Stargardt disease (juvenile macular degeneration): causes, symptoms and treatment. Treatment of Stargardt's disease: the impossible became possible Stargardt's dystrophy treatment with stem cells

It is pleasant to talk with Mikhail: he is smart and well-read, has many hobbies, and he can talk about the main thing - auto racing - for hours. An intelligent face - glasses decorate it. Calm, self-confident young man of 18 years old. And the more strange it is to listen to what he says.

Stargardt's dystrophy: the road to blindness

“My eyesight has always been poor. I have been seeing an ophthalmologist since childhood. I took it easy, the glasses did not interfere with me. And at the age of 16 he began to notice that in the dark I see worse and worse. In addition, some areas of vision began to fall out, literally: I see here, I don’t see here. To be honest, I was scared.

The point was put by a visit to the military registration and enlistment office. The medical commission issued a verdict: "abiotrophy of the retina."

At home with my parents, we turned the entire Internet upside down, through acquaintances we received consultations from several ophthalmologist professors, found access to clinics in Israel, Germany, the USA ... Wherever we thought medicine could do everything, we were told that there was no hope for a successful outcome of treatment.

I had no options other than blindness.”

“Abiotrophy Stargardt is a fairly common genetic disease. According to statistics, it occurs in one in 20,000 people. Thus, only in Russia there are about 7,000 patients who, because of it, lose or have already lost their sight.

Yellow-spotted fundus, another name for this syndrome, usually manifests itself just in adolescence and early adolescence - from 12 to 16 years. The loss of vision usually comes very abruptly - in the case of Mikhail, the process took only six months.

Mikhail got into UnikaMed at the age of 18, that is, a year and a half after he was diagnosed. By this time, he could hardly see anything in the dark, there were scotomas- loss of areas of vision.

Without correction, the right eye saw 20%, the left - 15%. After correction with optics, the right eye - 65%, the left - 55%.

The dynamics of the development of the process made it possible to assume complete loss vision by the age of 20.

Stargardt's degeneration is not a sentence

“We continued to search, and on the UnikaMed website we read that they treat Stargardt's syndrome! It was hard to believe, but we went to Moscow.

Already after the first session of regenerative therapy, I began to see better in the dark, my vision improved. It feels like someone finally washed the dirty windshield that blocked the view. Fiction!

In total, I have gone through three sessions so far - now I have a break. After 6 months, you will need to undergo another procedure. By the way, I have already returned to motorsport, including night races!”

“Of course, there are no miracles and no fantasy in the case of Mikhail.

In short, regenerative therapy is based on a unique autologous cell transplant that stimulates retinal renewal (the prefix "auto" means a transplant, the cells for which are taken from the person himself and transplanted to him).

The application of the method shows a positive effect in almost all patients. The field of view expands, its sharpness improves. And if the disease is not genetic or severely neglected, we always see a significant improvement in visual acuity and quality.

Complicated diseases, like Mikhail's, stop progressing. The condition of the retina and its nutrition improves - respectively, improves significantly and visual function.

In the case of Mikhail, three months after the first session of regenerative therapy, the scotomas disappeared, and the visual indicators changed as follows:

Without optics: right eye - 30%, left eye - 25%

With selected optics: right eye - 85%, left eye - 75%.

Now, after three treatment sessions, Mikhail does not need further therapy yet, but in 6-8 months he must come back for an examination: no matter how magical the method may seem, no one has yet learned how to reprogram genes, and to maintain the result, the treatment must be repeated periodically ."

Marina Yurievna, chief physician of the UnikaMed clinic

Mikhail's case is far from unique: we at UnikaMed are approached by people who have been rejected by other clinics. And even at the stage of non-vision, many of them, thanks to regenerative therapy, restore vision.

How is the procedure

Regenerative therapy does not require a hospital stay. Transplantation of cell material is performed on an outpatient basis within one day: the patient spends 10-12 hours in the clinic.

But what seems like a miracle from the outside is actually the result of painstaking work.

The production of a transplant begins with a fence bone marrow. Then it is prepared in a special way. The cell preparation procedure is very complex. It requires special equipment, the simultaneous participation of several top cell biologists in the process, and the precise sequential execution of a number of operations.

The material obtained by a special technology is introduced to the patient, depending on his disease and the condition of the organs of vision.

In the evening, after an examination by an ophthalmologist, you are discharged home until the next procedure. The interval between procedures is determined individually, but their effect is cumulative. And if it takes, say, three months between the first, second and third procedures, then six months can pass between the third and fourth. And so on.

Between procedures, the treatment of Stargardt's disease requires regular dynamic monitoring an ophthalmologist in order to "intercept" possible vision loss in time.

Of course, it is easier to get the effect when treating the disease at the earliest stage, without waiting for the loss of vision, complete or partial. If you notice that vision gets worse(especially in the dark or at twilight), if the field of view narrowed, if the colors began to seem less bright to you, take the time to see an ophthalmologist.

There are fewer and fewer incurable diseases - and at the UnikaMed clinic we have every opportunity for this. Regenerative therapy shows positive results not only in patients with Stargardt's disease, but also in the treatment of atrophy optic nerve, macular degeneration of different nature, other forms.

Stargardt's macular degeneration(Stargardt's macular dystrophy, STGD) - the most common hereditary macular degeneration, its occurrence is 1 in 10,000; the disease is inherited in an autosomal recessive manner. Most cases manifest with a decrease in central vision at the beginning of the second decade of life. Macular atrophy usually develops with yellow-white flaky deposits at the level of the retinal pigment epithelium (RPE) in the posterior pole of the eye.

Deposits may be round, oval, lunate, or fish-like (pisciform). Oval area of ​​macular atrophy early stages may have the appearance of "wrought bronze". However, flaky deposits may be absent early in the disease, and macular atrophy may be the only abnormality; but, as a rule, deposits appear later. A yellow-spotted fundus (fundus flavimaculatus, FFM) pattern develops with the appearance of flaky deposits in the absence of macular atrophy.

And yellow-spotted fundus are caused by mutations of the same gene; both types of changes can be seen in the same family. In most patients with yellow-spotted fundus subsequently macular atrophy develops.

