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X-linked retinal dystrophies represent a group of rare genetic diseases, which manifest themselves as alterations in the structure and function of the retina. They are hereditary diseases caused by sequence variations in genes on the X chromosome - which is why they are termed 'X-linked' - which means that they have a particular mode of transmission, predominantly affecting male individuals. Symptoms can range from a reduction in night vision to a progressive loss of central vision. In this guide, we will explore the main features of X-linked retinal dystrophies.

Introduction to Retinal Dystrophies

Hereditary retinal dystrophies constitute a diverse group of genetic disorders characterised by progressive degeneration of the retina. These diseases typically affect the photoreceptors, cones and rods, which are the nerve cells responsible for visual perception.

Hereditary retinal dystrophies are classified according to the type of photoreceptor most affected. In retinitis pigmentosa, mainly the rods are affected, whereas in achromatopsia and Stargardt's disease, mainly the cones are damaged. In some cases there can be a generalised dysfunction of the retinal photoreceptors, as in Leber's congenital amaurosis.

Hereditary retinal dystrophies include:

1. Leber's congenital amaurosis

2. Dystrophy of the cones

3. Hyaline dystrophy of the retina

4. Vitelliform dystrophy of Best

5. Vitreoretinal dystrophy

6. Stargardt's disease

7. Retinitis pigmentosa

8. Retinitis punctata albescens

Definition and Characteristics

Retinal dystrophies are diseases that cause a gradual loss of visual function, often leading to severe visual impairment and in severe cases to blindness.

In approximately 20% of cases, in addition to the retinal degenerative picture, there is impairment of other organs and apparatuses (syndromic forms) that enter into the differential diagnosis with forms with exclusive ocular involvement.

Transmission of retinal dystrophies can be autosomal dominant, autosomal recessive or X-linked. In rare cases, mutations in two different genes (digenic forms) or mitochondrial DNA mutations are present.

In 30-40% patients, the type of transmission remains undefined, as they may be isolated or multiple cases with uncertain familial classification. While some retinal dystrophies are caused by mutations in only a few genes, others such as retinitis pigmentosa may result from mutations in more than 50 different genes.

Some forms progress slowly, while others can advance rapidly. It is, therefore, essential to diagnose these diseases early in order to manage their symptoms and slow down their progression.

Each type of retinal dystrophy has distinct clinical signs and specific genetic tests can help identify the exact type.

How they affect vision

Common features of most retinal dystrophies include visual difficulties depending on which part of the retina is affected by the degenerative process.

Difficulties in night vision are a fairly common symptom due to the retina's inability to adapt to low light conditions.

They can also manifest themselves:

1. Difficulty seeing in poorly lit environments.
2. Loss of peripheral vision, leading to 'tunnel' vision.
3. Central vision impairment, a type of damage that affects the ability to read or recognise faces.

In advanced cases, vision loss may be total. It is very important to constantly monitor changes in visual function and to consult the eye doctor for appropriate evaluations. Management includes the use of visual aids and adaptation techniques to improve quality of life.

Genetics of X Chromosome-Related Retinal Dystrophies

Le X-chromosome-related diseases are genetic conditions transmitted through the X chromosome. Humans have two chromosomes X and Y, which are called sex chromosomes because they determine the sex of the unborn child and are XX for women and XY for men.

The X chromosome contains about 1000 genes, compared to about 70 on the Y chromosome. To balance this large difference, one of the two X chromosomes, in womenIt undergoes a phenomenon known as 'inactivation'. This is a physiological process that causes the random silencing of one of the two X chromosomes, whose genes are consequently not expressed.

Some of the X chromosome-related genes that have been identified as causes of retinal diseases, such as the RPGR, RP2 e CACNA1F (associated with retinitis pigmentosa and other retinopathies) all undergo complete inactivation.

In contrast, male individuals, who carry the genes that cause X-linked dystrophies, as the X chromosome is not inactivated, may manifest the disease more frequently, while female individuals often have no or mild symptoms.

Inheritance and Genetic Transmission

The inheritance of X-linked retinal dystrophies follows a particular pattern of transmission whereby the affected males do not transmit the condition to their sons, but all their daughters will be carriers. On the other hand, a carrier has a 50% chance of transmitting the mutated gene to each child.

1. Daughters of affected males: all carriers.
2. Children of carriers: 50% probability of being affected.
3. Daughters of carriers: 50% probability of being carriers.

This transmission pattern requires a detailed understanding for appropriate genetic counselling. It is important to inform families about potential risks and available genetic testing options for informed family planning.

The genes responsible

There are many forms of retinopathies linked to mutations or inactivation of genes on the X chromosome. Among these, some of the most frequent are linked to the following genes:

• RPGR

RPGR (retinitis pigmentosa GTPase regulator) was the first gene identified as the cause of X-chromosome-related retinitis pigmentosa.

The mutations of RPGR are responsible for several types of disease, including rod-cone dystrophy (70%), rod-cone dystrophy (6-23%) and cone dystrophy (7%).

