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The first patients with a rare ophthalmologic disease - Leber congenital amaurosis type 2 and retinitis pigmentosa type 20 were identified in Russia

Specialists at the Bochkov Research Centre for Medical Genetics (RCMG) have identified the first patients in Russia with a rare genetic disease - hereditary retinal dystrophy of the Leber amaurosis type 2 and retinitis pigmentosa type 20 and prepared them for gene therapy. This disease is ultra-rare, with an incidence of 1: 250,000 people in Russia.

The disease appears from the first days of a child's life and his vision rapidly decreases. However, it is extremely difficult to detect this at an early stage, at the age under 1 year. During a routine examination, the ophthalmologist does not always notice changes in the eye fundus, and parents do not pay attention to the first signs: the child begins to rub the eyes, reacts painfully to light. These manifestations are joined by nystagmus (involuntary movement of the eyeballs). 

Retinal pigment degeneration is a group of hereditary ophthalmic diseases that can be caused by mutations in more than 200 different genes. Today, gene therapy has been developed to treat the disease caused by mutations in the RPE65 gene, which can significantly increase functional vision and stop irreversible retinal death. Therefore, the issue of finding patients whose disease is caused by a mutation of this particular gene and the diagnosis molecular-genetic confirmation is particularly relevant today.

It is not possible to diagnose the hereditary Leber's amaurosis type 2/ retinitis pigmentosa 20 based on the clinical picture and results of the instrumental examination. Diagnosis requires molecular genetic testing that identifies a mutation in the RPE65 gene. For patients whose disease is caused by changes in other genes, the new genotherapy drug will be ineffective because it is aimed at replacing the product of the RPE65 gene specifically.

Specialists at the Bochkov Research Centre for Medical Genetics  developed a comprehensive interdisciplinary diagnostic method and conducted extensive organizational work with different regions of Russia. It resulted in discovering 14 patients, including 8 children, with congenital amaurosis Leber type 2/ retinitis pigmentosa  type 20 in Moscow, Republics of Dagestan, Buryatia, Tyva, Kursk Oblast, Yamalo-Nenets Autonomous Okrug.

“Patients were identified within 11 months only. Both Russian and foreign colleagues are surprised to see such a success,” Vitaly Kadyshev said, Candidate of med. sci., the geneticist, ophthalmologist of the highest qualification category, Head of the Ophthalmogenetics Department at the Institute for Higher and Further Vocational Training (IViDPO RCMG), Senior researcher at the RCMG Genetic Epidemiology Laboratory, curator for hereditary eye diseases of the Russian Federation. “The RCMG mission has determined its global role for the country as a whole. In a short time, we developed clinical criteria for genetic diagnostics of ophthalmologic diseases. This comprehensive approach allowed us to reach a scientific and clinical success with a practical application in health care. All patients underwent a comprehensive clinical (ophthalmological, laboratory, instrumental) and molecular genetic examination. Accurate clinical and genetic diagnoses were determined for the majority of patients and therapy was adjusted.”

The RCMG DNA-diagnostics Laboratory, together with the RCMG Genome Shared Resource Centre and ophthalmologists and geneticists from the RCMG Counseling Department, developed a panel including more than 200 genes whose changes lead to the hereditary eye diseases. The panel includes both the RPE65 gene and more than 60 other genes whose mutations are responsible for isolated and syndromic forms of hereditary retinal pathology.

“Hereditary retinal pathology is extremely genetically heterogeneous. The panel informativeness averages 70%; this was surprising even to us. This is not only comparable to the diagnostic efficiency of exome sequencing for this pathology, but also exceeds it due to a more detailed analysis and in-depth study of each of the identified variants,” - Olga Shchagina, Candidate of Medical Sciences, Head of the RCMG Molecular Genetic Diagnostics Laboratory, leading researcher of the RCMG DNA-diagnostics Laboratory, said. “Patients who were diagnosed with us and whose pathology was not confirmed nevertheless received a molecular diagnosis, which means that they can plan families, childbearing, and they have an opportunity to prevent cases of this pathology in the family.”

The program to identify patients whose disease is caused by mutations in the RPE65 gene required extensive organizational work both at the diagnostic stage and at the subsequent preparation of patients for gene replacement therapy. It is an extensive work made by regional chief freelance ophthalmologists and geneticists and regional Ministries of Health. Currently, 77 regions are included into the program of diagnostics of hereditary retinal dystrophies.

“The RCMG experts are in constant contact with regional specialists in ophthalmology and genetics. This includes the remote meetings and experts’ visiting the regions. This work allowed 14 patients with retinal dystrophy associated with mutations in the RPE65 gene to be identified quite quickly. Before the program began, they were only three. It is important that 8 of those newly identified were children, and they can receive gene therapy through the Circle of Kindness Foundation,” Sergey Kutsev, Doctor of med. sci., RCMG Director, Chief External Expert in medical genetics of the Russian Ministry of Health, RAS corresponding member said.