Outline

Danon disease is a disease caused by gene mutations that affects cardiac and skeletal muscle, and cognitive abilities. These mutations lead to a high prevalence of arrhythmias and sudden cardiac death. Understanding the physiology of the disease and its effect on patients is crucial to employing the best strategies to help patients.

What is danon disease?

Danon disease is a rare chromosomal condition caused by mutations within the LAMP-2 gene. This gene provides instructions for the creation of the protein lysosome-associated membrane protein 2 (LAMP-2), which is found in the membrane of lysosomes. This mutation impacts the ability of lysosomes to degrade and remove cellular waste, causing a build-up. This build-up of cellular waste causes cellular damage, and the cardiomyopathy, muscle weakness, and cognitive deficiencies seen in Danon disease. Danon disease is X-linked, meaning it affects men more severely, as men only have one X chromosome and any mutations within the chromosome cannot be compensated for by another X chromosome, such as in the case of women.¹

Pathophysiology of danon disease and the link with arrhythmias and cardiomyopathy

Danon disease is strongly linked to arrhythmias. The damage caused to muscle cells within the heart causes abnormal spaces within the muscle cells that do not fuse properly with the lysosomes for degradation, leading to their buildup. In a healthy heart, these vacuoles fuse properly with the lysosomes in a process called autophagy, and this allows for the degradation and recycling of debris.² This change in process leads to severe myocardial changes as these vacuoles accumulate and enlarge, leading to hypertrophic and dilated cardiomyopathy. Hypertrophic cardiomyopathy presents with enlarged heart muscle and a weakening of the heart muscle. Dilated cardiomyopathy occurs more frequently in women and is characterised by an enlargement of the heart chambers and the left ventricle of the heart, weakening and dilating, leading to an impairment in the ability of the heart to pump blood ³. This damaged and weakened heart muscle can impact the electrical system of the heart, specifically because of fibrosis. Fibrosis is the excessive formation of scar tissue as a response to injury or trauma, and within the heart, it can affect the way the electrical conduction occurs within the organ. As scar tissue is not conductive, it leads to irregularities in the coordination of electrical signals, causing arrhythmias.

Fibrosis can cause reentry circuits commonly seen in tachycardias, such as supraventricular tachycardia, that cause a continued excitation of the heart muscle, leading to an increased heart rate.⁴ Atrial fibrillation is caused by similar mechanisms and has a higher prevalence. However, atrial fibrillation carries an increased risk of blood clots, potentially causing strokes.⁵ Heart block can also be caused by Danon disease, and this occurs when the scar tissue acts as an insulator and prevents conduction, leading to an irregular, delayed, or slow heartbeat. Heart block can be categorised into three stages: stage 1, where there are very few symptoms, if any, although there may be a delay in the signal being conducted; stage 2, where skipped beats occur as the signal occasionally passes, whilst other times it does not. Stage 2 can be further split into Mobitz type 1 and type 2. Mobitz type 1 causes an accumulation of a delay that eventually causes a skipped beat, and this is less severe than type 2. Type 2 causes abnormal delays in the electrical signal, leading to a much higher prevalence of skipped beats, and this can cause symptoms that include: lightheadedness, breathlessness, dizziness, and fainting. Stage 3 heart block is the most severe and can be potentially life-threatening. In stage 3, very few signals can pass through, leading to an incredibly irregular and slow heart rate.⁶

Epidemiology of sudden cardiac death in danon disease

Sudden cardiac death is the abrupt stoppage of heart function, leading to unconsciousness and breathlessness, typically caused by electrical disruptions within the heart. As Danon disease impacts the electrical function of the heart severely, the incidence of sudden cardiac death is much higher. In one study, roughly 22% of patients exhibit sudden cardiac death. Sudden cardiac death occurs most frequently in men aged 20-39, as it is most associated with the presence of hypertrophic cardiomyopathy. In patients who exhibit rapid development and advancement of hypertrophic cardiomyopathy, heart transplants should be immediately considered, as these patients have an increased risk of sudden cardiac death.⁷

Risk stratification

Understanding biomarkers and potential risk factors for Danon disease is very important for the treatment and diagnosis of the condition. The diagnosis of Danon disease involves the analysis of clinical risk markers that potentially suggest the presence of the disease. These risk markers typically follow the investigation of the typical symptoms of Danon disease. Probing into a potential history of fainting, breathlessness, and heart palpitations. Family history of patients is also investigated to understand whether there is a potential congenital risk for the patient. As Danon disease is an X-linked inherited condition, mothers are more important for analysis. Mothers have a 50% chance of passing the faulty gene to their children, and if this is a son, he will inherit Danon disease. In the case of a daughter, the father will also pass down an X chromosome, and therefore, a daughter will instead be a carrier, and while symptoms may be present, they will typically be less severe because of the other healthy X chromosome.⁸ If there is a suspicion of Danon disease, imaging can be used for further insight into the state of the heart. Cardiac MRIs are used to analyse the structure and function of the heart, looking for characteristic features such as muscle hypertrophy or the presence of fibrosis.⁹ In cases where Danon disease is suspected, ambulatory ECG monitoring (AECGM) can also be used, and this is the monitoring of the heart over a lengthy period (24-72 hours) while the patient continues their regular daily activities. This would allow an insight into any potential arrhythmias endemic to Danon disease. In most cases, even after a diagnosis of Danon disease, AECGM is still used for routine monitoring twice a year.¹⁰ The testing of biomarkers is a final method that is used in the investigation of Danon disease. An elevated presence of Troponin in the blood can suggest Danon disease, as Troponin is a protein that is released into the blood when the heart is damaged. Troponin levels are directly proportional to the level of damage and so act as a reliable marker for understanding the state of injury within the heart.¹¹

Treatment methods

Depending on the specific symptoms and impact on quality of life, different treatment options are available for patients. Lifestyle changes are first suggested to patients, and the cessation of any extreme exertion or competitive sports is recommended. In cases of tachycardias, beta blockers such as bisoprolol can be used to manage the episodic behaviour of the heart. The aim of beta blockers is to reduce the workload of the heart and prevent further weakening.¹² Implantable cardioverter defibrillators (ICDs) can also be used to treat tachycardias. These devices send an electrical shock to the heart during episodes of dangerously high heart rates. These electrical shocks restore the heart to its normal pace. In the case of heart block, and specifically stage 3 heart block, a pacemaker is needed to restore the normal function of the heart.¹³ Advanced Danon disease cannot be treated by any of these options, and therefore, patients may require left ventricular assist devices (LVADs). These devices are used to assist the heart in place of a failing left ventricle and are used for patients with severe heart failure. The most advanced patients require heart transplants. Gene therapy treatments are currently being explored and developed, but are experimental.

Summary

Although Danon disease is a serious lifelong condition, the early diagnosis through the correct assessment of risk factors can significantly prolong a patient's life. Regular monitoring to monitor the progression of the condition and ensure the prevention of sudden cardiac death is paramount in the treatment of patients. Lifestyle changes, medications, and new technology can all assist patients in their navigation of the condition and as new treatments develop, patients' outlook will continue to improve.