And at Stargardt's disease, and at yellow-spotted fundus on fluorescein angiography, a dark or occult choroid is classically observed in the early phase. This is due to excessive accumulation of lipofuscin by the retinal pigment epithelium, as a result of which the fluorescence of the choroid capillaries is screened. Flocculent retinal deposits in the early stages of their development on FA appear hypofluorescent, but later they become hyperfluorescent due to atrophy of the retinal pigment epithelium.

In order to confirm the diagnosis, as an alternative to FAG, an autofluorescence study is performed, which is based on fixing the fluorescence of lipofuscin of the retinal pigment epithelium. Abnormal accumulation of lipofuscin, the presence of active and resorbable flocculent deposits, and RPE atrophy are characteristic features detected by autofluorescence studies. In children with visual impairment due to macular dysfunction and the absence of changes in the fundus, FAG is still informative; an inconspicuous fenestrated defect in the center of the macular zone or a dark choroid help confirm the diagnosis.

At optical coherence tomography(OCT) often reveals a loss or a pronounced violation of the architectonics of the outer layers of the retina of the central zone of the macular region, with the relative preservation of the structure of the peripheral zone of the macula.

b) electrophysiology. Electrophysiological changes in Stargardt's disease are variable. An abnormal electrooculogram (EOG) is often recorded, which indicates a generalized dysfunction of the retinal pigment epithelium. The pattern electroretinogram (PERG) and focal electroretinogram are usually faded or significantly reduced in amplitude, suggesting macular dysfunction. Ganzfeld-ERG at the time of diagnosis may not be changed (group 1) or indicate extensive retinal damage (groups 2 and 3):
Group 1: severe pattern ERG abnormalities with normal ganzfeld ERG.
Group 2; additionally generalized cone dysfunction.
Group 3: generalized dysfunction of cones and rods.

These groups do not depend on the age of the onset of the disease or its duration; electrophysiological groups may represent different phenotypic subtypes and therefore may be informative in making a prognosis. Patients of the first group have higher visual acuity, more limited areas of distribution of flocculent deposits and macular atrophy; in patients of the third group, there is a more severe decrease in visual acuity, a larger area of ​​distribution of flocculent deposits and total macular atrophy.

in) Molecular genetics and pathogenesis. The pathogenesis of Stargardt's disease / yellow-spotted fundus is based on mutations in the ABCA4 gene, which also cause the development of retinitis pigmentosa and cone-rod dystrophy. ABCA4 encodes a transmembrane rim protein of the disks of the outer segments of the rods and cones, which is involved in the transport of retinoids from the photoreceptor to the retinal pigment epithelium. A defect in this transport leads to accumulation of the fluorophore lipofuscin, A2E (N-retinylidene-N-retnylethanolamine) in the retinal pigment epithelium, which causes its death and leads to secondary photoreceptor degeneration.

More than 500 variants of the ABCA4 sequence have been described, demonstrating high allelic heterogeneity; as a result, the identification of the pathogenic sequence of such a huge (50 exons) polymorphic gene causes considerable difficulties. It can be safely predicted that nonsense mutations that have a pronounced effect on the encoded protein will be pathogenic. When analyzing missense mutations, great difficulties arise, since such sequence variants often occur in control samples; as a result, confirming the pathogenicity of the identified mutation can be very problematic.

Direct confirmation of pathogenicity can only be obtained by functional analysis of the protein encoded by the mutant gene. In Stargardt's disease, a mutation in the ABCA4 Gly-1961Glu gene is most often detected; the Ala1038Val mutation is also common.

It is often possible to establish a correlation between the type and combination of ABCA4 mutations and the severity of phenotypic manifestations. For example, biallelic null mutations usually cause a cone-rod dystrophy phenotype rather than Stargardt disease. The variability of phenotypic changes in the retina is explained by different combinations of ABCA4 mutations that occur within the same family; it is likely that additional modifier genes or environmental factors also influence intrafamilial variability.

Accumulation of lipofuscin metabolic products, including A2E, is observed in Stargardt's disease and in ABCA4 knockout mice (abca4-/-); this leads to the formation of free radicals, the release of pro-apoptotic mitochondrial proteins, and lysosome dysfunction. As a result, dysfunction and death of retinal pigment epithelium cells develops, leading to the death of photoreceptors.

A2E synthesis is slowed down when abca4-/-- mice are placed in complete darkness and accelerated when vitamin A is added to their food. It seems reasonable to recommend that patients with Stargardt's disease avoid additional vitamin A intake and use dark sunglasses with ultraviolet filters. We also recommend a diet rich in antioxidants that slowed photoreceptor death in animal models of retinal dystrophies. Sick children may need help with low vision and educational support.

The risk of having a sick child in a patient is 1% (this probability increases if the patient's partner is his close relative). The carrier frequency of Stargardt's disease is 1 in 50; The chance that a partner is an asymptomatic carrier of a pathogenic altered ABCA4 gene sequence is 1 in 50.

G) Promising areas of therapy. New therapeutic approaches to the treatment of Stargardt's disease include drugs that act on the ATP-dependent transport mechanism, and thus accelerate ABCA4-dependent retinoid transport, or slow down the visual cycle, reducing the production of A2E. It may be more effective to directly inhibit the toxic effects of A2E. Pharmaceuticals have been developed that act in each of these three areas; it is likely that human clinical trials will be conducted in the near future. Similar drugs may be effective in the treatment of other macular degenerations accompanied by the accumulation of lipofuscin, such as Best's disease.

Other avenues of therapy include gene supplementation, cell therapy, or stem cell therapies to increase growth factors or transplant retinal pigment epithelium/photoreceptor cells, respectively. Cell therapy/stem cell clinical trials are likely to take place soon.

Stargardt's disease is one of the most common central hereditary macular dystrophies and accounts for up to 7% of all retinal dystrophies. Despite the clinical and ophthalmoscopic criteria for Stargardt's disease and other hereditary retinal dystrophies clearly described in the literature, often the same disease is described by different doctors under different names or, on the contrary, very distant forms are combined into a single concept. The authors examined 32 patients (64 eyes) with a presumptive diagnosis of Stargardt's disease. When conducting differential diagnosis the diagnosis was confirmed in 31.3% of cases.

