Stargardt's eye disease treatment. Modern possibilities of differential diagnosis of Stargardt's disease. Treatment and prognosis of Stargardt's disease

Stargardt's disease, which is a classic example of central pigment degeneration, was described by K. Stargardt (1909, 1913) at the beginning of the 20th century. as a hereditary disease of the macular region, manifested 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 macular degeneration in children was described as early as the 19th century.

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

If visual impairment due to typical dystrophic changes macula, begins in the first two decades of life, it is preferable to use the term "Stargardt's 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 a redistribution of pigment
• Oval lesions of the "snail track" type or bronze reflex, which may be surrounded by white-yellow spots.
• "Geographical" atrophy, may look like a "bull's eye".

Classification

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

Yes, 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 the lesion of the retina does not affect the foveal region.

genetic research

Stargardt's dystrophy is most commonly 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 III and IV types of Stargardt's disease.

Locus determined by positional cloning disease-causing gene for Stargardt's disease, expressed in photoreceptors, which was named ABCR. It has been shown that ABCR is identical in its sequence to the human RmP gene.

The RmP protein is an integral membrane glycoprotein with a molecular weight of 210 kDa, which is localized at the edge of the disks of the outer segments of visual cells. It has been shown that RmP belongs to the superfamily of ABC carriers of ATP-binding cassettes that stimulate ATP hydrolysis and affect the ATP-dependent movement of specific substrates across cell membranes.

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

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

Using immunofluorescence microscopy and Western blot analysis, it was shown that ABCR is present in foveal and perifoveal cones, and therefore it is believed 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 age-related non-exudative 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's disease. However, this statement is not supported by all researchers, although there is no doubt that the phenotypic and genotypic manifestations of Stargardt's disease and AMD are associated with mutations in the ABCR gene.

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

Thus, the results of recent genetic studies indicate that, despite the clear differences in the clinical picture of retinitis pigmentosa, Stargardt's 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 detection clinical signs(from the first to the seventh decade of life), observed even in one family, makes it difficult to differentiate and predict changes in visual acuity. Angiography data, medical history, reduced visual function, altered cone components in the ERG, specific changes in local and multifocal ERG help in making a diagnosis.

Thus, in last years more and more importance for diagnosis is attached to the results of genetic studies. Yes, G.A. Fishman et al. (1999), examining a large group of patients with Stargardt's dystrophy and fundus flavimaculatus with ABCR gene mutations, showed that the variability of phenotypic manifestations in a certain way depends on the variation of the specific amino acid sequence. According to the results of fluorescein angiography, ophthalmoscopy, electroretinographic and perimetric studies, they identified three disease phenotypes

• One of these phenotypes is characterized, along with atrophic lesions of 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 change in the sequence in exon 42 of the ABCR gene was found, which consists in the replacement of glycine with glutamine (Gly]961Glu).
• Another phenotype was characterized by a dark choroid and yellowish-white spots more diffusely scattered over the fundus, but no Glyl961Glu substitution was detected.
• In the phenotype with severe atrophic changes in RPE and reduced rod and cone ERG, the ABCR mutation was found only in 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 and about the prognosis of visual acuity.

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

Clinical picture

line of sight

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

color vision

Most patients with Stargardt's disease type I have deuteranopia; in type II Stargardt's disease, color vision disorders are more pronounced and cannot be classified. The type of color anomaly seems to depend on which type of cones is predominantly involved in the pathological process, therefore, with fundus flavimaculatus, color vision may not be changed, or red-green dichromasia is noted.

Dark adaptation

According to O. Gelisken, J.J. De Jaey (1985), out of 43 patients with Stargardt's 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

With Stargardt's dystrophy, it is changed over 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 - a pattern of cone dystrophy.

Contrast sensitivity , on- and off-activity of the cone system, estimated 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 of 10° from the center.

Electroretinography and electrooculography

Of the electrophysiological methods, electroretinography and electrooculography in the diagnosis and differential diagnosis of diseases of the macular area 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 methods of electroretinography allows us to evaluate the topic functional disorders in the retina at the level of its various layers and divisions.

So, when registering a local ERG (LERG) using an LED mounted in a suction cup lens, the biopotentials of the macular region are subnormal already in initial stage dystrophy of Stargardt in contrast to the normal amplitudes of the ganzfeld-ERG. As the process progresses, LERG 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 20/20 - 20/30.

The use of zonal electroretinography made it possible to reveal the 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 sections in early stages Stargardt's disease with the preservation of the proximal layers of the retina.

