Danon disease is an uncommon disease that affects both males and females. The clinical presentations can be severe, and this disease can also be life-threatening to those who have it. This article aims to raise awareness of the gender differences of Danon disease. Read on to learn more about the presentation of Danon disease and how it can vary between the genders.

Introduction

Danon disease is a condition that affects a few people; it weakens muscles within the heart as well as muscles that are used for movement, and it can also cause intellectual disability.¹ This disease is inherited on the X chromosome and causes a LAMP-2 deficiency. People assigned male at birth are more affected than people who are assigned female at birth in most cases, and tend to show more severe symptoms.

X-linked inheritance leads to different expressions in males compared to females due to their genetic differences. Males have an XY chromosome pairing, whereas females have an XX chromosome pairing. This means that as males only have one copy of the X chromosome, they are more likely to express features that are linked to the X chromosome 2), in this case, Danon disease. Understanding these genetic differences allows practitioners to properly diagnose and manage Danon disease for both males and females.

This review aims to evaluate research and evidence of differing features of Danon disease presented in males and females.

Methods

Search strategy

This report uses databases such as NIH and Web of Science to find evidence of gender differences in the phenotypic expression of Danon disease. Specific keywords such as ‘Danon disease’, ‘gender differences’ and ‘phenotype’ are used to search for appropriate articles and research to support the gender differences in Danon disease

Inclusion criteria

This systematic report includes studies that report clinical expressions of Danon disease specific to gender. This includes evidence included in case reports, cohort studies and reviews.

Exclusion criteria

Studies that do not include human participants are not included in this review, as well as studies that do not provide sufficient evidence and data regarding gender related features of Danon disease, as these do not provide accurate or representative data appropriate for this review.

Data extraction & analysis

Data collected from studies will include gender-specific clinical characteristics of Danon disease. This may include skeletal, cardiac or neurological symptoms that each gender may experience. However, data such as the age of onset will also be collected and compared. Studies related to survival outcomes will be researched to provide evidence for gender specific survival outcomes of Danon disease. 

Results

Study selection

For this study, several sources were used, such as an international registry of Danon disease with patients located in the US and Europe between the years 2005 to 2022. Other sources, such as manuscripts, were used to collect evidence and data on the gender-specific presentations of Danon disease.

Phenotypic expression in males

Males tend to have an earlier onset of Danon disease than females, with males being diagnosed earlier than females, as early as childhood or adolescence.³

Males tend to show continuous thickening of the heart wall, which is known as hypertrophy. This often occurs until they face heart failure. The heart also shows signs of dilation, with the chambers becoming larger over time, again leading to issues such as heart failure.³

Danon disease often causes musculoskeletal problems for males, with males having a higher frequency of issues related to muscle enzymes than females.³ Musculoskeletal problems in males appeared more frequently in the proximal muscles, which are the muscles that are located closest to the core of the body.⁴

Evidence from a study shows that cognitive impairments are more common in males, with 80% of the patients affected being male. An IQ test conducted showed a below-average score ranging between 48 to 85, with the average IQ of the general population being between 90 and 110.⁴

Males with Danon disease suffer from a poor prognosis, with the average life expectancy being 19 years old.⁵

Phenotypic expression in females

Females with Danon disease tend to express characteristics at a later age than males, with males having an onset as early as childhood, whereas females' onset is adulthood.³ Females experience similar cardiac issues as males with Danon disease, such as thickening of the heart muscles and dilation of the heart, all of which can lead to heart failure; however, these clinical presentations may be more variable.

Females show musculoskeletal issues and muscle weakness within the body; however, this is less frequent than in males with Danon disease, despite the same presentation.  

Danon disease less commonly impacts females cognitively. Despite still causing cognitive impairments in a small minority, it is less frequent than in the male population with Danon disease.³

Despite their life expectancy still being below average, the prognosis for females with Danon disease is more expectant than males. Female life expectancy on average is 34 years old, making it longer than the average male life expectancy for those who have Danon disease.⁵

Comparative analysis

In females, clinical characteristics may be much less severe due to X chromosome inactivation in females. This is when one of the XX chromosomes becomes randomly inactivated so that females do not overexpress the genes that they have.⁶

Discussion

Interpretation of findings

Males tend to have an earlier onset of Danon disease than females do, with much more severe symptoms and clinical characteristics, whereas females show a delayed, less severe phenotype, with a later onset and milder symptoms.

Pathophysiological basis

Danon disease is inherited on the X chromosome, affecting males and females. However, females can have a randomly inactivated X chromosome, resulting in underexpression of the phenotype.

Clinical implications

Early screening is important for male relatives, as they may have inherited the X chromosome-linked disease. Screening allows for appropriate medical intervention to occur to allow for necessary support and advice to be provided.

Management of the disease should be gender-specific due to the differences in the phenotypic expression of Danon disease in males and females. Appropriate treatment should be accessible for both genders in response to their clinical characteristics.

Limitations of current evidence

Limitations of the evidence used in this report are that the sample sizes are relatively small due to how rare and uncommon this disease is. This means that samples are not representative of a wider population and may not be fully accurate or reliable.
There is also a limitation on follow-up data as there is not a mass amount of studies or research on Danon disease.

Future directions

More studies to be carried out in order to collect more evidence on gender specific phenotypic expression of Danon disease. This will allow for more accurate and reliable data to be accessible for the population.

Standardised guidelines should be created for the treatment of Danon disease, ones that are appropriate for each gender and the different clinical characteristics that they express.

Summary

Danon disease is inherited on the X chromosome and therefore impacts both males and females. Females tend to have a later onset and less frequent and severe symptoms; however still suffer majorly from cardiac issues. Males with Danon disease have an earlier onset and more severe symptoms that result in a shorter life expectancy than females.

Gender specific treatments and medical interventions should be curated for Danon disease to allow for appropriate and necessary support to be provided for those who require it.