Treatment of Stargardt disease: the impossible became possible. Stargardt's disease - causes of pathology, diagnostic measures, treatment methods Stargardt's disease

- a hereditary disease of the retina that manifests itself dystrophic changes its macular zone and leads to loss of central vision. The onset of the disease occurs in childhood or adolescence. Patients have central scotomas and color vision disturbances. Progression of Stargardt disease leads to complete blindness. Diagnosis is carried out using ophthalmoscopy, fluorescein angiography and EPI of the retina. For treatment, injection therapy (vitamins, antioxidants, angioprotectors), physiotherapy is used, revascularization operations are performed, and a method of autologous tissue therapy is being developed.

General information

Another name for Stargardt's disease - juvenile macular degeneration - reflects the essence of the disease: it begins at a young (juvenile) age and is characterized by damage to the macula - the receptor apparatus visual analyzer. The disease was described by the German ophthalmologist Karl Stargardt at the beginning of the twentieth century as a congenital lesion of the macular region of the eye, which was inherited in one family. Typical ophthalmoscopic signs of Stargardt's disease are polymorphic: “choroidal atrophy”, “bull's eye”, “broken (forged) bronze”. The pathogenetic name of the pathology is “yellow-spotted retinal abiotrophy” - reflects changes in the fundus of the eye.

In 1997, geneticists discovered a mutation in the ABCR gene, which causes a disruption in the production of a protein that should transfer energy to photoreceptor cells. Inferiority of the ATP transporter leads to the death of retinal photoreceptors. Different kinds Hereditary macular degeneration occurs in 50% of cases of eye pathology. Of these, Stargardt disease accounts for about 7%. The nosological form is diagnosed with a frequency of 1:10,000 and is characterized by a progressive course. Bilateral eye pathology begins at a young age (from 6 to 21 years) and leads to severe consequences, up to complete loss of vision. The disease has social significance, because it leads to disability at a young age.

Causes of Stargardt disease

Inheritance does not depend on the gender of the patient and parents. The pathology is transmitted predominantly in an autosomal recessive manner, that is, the inheritance of the pathology is not related to gender (autosomal - associated with non-sex chromosomes) and is not always transmitted to the future generation (recessive mode of inheritance). According to the latest data from geneticists, gene pathology can also be transmitted in a dominant manner. With a dominant type of inheritance of defects in the gene that controls the synthesis of the ATP transporter protein, the disease is milder and rarely leads to disability. Most receptor cells in the macula (apex) macular spot fundus function. In patients with a dominant type of inheritance, the disease occurs with a minimum of manifestations. Patients remain able to work and can even drive vehicles.

The main reason macular cells degenerate is that they suffer from energy deficiency. The gene defect leads to the synthesis of an defective protein that transports ATP molecules through the membrane of the cells of the macula - the center of the retina in which the graphic and color image is focused. There are no blood vessels in the macula area. Cone cells are nourished by ATP transport proteins from the nearby choroid (choroid). Proteins transport ATP molecules across the membrane into cone cells.

IN normal conditions Photoreceptor rhodopsin absorbs a photon of light, transforming into trans-retinal and opsin. Then trans-retinal, under the influence of ATP energy brought by carrier proteins, is converted into retinal, which combines with opsin. This is how rhodopsin is restored. When a gene is inherited, a defective carrier protein is formed. As a result, the restoration of rhodopsin is disrupted and trans-retinal accumulates. It is converted to lipofuscin and has a direct toxic effect to cone cells.

Classification of Stargardt disease

The types of disease depend on the extent of the affected area of the macula. In ophthalmology, the following forms of Stargardt disease are distinguished: central, pericentral, centroperipheral (mixed). In the central form, cells in the center of the macula are affected. This results in loss of central vision. The patient develops a central scotoma (from the gr. “skotos” - darkness). The central zone falls out of sight. The patient sees an image with a dark spot at the point of fixation of the gaze.

The pericentral form is characterized by the appearance of a scotoma away from the point of fixation. A person is able to focus his gaze, but notices loss in one of the sides from the center of the visual field in the form of a crescent. Over time, the scotoma takes on the appearance of a dark ring. The centro-peripheral form begins from the center and rapidly spreads to the periphery. The dark spot grows and completely blocks the field of view.

Symptoms of Stargardt disease

Manifestations of the disease begin at the age of 6-7 years. All patients, regardless of the type of inheritance, have central scotomas. With a favorable course, scotomas are relative: the patient sees bright objects with clear contours and does not distinguish objects with a weak color range. Many patients have a color vision disorder such as red-green dyschromasia, in which a person sees light green as dark red. At the same time, some patients do not notice changes in the perception of colors.