Modern possibilities of differential diagnosis of the disease Stargardt

Disease Shtargardt is one of the most common hereditary central macular dystrophy and up to 7% of all retinal dystrophies. Despite the well-described in the literature clinical and ophthalmoscopic criteria Shtargardt`s disease and other hereditary retinal dystrophies, often one and the same disease described by different doctors with different names or, alternatively, combined into a single concept of a very distant form. The authors examined 32 patients (64 eyes) with presumed diagnosis of the disease Shtargardt. In the differential diagnosis of the diagnosis was confirmed in 31.3% of cases.

Hereditary retinal abiotrophies are characterized by clinical polymorphism and genetic heterogeneity. Currently, about 50 clinical phenotypes of hereditary retinal abiotrophies have been described, represented by more than 100 genetic variants. The problem of early diagnosis of hereditary dystrophies has been and remains relevant in medical and social relations. This is due to the fact that hereditary retinal dystrophies, even with timely detection and adequate treatment, lead to low vision early, and, as a result, there are difficulties in self-care of patients and their social adaptation.

Stargardt's disease (SD) is one of the most common central hereditary macular dystrophies and accounts for up to 7% of all retinal dystrophies. BS is usually diagnosed in the first or second decade of life. The disease debuts with a decrease in the acuity of central vision, the presence of absolute or relative central scotoma, and impaired color vision. There is a gradual decrease in the frequency and amplitude parameters of photopic electroretinography (ERG) against the background of preserved scotopic ERG components. Clinically, SP is characterized by the development of atrophy of the photoreceptor layer and retinal pigment epithelium (RPE) in the macular region with a characteristic metallic sheen, and the absence of macular and foveal reflexes (Fig. 1).

Figure 1. Fundus of the left eye of patient Sh., 17 years old. Left eye. Diagnosis OU: Stargardt's disease. Vision 0.8 n/a. Weakening of the physiological reflex in the macular area. The changes are symmetrical in both eyes. When conducting a molecular genetic study of DNA samples, the Gly1961Glu mutation was found in the compound heterozygous state

In the literature, the terms BS are often combined and fundus flavimaculatus (FF), thus emphasizing the supposed unity of origin. Just like BS, FF is diagnosed in the first or second decade of life. Color vision disorders are noted, mainly due to green and red colors, with perimetry, relative and absolute scotomas in the projection of the posterior pole of the retina. The ERG registers a decrease in the amplitude of wave b of the global ERG, the frequency of the rhythmic ERG is reduced by 2-3 times, the amplitude indicators of the local ERG for red are absent, for blue and green they are reduced. Characteristic ophthalmoscopic signs of FF are decoloration of the optic discs from the temporal side, slight narrowing of the arteries, macular and foveal reflexes are slightly deformed, the macula is flat, the fovea is poorly differentiated, "metallic sheen", redistribution of pigment, white or yellowish-white deep defects in the pigment epithelium of the posterior pole - "spots" that differ within the same fundus in shape, size, opacity, density, and sometimes in apparent depth. Among the various geometric shapes, round or linear ones predominated.

HS is characterized by an autosomal recessive mode of inheritance, although a rarer autosomal dominant type that does not have phenotypic features has also been described.

Table 1.

Genetic variants of Stargardt's disease

Note: AP* - autosomal recessive type of inheritance. AD** - autosomal dominant type of inheritance

A significant role in ensuring the early diagnosis of HD is played by molecular genetic analysis aimed at searching for mutations in already known genes. It has been established that mutations in the ABCA4 gene are the cause of the development of four clinically polymorphic retinal abiotrophies: BS, FF, mixed pigmentary and central pigmented retinal abiotrophy.

Despite the clinical and ophthalmoscopic criteria for certain hereditary retinal dystrophies clearly described in the literature, often the same disease is described by different doctors under different names or, on the contrary, very distant forms are combined into a single concept.

The error in diagnosing BS is a fairly common occurrence in outpatient settings. According to some authors, out of 40 patients examined in one year, the diagnosis of BS was called into question in 12 (30%) patients.

Recent advances in image processing based on new technologies such as optical coherence tomography (OCT) allow previously unidentified structures to be revealed. High-resolution OCT makes it possible to differentiate the condition of the retinal layers under natural conditions and to detect microstructural changes (Fig. 2).

Figure 2. Optical coherence tomography of the left eye of patient Sh., 17 years old. Diagnosis OU: Stargardt's disease. Vision 0.8 n/a. In the fovea, there is a defect in the outer segments of photoreceptors. Sharp thinning of the photoreceptor layer. Thinning of the retina is parafoveal. Changes are symmetrical in both eyes

In addition to qualitative analysis, OCT allows for a quantitative assessment of the thickness of the fovea in patients with SD. However, the analysis of RPE cells in vivo has been impossible until some time. Today, autofluorescence (AF) recording provides in vivo information on the level and distribution of lipofuscin granules (LG) in RPE cells. It is known that LH accumulates both with age and with various hereditary and degenerative diseases of the retina (Fig. 3).

Figure 3. Registration of autofluorescence in the left eye of patient Sh., 17 years old. Diagnosis OU: Stargardt's disease. Vision 0.8 n/a. Decreased physiological hypoautofluorescence in the macular region. Diffusely scattered areas of hyperautofluorescence in the macular area, indicating the accumulation of LH in RPE cells. Changes are symmetrical in both eyes

The value of diagnosis, as you know, lies in the recognition of the disease at the earliest stage. For example, in the presence of signs of central retinal degeneration, the diagnosis of SD is often made, while similar clinical manifestations are also characteristic of a number of other monogenic hereditary diseases of the retina, for example, cone degeneration and the initial stage of development of cone-rod degeneration.

Clinical picture diseases in comparison with the results of studies and molecular genetic analysis help the correct diagnosis.

Target. Analysis of the spectrum of nosological forms of central retinal dystrophies in patients diagnosed with SD on referral, assessment of the diagnostic value of a complex of modern studies, including high-tech ones.

