Stargardt's disease: description, causes, symptoms and treatment features. Stargardt's disease and yellow-spotted fundus (fundus flavimaculatus) Stages of manufacturing new drugs for Stargardt

It’s a pleasure to talk to Mikhail: he is smart and well-read, has many hobbies, and can talk about the main thing - auto racing - for hours. An intelligent face - glasses adorn it. A calm, confident young man, 18 years old. And it’s even stranger to listen to what he says.

Stargardt's dystrophy: the road to blindness

“My vision has always been poor. I have been seeing an ophthalmologist since childhood. I took it calmly, the glasses didn’t bother me. And at the age of 16, I began to notice that in the dark I could see worse and worse. In addition, some areas of vision began to disappear, literally: I see here, I don’t see here. To be honest, I was scared.

A visit to the military registration and enlistment office put an end to it. The medical commission issued a verdict: “retinal abiotrophy.”

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

I had no options other than blindness.”

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

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

Mikhail came to UnikaMed at the age of 18, that is, a year and a half after his diagnosis. By this point, he could see practically nothing in the darkness, he was observed scotomas- loss of areas of vision.

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

The dynamics of the development of the process suggested complete loss of vision by the age of 20.”

Stargardt degeneration is not a death sentence

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

After the first session of regenerative therapy, I began to see better in the dark, my vision improved. It felt like someone had finally washed the dirty windshield that was blocking the view. Fantastic!

I've had three sessions in total so far - I'm taking a break now. After 6 months you will need to undergo another procedure. By the way, I’ve already returned to motorsport, including night racing!”

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

In short, regenerative therapy is based on a unique cellular autologous transplant that stimulates retinal renewal (the prefix “auto” denotes a transplant for which cells are taken from the person himself and transplanted into him).

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

Complex diseases, like Mikhail’s, stop progressing. The condition of the retina and its nutrition improves - accordingly, improves significantly and visual function.

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

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

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

Now, after three treatment sessions, Mikhail does not yet need further therapy, but in 6-8 months he should 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 isolated: people who have been rejected by other clinics come to us at UnikaMed. And even at the stage of blindness, many of them, thanks to regenerative therapy, restore their vision.

How does the procedure work?

Regenerative therapy does not require a hospital stay. Cellular material transplantation 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 the collection of 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 excellent cell biologists in the process, and the precise sequential execution of a series of operations.

The resulting material is administered to the patient using a special technology, depending on his disease and the condition of his visual organs.

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, say, three months are required between the first, second and third procedures, then six months may pass between the third and fourth. And so on.

Between procedures, treatment of Stargardt disease requires regular follow-up an ophthalmologist in order to “intercept” possible vision loss in time.

Of course, it is easier to get an effect when treating the disease at a very early stage, without waiting for loss of vision, complete or partial. If you notice that vision gets worse(especially in the dark or at dusk), if your field of vision has narrowed, if colors have begun 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 disease, but also in the treatment of optic nerve atrophy, macular degeneration of various natures, and other forms.

Stargardt disease is a dangerous disease that is quite rare in medical practice. It can lead to complete loss of vision and is not always treatable. The pathology is popularly called bull's eye. It provokes the destruction of the central shell of the retina - the macula, in which light-sensitive cells are localized.

Stargardt disease develops in childhood. It is usually diagnosed in children 8-11 years old, and less often in adolescents.

Why does retinal pigmentary dystrophy occur - the cause of Stargardt disease?

Retinal degeneration in Stargardt disease is not caused by any external factors. This is a genetically determined disease that is absolutely independent of gender. At the same time, Stargardt's dystrophy is not always transmitted to the children of sick people.

Types of Stargardt disease

Depending on the location and extent of the area of ​​retinal pigmentary degeneration, Stargardt disease is classified into three forms:

• Central. During an ophthalmological examination, it turns out that the cells located in the very center of the macula of the eye are damaged. The patient loses central vision. When examining objects, he sees a darker spot in their middle.
• Pericentral. The disease affects cells that are located to the side of the central spot - above, below, to the right or left of the point of fixation. Subjectively, this manifests itself as follows: while looking at some image, a person notices that one of its sides falls out of his field of vision and looks like a black moon. Over the years, the affected area takes the form of a black circle.
• Mixed. Retinal pigment abiotrophy begins in the middle of the central visual spot and quickly shifts to one side. As a result, the eye becomes completely blind.

How does Stargardt disease manifest?

