Articles

Amblyopia is a very common disorder and a cause of visual impairment, affecting between 1 and 3% of children worldwide. Despite available treatments, many patients may present with residual visual deficits that persist into adulthood. For this reason, research focuses on exploring genetic alterations related to amblyopia to better understand the role that genotype might play in the development of this disorder and why, given the same ocular risk factors, some children are affected while others are not. Through a study analysing common and rare genetic variants, new perspectives emerge to address this visual condition.

Visual pathology

Amblyopia, commonly known as 'lazy eye', can be defined as a developmental alteration in the visual function of one or both eyes that arises during the plastic period of development of the visual system. During this period, visual function is particularly vulnerable and may be affected by factors that interfere with normal developmental processes, leading to abnormal binocular interaction and/or failure to form sharp images on the retina.

Ambiopia in the growing years

Susceptibility to amblyopigens is greatest during the first four years of life, then gradually decreases until it disappears by the age of eight. In clinical practice, an eye is considered amblyopic if it has two-tenths less visual acuity than the contralateral eye.

Severe amblyopia involves such a marked reduction in visual capacity that only the perception of hand movements is possible.

While the plasticity of the visual apparatus in the early years of life exposes it to the influence of amblyopic factors, it is also fundamental to the rehabilitative treatment of the eye, and the earlier the diagnosis of amblyopia and its treatment, the greater the chances of a more rapid and successful visual recovery of the affected eye.

The treatment of amblyopia

The removal of the cause of amblyopia through correction of the visual defect with glasses or contact lenses in theanisometropic amblyopiawith the surgical correction of cataracts or ptosis in theamblyopia due to sensory deprivation, through the surgical correction of strabismus in thestrabismic amblyopia.

The elimination of the cause of amblyopia must be accompanied by anti-amblyopia treatments: currently the safest and most effective method for treating amblyopia is the total occlusion of the fixating eye, to force the amblyopic eye to reactivate visual function. It is important to correct any visual defects of the amblyopic eye at the same time.

Anti-amblyopic orthoptic treatments 

• Occlusion: consists of the covering of one eye; it may be live (the fixative eye is covered) or reverse (the amblyopic eye is covered to remove the abnormal retinal correspondence). The best treatment is occlusion total of the dominant eye (in at least 60%-80% of waking hours). It is performed by applying an adhesive bandage to the contour of the orbit. Occlusion partial (only a few hours a day or for a few days a week) is implemented either for those who cannot tolerate total occlusion or in those who require occlusion as maintenance therapy, or in patients with nystagmus.
•  Optical penalisation, implemented with Bangerter filters (lenses with different degrees of opacification, depending on the extent of the penalisation to be implemented) or with stronger or weaker lenses placed in front of the healthy eye to force the diseased one to work; like partial occlusion, it is implemented either for those who need a 'soft' occlusion as maintenance therapy
•  Pharmacological penalisation with cycloplegic eye drops instilled into the healthy eye to exclude it from the vision process and force the diseased one to work.
• Sectorisation: covering part of the visual field of the healthy eye with translucent adhesive films on the glasses.

 The importance of prevention

The effects of amblyopia can be detected throughout life, and since amblyopia can only be cured at an early age, early diagnosis and treatment are the primary goals to be pursued.

Risk factors such as heredity, lack of emmetropia ('emmetropia' is the condition of no visual defects), high hypermetropia at the age of one year, could justify preventive measures. There are, however, conditions, such as microstrabismus, that cannot be prevented.

Studies conducted on large population samples in various countries show that large-scale visual screening reduces the prevalence of amblyopia and improves the visual prognosis of amblyopic individuals in the long term. In an era of limited health service resources, however, it is necessary to carefully evaluate the cost/benefit ratio in the choice of screening method. Very recent studies indicate a better cost/benefit ratio for screening based on the determination of visual acuity in children of about 4 years of age.

Before that age, however, it is possible to arrive at a diagnosis of amblyopia indirectly, thanks to the parents' monitoring of the child's behaviour in relation to the environment and the paediatricians' monitoring of the child's normal psycho-physical development during scheduled visits. If one notices that the child is always annoying himself by covering one eye and forcing him to look with the other (the amblyopic one), if one notices an abnormal position of the eyes (strabismus) or of the head, if the child apparently has difficulty recognising clearly visible objects or people, it is always a good idea to send the child to the ophthalmologist for a careful ophthalmic and orthoptic assessment.

Importance of Genetic Research

Recent studies suggest that genetics may play a key role in the development of amblyopia. This perspective opens up new avenues for the early diagnosis and treatment of this disorder.