A decrease in the amplitudes of a- and 1a ERG waves in different areas of the retina (center, paracenter, 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 components of the ERG.

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

According to P. A. Blacharski (1988), after prolonged dark adaptation (45 min), in patients with fundus flavimaculatus, a greater (by 29%) degree of reduction in the photopic components of the ERG is noted than in healthy individuals. The responses of the scotopic ERG decrease slightly, by only 6-10%. According to J. B. M. Moloney et al. (1983), an increase in the cone ERG is 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 survey of a large group of patients with Stargardt's 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 distinguished according to the stages of the disease: 1-4. The average amplitudes of all ERG components turned out to be below normal values ​​with more pronounced changes in the retinal cone system. Photopic b-wave was 57.4% of the norm, scotopic b-wave - 77.9%, responses to the "white" flickering stimulus 32 Hz - 78.9%, a-wave - 87.7%, b-wave - 95.8% of the norm. The greatest decrease in all ERG components was observed in patients of group 3.

Timing parameters have also been changed; elongation 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 EOG coefficient (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 RPE in fundus flavimaculatus and a further lesion of 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 in terms of the Arden coefficient: in 75-80% of patients with FF. It should be taken into account that most publications present the results of examinations of a few groups of patients: from 3 to 29.

G.A. Fishman (1976, 1979) correlated the stages of fundus flavimaculatus with EOG results. He showed that in the disease of stages I-II, the EOG was not changed in all examined patients (28/28), while in stages III-IV, it was subnormal in 90% of patients. 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 the results of the studies 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 assess the state of RPE, rather than help in the differential diagnosis of Stargardt's disease and fundus flavimaculatus.

Differential Diagnosis

The clinical picture in some hereditary diseases may be similar to that in 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 are also described in non-hereditary diseases, such as chloroquine retinopathy or ocular manifestations of severe toxicosis of pregnant women.

On the basis of differences in the picture of the fundus, age, onset of the disease, data from functional research methods, S. Merin (1993) identified two main types of Stargardt's disease.

Stargardt disease type I

This type is most consistent with the originally described Stargardt's disease. This is juvenile hereditary macular degeneration, the clinical manifestations of which are observed in children as early as the age of 6-12 years. Boys and girls get sick with the same 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 an accumulation in the center of a 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, fluorescein-impervious center is surrounded by a wide ring of hypofluorescent dots, usually followed by another ring of hyperpigmentation. This pattern 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 acid mucopolysaccharides in 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's disease.

As the disease progresses, visual acuity decreases, resulting in low vision. If in the early stages of the disease ERG and EOG remain normal in the advanced stages, the responses of the cone system according to ERG data decrease and EOG indicators become moderately subnormal. In connection with the defeat of the predominantly cone system in patients, color vision is also impaired, more often by the type of deuteranopia.

In 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. Eagle et al. (1980) found a significant variability in the size of RPE cells - from 14 to 83 microns. Large RPE cells formed a granular substance, which corresponded to pathological (abnormal) lipofuscin in terms of ultrastructure, autofluorescence, and histochemical properties. The amount of melanin was reduced and the melanin granules were shifted towards the inside of the cell

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

F. Schutt et al. (2000) showed that in diseases of the retina associated with intensive accumulation of lipofuscin, including Stargardt's disease, AMD and aging of the retina, the retinoid fluorescent component of lipofuscin A2-E (N-retinylidene-N-retinyl -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, 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 area of ​​the retina, there are multiple and widespread FF spots on 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's disease occurs more slowly and, as a result, patients turn to the ophthalmologist later. Due to the fact that in Stargardt's disease type II there are more changes that go beyond the boundaries of the macular region, electrophysiological data differ from those in type I.

So, in the ERG, the responses of the rod system are significantly reduced. EOG parameters also changed in more. Availability in high percentage cases outside the macular area (macula) of yellowish spots make it difficult to clearly distinguish between Stargardt's disease and FF.

Fundus flavimaculatus

As a rule, fundus flavimaculatus, or yellow-spotted fundus, is combined with Stargardt's disease and is not common as an isolated form of retinal disease. In typical ("clean") cases, patients have practically no symptoms of the disease. Visual acuity, color vision, field of view are within normal limits. Dark adaptation may be normal or slightly reduced. On the fundus, the macula and the periphery of the retina are unchanged, only between the fovea and the equator are multiple grayish or yellowish spots visible various shapes: rounded, oval, elongated, in the form of a comma or fish tail, which can merge or be located separately from each other, be small - 200-300 microns or 3-5 times larger. Under dynamic observation, the color, shape, size of these spots can change. The spots, initially yellowish and well-defined, may become gray with indistinct borders or disappear after a few years.

