Inherited retinal dystrophies: clinical guidelines

List of Abbreviations

ICD-10 — International Classification of Diseases 10th Revision

IRD — Inherited Retinal Diseases

IRD — Inherited Retinal Dystrophies

RP — Retinitis Pigmentosa

SD — Stargardt Disease

BD — Best Disease

LCA — Leber Congenital Amaurosis

CD — Cone Dystrophy

CRD – cone-rod dystrophy

US – Usher syndrome

ERG – electroretinogram

EOG – electrooculogram

OCT – optical coherence tomography

FA - fluorescein angiography

ONH – optic nerve head

CME – cystoid macular edema

CNV – choroidal neovascularization

RPE – retinal pigment epithelium

AD – autosomal dominant

AR – autosomal recessive

XL – X-linked inheritance

BCVA – best-corrected visual acuity

Terms and Definitions

Inherited retinal dystrophies (IRDs) – an extensive group of phenotypically and genetically heterogeneous retinal disorders characterized by a progressive course leading to impaired visual function, up to blindness.

Retinitis pigmentosa (RP) – a clinically and genetically heterogeneous group of inherited retinal diseases characterized by diffuse progressive degeneration predominantly of rod photoreceptors, followed by subsequent degeneration of cone photoreceptors and the retinal pigment epithelium (RPE).

Juvenile macular dystrophy – a group of inherited disorders of the central retina manifesting in the 1st–2nd decade of life.

Stargardt disease (SD) – the most common form of juvenile macular dystrophies, most frequently with an autosomal recessive inheritance pattern.

Bestrophinopathy – a heterogeneous group of central retinal dystrophies caused by alterations in genes belonging to the bestrophin family, the most common of which is BEST1.

Best disease (BD) – vitelliform macular dystrophy, classified among bestrophinopathies with an autosomal dominant inheritance pattern, characterized in childhood by the appearance of a yellow or orange vitelliform lesion in the macular area. The disease has a staged course progressing over several years with progressive visual impairment. A distinctive feature of the disorder is a markedly abnormal electrooculogram (EOG) across all disease stages.

Leber congenital amaurosis (LCA) – a genetically heterogeneous group of inherited retinal disorders manifesting at birth (frequently) or in early childhood (rarely), with primary involvement of the rod system, leading to significant vision loss at an early age. Characteristic features of the pathology include a combination of nystagmus (typically roving), sluggish or nearly absent pupillary light reflexes, photophobia, and the oculo-digital sign. Given its etiopathogenesis, LCA is one of the leading causes of visual disability in early childhood among patients with IRDs.

Cone dystrophy (CD) and cone-rod dystrophy (CRD) – a genetically heterogeneous group of IRDs characterized exclusively (CD) or primarily (CRD) by pathological changes in retinal cone photoreceptors.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Inherited retinal dystrophies (IRDs) are an extensive group of phenotypically and genetically heterogeneous retinal disorders with a progressive course leading to impaired visual function, up to blindness. Some IRDs are characterized by slow progression with a late onset, whereas others exhibit rapid progression and early onset (infancy/early childhood). IRDs can be divided into isolated and syndromic forms involving other organ systems. This group of disorders can exhibit any inheritance pattern: autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), or digenic.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Over 260 genes are associated with various retinal disorders, the vast majority of which are linked to IRDs [1]. IRDs are characterized by genetic heterogeneity and clinical polymorphism. Thus, mutations in a single gene can cause different forms of IRDs, while similarly, comparable phenotypic manifestations can result from mutations in different genes. The pathogenetic mechanisms of IRDs are extremely diverse and depend on the affected gene(s) and mutation type.

