disease is a rare condition, but the exact prevalence is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Gait disturbance · Very frequent (99-80%)

The term gait disturbance can refer to any disruption of the ability to walk.

Hypertrophic cardiomyopathy · Very frequent (99-80%)

Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.

Muscle flaccidity · Very frequent (99-80%)

A type of paralysis in which a muscle becomes soft and yields to passive stretching, which results from loss of all or practically all peripheral motor nerves that innervated the muscle. Muscle tone is reduced and the affected muscles undergo extreme atrophy within months of the loss of innervation.

Palpitations · Very frequent (99-80%)

A sensation that the heart is pounding or racing, which is a non-specific sign but may be a manifestation of arrhythmia.

Syncope · Very frequent (99-80%)

A transient loss of consciousness (i.e., characterized by a rapid onset, a short duration, and a spontaneous and complete recovery) due to cerebral hypoperfusion.

Cardiorespiratory arrest · Very frequent (99-80%)

Blurred vision · Frequent (79-30%)

Lack of sharpness of vision resulting in the inability to see fine detail.

Chest pain · Frequent (79-30%)

An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the chest.

Other findings in the same source

From: Orphanet

Additional reported features include Cough (Frequent (79-30%)); Dyspnea (Frequent (79-30%)); Elevated circulating creatine kinase concentration (Frequent (79-30%)); Elevated circulating hepatic transaminase concentration (Frequent (79-30%)); Intellectual disability (Frequent (79-30%)); Muscle weakness (Frequent (79-30%)); Myopia (Frequent (79-30%)); Progressive proximal muscle weakness (Frequent (79-30%)); Specific learning disability (Frequent (79-30%)); Wheezing (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Danon disease is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.