Stargardt's macular degeneration, as the disease described is also called, begins to make itself felt when the child turns 6 or 7 years old. The patient begins to complain of a black spot, which he sees when looking at any objects. It prevents him from looking at them. He sees bright objects of saturated colors better, pale, black and white objects - worse. It is also possible that the perception of the usual color scheme will change.

At first, the black spot is small in size, but as the disease progresses, its volume increases. This can lead to irreversible blindness and destruction of the optic nerve.

How quickly does Stargardt disease progress?

It is difficult to predict the course of the disease. It can progress slowly and then “freeze.” When the patient relaxes and believes that his vision will no longer deteriorate, Stargardt's disease can manifest itself with renewed vigor and in a few years cause the development of complete blindness.

According to statistics, by the age of 50, half of sick people have very poor vision - 20/200, while the norm is expressed as 20/20. As a result, it decreases to 20/400.

Since Stargardt's disease disrupts the functioning of the visual organs and causes nerve tissue to die, it is impossible to correct the situation with glasses, contact lenses, or even modern refractive surgery methods.

Diagnostic measures for Stargardt disease

Stargardt disease occurs in one in 20 thousand people, so not all ophthalmologists encounter it in their medical practice. To understand that the patient has this particular genetic disease, the doctor must conduct a comprehensive examination and competent differential diagnosis. It includes:

1. Visometry - determination of visual acuity when a person looks into the distance (usually a special ophthalmological table with letters is used).
2. Tonometry - measurement of intraocular pressure.
3. Refractometry is an assessment of the optical power of the organ of vision.
4. Study of color vision using special Rabkin ophthalmological tables.
5. Perimetry is a technique for studying a patient’s peripheral vision.
6. Electrooculography - recording the constant potential of the eye by applying special electrodes fixed directly to the lower eyelid area on both sides. The method makes it possible to identify abnormal changes in the pigmented epithelium of the retina and study photoreceptors.
7. Ophthalmoscopy - examination of the fundus, blood vessels and retina.
8. Electroretinography is an informative way to study the functional state of the retina.
9. Campimetry - determination of the central field of vision.
10. Electrophysiological study - aimed at studying the functions of the retina, optic nerve, and assessing the condition of the cerebral cortex.
11. Fluorescein angiography is a technique for studying the vessels that supply the retina.
12. OTC (optical coherence tomography) is an optical coherence tomography used to detect diseases of the retina and optic nerve.

One of the main signs of the disease is its onset at the age of 6-8 years. A child complains to his parents about a black spot that he constantly sees. During the examination, the doctor discovers a spot of reduced pigmentation with a dark center in the eye. Around it are pigmented cells. Visually, it resembles the eye of a bull (hence the above-mentioned popular name).

In the macula zone there are yellowish or whitish spots of different sizes and shapes. Over time, the clear boundaries of these formations disappear - they become blurred and acquire a grayish tint. They can completely dissolve.

One should not think that with Stargardt's disease the patient always goes blind very quickly. A child may have good visual acuity for a long time and experience difficulties only because of poor adaptation to movement in the dark.

Molecular genetic examination can finally confirm or refute the preliminary diagnosis of retinal abiotrophy.

Treatment of Stargardt disease

It is impossible to eliminate the causative factors and thus avoid the development or progression of an ophthalmological disease. Usually, to improve the condition of patients and slow down the pathological process, patients are prescribed:

• Antioxidant drugs;
• Injections of the amino acid taurine;
• Vasodilator drops;
• Hormonal solutions;
• Vitamins (especially important A, B, C, E);
• Means to improve blood circulation.

Among the physiotherapeutic procedures, the ophthalmologist can prescribe electrophoresis using a number of drugs, laser stimulation of the retina, and ultrasound.

Radical methods of treating Stargardt disease

Today, modern techniques such as:

1. Retinal revascularization;
2. Autologous tissue therapy.

In the first case, the surgeon installs a bundle consisting of muscle fibers in the area of ​​the affected macula. This preserves visual function for some time, as the atrophied nerve is replaced. But the transplant does not avoid blindness - over the years the dark spot becomes wider.

As for autologous tissue therapy, this is a more modern technique. It involves the use of stem cells obtained from the patient's own adipose tissue. The technology was developed by Russian scientist V.P. Filatov. According to his theory, Stargardt disease must be treated at the cellular level.

This therapy is safe, since destroyed eye cells are replaced with new, healthy ones.