According to the International Classification of Diseases, 10th Revision (ICD-10), in the clinical practice of ophthalmologists, the following main IRDs are distinguished [2–4]:

1. Retinitis pigmentosa (RP)

2. Stargardt disease (SD)

3. Vitelliform macular dystrophies (bestrophinopathies, including Best disease (BD))

4. Leber congenital amaurosis (LCA)

5. Cone dystrophy (CD) and cone-rod dystrophy (CRD)

Etiology and pathogenesis of RP

The etiological factor of RP, classified among isolated inherited disorders, is the presence of pathological nucleotide sequences (mutations) in one of more than 100 genes [5]. Genes causing RP can be categorized into those affecting the phototransduction cascade, the retinoid cycle, photoreceptor structure, or other biological functions of photoreceptors and the retinal pigment epithelium (RPE) [6]. Patients with the same genetic defect may exhibit varying degrees of disease severity at a given age. Despite advances in molecular genetic diagnostics, approximately 30% of cases are considered to be of unclear etiology [7, 8]. Retinitis pigmentosa can have autosomal recessive (frequently), autosomal dominant (less frequently), and X-linked (rarely) inheritance patterns.

Etiology and pathogenesis of SD

SD is a genetically heterogeneous disorder caused in the majority of cases by mutations in the ABCA4 gene. The disease can have autosomal recessive (frequently) and autosomal dominant (rarely) inheritance. The ABCA4 protein, encoded by the gene of the same name, belongs to the large family of transmembrane ATP-binding cassette transporters and is a retina-specific membrane protein expressed in the discs of the outer segments of rod and cone photoreceptors. This protein utilizes ATP energy to transport N-retinylidene-phosphatidylethanolamine (A2E), which is involved in retinoid recycling and plays a vital role in the visual cycle. Accumulation of A2E in the RPE causes damage to the RPE itself, leading to secondary alteration and death of photoreceptors [9]. Pathogenic alterations in the PROM1 gene are an etiological factor for Stargardt disease with an autosomal dominant inheritance pattern. Currently, mutations in the ELOVL4 gene are associated with the onset of autosomal dominant Stargardt-like retinal dystrophy. More than 900 different mutations in the ABCA4 gene have been described, including missense, nonsense, splice site mutations, deep intronic mutations, and frameshift deletions, which have been shown to correlate with retinal degenerations [10].

Etiology and pathogenesis of bestrophinopathies

Mutations in the BEST1 gene are associated with a growing number of inherited ophthalmic disorders collectively termed "bestrophinopathies" [11]. More than 200 mutations in BEST1 are known to cause at least 5 IRDs, including Best vitelliform macular dystrophy (BVMD), autosomal recessive bestrophinopathy (ARB), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC).

Leber congenital amaurosis (LCA) – a genetically heterogeneous group of inherited retinal disorders manifesting at birth (frequently) or in early childhood (rarely), with primary involvement of the rod system, leading to significant vision loss at an early age. The disease most commonly exhibits an autosomal recessive inheritance pattern, although autosomal dominant variants also exist.

Characteristic features of the pathology include a combination of nystagmus (typically roving), sluggish or nearly absent pupillary light reflexes, photophobia, and the oculo-digital sign. Given its etiopathogenesis, LCA is one of the leading causes of visual disability in early childhood among patients with IRDs.

Twenty-four clinical and genetic forms have been established. Major genes (GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, NMNAT1, CEP290, IMPDH1, RD3, RDH12, LRAT, TULP1, KCNJ13) associated with this group of disorders play a crucial role in several pathways of retinal development and physiology. It is currently known that alterations in the CEP290 (15%), GUCY2D (12%), CRB1 (10%), and RPE65 (8%) genes are the most frequent causes of LCA [12, 13]. Mutations in target genes disrupt phototransduction (GUCY2D, AIPL1), photoreceptor development and structure (CRB1, CRX), the retinoid cycle (RDH12, LRAT, RPE65), and protein transport through photoreceptor cilia (TULP1, RPGRIP1, CEP290). One of the pathogenetic mechanisms of LCA is linked to impaired phototransduction due to disruption of the visual cycle.

The visual cycle is a series of enzymatic reactions between the RPE and the neurosensory retina aimed at metabolizing dietary vitamin A into 11-cis-retinal to form a photopigment. Without 11-cis-retinal, the phototransduction cascade cannot be initiated; thus, visual neuronal signals are not transmitted to the visual cortex. A functional mutation in any of the genes encoding proteins that catalyze any of the enzymatic reactions producing 11-cis-retinal can block the visual cycle and lead to LCA symptoms. The link between congenital vitamin A metabolic disorders in the retina and photoreceptor degeneration remains controversial and is currently an active area of biomedical research.