Materials and methods. 32 patients (64 eyes) were examined, including 19 women and 13 men, with a presumptive diagnosis of Stargardt's disease. 27 families had isolated cases of the disease, in one family - 2 sick siblings, and one family with an autosomal dominant form in two generations. By national composition, the study group consisted of Russians (79%), Chechens (9%), Lezgins (3%), Armenians (3%), Gypsies (3%). The minimum age of the patient at the time of the examination is 7 years, the maximum is 52 years. All patients underwent a complex of clinical and molecular genetic studies. Clinical studies included visometry, static perimetry, color vision testing (Rabkin's polychromatic tables), electrophysiological studies according to the international standard, including registration of photopic and scotopic ERG, mixed, flickering ERG at 30 Hz (RETI-port/scan 21, Roland Consult, Germany ). Additionally, optical coherence tomography (Cirrus HD-OCT 4000, Carl Zeiss Meditec Inc. Dublin, USA), fluorescein angiography, and autofluorescence registration on an HRA-2 retinal angiograph (Heidelberg, Germany) were performed. All patients underwent a molecular genetic study of DNA samples in order to search for the three most common mutations Gly863Ala, Ala1038Val, Gly1961Glu in the ABCA4 gene.

Results and discussion

According to the results of our research, all patients were divided into 3 groups. The first group included patients (n=10, 31.3%) with a confirmed diagnosis of SD. The second group (n=10, 31.3%) consisted of patients who were diagnosed with FF based on the results of clinical trials. The third group (n=12, 37.5%) included patients with other clinical diagnoses.

The examined group I had a typical ophthalmoscopic picture of BS. According to the anamnesis, the disease manifested by a decrease in central visual acuity at an average of 14.5 years (5-25 years). At the time of examination, visual acuity was 0.25 (0.02-0.8). All of them had color vision disorders in red and green colors. Absolute central scotoma up to 10º was recorded in 9 cases. Normal mixed ERG was registered in 7 patients (14 eyes), subnormal - in 3 (6 eyes). All patients had a normal scotopic ERG. All patients showed a decrease in the thickness of the retina in the fovea, which amounted to 129±31.2 µm. When registering autofluorescence in all patients, a decrease in physiological hypoautofluorescence in the macular region was recorded, with a simultaneous increase in pathological, which, as a rule, has the shape of an elongated oval. When assessing the area of ​​pathological hypoautofluorescence, it averaged 1.91 mm² (from 0.36 to 5.43 mm²). In group I of 10 patients, mutations in the ABCA4 gene were found in 5 patients. Gly1961Glu in the compound heterozygous state in 4 patients, Ala1038Val in the homozygous state in one patient.

The examined group II had a typical ophthalmoscopic picture of FF. According to the anamnesis, in all patients the disease manifested by a decrease in central visual acuity, on average, at 14.1 years (5-30 years). At the time of examination, visual acuity was 0.15 (0.03-0.4). All of them had color vision disorders in red and green colors. In cases, an absolute central scotoma from 10º to 20 was recorded. Mixed and scotopic ERG in all patients were subnormal. All patients showed a decrease in the thickness of the retina in the fovea, which amounted to 125±21.8 µm. When registering autofluorescence in all patients, a decrease in physiological hypoautofluorescence in the macular region was recorded, with a simultaneous increase in pathological, which, as a rule, has the shape of an elongated oval. When assessing the area of ​​pathological hypoautofluorescence, it averaged 6.6 mm² (from 0.47 to 24.66 mm²). In group II of 10 patients, molecular genetic testing of DNA samples revealed mutations in 8 patients. All mutations were in the compound heterozygous state: Ala1038Val - in 4, Gly1961Glu - in 3, Gly863Ala - in one patient.

Group III included patients whose nosological spectrum of pathology is presented in Table 2.

Table 2.

Distribution of phenotypes of retinal diseases and found mutations in examined patients

AT III group out of 12 patients, 2 had the Ala1038Val mutation, in the compound-heterozygous and homozygous state. It should be noted that both patients had a clinical picture of mixed retinal pigment abiotrophy. In the remaining 10 patients of the third group, the desired mutations were not detected.

conclusions

1. During the differential diagnosis of BS with other hereditary and secondary lesions of the macular area using the entire spectrum of diagnostic equipment required, the diagnosis of BS was confirmed in only 31.3% of cases.

2. Optical coherence tomography and autofluorescence registration are a necessary and important addition to the standard set of diagnostic studies performed in the diagnosis of BS, providing objective information about the level and nature of the pathological process. in vivo.

S.A. Borzenok, M.F. Shurygina, O.V. Khlebnikova, V.A. Solomin

MNTK "Eye Microsurgery" acad. S.N. Fedorov, Ministry of Health of the Russian Federation, Moscow

Medical Genetic Research Center of the Russian Academy of Medical Sciences, Moscow

Shurygina Maria Fedorovna - post-graduate student of MNTK "Eye Microsurgery" named after A.I. S.N. Fedorova

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Characteristic signs and consequences of retinal abiotrophy and its prevention

Retinal abiotrophy is a rare pathology that manifests itself in retinal dystrophy, which can be congenital or acquired. The reason for its development is numerous mutations, which led to a variety of options for the course of the disease. Because of this, the prognosis of the disease is uncertain: some forms of abiotrophy contribute to a decrease in the sharpness of peripheral vision, while others provoke blindness.

The term "abiotrophy" means a hidden anomaly of an individual organ or body system.

Abiotrophy of the retina (retina) is a complex genetic degeneration that belongs to rare pathologies and is characterized by damage to the most important cells of the photoreceptors of the organ of vision - rods and cones. The disease occurs as a result of damage to the genes that are responsible for the functioning of the retina and ensuring the process of supplying nutrients to it. Under such conditions, a slow but irreversible degenerative process occurs. It extends to the outer layer of the retina, where the rods and cones are located, which are also part of the photoreceptors.

The first of them are located over the entire surface of the retina, but most of them are distant from the center. The main function of the sticks is to ensure the development of the visual fields and full vision in the dark.

Cones are located in the central part of the reticular region eyeball. Their function is to perceive the color spectrum and ensure the quality of the central region of vision.

The first attempts to explain what retinal abiotrophy is were made in the second half of the 19th century. The pathology was called "retinitis pigmentosa". In the future, the disease began to be called primary tapetoretinal or rod-cone dystrophy.

Usually the pathological process captures both organs of vision at once. If a child has retinal degeneration, then the first signs of the disease are detected at an early age. By about the age of 20, this leads to serious disorders: loss of vision, the development of glaucoma, clouding of the lens.

Another dangerous complication dystrophic lesions of the retina is the degeneration of the affected cells into malignant ones. In this case, melanoma develops.