In the initial phase of the disease, the boundaries do not change peripheral vision, with progression, central scotomas expand, which leads to complete blindness. Simultaneously with the appearance of loss of central vision, its acuity decreases. In the final stage of Stargardt's disease, the optic nerve atrophies. The person completely loses his sight. There are no changes in other organs, either in the initial or in the terminal stages of the disease.

Diagnosis of Stargardt disease

The disease begins in childhood– this is one of the main signs for differential diagnosis. Ophthalmoscopy reveals a wide ring of decreased pigmentation that surrounds a dark center. Around the pallidum there is a further ring of hyperpigmented cells. The painting resembles a bull's eye or hammered bronze. The foveal reflex is negative. The macular elevation is not detected. When examining the macula, yellowish-white spots of varying sizes and configurations are noted. Over time, the boundaries of the inclusions blur, the spots acquire a gray tint or completely disappear.

During perimetry in case of Shtangardt's disease, positive or negative (the patient does not feel them) central scotomas are noted. In the central form of the disease, red-green deuteranopia develops. The peripheral form is not characterized by impaired color perception. Spatial contrast sensitivity varies over the entire range: absent in the region high frequencies(in the central region up to 6-10 degrees) and decreases in the mid-frequency region.

IN initial stage disease, there is a decrease in macular electrography indices in the central form of dystrophy. With further progression, electrical potentials are not recorded. When dystrophy is located in the middle peripheral zone, normal electrography and electrooculography are noted in the initial stage. Then the values of the cone and rod components of electroretinography decrease to subnormal. The disease is asymptomatic - without impairment of visual acuity and color perception. The boundaries of the visual field are within normal limits. Dark adaptation is slightly reduced.

With the help of fluorescein angiography, against the background of the “bull’s eye”, hypofluorescence zones are not detected, capillaries, “silent” or “dark” choroid are visible. In areas of atrophy, hyperfluorescent areas of retinal pigment epithelial cells are noticeable. Histological examination in the central zone of the fundus reveals an increased amount of pigment - lipofuscin. There is a combination of hypertrophied and atrophied pigment epithelial cells.

Molecular genetic analysis makes it possible to detect a gene mutation before the onset of disease manifestations. To detect nucleotide substitutions, real-time PCR is performed using several DNA probes - “molecular beacons”. Differential diagnosis of Stargardt disease is carried out with acquired drug dystrophies, Kandori retinal spots, familial drusen, juvenile retinoschisis, dominant progressive foveal, cone, cone-rod and rod-cone dystrophy.

Treatment and prognosis of Stargardt disease

There is no etiological treatment. As a general auxiliary treatment, parabulbar injections of taurine and antioxidants, the introduction of vasodilators (pentoxifylline, a nicotinic acid), steroid drugs. Vitamin therapy is carried out to strengthen blood vessels and improve blood supply (vitamin groups B, A, C, E). Physiotherapeutic methods of treatment are indicated: medicinal electrophoresis, ultrasound, laser stimulation of the retina. A technique is used for retinal revascularization by transplanting a bundle of muscle fibers into the macula area. Pathogenetic regeneration is being developed ophthalmic technology autologous tissue therapy using stem cells from the patient's adipose tissue.

Stargardt disease begins in early age and quickly leads to visual impairment. In rare cases, with a dominant type of inheritance, vision declines slowly. Patients are recommended to observe an ophthalmologist, take vitamin complexes and wear sunglasses.

Stargardt disease is a hereditary disease in which the retina of the eye is affected and blindness gradually develops.

Today, three genes are known whose mutations are associated with this disease: ABCA4 (type I disease), ELOVL4 (type II) and PROM1 (type III). The most common mutations are in the first gene. In general, the prevalence of the disease is estimated at 1 case in 10 thousand. Moreover, up to 40% of the population Northern Europe are carriers of a mutation in the ABCA4 gene, in southern countries this is less common.

Stargardt disease is inherited in an autosomal recessive manner: if both parents are carriers of mutations, the child can be born with this pathology with a 25% chance.

Genetic mutations lead to defective cell functioning, due to which lipofuscin (a toxic pigment) accumulates in the cells, and the process of restoration of the main visual pigment is disrupted.

