Leber's congenital amaurosis in children? Dr. Silvia Stoeva speaks to FAKTI

Dr. Silvia Stoeva, a specialist in ophthalmology at “Alexandrovska Hospital“, was awarded the Best Poster Award for a young scientist under 35 years of age at the 51st annual meeting of the European Society of Pediatric Ophthalmology (EPOS), held in Bucharest, Romania. The awards were won in competition with 74 international developments presented by leading European clinics and university centers. Dr. Stoeva was awarded in the “Neurophthalology and Ophthalmogenetics“ category for the best poster “Genetic profile of patients with Leber's congenital amaurosis in Bulgaria”. Here is what Dr. Silvia Stoeva shared with FACT.

- Dr. Stoeva, what is Leber's congenital amaurosis and how does it affect children's vision?
- Leber Congenital Amaurosis (LCA) is a rare, mostly hereditary degenerative disease of the retina and is among the main causes of congenital blindness in childhood. The disease is most often transmitted in an autosomal recessive manner, which means that parents are usually healthy carriers of the altered gene. LCA is actually a group of diseases - over 25 different genes have been described, mutations in which are responsible for 70-80% of all cases, and the identification of the rest is ongoing. These genes control vital processes for the eye, including the structure and function of photoreceptors (rods and cones), cellular transport and the so-called. visual cycle, through which the light signal is converted into a nerve impulse to the brain.

When these physiological mechanisms are disrupted from birth, progressive damage and loss of retinal cells occurs.

In clinical practice, this is expressed in severely reduced visual acuity or practically complete lack of vision in the first months of the child's life.

- What are the first signs of the disease and at what age do they usually appear?
- The first symptoms are usually noticed in the first few months after birth - most often between the 2nd and 6th months. Parents usually find that the baby does not make eye contact and does not look at them or at bright objects. Other characteristic signs are:
-- Nystagmus: Rapid, involuntary eye twitching movements.
-- Franceschetti's symptom: The child often presses or rubs his eyes with fists or fingers, stimulating light sensations (phosphenes)
-- Weak or absent pupil reaction to light.

- What is the genetic profile of the patients and what motivates you to study this disease in Bulgaria?
- The genetic profile shows the specific mutation in the DNA that is responsible for the disease in each individual patient. We are motivated by the fact that for a long time there was no treatment for this disease, and the diagnosis was limited to a medical conclusion on paper, which stated the problem without providing a real solution. Today, with the introduction of gene therapies in ophthalmology, accurate genetic diagnosis is no longer just a statement on a piece of paper, but a real hope for patients and their families. In order for Bulgarian children to have equal access to these modern therapies and the opportunity to participate in future clinical trials, it was extremely necessary for our team at the University Hospital “Aleksandrovska“ to first map the genetic profile of patients in our country.

- Which genetic changes can cause Leber congenital amaurosis and why is it important to identify them early?
- LCA is an extremely genetically heterogeneous disease – over 25 different genes are known (such as RPE65, CEP290, CRB1, GUCY2D, etc.), mutations in which can lead to a similar clinical picture. Early identification is of key importance, because gene therapies are most effective when applied early in life – before complete and irreversible atrophy of the retinal cells has occurred.


- How is the diagnosis made and what is the role of genetic testing in this process?
- Diagnosis is a complex process. It includes a precise ophthalmological examination, electrophysiological tests (such as electroretinography – ERG, which in LCA shows a strongly suppressed or absent signal) and highly effective imaging methods such as optical coherence tomography (OCT). However, the final and definitive diagnosis is made precisely through genetic testing – by targeted next-generation sequencing (NGS panels for hereditary retinal dystrophies).

- What do the results of your study show in Bulgarian patients? Have you identified any genetic features that deserve special attention?
- Our study analyzes for the first time the genetic spectrum in Bulgarian patients with Leber's congenital amaurosis in a structured manner. The results confirm the expected overlap with the known European mutation profiles, but at the same time highlight specific frequent genetic variants characteristic of the Bulgarian population. This discovery is of great practical importance - it allows us to optimize the diagnostic algorithm for the country, save valuable time and resources of families in searching for a diagnosis and give a clear picture of the number of potential candidates for already approved gene therapies (such as the one for affecting the RPE65 gene).

- How many and what options are there for treating the disease and can genetic diagnosis help in choosing the appropriate therapy?
- There is currently an approved gene therapy for the disease caused by a biallelic mutation (presence of damage in both copies of the gene) in the RPE65 gene (voretigene neparvovec). It delivers a functional copy of the gene directly to the cells of the retina. For a number of other genes, successful phases of clinical trials are currently underway. Genetic diagnosis is the only key that determines whether a patient is a suitable candidate for a specific gene treatment.

- What should parents who notice vision problems in their child know?
- The most important thing is not to postpone the consultation with a pediatric ophthalmologist at the first suspicions. If you notice that the baby does not make eye contact and does not look, has unusual/involuntary eye movements or constantly rubs and presses them, an examination by a specialist is an absolutely mandatory step. Early diagnosis allows for timely support, visual rehabilitation and timely planning of genetic testing. Here I would like to remind parents of completely healthy, full-term children not to miss preventive examinations either. The first one should be performed at 6 months of age (unless there are specific symptoms requiring an earlier consultation), because a number of vision problems can proceed unnoticed at the very beginning.

- Why are early diagnosis and genetic consultation so important?
- Early diagnosis provides the opportunity for timely medical intervention, prevention of possible complications, proper planning of training and visual rehabilitation, as well as the opportunity for rapid inclusion in appropriate treatment programs or clinical trials. Genetic consultation, in turn, is extremely important for the entire family. It clarifies the exact type of inheritance of the disease, gives clear answers to parents about the risk in subsequent pregnancies and helps make informed decisions for the future.