Etiology and pathogenesis of CD and CORD. CD and CORD are a genetically heterogeneous group of inherited retinal diseases with autosomal dominant, autosomal recessive, or X-linked inheritance patterns. In cone dystrophies, only the retinal cone system is involved in the pathological process, whereas in cone-rod dystrophies, the rod system is also secondarily affected [14]. Most CD and CORD genes encode photoreceptor structural proteins or proteins involved in phototransduction. There are 6 known genes causing predominantly CD (CACNA2D4, CNGB3, PDE6C, PDE6H, OPN1LW, OPN1MW) and more than 30 genes causing CORD. At least 10 genes (most commonly GUCY2D, CRX) cause AD inheritance, and at least 2 (RPGR, CACNA1F) cause X-linked recessive inheritance. Furthermore, a number of genes (GUCA1A, ABCA4, CNGA3, RPGR) are associated with the development of both CD and CORD.

1.3 Epidemiology of the Disease or Condition

Although IRDs are classified as rare (orphan) diseases, they are socially significant due to profound visual impairment and disability in children and working-age individuals.

RP occurs with a frequency of 1:3000 to 1:5000 [15] and is a leading cause of visual impairment and blindness affecting more than 1.5 million patients worldwide.

Stargardt disease (STGD) occurs with a frequency of 1:8000 to 1:10000.

STGD accounts for approximately 7% of all retinal degenerations [16]. STGD is the most frequent inherited AR childhood macular dystrophy.

Bestrophinopathies (vitelliform dystrophies) – the prevalence of BD is 1:5000 to 1:6700 [17]. The prevalence of adult-onset vitelliform macular dystrophy is 1:7400 to 1:8200 [17].

Leber congenital amaurosis – prevalence ranges from 1:30000 to 1:81000. This condition is the most common cause of inherited childhood blindness and accounts for more than 5% of all childhood retinal dystrophies. LCA is the cause of blindness in more than 20% of children attending schools for the blind and visually impaired.

Cone and cone-rod dystrophies. Prevalence is estimated at 1:40000 [14].

1.4 Features of Coding the Disease or Condition

H35.5 – Hereditary retinal dystrophies

1.5 Classification of the disease or condition

Based on etiopathogenesis, the clinical presentation of IRDs, and literature data, it is currently advisable to systematize the group of diseases in question as follows (adapted from Berger, 7):

1) dystrophies with a predominance of rod photoreceptor dysfunction over cone dysfunction. Dystrophies with predominant rod dysfunction include the most common ones – retinitis pigmentosa and rod-cone dystrophy. Retinitis pigmentosa is the cause of low vision or blindness in 1.5 million patients. This group also includes Leber congenital amaurosis (LCA), early-onset severe retinal dystrophy (EOSRD), and early childhood-onset severe retinal dystrophy (SECORD) with congenital or early impairment of visual functions.

2) dystrophies with a predominance of cone photoreceptor dysfunction over rod dysfunction (including hereditary macular dystrophies). Degenerations with predominant cone dysfunction include cone and cone-rod dystrophies; this group also includes macular degenerations (Stargardt disease, Best disease, etc.).

Retinal dystrophies can be nonsyndromic, or isolated, and syndromic involving other organ systems (Usher syndrome, Laurence-Moon-Bardet-Biedl syndrome, etc.).

1.6 Clinical presentation of the disease or condition

Clinical manifestations of RP – Visual disturbances usually manifest as nyctalopia and progressive visual field loss, which are caused by damage to the retinal rod system. The clinical presentation is represented by the classic "triad": pigmentary changes in the retina (which may be hypopigmentation and/or hyperpigmentation in the form of "bone-spicule" pigment clumps), arteriolar attenuation, and "waxy" optic disc pallor. Characteristic pigmentary changes occur in the mid-periphery of the fundus, which is predominantly populated by rods; the fundus changes are symmetrical [2,4,6]. In some patients, complications of RP include posterior subcapsular cataract (45%), cystoid macular edema (CME) (10–50%), and epiretinal membrane (ERM) formation [6,18].