The risk of their rejection is minimal, since during the operation not donor material is used, but material obtained from the patient himself. It quickly takes root and restores the functions of the visual organs.

It is impossible to say that autologous tissue therapy provides a 100% guarantee of vision restoration. But today this is the only technique that effectively resists the further development of the disease and helps improve visual acuity even when the patient sees the world around him very poorly.

DEFINITION

Stargardt disease is a degeneration of the macular region of the retina, which begins in the RPE and manifests itself with a bilateral decrease in visual acuity at the age of 10-20 years.

ICD-10 CODE

H35.5 Hereditary retinal dystrophies.

CLASSIFICATION

There are four forms of Stargardt disease depending on the localization of the pathological process: in the macular region, in the middle periphery (fundus flavimaculatus), in the paracentral region, as well as a mixed form when localized in the center and on the periphery.

ETIOLOGY

Currently, with the help of genetic studies, it has been proven that Stargardt disease and yellow-spotted fundus are phenotypic manifestations of the same disease with an autosomal recessive, rarely autosomal dominant form of inheritance.

Positional cloning identified the main locus of the ABCR gene for Stargardt disease, which is expressed in photoreceptors. ABCR is a member of the ATP-binding cassette transporter superfamily. In the autosomal dominant type of inheritance of Stargardt disease, the localization of mutated genes on chromosomes 13q and 6q14 was determined; linkage analysis of locus mapping for central and peripheral forms of Stargardt disease.

PATHOGENESIS

Intensive accumulation of lipofuscin occurs in the RPE. It weakens the oxidative function of lysosomes, increases the pH of RPE cells, which leads to disruption of membrane integrity.

CLINICAL PICTURE

In the central form of Stargardt's dystrophy, as the process develops, the ophthalmoscopic picture of the macular area has a different appearance: from “broken metal” to “bull's eye”, “forged bronze” and choroidal atrophy.

The bull's eye phenomenon is seen ophthalmoscopically as a dark center surrounded by a wide ring of hypopigmentation, usually followed by another ring of hyperpigmentation. The retinal vessels are not changed, the optic disc is pale on the temporal side, which is associated with atrophy of nerve fibers in the papillomacular bundle. The foveal reflex and macular eminence (umbo) are absent.

The presence of yellowish-white spots in the posterior pole of the eye in the retinal pigment epithelium of various sizes, shapes and configurations is a characteristic sign of a yellow-spotted fundus (fundus flavimaculatus). Over time, the color, shape, and size of these spots may change. Initially yellowish spots with clearly defined edges, after a few years they may become gray with unclear boundaries or disappear.

DIAGNOSTICS

Anamnesis

The time of onset of the disease (in childhood or adolescence) can play an important role in its diagnosis.

Laboratory research

Histologically, an increase in the amount of pigment in the central zone of the fundus, atrophy of the adjacent RPE, and a combination of atrophy and hypertrophy of the pigment epithelium are noted. The yellow spots are represented by lipofuscin-like material.

Instrumental studies

During perimetry, relative or absolute central scotomas of varying sizes are detected in all patients with Stargardt disease, depending on the timing and spread of the process from early childhood or adolescence. With a yellow-spotted fundus, no changes are noted in the macular area; the field of vision may not be changed.

The form of color anomaly in most patients with central localization of the process is of the type deuteranopia, red-green dyschromasia, or more pronounced.

With yellow-spotted fundus, color vision may not be affected. Spatial contrast sensitivity in Stargardt dystrophy is significantly altered throughout the entire range of spatial frequencies with a significant decrease in the medium range and its complete absence in the high spatial frequency range - “pattern cone dystrophy”. Contrast sensitivity (on- and off-activity of the cone system) is absent in the central region of the retina within 6-10 degrees.

ERG and EOG. Macular ERG decreases already in the initial stages of the central form of Stargardt dystrophy and is not recorded in the advanced stages.

In the initial stages of fundus flavimaculatus ganzfeld, ERG and EOG remain within normal limits: in advanced stages, the cone and rod components of ERG decrease, which becomes subnormal, and EOG indicators also change. Patients with this form have no symptoms. Visual acuity, color vision, and field of vision are within normal limits. Dark adaptation may be normal or slightly reduced.

