Danon disease is an inherited lysosomal storage disorder caused by the LAMP2 gene. Each body cell has a lysosome, which is responsible for breaking down cell components.¹ In Danon disease, these cell components cannot reach the lysosome and therefore cannot be broken down. This leads to the accumulation and storage of various products, such as glycogen and lipid droplets. This buildup is common in cells that make up cardiac muscle, skeletal muscle and neurons.²

Danon disease is rare, with a prevalence of under 1 in 100,000. IT is also X-linked dominant, meaning that it is often more severe in males, as they only have one X chromosome. In contrast, as females have two X chromosomes, they might present with milder symptoms or, due to X inactivation, might present as asymptomatic.³ Danon disease has a high morbidity, especially without coordinated intervention. Due to the cells that Danon disease affects, a patient requires neurological, cardiological and genetic support. 

Clinical features 

Danon disease often manifests with cardiac issues. One of the key presentations is hypertrophic cardiomyopathy. This is when the walls of the heart thicken marginally harder, making it harder for the heart to pump blood around the body. Patients can also present with dilated cardiomyopathy, where the heart is enlarged, also preventing effective blood pumping. 

Occasionally, hypertrophic cardiomyopathy can develop into dilated cardiomyopathy.  This puts the patient at risk of arrhythmias as the disorganisation of the muscle fibres can disrupt the normal electrical signals throughout the heart. In severe cases, it can even lead to a heart attack. In a patient with Danon disease, an ECG might show pre-excitation.

 This suggests that this patient is exhibiting Wolff-Parkinson-White syndrome, which is common in those with Danon disease, occurring in 69% of patients, with increased prevalence in males with Danon disease.⁴ This early depolarisation occurs due to the damage to the cardiac conduction system and accessory pathways, resulting from abnormal tissue development caused by glycogen accumulation. 

Patients might also suffer from proximal weakness due to skeletal myopathy (weakening of the muscles), seen in 80-90% of patients.  This can also be seen via elevated creatine kinase levels in the blood, which indicates muscle damage ⁵. LAMP2 deficiency leads to vacuolar myopathy, which is when the vacuoles of cells fill with glycogen. This then disrupts the normal muscle cell function and energy metabolism, leading to muscle weakness.⁶ Another cognitive symptom of Danon disease is cognitive impairment and intellectual disability, affecting 70-100% of males.⁷ While often mild to moderate, it can lead to learning difficulties or attention deficits. Like much of Danon disease, this symptom is more common in males. 

This happens because the brain relies on autophagy and degradation to occur, specifically in the neurons. When this does not happen and there is an accumulation of waste products, this can impact synaptic function and lead to neurodegeneration. Less common symptoms of Danon disease include seizures and EEG abnormalities.

Other symptoms of Danon disease can lead to:

• Gastrointestinal (GI)
• Endocrine and 
• Ocular symptoms

Whilst the cardiac, muscular and neurological symptoms are the most common, Danon disease is a multisystem disorder and can affect most tissues in the body. Ocular symptoms include retinal dystrophy, with patients reporting trouble seeing at night or reduced peripheral vision. This occurs because there is an accumulation of undirected photoreceptor debris and slower-turn-off retina proteins.⁸ GI symptoms include an enlarged liver, which may be seen on imaging. LAMP2-negative staining confirms that this enlargement of the liver is due to Danon disease. Finally, endocrine symptoms can include delayed onset of secondary sexual characteristics due to impaired hormone secretion. This can be monitored clinically through checking bone age or gonadotropin levels. 

Diagnostic workflow 

If a young male presents with cardiomyopathy, skeletal myopathy and intellectual disability, this combination would raise clinical suspicion and prompt the clinician to order further investigation to explore a possible diagnosis. These tests would include a blood test to check for elevated creatine kinase, which would be elevated in the case of muscle damage. Elevated AST and ALT are liver enzymes that become elevated in Danon disease due to liver involvement, resulting in glycogen accumulation. Finally, an elevated BNP (B-type Natriuretic peptide) is when this hormone is secreted by the heart muscles in response to increased wall stress or volume overload, which occurs in hypertrophic or dilated cardiomyopathy. For more definitive testing, genetic sequencing can be done to test for the presence of the LAMP2 gene. If it is found to be mutated, then these symptoms can be said to be caused by Danon disease.