Retinitis pigmentosa (RP) shows X-chromosome-related inheritance in 8-16% patients with a prevalence of affected males of approximately 1:15,000-1:26,000. The gene RPGR is responsible for more than 70% of these cases. X-linked RP tends to have a more severe phenotype and often occurs during childhood (on average at 5 years of age).

• RP2

The retinitis pigmentosa gene RP2 was the second gene identified as the cause of X-linked RP. Mutations in this gene are responsible for approximately 10-20% of cases of X-linked RP. Patients show typical features of RP, including night blindness, constriction of the visual field and subsequent reduction in visual acuity.

• CHM

Gene variants CHM are responsible for chorioretinal degeneration in choroideremia.

Choroideremia affects 1:50,000 to 1:100,000 people, with a high prevalence in Finland. Males develop symptoms of nictalopia in the first decade of life, followed by progressive visual field constriction. It has also been reported that patients with choroideremia have a generalised reduction in colour vision, evident from the very beginning of the disease. Choroideremia is usually an isolated retinal disease, but syndromic associations have also been observed. In these cases the disease is associated with hearing loss, cognitive impairment, cleft lip and palate, skeletal deformities, and acrokeratosis.

• RS1

X-linked retinoschisis is a condition that affects approximately 1:15000-1:30,000 male individuals, who typically present with symptoms of reduced central vision at school age, strabismus or anisometropia. The prognosis is often relatively good in childhood, unless retinal detachment or vitreous haemorrhage occurs, which are associated with a poor prognosis. Approximately 50% of patients also have peripheral retinal changes. A subgroup of patients presents with bullous retinoschisis, which tends to present in childhood with strabismus, significant reduction in vision, nystagmus, flying flies secondary to vitreous haemorrhage or irregularly shaped pupils.

Symptoms and Diagnosis

The symptoms of retinal dystrophies vary widely, making diagnosis a complex but essential process. Recognising the warning signs and performing the appropriate clinical tests is crucial for effective management.

Early Warning Signs

Recognising the warning signs as early as possible is crucial for early diagnosis. Common symptoms include difficulty seeing in low light and a gradual loss of peripheral vision. Other signs may be difficulty recognising faces or reading texts.

Tunnel vision, where peripheral vision is progressively reduced, is a hallmark. Changes in colour perception and blurred central vision are further indications to be monitored.

Early identification of these symptoms and consulting a doctor can improve treatment options and slow down the progression of the disease.

Clinical Diagnostic Methods

The diagnosis of retinal dystrophies requires specific clinical tests. Ophthalmological examinations include the electroretinogram (ERG) to measure electrical activity in the retina. Another procedure common is optical coherence tomography (OCT) to visualise retinal structures.

1. ERG: Analyses the electrical response of the retina.
2. OCT: It assesses retinal thickness and structure.
3. Genetic testing: They identify specific mutations.

The combination of these tests provides an accurate diagnosis. It is essential to work with specialists to establish a comprehensive diagnostic plan to best manage the condition.

Treatment and Management

Addressing retinal dystrophies requires an integrated approach that includes medical therapies and daily management strategies to improve patients' quality of life.

Available Treatment Options

At present, there is no definitive cure for retinal dystrophies, but treatment options and precautions are available that can slow down the disease's course: first and foremost, protection from sunlight (which is an accelerator of the disease) and the administration in high doses of antioxidants, including vitamin A and lutein, astaxanthin, zeaxanthin, omega 3.

The gene therapy represents today the true horizon of care. For Leber's congenital amaurosis, one therapy has already been developed; for others, clinical trials are under development. Some experimental treatments are showing promising results in restoring retinal function.

It is important to consult an experienced ophthalmologist to assess the available treatment options and to tailor the therapy to the patient's specific needs.

Strategies for Daily Management

An integral part of the treatment is the visual rehabilitation, both to psychologically accept the progressive loss of visual capacity and to train the visual residual and learn the techniques and knowledge of optical and or computer aids that allow autonomy to be maintained.

Some strategies include:

• Use of applications for reading texts.
• Environmental adaptations to improve lighting.
• Visual rehabilitation programmes to develop new skills.

Incorporating these strategies into daily routines can significantly improve the autonomy and quality of life of affected persons.

Support and Resources for Families

Families play a crucial role in supporting patients with retinal dystrophies. There are many resources and organisations that offer support and useful information.

Organisations and Support Groups

Specialist organisations offer valuable support to families affected by retinal dystrophies. These groups provide up-to-date information on research and treatments, as well as creating a community of support.

• Foundation for Rare Retinal Diseases: offers resources and advice.
• Local support groups: they organise meetings and information seminars.
• Online forums: allow the exchange of experiences and advice.

Participating in these groups can provide families with the necessary emotional support and access to essential information to cope with daily challenges.

Educational and Information Resources

Educational resources are key to a better understanding of retinal dystrophies. Information materials online and offline can help families stay up-to-date on medical advances and management strategies.

1. Practical books and guides: they offer detailed explanations of the condition.
2. Online courses: offer training on adaptation techniques.
3. Webinars: presenting experts discussing the latest findings.

Accessing these resources can improve understanding and management of the condition, providing practical tools to cope with changes in daily life.

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