Stargardt disease does not affect other organs and systems and usually develops between the ages of 6 and 20 years. Effective treatment does not exist yet, but clinical studies are actively underway, which have already shown encouraging results.

Diagnostics

Genetic testing of parents at the stage of family planning is the most effective method prevention of this disease in a child. If both parents are carriers of the mutation, then the probability of having a child with the disease is 25%. Genetic tests can be done only for this disease or in combination with other hereditary ones. The test usually takes blood or saliva, and the results are ready within a few weeks. If both parents are carriers of the mutation, consultation with a geneticist is recommended.
Prenatal screening. Typically, mutations associated with Stargardt disease are not included in this diagnostic method, since they do not affect fetal development and early development. However, if there were cases of blindness in the family and for some reason it was not done genetic testing at the stage of planning a child, these indicators can be included in prenatal screening: the earlier prevention begins, the longer vision can be preserved.
Optical coherence tomography (OCT). This is one of the most informative methods for doctors who specialize in retinal diseases. The method is a high-precision retinal scan based on the reflection of infrared radiation. As a result, the doctor receives an objective image of the condition of the retina. This helps to determine the extent and nature of the lesion and subsequently monitor the dynamics of changes.
Molecular genetic diagnostics. If Stargardt disease is suspected, genetic analysis is necessary to confirm the diagnosis. If there were no cases of the disease in the family, and a mutation was found, then it should be double-checked by direct sequencing - this is a more accurate method of completely reading the gene that contains the mutation.
Autofluorescence recording. The method is based on the fact that foci of lipofuscin, which accumulates in the retinal tissue, become clearly visible under the influence of a certain type of laser. This method allows you to obtain an objective picture of retinal damage and monitor the dynamics of the disease. According to experts, the method can successfully replace fluorescein angiography of the retina.
Electrophysiological examination of the eyes (EPI, ERG). The technique allows you to assess the functionality of retinal cells. While OCT checks the structural integrity of the retina, EPI is necessary to assess function, since the structural picture may be satisfactory, but the cells may not be working properly.
Fluorescein angiography of the retina. This examination is necessary with a confirmed diagnosis to assess the extent of retinal damage. A special contrast agent is injected into the vein, which “highlights” the affected vessels when examined with a machine.

Symptoms

In the first years of a child's life, Stargardt's disease does not manifest itself in any way.

Complaints about vision can appear from the age of 6; the child may complain of blurriness, color distortion and blurred vision in poor lighting.

The main symptom is a gradual decrease in vision in both eyes at once.

If there is a family history of Stargardt's disease or blindness, any signs of visual impairment should be examined as soon as possible.

A distinctive symptom of Stargardt's dystrophy is the deterioration of central vision while maintaining (in most cases) peripheral vision. But in some cases, peripheral vision is also seriously affected, which is due to the severity of the mutations.

Treatment

Today, a complete cure is not yet possible. Patients diagnosed with Stargardt's dystrophy receive supportive treatment aimed at slowing the progression of the disease.

In some cases, the attending physician may prescribe taurine injections under eyeballs and physical therapy, such as low-energy infrared laser stimulation.

At the same time, scientists are actively developing a stem cell-based drug that can remove lipofuscin from retinal cells.

In recent years, gene therapy methods for this disease have also been actively studied. Gene therapy is based on the use of special viral vectors that introduce a healthy version of the ABCA4 gene into retinal cells, which leads to a slowdown in the accumulation of toxic lipofuscin. This technique is being researched by Oxford Biomedica, and is currently undergoing the first phase of clinical trials. It is important to understand that in this method not some harmful viruses are used, but, on the contrary, useful feature viruses effectively integrate into the genome.

Another treatment that is currently undergoing clinical trials is based on the use of modified vitamin A. Drugs based on it can slow down metabolism in the retina and, as a result, reduce the accumulation of toxic substances.

A method of retinal pigment epithelium transplantation is also at the testing stage.

All these methods have successfully passed the first phases of testing. It is likely that they will be approved in the coming years.

How to live with it

Modern medicine has sufficient tools for diagnosing Stargardt disease and supporting therapy.

It is important to understand that a person with such a diagnosis does not lose vision overnight and suddenly, this happens gradually. Therefore, you need to slow down this process as much as possible, using all available means: from wearing glasses with UV protection to following the individual instructions of your doctor.