Currently, treatments focus on symptoms, but identifying the genetic mechanisms underlying amblyopia offers the opportunity to develop earlier diagnostic tests, which would allow earlier intervention and more effective preventive measures or treatments.

Another advantage of genetic research is the possibility of personalising therapies. Understanding which genetic variants are involved can help doctors choose the most appropriate treatment for each patient, thus improving clinical outcomes and reducing recovery times.

Case Study

Research Structure and Method

The case-control study is a research method used to identify genetic differences between individuals with a disease and healthy individuals. This type of study makes it possible to isolate specific genetic factors that may contribute to the onset of the disease.

1. Selection of participants: Individuals with the condition and healthy controls are carefully chosen to ensure an accurate comparison.
2. Data collection: Detailed genetic data are collected through whole genome sequencing.
3. Data analysis: Genetic variants are compared between the two groups to identify those associated with the disease.

This methodology is particularly useful because it makes it possible to identify not only genetic variants, but also genes that may play a significant role in the course of the disease. This approach has already led to promising results, highlighting the genetic complexity of amblyopia.

Participants and Data Collected

The study involved a large population of adults of European origin, selected through the 'All of Us Research Program'. 764 subjects diagnosed with amblyopia were compared with 122,305 controls with no previous record of the condition. This large database allowed a detailed analysis of genetic variants.

This extensive data collection was crucial because it made it possible to identify common and rare genetic variants that could be linked to amblyopia. The information thus obtained could be used to develop new diagnostic and therapeutic approaches.

Genome-Wide Association Study

The Genome-Wide Association Study (GWAS) is a powerful tool for identifying common genetic variants linked to amblyopia. By analysing the entire genome, genetic loci associated with the condition can be identified.

This study revealed four loci approaching statistical significance: rs56105618, rs1349660, rs7958343 and rs138693522. Each of these variants is associated with genes expressed in the brain or linked to neural development, suggesting direct involvement in neuroevolutionary processes.

The information gathered through GWAS is crucial to understanding how common genetic variants may influence the propensity to develop amblyopia, paving the way for more targeted and preventive interventions.

Rare Variants Association Study

The Rare Variant Association Study (RVAS) focuses on the analysis of less common, but potentially influential genetic variants in the development of amblyopia. These variants, although less frequent, can have significant effects.

RVAS identified 15 genes with statistically significant variant loadings, including DCP1B, OR12D2, PCDHA4, and others. Many of these genes are known to play a role in neurodevelopment, suggesting that amblyopia could be linked to primary neurodevelopmental deficits.

Significant Results

Loci and Identified Genetic Variants

The table summarises recent findings, which pave the way for understanding the genetic basis of amblyopia and may explain why some individuals are more susceptible to persistent visual impairment in adulthood.

Neuroevolutionary implications

The neuroevolutionary implications of genetic discoveries are relevant. The genetic variants identified not only contribute to amblyopia, but may also influence neural development. This suggests that amblyopia may not only result from abnormal visual experiences, but also from genetic alterations that influence brain development.

This result opens up new avenues to address amblyopia, considering not only the treatment of visual symptoms, but also the underlying neuroevolutionary causes.

Conclusions and Future Perspectives

Contribution of Genetics in the Development of Amblyopia

Findings on the genetic basis of amblyopia highlight how neurodevelopmental changes can interact with abnormal visual experiences to determine this pathological condition. This suggests that amblyopia is not only a matter of vision, but also of brain development.

The implications of these findings are significant and offer an explanation as to why some children develop amblyopia while others do not, even in the presence of the same ocular risk factors. This could also explain the differences in treatment outcomes between different patients.

New Treatment Possibilities and Therapeutic Approach

The identification of genes linked to amblyopia opens up new possibilities for treatment. Therapeutic approaches could be developed that specifically target the genetic variants involved, allowing for more personalised treatment.

• Developing gene therapies targeting the genes involved.
• Adopting neurological approaches aimed at improving brain function.
• Implementing genetic testing for early diagnosis and prevention.

These new possibilities offer the hope of more effective and personalised treatments aimed at improving the quality of life of young patients with amblyopia.

See also:

Amblyopia and cardio-metabolic risk - Oculista Italiano

1. Lee, Kyoung A. Viola et al. Genome-Wide and Rare Variant Association Studies of Amblyopia in the All of Us Research Program Ophthalmology, Volume 132, Issue 7, 758 - 766
2. McConaghy JR, McGuirk R. Amblyopia: Detection and Treatment. Am Fam Physician. 2019 Dec 15;100(12):745-750. PMID: 31845774.