In parallel, the picture revealed by fluorescein angiography becomes different: areas with hyperfluorescence become hypofluorescent. At subsequent stages of the development of the disease, RPE atrophy manifests itself as the disappearance of individual spots and their replacement by irregular areas of hypofluorescence.
Similar changes in spots in fundus flavimaculatus (FF) are characteristic of both types of Stargardt's disease, however, in 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 supposed, but in some cases it is not possible to establish the hereditary nature of this pathology.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other avenues of therapy include gene supplementation, cell therapy, or stem cell therapies aimed at boosting growth factors or transplanting retinal pigment epithelial cells/photoreceptors, respectively. Cell therapy/stem cell clinical trials are likely to take place soon.

Stargardt's disease provokes a degenerative process in the macula. There are many diseases, the clinic of which is similar to this pathology. They are caused by mutations in various genes. Therefore, the disease is classified as a hereditary pathology.

Main clinical manifestation disease is a degenerative process in the macula, as well as central pigment retinitis, causing visual loss with the development of central scotoma.

Features of the disease

Stargardt's disease is one of the rare but very serious pathologies. It manifests itself at a young age - from 6 to 20 years old with a frequency of 1: 20,000 people. In other age categories, pathology, as a rule, does not occur. The consequences of the disease are catastrophic. Complete loss of vision is not ruled out.

The disease has a genetic basis. The dystrophic process affects the macular region and originates in the area of ​​the pigment epithelium, which leads to loss of vision. The process is two-way.

Forms of pathology

There is a clear distinction between pathology into four types, depending on the area of ​​localization of the inflammation zone:

The degenerative process can be marked:

• in the middle peripheral zone;
• in the macular area;
• in the paracentral zone.

There is also a mixed form of the disease, which involves the localization of inflammation in the central part of the eyes and on the periphery.

Mechanisms of disease development

The causes of the disease were described by the doctor K. Stargardt in the first half of the 20th century. The disease is named after him. Pathology is related to the macular region and, according to the scientist, is inherited within the same family. Usually, a polymorphic ophthalmoscopic picture is indicated, which is called "broken bronze atrophy", etc.

Through positional cloning, the main locus of the gene was identified, which causes the most pronounced in photoreceptors. In science, he received the name ABCR.

The basis of therapy is the use of stem cells from the adipose tissue of a diseased person. Therapeutic method was developed earlier by the scientist V.P. Filatov. Thanks to innovative technology patients are given the opportunity to restore lost vision and ensure a full life.

Dr. A. D. Romashchenko registered a set of technologies in the field of biomedicine and patented the following methods:

• combined method of eliminating the wet form of the disease;
• complex method of pathogenetic therapy of central and tapetoretinal dystrophy.

In which clinic is the treatment carried out?

Treatment of the most complex disease ophthalmological center"He Clinic." The center is located in a city like St. Petersburg. It is possible to treat Stargardt's disease only in this center, as it is the only one in Russia where such technology is used.

Is stem cell therapy safe?

Experts can confidently confirm that therapy according to the technology developed by A. D. Romashchenko is absolutely safe. For therapy, the patient's cells are used, which eliminates the possibility of their rejection or the development of other negative consequences.

Conclusion

Stargradt's disease debuts in early age and quickly leads to complete loss of vision. In very rare cases, when inherited according to the dominant type, vision falls at a slow pace. Patients are advised to visit an ophthalmologist, take vitamins and wear sunglasses. Stem cell therapy is considered the most effective way to eliminate pathology.

- a hereditary disease of the retina, which is manifested by dystrophic changes in its macular zone and leads to loss of central vision. The onset of the disease occurs in childhood or adolescence. Patients present with central scotomas and color vision disorders. The progression of Stargardt's disease leads to complete blindness. Diagnosis is carried out using ophthalmoscopy, fluorescein angiography and retinal EFI. Used for treatment injection therapy(vitamins, antioxidants, angioprotectors), physiotherapy, revascularization surgeries are being carried out, 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 of the visual analyzer. The disease was described by the German ophthalmologist Karl Stargardt at the beginning of the 20th 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: "atrophy of the choroid", "bull's eye", "broken (forged) bronze". Pathogenetic name of the pathology - “yellow-spotted retinal abiotrophy" - reflects changes in the fundus area.