On FA, with a typical “bull’s eye” phenomenon, zones of “absence” or gynofluorescence, with visible choriocapillaris, and a “dark” or “silent” choroid are detected against a normal background. The lack of fluorescence in the macular area is explained by the accumulation of lipofuscin, which screens fluorescein. Areas with hypofluorescence may become hyperfluorescent, which corresponds to an area of ​​RPE atrophy.

Differential diagnosis

The similarity of the clinical picture of various dystrophic diseases of the macular region makes diagnosis difficult. Differential diagnosis of Stargardt disease should include familial drusen, fundus albipunctatus, retinal Kandori spots, dominant progressive foveal dystrophy, cone, cone-rod and rod-cone dystrophy, juvenile retinoschisis, vitelliform macular degeneration, acquired drug-induced dystrophies (eg, chloroquine ret inopathy).

Stargardt disease (juvenile macular degeneration, yellow-spotted retinal abiotrophy) is a juvenile form of central retinal degeneration, which is characterized by progressive damage to the macular area. The disease has a predominantly autosomal dominant, less often an autosomal recessive or sex-linked mechanism of inheritance. The pathology occurs with a frequency of 1:10,000 and manifests itself between the ages of 6 and 20 years.

The disease was first described by the German ophthalmologist Karl Stargardt at the beginning of the 20th century. In 1997, geneticists discovered a defect in the ABCR gene, causing a disruption in the synthesis of the protein that transfers ATP to the photoreceptors of the retina. It is energy deficiency that leads to the death of different types of cones in the macula area. It should be noted that yellow-spotted retinal abiotrophy can occur with mutations in CRB1, RP2 and about 150 other genes.

Classification

There are two main types of Stargardt disease: with and without fundus flavimaculatus.

The first is characterized by the presence of typical changes in the form of yellow-white stripes and dots, while the second is characterized by their absence.

Depending on the location, there are the following forms of the disease:

• central;
• pericentral;
• centro-peripheral (mixed).

Considering the nature of changes in the fundus, the following types of pathology are distinguished:

1. degenerative changes in the macula without speckling;
2. macular degeneration with parafoveal mottling;
3. degeneration with diffuse mottling;
4. diffuse mottling without degenerative changes in the macular area.

Symptoms

The first manifestations of the disease usually occur at the age of 6-7 years. Juvenile macular degeneration is characterized by symmetrical damage to both eyes. All children with this pathology note the appearance of absolute or relative scotomas - black or colored spots in the field of vision. The location of the scotoma directly depends on the location of the pathological focus.

The central form of juvenile macular degeneration is characterized by loss of the visual field at the very point of fixation. With the paracentral form, scotomas appear away from the point of fixation. They may look like a crescent moon or a black ring. The centroperipheral form of the disease is characterized by rapid growth of the scotoma, which is why it can cover most of the visual field.

Some patients have deuteranopia, red-green dichromasia, and other unclassifiable color vision disorders. Many children complain of photophobia and a progressive decrease in visual acuity.

In children, a violation of dark adaptation and a decrease in contrast sensitivity are often detected.

Diagnostic methods

The disease is characterized by polymorphic changes, however, patients almost always exhibit areas of depigmentation and pigmented round dots. With ophthalmoscopy, characteristic changes in the form of a bull's eye, a snail's mark, broken (forged) bronze, choroidal atrophy, and geographic atrophy are visible in the fundus.

In addition to a standard ophthalmological examination, people with Stargardt disease are prescribed electrophysiological research methods. The most informative are electroretinography (ERG) and electrooculography (EOG). These methods allow you to assess the functional state of the retina of the eye.

In the video, the doctor talks about the causes, symptoms and treatment of the disease:

Treatment

To date, there is no etiological treatment for the disease.

As an auxiliary therapy, the patient may be prescribed physiotherapeutic procedures, vitamins, antioxidants, taurine, vasodilators, and steroid hormones.

Stargardt's disease, which is a classic example of central pigmentary degeneration, was described by K. Stargardt (1909, 1913) at the beginning of the 20th century. as a hereditary disease of the macular region, manifesting itself in childhood and young age (7-20 years). Changes in the fundus, although polymorphic, are characterized by the appearance in both eyes of pigmented round dots, areas of depigmentation and atrophy of the retinal pigment epithelium (RPE), in some cases of the “bull’s eye” type, often combined with whitish-yellowish spots in the paramacular zone. A similar clinical picture of progressive degeneration of the macular region of the retina in children was described back in the 19th century.