In 2017, the Order of the Ministry of Labor and Social Protection of the Russian Federation dated June 13, 2017 No. 486n “On approval of the Procedure for the development and implementation of an individual rehabilitation or habilitation program for a disabled person, a disabled child, issued by federal government agencies medical and social examination, and their forms,” according to which you can get special magnifying devices for hereditary retinal dystrophy: a manual or stationary video magnifier, a device for reading audiobooks, a backlit magnifying glass. To get into this program, you must receive a doctor's referral from the bureau of medical and social examination and pass a commission.

Useful sites

http://looktosee.ru/- Interregional public organization “To see!” (information support and assistance to patients with hereditary retinal dystrophy and their families)
www.clinicaltrials.gov – database of private and public clinical trials conducted around the world
www.centerwatch.com – database of privately funded clinical trials

Stargardt's disease - dangerous disease, which occurs in medical practice quite rare. It can lead to complete loss 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 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, destruction 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 organs of vision, nerve tissues die, correct the situation with the help of glasses, contact lenses and even the methods of modern refractive surgery are impossible.

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:

Visometry - determination of visual acuity when a person looks into the distance (usually a special ophthalmological table with letters is used).
Tonometry - measurement of intraocular pressure.
Refractometry - assessment optical power organ of vision.
Study of color vision using special Rabkin ophthalmological tables.
Perimetry is a technique for studying a patient’s peripheral vision.
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.
Ophthalmoscopy - examination of the fundus, blood vessels and retina.
Electroretinography - an informative way to study functional state retina of the eye.
Campimetry - determination of the central field of vision.
Electrophysiological study - aimed at studying the functions of the retina, optic nerve, and assessing the condition of the cerebral cortex.
Fluorescein angiography is a technique for studying the vessels that supply the retina.
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).

There are yellowish or whitish spots in the macula area different sizes and forms. 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. The child can for a long time have good visual acuity and experience difficulties only due to 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:

Retinal revascularization;
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 a transplant does not avoid blindness - over the years dark spot is getting 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 resists well further development illness and helps improve visual acuity even when the patient sees the world around him very poorly.

Stargardt's macular dystrophy(Stargardt’s macular dystrophy, STGD) is the most common hereditary macular dystrophy, its incidence is 1 in 10,000; the disease is inherited in an autosomal recessive manner. Most cases present with decreased central vision early in the second decade of life. Typically, macular atrophy develops with yellow-white flocculent deposits at the level of the retinal pigment epithelium (RPE) in the posterior pole of the eye.

The shape of deposits can be round, oval, semi-lunar or fish-shaped (pisciform). The oval area of macular atrophy in the early stages may have a “wrought bronze” appearance. However, early in the disease, flocculent deposits may be absent and macular atrophy may be the only abnormality; but, as a rule, deposits appear later. The fundus flavimaculatus (FFM) pattern develops with the appearance of flocculent deposits in the absence of macular atrophy.

AND yellow-spotted fundus caused by mutations of the same gene; both types of changes can be observed in the same family. Most patients with fundus sallow subsequently develop macular atrophy.

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

In order to confirm the diagnosis, as an alternative to FA, an autofluorescence study is performed, which is based on recording the fluorescence of lipofuscin in the retinal pigment epithelium. Abnormal accumulation of lipofuscin, the presence of active and resorbable flocculent deposits and atrophy of the RPE - characteristic features, detected by autofluorescence studies. In children with deterioration of vision due to macular dysfunction and no changes in the fundus, FA is still informative; a subtle fenestrated defect in the center of the macular zone or a dark choroid helps confirm the diagnosis.

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

Yellow-white flocculent deposits at the level of the retinal pigment epithelium of the posterior pole.
Early-onset macular atrophy.

b) Electrophysiology. Electrophysiological changes in Stargardt disease are variable. An abnormal electrooculogram (EOG) is often recorded, indicating generalized retinal pigment epithelial dysfunction. Pattern electroretinogram (PERG) and focal electroretinogram are usually extinct or their amplitude is significantly reduced, indicating macular dysfunction. Ganzfeld-ERG at the time of diagnosis may not be changed (group 1) or indicate extensive damage to the retina (groups 2 and 3):
Group 1: severe pattern ERG abnormalities with normal ganzfeld ERG.
Group 2; additionally generalized cone dysfunction.
Group 3: generalized cone and rod dysfunction.

These groups do not depend on the age of onset of the disease or its duration; electrophysiological groups may represent different phenotypic subtypes and therefore may be informative in 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, a more severe decrease in visual acuity, a larger area of distribution of flocculent deposits and total macular atrophy are observed.