It must be taken into account that RP can be part of a syndromic condition, including Usher syndrome, Bardet-Biedl syndrome, neuronal ceroid lipofuscinosis (Batten disease), Refsum disease (polyneuritiform hemeralopic heredoataxia), abetalipoproteinemia (Bassen-Kornzweig disease), familial juvenile nephronophthisis (Senior-Løken syndrome), and several others.

Age of onset and rate of progression: visual function impairment manifests as defects in the mid-periphery of the visual field at a young age. However, the onset of RP often occurs in adolescence.

Clinical manifestations of STGD. STGD is characterized by bilateral central vision loss with the presence of absolute/relative polymorphic scotomas. Visual deterioration progresses rapidly. Visual acuity can range from 1.0 to 0.005, with very few patients experiencing vision reduction to hand motion in front of the face. Peripheral vision is usually spared, and color vision is impaired. Symptoms first appear in the 1st-2nd decade of life. As a rule, with normal functional activity of the peripheral retina, atrophic lesions are detected in the macula. A characteristic feature of the fundus is yellowish flecks that may be located around the fovea, restricted to the macular area, or occupy the entire posterior pole within the vascular arcades or extend up to the equator. The size of the flecks varies from 100 to 200 µm, with varying degrees of border definition. As the disease progresses, the flecks may merge and disappear, leaving areas of RPE and choriocapillaris atrophy. Visual prognosis depends on the age of disease onset, with patients having significantly reduced vision at an earlier age having a worse prognosis [2,4,19].

Flecked retina syndrome is a rare form of IRD, appearing in adults in the absence of macular changes, and may be asymptomatic and an incidental finding during an ophthalmological examination. Visual acuity and color vision are impaired only when macular changes occur [2,4,19].

Clinical manifestations of BD

Best disease has 6 clinical stages [2,4,20]:

Stage I (Previtelliform): normal vision, normal or only minor RPE changes with abnormal EOG.

Stage II (Vitelliform-yellow): classic "egg-yolk" lesion. 30% have ectopic lesions. Normal vision or slight vision loss.

Stage III (Pseudohypopyon): redistribution of lipofuscin. Vision is the same as in Stage II.

Stage IV (Vitelliform disease): breakdown of material gives the focus a "scrambled-egg" appearance. Vision may be similar or slightly reduced compared to Stages I–III.

Stage V (Atrophic): central RPE and retinal atrophy. Vision may range from 0.6 to 0.1.

Stage VI (CNV): this complication occurs in approximately 20% of patients. Vision often drops to 0.1 or lower.

Up to 30% of patients may have multiple lesions – so-called multifocal BD. In this case, the lesions are localized in the fovea and extrafoveally, typically being smaller in size and tending to be located more superiorly in the macula [21]. BD is most commonly a bilateral process, though monocular involvement also occurs. Starting from the pseudohypopyon stage, BD can be complicated by the development of CNV (5–91%), and in rare cases, macular hole formation is observed.

In the adult-onset variant of the disease (AVMD), multiple small lesions located both in the macula and extramacularly are more frequently observed.

Clinical manifestations of LCA.

LCA is a group of genetically heterogeneous hereditary retinal disorders, mainly characterized by a marked decrease in visual functions from infancy, although there is variability depending on the genetic form [13, 22]. LCA is characterized by at least three features: severe and early impairment of visual functions, sluggish or absent pupillary responses, and a sharply subnormal or non-recordable ERG. It can be suspected in early childhood or infancy in children with nystagmus, pupils poorly responsive to light, and a non-recordable ERG, sometimes accompanied by the "oculodigital sign"; at the same time, ophthalmoscopic changes may be absent and manifest later as abnormal pigmentation, "mottled" fundus, atrophic areas, and waxy pallor of the optic disc. The diagnosis in this disease is clinical and requires molecular genetic verification of the genetic form. Confirmation of the clinical and genetic form of the disease is based on funduscopy, ERG, OCT findings, and molecular genetic testing.