In 1997, geneticists discovered a mutation in the ABCR gene, causing violation production of a protein that should carry energy to photoreceptor cells. Inferiority of the ATP transporter leads to the death of photoreceptors in the retina. Different kinds hereditary macular degeneration occurs in 50% of cases of eye pathology. Of these, Stargardt's 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 a social significance, because it leads to disability at a young age.

Causes of the development of Stargardt's disease

Inheritance does not depend on the gender of the patient and parents. Pathology is transmitted mainly by an autosomal recessive type, that is, the inheritance of the pathology is not associated with sex (autosomal - associated with non-sex chromosomes) and is not always transmitted to the future generation (recessive inheritance). According to the latest data from geneticists, the pathology of a gene can also be transmitted according to the dominant type. With a dominant type of inheritance of defects in the gene - the controller of the synthesis of the ATP transporter protein - the disease proceeds more easily and rarely leads to disability. Most of the receptor cells of the macula (top) of the macula of the fundus are functioning. In patients with a dominant type of inheritance, the disease proceeds with a minimum of manifestations. Patients remain able to work and can even drive vehicles.

The main cause of macular cell degeneration is that they suffer from energy deficiency. The gene defect leads to the synthesis of an incomplete protein that transports ATP molecules through the cell membrane of the macula - the center of the retina, in which the graphic and color image is focused. No macular area blood vessels. The cone cells are powered by ATP carrier proteins from the nearby choroid (choroid). Proteins transport ATP molecules through the membrane into cone cells.

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

Classification of Stargardt's disease

Types of the disease depend on the prevalence of the zone of damage to the macula. In ophthalmology, the following forms of Stargardt's disease are distinguished: central, pericentral, centroperipheral (mixed). In the central form, cells in the center of the macula are affected. This is expressed in the loss of central vision. The patient develops a central scotoma (from the Greek "skotos" - darkness). The central zone falls out of sight. The patient sees an image with a dark spot at the point of gaze fixation.

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 dropouts in one of the sides from the center of the field of view in the form of a crescent. Over time, the scotoma takes the form of a dark ring. The centro-peripheral form starts from the center and rapidly spreads to the periphery. dark spot grows and completely covers the field of view.

Symptoms of Stargardt's 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 gamut. Many patients have a violation of color vision of the type of 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 of peripheral vision do not change; with progression, the central scotomas expand, which leads to complete blindness. Simultaneously with the appearance of loss of central vision, its sharpness decreases. In the final stage of Stargardt's disease optic nerve atrophies. The person loses his sight completely. There are no changes in other organs, both in the initial and in the terminal stages of the disease.

Diagnosis of Stargardt's disease

The disease starts at childhood is one of the main features for differential diagnosis. With the help of ophthalmoscopy, a wide ring of reduced pigmentation is found that surrounds the dark center. Around the pale ring, the next ring of hyperpigmented cells is noted. The painting is reminiscent of "bull's eye" or "wrought bronze". Foveolar reflex is negative. Macular elevation is not defined. When examining the macula, yellowish-white spots of various sizes and configurations are noted. Over time, the boundaries of the inclusions are blurred, the spots acquire a gray tint or completely disappear.

During perimetry in Stangardt's disease, positive or negative (the patient does not feel them) central scotomas are noted. With the central form of the disease, red-green deuteranopia develops. The peripheral form is not characterized by a violation of color perception. Spatial contrast sensitivity changes over the entire range: it is absent in the high frequency region (in the central region up to 6-10 degrees) and decreases in the medium frequency region.

In the initial stage of the disease, there is a decrease in macular electrography 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 are reduced to subnormal. The disease is asymptomatic - without impaired visual acuity and color perception. The boundaries of the visual field are within the normal range. Dark adaptation is slightly reduced.

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

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

Treatment and prognosis of Stargardt's disease

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

Stargardt's disease begins at an early age and quickly leads to visual impairment. In rare cases, with a dominant type of inheritance, vision falls slowly. Patients are advised to see an ophthalmologist vitamin complexes and wearing sunglasses.

Juvenile macular degeneration or Stargardt's disease is a type of hereditary macular degeneration of the retina. The disease is detected at 12-20 years of age and is manifested by a progressive decrease in visual acuity in both eyes.