Changes in the form of yellowish-whitish dots and stripes with or without changes in the macular area were designated by A. Franceschetti with the term “fundus flavimaculatus”. In the literature, the terms “Stargardt disease” and “fundus flavimaculatus” are often combined (Stargardt disease/fundus flavimaculatus), thereby emphasizing the presumed unity of origin and/or transition from one form of the disease (Stargardt disease) to another (fundus flavimaculatus) as it develops .

If vision loss, caused by typical dystrophic changes in the macula, begins in the first two decades of life, then it is preferable to use the term “Stargardt disease.” If changes appear in the central and peripheral parts of the retina at a later age and the disease progresses more acutely, then it is recommended to use the term “fundus flavimaculatus”.

It has been established that this is a heterogeneous group of diseases with hereditary transmission.

Symptoms (in order of appearance):

• In the fovea - without changes or with redistribution of pigment
• Oval lesions of the "snail track" type or bronze reflex, which may be surrounded by white-yellow spots.
• "Geographic" atrophy may have a "bull's eye" appearance.

Classification

Along with the classical distinction of two types of Stadgardt's disease, including dystrophy of the macular region with and without fundus flavimaculatus, several other classifications have been proposed based on variations in the clinical picture of the fundus.

So, K.G. Noble and R.E. Carr (1971) identified four types of diseases:

• Type I - macular degeneration without spots (mottling). Visual acuity decreases early.
• II - with parafoveal mottling,
• III - macular degeneration with diffuse mottling,
• Type IV - diffuse mottling without macular degeneration. Visual acuity remains quite high, since retinal damage does not affect the foveal region.

Genetic research

Stargardt's dystrophy is most often inherited in an autosomal recessive manner, but many families have been described in which the disease is transmitted in an autosomal dominant manner. There is an opinion that the dominant type of inheritance is characteristic mainly of types III and IV of Stargardt disease.

Positional cloning identified a disease-causing gene locus for Stargardt disease expressed in photoreceptors, which was named ABCR. ABCR has been shown to be identical in sequence to the human RmP gene.

The RmP protein is an integral membrane glycoprotein with a molecular weight of 210 kDa, which is localized along the edge of the discs of the outer segments of visual cells. RmP has been shown to belong to the ABC superfamily of ATP-binding cassette transporters, which stimulate ATP hydrolysis and influence the ATP-dependent movement of specific substrates across cell membranes.

Genes for several members of the ABC transporter superfamily have been found to be involved in the development of a number of hereditary diseases of the human retina. Thus, in the autosomal dominant type of inheritance of Stargardt disease, the localization of mutated genes on chromosomes 13q and 6ql4 was shown, and the gene for a new dominant form of Stargardt-like retinal disease (possibly related to type IV) was mapped on chromosome 4p between markers D4S1582 and D4S2397.

The human RmP gene is mapped between markers D1S424 and D1S236 on the lp chromosome (Ip21-pl3). The genes for the most common autosomal recessive form of Stargardt's dystrophy and fundus flavimaculatus are also localized there, and the location of the gene for the autosomal recessive form of retinitis pigmentosa RP19 is determined between markers D1S435-D1S236 on the lp chromosome. In the study by S.M. Azarian et al. (1998) established the complete thin intron-exon structure of the ABCR gene.

Immunofluorescence microscopy and Western blot analysis have shown that ABCR is present in foveal and perifoveal cones, suggesting that the loss of central vision in Stargardt's dystrophy may be a direct consequence of foveal cone degeneration caused by mutations in the ABCR gene.

It was also revealed that ABCR mutations are present in a subpopulation of patients with non-exudative age-related macular degeneration (AMD) and cone-rod dystrophy, which suggests the presence of a genetically determined risk of developing AMD in relatives of patients with Stargardt disease. However, not all researchers support this statement, although there is no doubt that the phenotypic and genotypic manifestations of Stargardt disease and AMD are associated with mutations of the ABCR gene.

J.M. Rozet et al. (1999), examining a family that included among its members patients with both retinitis pigmentosa and Stargardt disease, showed that heterozygosity of the ABCR gene leads to the development of Stargardt dystrophy, and homozygosity leads to the development of retinitis pigmentosa.

Thus, the results of genetic studies in recent years indicate that, despite the obvious differences in the clinical picture of retinitis pigmentosa, Stargardt disease, fundus flavimaculatus and AMD, they are allelic disorders of the ABCR locus.