V) Molecular genetics and pathogenesis. The pathogenesis of Stargardt disease/spot fundus is based on mutations in the ABCA4 gene, which also cause the development of retinitis pigmentosa and cone-rod dystrophy. ABCA4 encodes the transmembrane rim protein of the discs of the outer segments of 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 the accumulation of the fluorophore lipofuscin, A2E (N-retinylidene-N-retnylethanolamine) in the retinal pigment epithelium, which causes its death and leads to secondary degeneration of photoreceptors.

More than 500 ABCA4 sequence variants have been described, demonstrating high allelic heterogeneity; As a result, identifying the pathogenic sequence of such a huge (50 exons) polymorphic gene poses significant difficulties. It is safe to predict that nonsense mutations that have a significant effect on the encoded protein will be pathogenic. The analysis of missense mutations poses great challenges because such sequence variants are often found in control samples; As a result, confirming the pathogenicity of an 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 disease, the ABCA4 Gly-1961Glu gene mutation 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 the development of the 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 variation.

Accumulation of lipofuscin metabolic products, including A2E, is observed in Stargardt disease and in ABCA4 knockout mice (abca4-/-); this leads to the formation of free radicals, release of proapoptotic mitochondrial proteins, and lysosomal dysfunction. As a result, dysfunction and death of retinal pigment epithelial 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 diet. It seems reasonable to recommend that patients with Stargardt disease avoid supplemental vitamin A intake and use dark sunglasses with ultraviolet filters. We also recommend a diet rich in antioxidants, which has been shown to slow photoreceptor death in animal models of retinal dystrophies. Affected children may need low vision care and educational support.

The patient's risk of having an affected child is 1% (this probability increases if the patient's partner is his close relative). The carriage rate of Stargardt disease is 1 in 50; the likelihood 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 for the treatment of Stargardt disease include drugs that act on the ATP-dependent transport mechanism, and thus accelerate ABCA4-dependent retinoid transport, or slow the visual cycle, reducing A2E production. Direct inhibition may be more effective toxic effects 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 lipofuscin accumulation, such as Best's disease.

Other treatment options include gene supplementation, cell therapy, or stem cell therapies, respectively targeting growth factor enhancement or retinal pigment epithelial cell/photoreceptor cell transplantation. Cell therapy/stem cell clinical trials are likely to be conducted soon.

Fluorescein angiogram; “dark choroid” and leakage points are visible.
For comparison, a photograph of the fundus is shown above.

A characteristic picture when examining fundus autofluorescence shows abnormal accumulation of lipofuscin,
active and resorbing flocculent deposits and RPE atrophy.
For comparison, a photograph of the fundus is shown (above).

Stargardt's disease. Spectral domain optical coherence tomography (SD-OCT),
There is a loss of the architectonics of the outer layers of the retina in the central zone of the macular region, with relative preservation of the structure of the retina in the peripheral zones of the macula.
In the area of the central fovea, destruction of the outer layers of the retina is visible.

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 as “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.

Locus determined by positional cloning disease-causing gene 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.

Wide range of phenotypic manifestations of Stargardt's dystrophy and age of diagnosis clinical signs(from the first to the seventh decade of life), observed even in one family, makes it difficult differential diagnosis and prognosis of changes in visual acuity. 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 last years The results of genetic studies are becoming 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 dark choroid and yellowish-white spots more diffusely scattered across the fundus, but no replacement for Glyl961Glu 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 genetic diseases retina, but also to search for possible therapy.

Clinical picture

line of sight

With fundus flavimaculatus, the visual field 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 in the diagnosis and differential diagnosis diseases of the macular region of the retina are the most informative.
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 evaluate the topic 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 identify 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 disease with preservation of the proximal layers of the retina.

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 survey results large group 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 at more pronounced changes 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 when the disease I-II stages in all examined patients the EOG was not changed (28/28), whereas in III-IV stages in 90% of patients it is subnormal. According to G.A. Fishman et al (1976 1977 1979), only in case of defeat pathological process large area of the retina, the EOG will 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

Clinical picture with some hereditary diseases may be similar to that of Stargardt's 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 histological examination of two eyes of a patient with typical disease Stargardt Type I, killed in a car accident, R.C. Eagl et al. (1980) found significant variability in the size of RPE cells - from 14 to 83 μm. Large cells RPE 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 more late stages Stargardt disease revealed the disappearance of most of the photoreceptors and RPE cells from the macular region of the retina. 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 multiple grayish or yellowish spots are visible between the fovea and the equator 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.