Usually the pathological process captures both organs of vision at once.

Retinal damage occurs as a result of genetic mutations that occur:

• autosomal dominant (passes from father to son, while manifestations of pathology are observed in the first generation);
• autosomal recessive (from both parents with manifestations in the second or third generation);
• by linkage along the X chromosome (pathology is transmitted to men who are relatives to each other on the mother's side).

Acquired retinal dystrophy is usually diagnosed in older people. This type of pathology occurs with severe intoxication, hypertension, pathologies thyroid gland.

Most often, manifestations of retinal abiotrophy first occur in childhood. It happens much less often in adulthood.

Varieties of pathology

According to the generally accepted classification, the following types of retinal dystrophy of the eye are distinguished:

• peripheral degenerations. Pathology of this type begins with the defeat of the rods of photoreceptors. Violations extend either to the retina and choroid, or to the vitreous body. Peripheral degenerations include pigmentary dystrophy, white dotted abiotrophy, Goldmann-Favre disease and Wagner's disease. With peripheral abiotrophy, a violation of peripheral vision occurs, a narrowing of the visual fields occurs. The disease can develop for many years or proceed quickly, causing a decrease in vision and complete blindness;
• central degeneration. Cone cells are damaged. Violations occur in the macula, macula. With central degenerations, a pronounced violation of visual function occurs, the ability to perceive colors is impaired. Blind spots may appear in the visual field. To macular degeneration of the retina include Stargardt's syndrome, Best's disease, age-related abiotrophy;
• generalized (mixed) degenerations. With this form of deviation, all parts of the retina are damaged. This is retinitis pigmentosa, congenital stationary night blindness.

Depending on what form of pathology is diagnosed in a patient, certain signs predominate.

Characteristics of pigmentary dystrophy

Pigmented abiotrophy retina (primary tapetoretinal retinal abiotrophy) is a disease of the inner lining of the eye, in which retinal rods are affected. This disease is characterized by the degeneration of photoreceptors and pigment epithelium, resulting in the termination of signal transmission from the retina to the cerebral cortex.

Pigmented retinal abiotrophy is hereditary.

Tapetoretinal abiotrophy is hereditary. A distinctive feature of this form of retinal degeneration is a long progressive course with alternating visual impairment and remissions. Usually, if pigmentary dystrophy manifests itself in adolescence, then by the age of 20-25 the patient loses his sight, which leads to disability.

The prevalence of pathology is 1 case of the disease per 5000 people.

The reasons for the development of pathology have not been reliably studied, but most scientists are inclined to believe that it arises as a result of genetic mutations. Other possible factors contributing to the development of retinal dystrophy are:

• severe toxic damage to the body;
• disease endocrine system;
• avitaminosis.

This form of deviation is characterized by the following manifestations:

• disorientation in the dark, associated with visual impairment;
• the formation of pigment in the fundus;
• narrowing of the boundaries of peripheral vision;
• headache;
• severe eye fatigue;
• light flashes in the eyes;
• difficulty in differentiating colors.

Tapetoretinal abiotrophy can be detected using the following diagnostic measures:

• ophthalmoscopy (examination of the fundus of the eye);
• study of visual functions;
• Ultrasound of the internal structures of the organs of vision;
• measurement of intraocular pressure;
• angiography.

Ophthalmoscopy helps to identify tapetoretinal abiotrophy.

Treatment of pathology provides for a specific approach. Required:

• the use of drugs to stimulate the nutrition and blood supply of the retina ("Mildronate" in the form of injections, drops "Taufon");
• carrying out physiotherapeutic procedures (ozone treatment, electrical stimulation);
• surgical treatment. In order to stimulate blood flow in the area of ​​the retina, an operation is performed to transplant the eye muscles.

Also in ophthalmology, the domestic remedy Alloplant is used to treat retinal degenerations. This is a biological tissue that strengthens the sclera. With abiotrophy, the agent is used to restore vascular blood supply. The fabric is characterized by good survival.

White dot (non-pigmented) degeneration

Non-pigmented abiotrophy, like pigmented abiotrophy, develops slowly and is of a genetic nature. The main feature of this form of pathology is the appearance of white, small foci on the periphery of the fundus. This is a type of tapetoretinal retinal degeneration.

The main factor provoking the development of pathology is gene mutations.

The characteristic manifestations of the pathology are as follows:

• narrowing of the field of view;
• progressive deterioration of central vision;
• the appearance of white dots over the entire area of ​​\u200b\u200bthe retina.

With white dotted abiotrophy of the retina, the optic nerve atrophies.

Pigmentless abiotrophy is genetic in nature.

Pathology is detected during such manipulations as:

• Ultrasound of the internal structures of the eyes;
• optical coherence tomography for layer-by-layer study of eye structures;
• fundus examination;
• study of the state of the visual fields.

With non-pigmented retinal dystrophy, the patient is prescribed:

• taking anticoagulants, vasodilators, vitamin B;
• intradermal administration of the hormone of the middle lobe of the pituitary gland to stimulate the activity of still preserved cones and rods;
• surgery.

The effect of therapeutic measures is usually temporary.

Stargardt disease

Yellow-spotted retinal abiotrophy is a condition in which central vision deteriorates at an accelerated rate.

The main reason for the development of pathology is genetic mutations. Gene defects create an energy deficit.

Stargardt's dystrophy manifests itself in the following symptoms:

• the inability of the patient to distinguish objects with a weak color gamut;
• loss of central vision and a decrease in its sharpness;
• the appearance of yellow-white spots in the posterior pole of the eyes;
• Difficulty with orientation in low light.

In the final stage of the disease, the optic nerve atrophies, causing blindness.

Yellow-spotted retinal abiotrophy is also called Stargardt's disease.

For the diagnosis of pathology is carried out:

• collection of anamnesis;
• molecular genetic analysis;
• histological examination in the central zone of the fundus.

For the treatment of Stargardt's disease, therapy is carried out with the introduction of vasodilators, taking vitamins. Physiotherapeutic procedures are shown - laser stimulation, ultrasound therapy.

With Stargardt's dystrophy, a stem cell treatment technique is used. Stem cells implanted in the eye move to the damaged area and merge with the affected tissues, after which they turn into healthy cells. A simple lens is usually used to fix the graft. This method is considered a breakthrough in modern ophthalmology.