Retinal changes are not a pathognomonic sign specific to a particular subtype. Photophobia, nyctalopia, and decreased visual functions (usually ranging from 0.1 to complete blindness) are also characteristic of LCA.

In rare cases, keratoconus may occur [23].

Clinical Manifestations of CD and CCOD

The initial symptoms of these diseases are decreased visual acuity, photophobia, impaired color vision, and possible nystagmus. CD and CCOD more frequently debut in childhood; however, similarly to progressive CD, the age of onset, rate of progression, and severity vary widely even within the same genotype, which characterizes clinical polymorphism. Nyctalopia appears later in the course of the disease when the rod system becomes involved.

The fundus appearance in early-stage CD and CCOD is normal or shows slight temporal optic disc (OD) pallor. As the disease progresses, pigment "migration" and atrophy in the macula are observed, presenting as a "beaten bronze" appearance, geographic atrophy, or a "bull's-eye" maculopathy, along with arterial attenuation and OD pallor. In rod involvement, peripheral changes similar to RP are seen.

Visual acuity varies; in severe disease courses during middle age, low vision (i.e., BCVA below 0.05) may develop, which occurs earlier than in RP.

CD and CCOD are less likely than RP to be part of a syndrome.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Comments: The diagnosis of inherited retinal dystrophies (IRD) is established based on complaints, medical history, and clinical ophthalmological examination results, which include a set of standard and highly informative additional diagnostic methods, as well as molecular genetic testing results (next-generation sequencing [NGS], direct Sanger sequencing). A complete ophthalmological examination includes visometry, tonometry, biomicroscopy, and ophthalmoscopy, along with optical coherence tomography (OCT) of the macular area and perimetry. Fundus biomicrophotography is performed. In some patients, fundus examination is impossible (due to media opacities caused by lens changes) or limited due to pronounced nystagmus. Mandatory electrophysiological testing includes electroretinography (maximal [panretinal, rod-cone] ERG). If macular changes are present, macular [local] ERG or multifocal ERG [mfERG], or pattern ERG if possible, is performed.

2.1 Complaints and Anamnesis

Comments:

In patients with RP, initial complaints include difficulty with dark adaptation and night blindness (nyctalopia), along with complaints of visual field loss. As a rule, when the patient reaches middle age, degeneration of central cones leads to decreased visual acuity. One of the complaints in patients with RP may be photopsia [24]. Patients with RP may also experience photophobia and color vision impairment—dyschromatopsia.

As with all macular dystrophies, in Stargardt disease and Best disease, patients complain of blurred vision with dark areas (central scotomas) and impaired color vision. Peripheral vision is usually unimpaired.

In Best disease at stages II–III, metamorphopsias—distortions in the central visual field—are also noted [2].

LCA may be suspected by a physician or parents in an infant presenting with abnormal pupillary responses, nystagmus, absence of fixation, and the oculodigital sign (Franceschetti sign) [2].

In CD and CCOD, patients complain of photophobia and decreased vision.

Comments:

It is necessary to ascertain the presence of IRD cases among close relatives, as well as concomitant ocular and systemic diseases for diagnostic and prognostic assessment purposes.

Stargardt disease, as a rule, manifests in childhood and is also classified among juvenile macular dystrophies. The family history typically corresponds to an autosomal recessive (AR) inheritance pattern, with autosomal dominant (AD) inheritance being rare.

Best disease, as a rule, manifests in childhood and is also classified among early juvenile macular dystrophies. The family history corresponds to an autosomal dominant (AD) inheritance pattern.

In LCA, the medical history is characterized by significant vision loss in infancy. The family history typically corresponds to an autosomal recessive (AR) inheritance pattern.

CD and CDE Can occur in childhood, adolescence, or adulthood. A family history may be consistent with AD, AR, or X-linked inheritance patterns.

2.2 Physical Examination

Physical examination is uninformative.