The wide range of phenotypic manifestations of Stargardt's dystrophy and the age of detection of clinical signs (from the first to the seventh decade of life), observed even in one family, makes differential diagnosis and prognosis of changes in visual acuity difficult. Angiography data, medical history, reduced visual function, altered cone components in the ERG, the specifics of changes in local and multifocal ERG help in making a diagnosis.

Thus, in recent years, the results of genetic studies have become increasingly important for diagnosis. So, G.A. Fishman et al. (1999), having examined a large group of patients with Stargardt's dystrophy and fundus flavimaculatus with mutations of the ABCR gene, showed that the variability of phenotypic manifestations in a certain way depends on variations in the specific amino acid sequence. Based on the results of fluorescein angiography, ophthalmoscopy, electroretinographic and perimetric studies, they identified three disease phenotypes

• One of these phenotypes is characterized, along with atrophic damage to the macula, by the appearance of perifoveal yellowish-white spots, the absence of a dark choroid and the normal amplitude of ERG waves. In this phenotype, a sequence change was identified in exon 42 of the ABCR gene, consisting of the replacement of glycine with glutamine (Gly]961Glu).
• The other phenotype was characterized by a dark choroid and yellowish-white spots more diffusely scattered across the fundus, but no Glyl961Glu substitution was detected.
• In a phenotype with pronounced atrophic changes in the RPE and reduced rod and cone ERGs, the ABCR mutation was found in only one patient out of 7.

Due to the fact that ABCR mutations are accompanied by various phenotypic manifestations, it is believed that advances in identifying correlations between specific gene mutations and clinical phenotypes will facilitate counseling of patients regarding the prognosis of visual acuity.

All these studies are aimed not only at revealing the subtle mechanisms of genetic diseases of the retina, but also at finding possible therapies for them.

Clinical picture

line of sight

With fundus flavimaculatus, the field of vision may not be changed, especially in the first two decades of life; in all patients with Stargardt disease, relative or absolute central scotomas of varying sizes are detected, depending on the distribution of the process in the macular region.

Color vision

Most patients with type I Stargardt disease have deuteranopia; in type II Stargardt disease, color vision impairments are more pronounced and cannot be classified. The type of color abnormality appears to depend on which type of cones is predominantly involved in the pathological process, therefore, with fundus flavimaculatus, color vision may not be affected or red-green dichromasia may be observed.

Dark adaptation

According to O. Gelisken, J.J. De Jaey (1985), of 43 patients with Stargardt disease and fundus flavimaculatus, 4 had an increased final threshold of light sensitivity, 10 had no cone segment of the dark adaptation curve.

Spatial contrast sensitivity

In Stargardt's dystrophy, it is changed throughout the entire frequency range with a significant decrease in the region of medium spatial frequencies and its complete absence in the region of high spatial frequencies - the pattern of cone dystrophy.

Contrast sensitivity , on- and off-activity of the cone system, assessed by the time of the sensorimotor reaction upon presentation of a stimulus darker and lighter than the background, are absent in the central region of the retina with some preservation of off-sensitivity in the zone 10° from the center.

Electroretinography and electrooculography

Of the electrophysiological methods, electroretinography and electrooculography are the most informative in the diagnosis and differential diagnosis of diseases of the macular region of the retina.
According to the literature, in the initial stages of Stargardt's dystrophy and fundus flavimaculatus, the general, or ganzfeld, ERG is normal. However, the use of various methodological techniques of electroretinography makes it possible to assess the topic of functional disorders in the retina at the level of its various layers and sections.

Thus, when recording local ERG (LERG) using an LED mounted in a suction lens, the biopotentials of the macular region are subnormal already in the initial stage of Stargardt dystrophy, in contrast to the normal ganzfeld ERG amplitudes. As the process progresses, LERH decreases until it disappears completely. Other authors also note an increase in peak latency and a decrease in the amplitudes of local foveal responses; in 64% of patients with fundus flavimaculatus with visual acuity of 20/20 - 20/30.

The use of zonal electroretinography made it possible to detect inhibition of the reaction of the outer layer of the retina (photoreceptors) not only in the macular zone, but also in the paramacular and peripheral parts in the early stages of Stargardt's disease while the proximal layers of the retina were preserved.

A decrease in the amplitudes of a- and 1a ERG waves in different zones of the retina (center, paracentre, periphery) indicates a generalized lesion of the entire photoreceptor layer of both systems (cone and rod) already in the first stage of the disease. The development of the process is accompanied by the spread of pathological changes deep into the retina, which is expressed in an increase in the frequency of detection and the severity of changes in all ERG components.