Abiotrophy of the retina Besta

What is Best retinal abiotrophy? A similar pathology is a bilateral retinal dystrophy in the macular zone. It develops as a result of gene mutations.

Best's disease develops asymptomatically, so it is usually detected incidentally.

In the course of diagnostic measures, such symptoms of pathology as the appearance of yellow spots in the macula and the development of subretinal hemorrhages are determined.

Main diagnostic method- Fluorescein angiography.

In case of Best's disease, maintenance therapy is carried out with the use of Mildronate, Emaxipin, Meksmdol.

If necessary, laser photocoagulation is performed.

Fluorescent angiography helps to diagnose Best's retinal abiotrophy.

congenital stationary blindness

This form of pathology is a non-progressive disease in which night vision is impaired.

The disease develops as a result of gene mutations.

The general visual acuity does not change. During the examination of the fundus, multiple yellow-white dots are found.

For the diagnosis of pathology, a study of the visual field, electroretinography, electrooculography is carried out.

There is no effective treatment for this disease.

Likely outcome

The prognosis is directly related to the type of pathology. Forms of the disease (except congenital stationary blindness) are constantly evolving and eventually cause loss of vision. The consequence of this is the disability of the patient.

The goal of the treatment is to alleviate the symptoms of pathology and slow down the pathological process.

Prevention

Since retinal degeneration is caused by gene mutations, there are no effective measures to prevent pathology.

• regularly visit an ophthalmologist;
• correct visual acuity with the help of physiotherapy procedures and medicines;
• lead healthy lifestyle life;
• dose the load exerted on the organs of vision;
• protect eyes from direct sunlight;
• eat rationally;
• perform sets of exercises aimed at working out the eye muscles and eliminating fatigue of the organs of vision;
• to refuse from bad habits.

The appearance of the first with visual impairment requires urgent medical attention. Don't rely on folk methods treatment: in the case of retinal abiotrophy, they will only aggravate the process and accelerate the development of blindness.

Nov 20, 2017 Anastasia Tabalina

STARGARDT DYSTROPHY: CLINIC, DIAGNOSIS, TREATMENT

I.V. Zolnikova, E.V. Rogatin

Federal State Institution Moscow Research Institute of Eye Diseases. Helmholtz Rosmedtekhnologii

Contacts: Inna Vladimirovna Zolnikova [email protected]

Therapists are well aware of the ophthalmic manifestations of such common diseases in the population as arterial hypertension and diabetes- hypertensive and diabetic retinopathy. At the same time, in practice, it happens when changes in the fundus cause difficulties in making a diagnosis, even for ophthalmologists who specialize in the diagnosis and treatment of retinal diseases. Hereditary retinopathy is not well known to clinicians. Below is the current information on the pathogenesis, diagnosis and clinical presentation of Stargardt's dystrophy, one of the well-studied hereditary diseases of the retina. The proposed data serve as prerequisites for the development of new evidence-based treatments with proven efficacy.

Keywords: Stargardt's dystrophy, yellow-spotted fundus, color perception, electroretinography, genetic diagnosis, pathogenesis, treatment

STARGARDT'S DYSTROPHY: CLINICAL PICTURE, DIAGNOSIS, TREATMENT

I.V. Zolnikova, E.V. Rogatina

Hemholtz Moscow Research Institute of Eye Diseases, Russian Agency for Medical Technologies

Therapists are well familiar with the ophthalmologic presentations of common diseases, such as essential hypertension and diabetes mellitus, namely: hypertensive and diabetic retinopathy. At the same time in actual practice, even ophthalmologists specializing in the diagnosis and treatment of retinal diseases run into the diagnostic problems associated with eye ground changes. Clinicians are inadequately familiar with inherited retinopathies. The paper gives an update on the pathogenesis, diagnosis, and clinical presentations of Stargardt's dystrophy, one of the well studied inherited retinal diseases. The proposed data are prerequisites for the development of new justified treatment options with documented efficiency.

Key words: Stargardt's dystrophy, fundus flavimaculatus, chromatic sensitivity, electroretinography, genetic diagnosis, pathogenesis, treatment

Stargardt's dystrophy was first described by the German ophthalmologist K. Stargardt in 1909 as a progressive macular degeneration inherited in an autosomal recessive manner. The term fundus flavimaculatus - "yellow-spotted fundus" - was proposed in 1962 by the Swiss ophthalmologist A. Francescetti, who described a special form of this disease, in which yellow polymorphic foci are diffusely scattered throughout the posterior pole of the fundus. Macular degeneration is detected only in 50% of patients; in most cases, the disease manifests itself over the age of 25 years. Stargardt's dystrophy and fundus flavimaculatus are now considered to be 2 distinct phenotypes in the disease continuum, ie. they are one nosological unit, which is confirmed by molecular genetic studies. The prevalence of the disease, according to some authors, is 1:10,000. Stargardt's dystrophy refers to diseases of the retinal pigment epithelium and photoreceptors.

Etiology

Discoveries in the field of molecular genetics have led to the identification of the etiological gene (STYL01, ABCA4, previously ABCL, localized on 1p21-p13), mutations in which lead to the emergence of an autosomal recessive form of Stargardt's dystrophy and yellow-spotted fundus. A rare form of dystrophy with an autosomal dominant type of inheritance is caused by mutations in the EJUA4 gene (6sen^14).

Pathogenesis

The ABCA4 protein belongs to the ABC transporter family and is a retinospecific (retinal-specific) membrane protein that is expressed in the disks of the outer segments of the rod and cone photoreceptors.

As a result of phototransduction - an electrochemical process that causes a visual sensation - transretinal is in a free state in the phospholipid environment of the photoreceptor

membrane and must be rapidly removed from the photoreceptor membrane of the disc. With the missing or defective ABCA4 protein in Stargardt's dystrophy, such removal does not occur; on the contrary, phototoxic metabolites of N-ret-PE retinal and its derivative A2E accumulate in the intradiscal space. Despite the fact that the ABCA4 protein is a structure of both cone and rod photoreceptors, the greatest clinical and functional manifestations of the disease are characteristic of the central retina, where cones are located, which determine visual acuity.