Comments: the choice of specialist profile is determined depending on whether the patient has symptoms of a syndromic disease, for example, referral to an otolaryngologist-audiologist to confirm Usher syndrome. Referral of all patients to a geneticist is recommended

2.3 Laboratory Diagnostics

Comments: DNA extraction from peripheral blood leukocytes of patients collected in an EDTA (ethylenediaminetetraacetic acid) tube is carried out according to one of the standard DNA purification protocols.

Comments: The method is not intended to determine the cis- or trans-position of heterozygous mutation pairs, nor to assess methylation levels, detect chromosomal rearrangements, polyploidy, or identify mosaic mutations.

In case pathogenic nucleotide sequences are detected, the second stage of diagnostics must be performed.

If no pathogenic nucleotide sequences are detected due to method limitations that prevent the detection of insertions and deletions longer than 10 base pairs, intronic mutations (except for canonical splice sites), repeat length variations (including triplet expansions), homopolymer length variations (more than 4 nucleotides), as well as mutations in genes that have a close sequence paralog (pseudogene) in the genome, multiplex ligation-dependent probe amplification (MLPA analysis) may be performed according to indications.

Comments: The pathogenicity of newly discovered intragenic mutations in the genes of interest in IRD is confirmed using predictive analysis software, evidence of the absence of this variant in a cohort of healthy individuals and/or healthy family members, and, if necessary, functional analysis.

2.4 Instrumental Diagnostics

Comments:

In retinitis pigmentosa (RP), the best-corrected visual acuity (BCVA) often remains high until the end-stage of the disease; BCVA reduction occurs when the cones of the central retina are involved in the pathological process [28].

Bestiform dystrophy (BD) most commonly manifests as bilateral symmetric progressive reduction in BCVA down to 0.2 - 0.005 [29].

In Bardet-Biedl syndrome (BBS), a mild decrease in visual acuity is detected at stages 2-3 of the disease and progresses over time. Visual acuity may decrease to varying degrees in different eyes [30].

In Leber congenital amaurosis (LCA), some children exhibit a decrease in visual acuity that can be measured using charts, while in others, visual reduction cannot be quantified using charts due to the child's young age or very low vision, corresponding instead to finger counting at a face, hand motion at a face, or accurate light projection [31].

In cone dystrophy (CD) and cone-rod dystrophy (CRD), decreased visual acuity is the earliest symptom [32].

Comments: ocular biomicroscopy is necessary to assess the state of structures in order to evaluate the transparency of optical media, detect lens opacities (including posterior subcapsular cataracts in RP) or keratoconus in certain clinical and genetic forms of LCA [23] and other pathologies [35-37]. The incidence of cataracts in RP is 46.4%, with 93.6% of these being posterior subcapsular cataracts [35].

Comments: Color vision testing is extremely important for diagnosing inherited retinal dystrophies. To assess color vision, polychromatic color perception tables (Rabkin tables) are mainly used; the Farnsworth-Mansell hue test can also be used. Color vision testing is feasible only in children over 6 years of age.. When the cone system of the retina is involved later in the course of the disease inRP, color vision impairment occurs. Color vision in patients withBDis usually impaired in the late stages of the disease; in the early stages, mild red-green dyschromatopsia can be detected. Furthermore, when these patients undergo the Farnsworth-Mansell hue test, axis deviations in the blue part of the spectrum can be noted. Color vision in patients withBBS is usually impaired starting from stages 2-3 of the disease. InLCA, there is a pronounced color vision impairment. In CD and CRD , red-green dyschromatopsia can be detected..

Comments: peripheral vision testing is important for diagnosing, staging, and assessing the dynamics of inherited retinal dystrophies. It should be noted that perimetry is feasible only in older children (on average after 10 years of age) with a sufficient level of intellectual development. In this regard, assessing the visual field using both moving (kinetic perimetry) and stationary stimuli (static perimetry) is relevant.