However, already in the initial (I-II) stages of Stargardt's disease, a greater degree of suppression of the cone ERG components is revealed compared to the rod components.

According to P. A. Blacharski (1988), after long-term dark adaptation (45 min) in patients with fundus flavimaculatus, a greater (29%) degree of decrease in photopic ERG components is noted than in healthy individuals. The scotopic ERG responses decrease slightly, by only 6-10%. According to J. B. M. Moloney et al. (1983), suppression of the cone ERG was detected in 100% of those examined and a decrease in the rod ERG in 50%.

R. Itabashi et al. (1993) presented the results of a study of a large group of patients with Stargardt disease, comparing the degree of inhibition of various ERG components.

According to the classification proposed by K.G. Noble and R.E. Sugg (1971), several groups of patients were identified according to the stages of the disease: 1-4. The average amplitudes of all ERG components were below normal values ​​with more pronounced changes in the cone system of the retina. The photopic b-wave was 57.4% of normal, the scotopic b-wave was 77.9%, responses to a “white” flickering stimulus of 32 Hz were 78.9%, the a-wave was 87.7%, the b-wave was 95.8% of normal. The greatest decrease in all ERG components was observed in patients of group 3.

Timing parameters have also been changed; the prolongation of the peak time is most significant for the a-wave, especially in patients of group 3. This stage is also characterized by the most frequent detection of a subnormal light-dark coefficient of the EOG (73.5%). According to the authors, the prognosis for patients in group 3 is the most unfavorable.

Observation of patients for 7-14 years made it possible to trace the dynamics of electrophysiological parameters in comparison with the clinical process. More pronounced ophthalmoscopic changes were accompanied by a decrease in both electroretinographic and electrooculographic parameters. These results are consistent with the opinion of other researchers who, based on electroretinographic and histological data, suggest an initial lesion in the RPE in fundus flavimaculatus and further damage to the retinal photoreceptors in Stargardt's dystrophy.

There are certain discrepancies in the results of electrooculography in the literature. Most often, a normal or slightly reduced EOG is noted in most patients with fundus flavimaculatus and Stargardt's dystrophy. However, a number of researchers note a high percentage of subnormal EOG based on the Arden coefficient: in 75-80% of patients with FF. It should be taken into account that most publications present the results of examination of small groups of patients: from 3 to 29.

G.A. Fishman (1976, 1979) made a correlation between fundus flavimaculatus stages and EOG results. He showed that in the disease of stages I-II in all examined patients the EOG was not changed (28/28), whereas in stages III-IV in 90% of patients it was subnormal. According to G.A. Fishman et al (1976 1977 1979), only if a significant area of ​​the retina is affected by the pathological process will the EOG be abnormal. Other researchers also note the absence of EOG changes in the vast majority of patients with fundus flavimaculatus. It is possible that research results are influenced by differences in methodological techniques, despite attempts to standardize them.

Thus, electrophysiological studies are more likely to reveal the presence and severity of changes in the cone and rod systems of the retina, as well as to assess the condition of the RPE, rather than help in the differential diagnosis of Stargardt disease and fundus flavimaculatus.

Differential diagnosis

The clinical picture of some hereditary diseases may be similar to that of Stargardt disease. Such diseases include dominant progressive foveal dystrophy, cone-rod and rod-cone (retinitis pigmentosa) dystrophy, juvenile retinoschisis. Atrophic macular degeneration has been described in various spinocerebral and cerebral spastic disorders, including oligopontocerebral atrophy. Similar morphological findings have been described in non-hereditary diseases, for example, chloroquine retinopathy or ocular manifestations of severe toxicosis of pregnancy.

Based on differences in the fundus picture, age, onset of the disease, and data from functional research methods, S. Merin (1993) identified two main types of Stargardt disease.

Stargardt disease type I

This type is most consistent with the originally described Stargardt disease. This is a juvenile hereditary macular degeneration, the clinical manifestations of which are observed in children aged 6-12 years. Boys and girls get sick with equal frequency; hereditary transmission is carried out according to an autosomal recessive type.

The disease manifests itself bilaterally and symmetrically. In advanced stages, the foveal reflex is absent. Changes at the level of the retinal pigment epithelium (RPE) appear as a central cluster of brownish pigment, surrounded by areas of hyper- and depigmentation. The clinical picture resembles a bull's eye.