According to J. Sparrow, expressed by him in 2003, the development of dystrophy in the macular region is associated with a high physiological concentration of retinal, which reflects a high density of cone photoreceptors in the foveolus. A large functional load with a defective ABCR protein can lead to an increase in the concentration of the phototoxic retinal derivative A2E in the macular region. Assume that the severity of the disease correlates with the residual activity of the ABCR protein.

More than 400 mutations of the ABCA4 gene are known, most of which are missense mutations in highly conserved amino acid sequences.

Clinic of Stargardt dystrophy and yellow-spotted fundus

Stargardt's dystrophy is usually diagnosed in the first or second decade of life.

Ophthalmoscopic picture

Depending on the phenotype, Stargardt's dystrophy is characterized by 2 main features: changes in the macular region (macular degeneration) and yellow spots, the nature and localization of which are variable.

macular degeneration. In all patients with complaints of decreased central vision, symmetrical changes in the macula are detected: from the expansion of the macular reflex with delicate pigment granularity to severe atrophy of the macular area. At the initial stage, changes in the macula may be absent or limited to the redistribution of pigment. With the progression of dystrophic changes, gross dispigmentation occurs: the accumulation of clumps of pigment in some areas and focal defects (atrophy) of the retinal pigment epithelium (RPE) in others, which may look like mottling of the macular area or like a "bull's eye" pattern. In the advanced stages of the disease in the macular region, a special character of light reflection can be observed ophthalmoscopically, giving the impression of "forged bronze". The terminal stages of the disease (by the age of 30 and later, depending on the age at the time of onset) are characterized by atrophy of the RPE, the choriocapillary layer of the choroid and the neuroretina in the macular region.

sti. Temporal decoloration of the optic nerve, often described by ophthalmologists with partial atrophy of the optic nerve, is characteristic of Stargardt's dystrophy and is secondary. The caliber of the vessels, as a rule, remains normal; with extensive areas of peripheral chorioretinal atrophy, narrowing of the retinal vessels is possible.

yellow spots. A feature of the fundus are yellowish spots, which can be located around the fovea, limited to the macular region, or occupy the entire posterior pole within the vascular arcades (see figure), or extend up to the equator. The spot sizes vary from 100 to 200 µm, the boundaries have different degrees of clarity. With the progression of the disease, the spots spread to the equator of the eyeball, their number increases, they can merge and disappear, leaving areas of atrophy of the RPE and choriocapillaries.

The fundus of the eye central form Stargardt's dystrophy: a - dystrophic changes in the center of the macular region, pigmentation; white-yellow spots are visualized within the macular region; b - dystrophic changes in the macular region are surrounded by an extensive area of ​​white-yellow spotting, which extends up to the vascular arcades

Yellow-spotted fundus manifests itself in adults in the absence of changes in the macular area, may be asymptomatic and be an incidental finding detected during an ophthalmological examination. Visual acuity and color perception change only with changes in the macular area.

First clinical signs are bilateral white-yellow spots with indistinct borders at the level of the RPE in the posterior pole and in the middle periphery. Spots found at an early stage have clear boundaries and are located closer to the center. They are round, oval, linear, translucent or in the shape of a fish tail. With progression, new spots appear, closer to the equator of the eyeball, and the old ones acquire more blurred borders and a confluent character. In some cases, "geographic" atrophy develops. With the progressive nature of the disease, the number of peripheral spots increases and atrophic changes in the macular region appear, which become more extensive and clearly limited.

Classification

The main classification is proposed by K. Noble and R. Carr, classification by stages - T. Aaberg and G. Fishman. K. Noble and R. Carr (1979) distinguish 3 variants of the ophthalmoscopic picture of Stargardt's dystrophy (macular degeneration without yellow spotting, macular degeneration with parafoveal yellow spotting, macular degeneration with diffuse yellow spotting) and diffuse yellow spotting without macular degeneration (yellow spotted fundus, or fundus flavimaculatus).

Functional symptoms

Visual acuity. The first symptom of Stargardt's dystrophy is an uncorrected decrease in visual acuity, initially gradual to 0.5, and then rapidly to 0.1-0.05. Low visual acuity may not correspond to the severity of changes in the fundus so that the child may be suspected of simulation.

Color vision. Violation of color vision occurs at the initial stages of the development of dystrophy, in the early stages of the disease. Despite the fact that children aged 7-8 years rarely complain of a color vision disorder, it can be detected earlier than a decrease in visual acuity and a violation of contrast sensitivity, which is an important criterion for initial diagnosis. The perception of the red and green parts of the spectrum is impaired by the type of red-green dyschromasia and is detected using Rabkin-type polychromatic tables for acquired disorders, Ishihara tables, Yustova tables and other methods for studying color vision (for example, the 100-hue Farnsworth test). The study of the topography of a violation of color sensitivity is possible using computer technology (color campimetry), which makes it possible to evaluate various parts of the central field of vision.

The topography of contrast sensitivity is studied using achromatic stimuli darker and lighter than the background - on-off-activity of the cone system (the "Offon" program, developed jointly with the scientific and medical company MBN, RF)

In the initial stage, contrast sensitivity is reduced to a greater extent by a stimulus lighter than the background, followed by a decrease by a stimulus darker than the background, which indicates the primary lesion of the light channels of the retinal cone system. Topographically, changes appear in the area 1° from the center, to a lesser extent, 5° from the fixation point. In the advanced stages of the disease, with a combination of dystrophy in the central sections with peripheral localization, contrast and color sensitivity decreases in zones 1, 5 and 10 °.

Spatial contrast sensitivity (assessed using the computer program "Zebra", "Astroinform", RF) in Stargardt's dystrophy is reduced in the region of medium and high pro-

strange frequencies in the early stages and is absent at these frequencies (when using achromatic and color - red, green and blue - gratings) in the later stages of the disease; it is preserved at low frequencies.

Perimetry. When examining the visual field and light sensitivity in patients with Stargardt's disease, a decrease in light sensitivity, relative or absolute central scotomas of various sizes, depending on the spread of the process in the macular region, are revealed. With fundus flavimaculatus, the visual field may not change, especially in the first 2 decades of life. The absence of functioning cones in the foveolus leads to the appearance of a new preferred fixation locus, detected by microperimetry using a scanning laser ophthalmoscope (SLO).