In RP, Goldmann kinetic perimetry typically reveals a ring scotoma in the mid-periphery of the visual field. These usually begin as a group of isolated scotomas about 20 degrees from fixation and gradually coalesce to form a partial ring, followed by a complete one. The outer edge of the ring expands relatively rapidly toward the periphery, while the inner edge slowly narrows toward fixation. Patients often maintain good central vision from a small central island ("tunnel vision" or "tubular vision") up to 50 or 60 years of age. Visual field testing is useful for monitoring disease progression and documenting legal status for low vision and blindness [41].

When testing the visual field in patients with BBS, results are often normal in the early stages of the disease. Over time, relative central scotomas progress to absolute central scotomas. Typical patients with BBS generally preserve their peripheral visual fields [42]. However, in severe cases with widespread retinal atrophy, constriction of their peripheral boundaries may occur. Another particularly important fact is the shift in the preferred retinal locus of fixation. Early in the natural course of BBS, most patients retain foveal fixation, but as the disease progresses, absolute central scotomas develop, and the preferred retinal fixation becomes eccentric, which is objectively recorded by microperimetry. In most cases, the new fixation point is located above the fovea, where contrast sensitivity to stimuli with low spatial and high temporal frequency is better. This is also consistent with the fact that the superior half of the retina has a higher density of ganglion cells.

When testing the visual field in patients with BBS, it is often normal in the early stages of the disease. Over time, relative central scotomas may appear and progress to absolute central scotomas. Normal peripheral visual fields are preserved [39].

LCA is characterized by a marked impairment of retinal photosensitivity and visual field defects, up to concentric constriction [39].

In CD and CRD, a central scotoma appears, leading to reading impairment, followed by focal defects in the peripheral vision [39].

Comments: ERG and its components serve as an objective indicator of the functional state of the retina in adults and children with inherited retinal dystrophies. ERG includes standard full-field (synonyms: maximal, rod-cone ERG), scotopic, photopic, flicker ERG, and pattern ERG (PERG, mfERG). ERG and VEP are performed in adults and children in the absence of contraindications (photosensitive epilepsy), both during wakefulness and under sedation or general anesthesia. Electrooculography is a method for recording the standing potential of the eye. EFT data are particularly important when visual acuity and the condition of the posterior segment cannot be assessed due to the child's young age, making visualization of the posterior pole structures impossible.

In the early stages of RP, a decrease in the amplitudes of ERG a- and b-waves is observed (i.e., a subnormal ERG is recorded), and latency may be prolonged or normal. In patients with terminal stages, the ERG is undetectable [43-45].

In BS, the amplitude of a- and b-waves of the macular (local) ERG, the retinal P1 density, and the amplitudes of N1 and P1 components of mfERG decrease in the central hexagon and paracentral rings. The amplitude of the P50 component of the pattern-ERG decreases. The global (maximal) ERG in patients with BS typically reveals preserved normal or subnormal electroretinographic scotopic (rod) and photopic (cone) responses recorded according to the standards of the International Society for Clinical Electrophysiology of Vision (ISCEV). However, patients with more widespread disease may have markedly abnormal scotopic and photopic ERGs [46, 47].

BS EOG: altered, "flat" appearance, with an Arden ratio (Ar = [A max : A min] × 100%, where A max is the maximum amplitude of the standing potential during light adaptation, µV/deg, and A min is the minimum amplitude during dark adaptation) of 1.5 or less. ERG: normal [20].

For BSS, a non-recordable / extinguished ERG is characteristic, or a severely reduced amplitude of the scotopic and photopic electroretinogram (ERG). A normal ERG excludes the diagnosis of BSS. Visual evoked potentials are variable [48].

InCDonly a decrease in photopic ERG components is recorded (photopic and 30 Hz flicker ERG). Rod responses (scotopic ERG) are reduced to a lesser extent inCRD.InCDiCRDshows a decreased amplitude of a- and b-waves of the macular (local) ERG, retinal P1 density, and amplitudes of N1 and P1 components of mfERG in the central hexagon and paracentral rings. The amplitude of the P50 component of the pattern-ERG is decreased [49].