Fluorescein angiography confirms the typical bull's eye phenomenon. The dark, non-fluorescein-permeable center is surrounded by a wide ring of hypofluorescent dots, usually followed by another ring of hyperpigmentation. This picture is explained by an increase in the amount of pigment in the central zone of the fundus, atrophy of adjacent RPE cells, and a combination of atrophy and hypertrophy of the pigment epithelium. The absence of fluorescein in the macular region is called “silent choroid” or dark choroid and is explained by the accumulation of acidic mucopolysaccharides in the RPE. According to D.A. Klein and A.E. Krill (1967), the bull's eye phenomenon is detected in almost all patients with type I Stargardt disease.

As the disease progresses, visual acuity decreases, resulting in the development of low vision. If in the early stages of the disease the ERG and EOG remain normal, in the advanced stages the responses of the cone system according to the ERG data decrease and the EOG indicators become moderately subnormal. Due to damage to the predominantly cone system, patients also have impaired color vision, often of the deuteranopia type.

During a histological examination of two eyes of a patient with typical Stargardt disease type I, who died as a result of a car accident, R.C. Eagl et al. (1980) found significant variability in the size of RPE cells - from 14 to 83 μm. Large RPE cells formed a granular substance, which in its ultrastructure, autofluorescent and histochemical properties corresponded to pathological (abnormal) lipofuscin. The amount of melanin was reduced and melanin granules were shifted towards the inside of the cell

In later stages of Stargardt disease, the disappearance of most of the photoreceptors and RPE cells from the macular region of the retina is revealed. At the same time, some of the RPE cells were in the stage of degeneration with the accumulation of lipofuscin; hyperplasia of RPE cells was observed at the edges of the areas of atrophy.

F. Schutt et al. (2000) showed that in retinal diseases associated with intense accumulation of lipofuscin, including Stargardt disease, AMD and retinal aging, the retinoid fluorescent component of lipofuscin A2-E (N-retinylidene-N-retinyl) plays a role in RPE dysfunction -ethanol-amine). It weakens the degradative function of lysosomes and increases the intralysosomal pH of RPE cells, leading to the loss of their membrane integrity. In addition to lysosomotropic properties, the photoreactive properties of A2-E and its phototoxicity are shown.

Stargardt disease type II

Unlike type I, in addition to typical changes in the macular region of the retina, there are multiple and widespread FF spots in the fundus, which can reach the equator. The disease begins somewhat later, although this may be due to the fact that the decrease in visual acuity in type II Stargardt disease occurs more slowly and, as a result, patients turn to the ophthalmologist later. Due to the fact that in type II Stargardt disease there are more changes beyond the boundaries of the macular region, electrophysiological data differ from those in type I.

Thus, in the ERG the responses of the rod system are significantly reduced. EOG indicators are also changed to a greater extent. The presence of yellowish spots in a high percentage of cases outside the macular area (macula) makes it difficult to clearly distinguish Stargardt disease from FF.

Fundus flavimaculatus

As a rule, fundus flavimaculatus, or yellow-spotted fundus, is combined with Stargardt disease and is not common as an isolated form of retinal disease. In typical (“pure”) cases, patients have virtually no symptoms of the disease. Visual acuity, color vision, and field of vision are within normal limits. Dark adaptation may be normal or slightly reduced. In the fundus of the eye, the macula and periphery of the retina are unchanged, only between the fovea and the equator are visible multiple grayish or yellowish spots of various shapes: round, oval, elongated, comma- or fish-tail-shaped, which can merge or be located separately from each other, be small - 200-300 microns or 3-5 times more. During dynamic observation, the color, shape, and size of these spots may change. The spots, initially yellowish and clearly defined, after a few years may become gray with unclear boundaries or disappear.

In parallel, the picture revealed by fluorescein angiography becomes different: areas with hyperfluorescence become hypofluorescent. At subsequent stages of disease development, RPE atrophy manifests itself as the disappearance of individual spots and their replacement by irregular areas of hypofluorescence.
Similar changes in spots with fundus flavimaculatus (FF) are characteristic of both types of Stargardt disease, however, with the “pure form” of FF they are less pronounced.

The onset of the disease, and most likely the time of its detection, does not depend on age. An autosomal recessive type of inheritance of FF is assumed, but in some cases it is not possible to establish the hereditary nature of this pathology.