Depending on the location of the pathology, it is customary to distinguish 4 forms of juvenile macular degeneration:

• In the area of ​​the macula;
• On the middle periphery;
• In the paracentral region;
• In the central and peripheral regions (mixed form).

Genetic studies currently underway prove that juvenile macular degeneration and Franceschetti's disease (yellow-spotted fundus) are phenotypic features of the same disease.

Causes

The disease is transmitted in an autosomal recessive way of inheritance, rarely autosomal dominant. Major locus identified by positional cloning for juvenile macular degeneration disease-causing gene. It is expressed in photoreceptors and is called ABCR. ABCR is a member of the so-called superfamily. ATP-binding cassette transporter, identical in sequence to the human RmP gene.

With an autosomal dominant inheritance of the disease, the localization of mutation genes in chromosomes 13q, as well as 6q14, was determined. It was revealed that ABCR mutations are present in a subpopulation of patients with non-exudative form of macular degeneration associated with age and cone-rod degeneration, which suggests a genetically determined risk of developing AMD in blood relatives of patients.

Video of our specialist about the disease

Symptoms of the disease

In the pigment epithelium retina eyes there is an intense accumulation of lipofuscin. The process is accompanied by a weakening of the oxidative function of lysosomes, with an increase in pH in the cells of the pigment epithelium, which leads to a change in their membrane integrity.

With the central form of juvenile dystrophy, as the disease develops, the ophthalmoscopic picture of the macula area has next view: "broken metal", then "bull's eye", then "forged bronze" and, as a result, atrophy of the choroid.

Ophthalmoscopy at the stage of the "bull's eye" phenomenon reveals a dark center, which is surrounded by a wide ring of hypopigmentation and, following it, another ring of hyperpigmentation. The retinal vessels are unchanged, the optic disc is pale on the temporal side, which is due to atrophy of the nerve fibers of the papillomacular bundle. The foveolar reflex is absent, as is macular elevation.

The presence of yellowish-white spots is found in the retinal pigment epithelium of the posterior pole of the eye. The spots have a different size, shape and configuration - this is the most characteristic symptom yellow-spotted fundus. Over time, the shape, color and size of the spots may change. Initially yellowish spots, with clearly defined edges, often become gray after a few years, their borders are smeared or disappear.

Diagnosis of the disease

In the process of collecting an anamnesis, it turns out the time of onset of the disease (age of manifestation), which plays an important role in diagnosis.

With laboratory histological studies in the central region of the fundus, an increase in pigment, atrophy of the adjacent retinal pigment epithelium, combined atrophy and hypertrophy of the pigment epithelium are noted. Representation of yellow spots by lipofuscin-like material.

During instrumental research, with perimetry in patients with juvenile macular degeneration, relative or absolute central scotomas of different sizes are found, which depends on the timing of the process and its prevalence - from early childhood or adolescence. In the case of a yellow-spotted fundus, there are no changes in the macula, the field of view is often not changed.

Color anomalies in most patients with a central localization of the pathological process develop as deuteranopia or red-green dyschromasia, often more pronounced.

Color vision in the case of a yellow-spotted fundus may not change. Spatial contrast sensitivity is significantly changed in all ranges of spatial frequencies, significantly reduced in the middle zone and completely absent in the zone of high spatial frequencies (the so-called pattern-cone dystrophy). Contrast sensitivity is absent in the central zone of the retina within 6-10 degrees.

Visual acuity, visual field and color vision are normal. Dark adaptation is usually normal or slightly reduced.

On FAG, in the case of a typical "bull's eye" phenomenon, with a normal background, zones of "absence" or in some cases gynofluorescence are revealed, with the presence of visible choriocapillaries, as well as a "dark" or "silent" choroid. The absence of fluorescence in the macular area is explained by the accumulation of lipofuscin, which shields fluorescein. Areas with hypofluorescence sometimes become hyperfluorescent in accordance with areas of atrophy of the pigment epithelial layer.

Differential Diagnosis

Diagnosis is seriously hampered by the similarity of the clinical picture of many degenerative diseases in the macula. The differential diagnosis of juvenile macular degeneration is carried out with familial drusen, Kandori retinal spots, progressive dominant foveal dystrophy; juvenile retinoschisis; cone, cone-rod, rod-cone dystrophies; vitelliform macular degeneration; medicinal dystrophies.

Treatment and prognosis

To date, there is no pathogenetically substantiated treatment for juvenile macular degeneration. It is necessary to constantly monitor a specialist, control the field of view, monitor ERG, EOG.