Electroretinographic symptoms

Electroretinography (ERG) allows you to objectively assess the function of the retina and identify various types of dystrophy / dysfunction - macular and generalized cone. To assess the function of the macular area of ​​the retina, multifocal or macular local electroretinography is recommended. Multifocal ERG is a new high-tech method for assessing the topography of the bioelectrical activity of the macular area, paramacular parts of the retina, para-central areas of the retina and its middle periphery.

When registering macular ERG (M-ERG), the biopotentials of the macular region are subnormal already in the initial stage I of Stargardt's dystrophy. Also, in stages I-II of Stargardt's disease, a greater degree of inhibition of the cone components of the ERG is revealed compared to the rod ones. As the process progresses, M-ERG indicators decrease, up to complete disappearance.

In the study of the topography of bioelectrical activity by the method of multifocal ERG in patients with Stargardt's dystrophy, a decrease or complete absence response in the central region of the retina while maintaining the amplitude and latency of bioelectric responses in the peripheral rings. In the advanced stage of Stargardt's dystrophy, there was a lack of response in the macular region within the central 10° and a decrease in it in the paracentral regions (17-30°), which was accompanied by an increase in the response latency of the N1- and P1-components in these zones. When using SLO to control gaze fixation with a stimulus with a radius of 12° in Stargardt's dystrophy, similar data were obtained.

In stages I-II of the disease, the general ERG is normal. With progression, the amplitude of the total ERG

decreases. According to R. Itabashi et al.

The decrease in various components of the ERG occurs in accordance with the stage of the disease.

A subnormal rod response is recorded with a mixed form of Stargardt's dystrophy / fundus flavimaculatus. In the later stages, the amplitude of both photopic and scotopic ERGs decreases. J.D. Armstrong et al. in the course of a retrospective study, a decrease in cone ERG was found in 5.4% of patients with the central form of Stargardt's dystrophy and did not reveal a decrease in rod ERG in this group of patients. In patients with yellow-spotted fundus, a decrease in rod ERG was found in 21.1%, photopic ERG - in 32.4%, while the degree of ERG decrease correlated with the duration of the disease.

pathohistology

The main pathohistological sign of the yellow dot fundus is the excessive accumulation of material in the RPE cells, which corresponds in its characteristics to lipofuscin. In RPE, lipofuscin is an undigested degradation derivative of the outer segment of photoreceptors. Light microscopy of RPE reveals apical displacement of melanin granules associated with the accumulation of large intracellular vacuoles containing PAS-positive granules.

Modern Method autofluorescence has found its use to assess hypo- and hyperfluorescence and is used to confirm the diagnosis of Stargardt's dystrophy, especially the prevalence of pigment epithelial changes. Accumulation of lipofuscin has been documented in a patient with an autosomal dominant form of the disease.

Fluorescein angiography

Fluorescein angiography reveals a triad of bull-eye maculopathy, yellow-spotted foci, and choroidal silence.

Molecular genetic diagnosis of Stargardt's dystrophy

More than 400 mutations in the ABCR gene lead to various clinical and functional manifestations of Stargardt's dystrophy.

Differential Diagnosis and prognosis of Stargardt's dystrophy

It is necessary to differentiate between Stargard's dystrophy, diseases of the macular region (cone and cone-rod dystrophy, juvenile retinoschisis, maculitis, toxic and secondary (post-inflammatory) maculopathy, as well as achromatopsia and amblyopia) and diseases of the "spotted retina" group (dominant drusen, white dot retinitis,

white-dotted fundus, spotted retina of Kando-ri, Bietti's crystalline dystrophy, oxalosis).

Visual acuity in the central form (Stargardt's dystrophy) in 90% of patients decreases to 0.1 by the age of 20, to 0.05 by the age of 40-50, to 0.01-0.02 by the age of 60-70. Functions peripheral retina, as a rule, persist in most patients throughout life, despite low visual acuity. The prognosis of the yellow-spotted fundus is relatively favorable. Symptoms may not appear for many years unless patches appear in the fovea or “geographical” atrophy develops.

To date, there is no effective method for the treatment of Stargardt dystrophy, however, intensive scientific research is being carried out in this direction in the experiment and clinic.

In Stargardt's dystrophy, the phototoxic effect of retinal derivatives accumulating in RPE and photoreceptors has been proven. Therefore, the modifying role of the “correct” illumination of the retina with natural light, established on experimental models, makes it possible to recommend special light filters for patients that prevent the penetration of short-wave rays of the visible part of the spectrum and ultraviolet. Light filters increase the contrast of the image and reduce photophobia - a rare symptom in Stargardt's dystrophy. Both filters and optical instruments and electronic devices used systemically for low vision can significantly improve the quality of life of many patients.

Data on the effectiveness of many of the treatments used are very scarce. It is assumed that antioxidants slow down the processes of peroxidation, which are the pathogenetic link of Stargardt's dystrophy. Some authors expect to appear in the near future pharmacological preparations, leading to an increase in the access of oxygen to intracellular structures without enhancing the processes of synthesis of free radicals.

According to a number of researchers, retinalamine gives a positive therapeutic effect in most patients with retinal dystrophies manifesting in the early stages. Retinalamin belongs to the group of peptide bioregulators (cytomedins) and is a complex of polypeptides isolated from the retina of cattle. The exact mechanism of action of retinalamine is unknown. It is believed that it stimulates the function of the cellular elements of the retina, improves the functional interaction between RPE and the outer segments of photoreceptors, etc.

The use of docosahexaenoic acid (DHA) is very promising. Mouth-

It has been found that the LOYL4 protein, whose gene mutations are found in the dominant form of Stargardt's dystrophy, is structurally similar to the enzyme involved in the biosynthesis of this acid. BNL in the human body is synthesized from precursors in a small amount, which may not be enough for the normal functioning of the retina. In this regard, it is proposed to use BNA in the form biological additive for the treatment of Stargardt's dystrophy, about which there are still isolated reports in the literature.

Some authors consider fenretinide a promising drug in the treatment of Stargardt's dystrophy and yellow dot fundus, the action of which is aimed at reducing the synthesis of retinylidene-phosphatidylethanolamine and L2E, however, the limitation of use is associated with its teratogenic properties.

As a promising treatment for Stargardt's dystrophy, which can be introduced into clinical practice in the next decade, gene therapy is being considered.

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