Further imaging can be done to scope out possible structural abnormalities and the extent of organ involvement. An echocardiogram can be used to visualise the heart and detect whether the patient suffers from hypertrophic cardiomyopathy or dilated cardiomyopathy. Other cardiac tests might be ordered, such as an electromyography, to measure the electrical activity of the heart muscle.  A neuropsychological test will be used to build up a cognitive profile of the patient. Each of these tests will be done by a specialist. This information will help clinicians come up with a specific treatment plan for the patient. 

Cardiology 

The cardiology team will monitor the patient with regular ECGs and echocardiograms to assess how well the heart is adapting to any changes.  The patient might be prescribed beta blockers to manage the hypertrophic cardiomyopathy and reduce symptoms by reducing heart rate and the risk of arrhythmias. In order to decrease the stress on the heart, ACE inhibitors might be prescribed in order to reduce afterload on the heart and blood pressure ⁹. 

In some cases, devices might be considered in order to allow continuous monitoring to occur. This includes an implantable cardioverter-defibrillator (IDC). An ICD is implanted underneath the skin and is able to treat arrhythmias through shocks. In more serious cases, especially those in late adolescence, a cardiac transplant might be considered if there is irreversible cardiac damage and the heart can no longer sustain adequate function. 

Neurology 

The neurology team will work with the patient to provide tailored learning support and individualised education plans for those who have had delayed development. This will include using a developmental assessment to determine where the patient currently is in terms of development. The neurology team will also carry out strength and function tests in order to track skeletal muscle involvement over time. These tests might involve manual muscle testing, as well as functional tests such as the 6-minute walk test. In addition, regular CK tests will be ordered to track muscle degradation on a biochemical level. In addition, the neurology team, along with an ophthalmologist, will monitor the rate of retinal myopathy and be able to manage the symptoms such as night blindness 

Genetics

A geneticist will be able to confirm the diagnosis of Danon disease if a LAMP2 mutation is detected. As Danon disease is X-linked dominant, it is important to identify any other family members who might be affected by the condition. This can be done through cascade genetic testing, where first-degree relatives of the patient are offered testing. This can then determine whether they are affected, a carrier, or unaffected. Due to the nature of the inheritance, all daughters of an affected male are obligate carriers as they inherited his only X chromosome. 

However, his sons will be unaffected. In female carriers, they might not express the condition to the same extent as their male counterparts due to X chromosome inactivation. If Danon disease is detected early through genetic testing, this allows cardiac and neurological surveillance to be put into place before symptoms appear. 

With families with a known LAMP2 mutation, reproduction options include prenatal testing and preimplantation genetic diagnosis during in vitro fertilisation. This allows embryos without the mutation to be selected. These approaches allow parents to make an informed decision about family planning as well as prevent the transmission of the disease. Genetic counselling is offered to those with Danon disease wanting to have children, to discuss inheritance risks, reproductive choices and implications for any future offspring. 

Integration 

The core team for a patient with Danon disease would be those directly involved in their cardiac, neurological and genetic care. An expanded team would include a psychologist, a dietician, an endocrinologist, as well as potentially a transplant team. Combined care, such as neuromuscular-cardiology clinics, has been shown to have improved outcomes for the patient.  Not only is it important to think about care across different specialities, but also across ages. Pediatric to adult care should start to transition at around age 14.  

Summary 

Overall, Danon disease is a condition that affects many aspects of the body, and therefore, it is important to have a team working together to manage all the different symptoms that can arise. Not only is a primary team critical to the patient's health, but an additional team to provide dietary, psychological and hormonal aid can help improve the patient's quality of life.