Comments:

For RP, thinning of the outer and, to a lesser extent, inner retinal layers is characteristic [50, 51]. A defect of the three-layer outer retinal structure in the periphery with loss of the ellipsoid zone (inner/outer segment junction line of photoreceptors) is detected at the periphery of the scan [52–54]. Loss or discontinuity of the ellipsoid zone characterizes the transition from healthy to affected retina. OCT is used to detect cystoid macular changes [55–58], epiretinal membrane, and vitreomacular traction syndrome observed in some patients with RP who have reduced central vision [59]. In CME associated with retinitis pigmentosa, OCT reveals numerous polymorphic cystoid spaces at the level of the inner nuclear layer [55–58].

OCT in BS allows early detection of lipofuscin accumulation in the RPE and disorganization of the photoreceptor layer. A defect in the three-layer structure of the outer retina with loss of the ellipsoid zone (inner/outer segment junction line) is detected centrally. Combined with autofluorescence data, OCT helps to clarify the severity of the disease. OCT reveals thinning of the retina in the foveolar zone, loss of the RPE and photoreceptors, and increased choroidal signal transmission [60].

narod In Best disease (BD) , OCT is used to assess the localization of the vitelliform lesion in the subretinal space and visualize thickening of the outer segments of cones. OCT can be used to assess fluid associated with CNV. At the vitelliform stage of BD, OCT reveals a subfoveal dome-shaped vitelliform lesion between the RPE and Bruch's membrane—a pigment epithelium detachment filled with homogeneous hyperreflective contents. At the pseudohypopyon stage, vitelliform material settles in the inferior subretinal space, while an optically empty zone forms superiorly, clearly visualizing a horizontal interface between the two media. Vertical OCT scanning shows clear fluid above and a distinct border of deposited hyperreflective yellowish material. Patients with BD exhibit progressive disorganization and thinning of the submacular RPE on OCT compared to normal controls, including at stage IV of the disease. At the atrophic stage of the disease, OCT may show retinal thinning similar to geographic atrophy in age-related macular degeneration: characteristic structural changes are detected, manifested by the absence of the outer nuclear layer, external limiting membrane, outer and inner segments of photoreceptors, and RPE [61].

In AOFD , retinal atrophy is frequently observed on OCT [62].

CD On OCT, a defect of the three-layer structure of the outer retina with loss of the ellipsoid zone is detected in the fovea. In CPD, the junction line defect extends beyond the fovea up to complete absence of the ellipsoid zone. Disorganization of the retina is detected throughout the entire scan [63-64].

Comments: the necessity and frequency of OCT-A are determined by the ophthalmologist based on the specific clinical course of the disease.

Comments: the necessity and frequency of autofluorescence imaging are determined by the ophthalmologist based on the specific features of the disease course.

In RP areas of hypoautofluorescence are visualized in the peripheral retina due to photoreceptor and RPE degeneration. A parafoveal hyperautofluorescent ring, known as the Robson–Holder ring, is identified, which serves as a border between the functionally normal and altered retina. A narrowing of the ring diameter can serve as an objective criterion for disease progression [66-67].

Cystoid macular edema in RP is visualized as multifocal hyper- or isofluorescence in the center of the macula, resembling "petaloid" shapes [68].

In ST pathological autofluorescence is an early sign of the ABCA4-related form and correlates well with the severity of local changes. Increased autofluorescence with all other parameters being normal suggests that lipofuscin deposition in the RPE may be the earliest sign of ABCA4-associated disease. Yellowish flecks are hyperautofluorescent immediately upon appearance; subsequently, their fluorescence decreases, and they become hypoautofluorescent with RPE atrophy. Evidence indicates that long-wavelength (infrared) AF changes, primarily due to melanin fluorescence, are detected earlier in ST than short-wavelength autofluorescence. At the terminal stage, a central zone of atrophy is visualized, which may be surrounded by polymorphic yellow perifoveolar flecks.

BV Autofluorescence of the vitelliform material is typically characterized by homogeneous increased fluorescence (the vitelliform material is hyperautofluorescent) and appears round or oval at the vitelliform stage. At the pseudohypopyon stage, increased autofluorescence is visible in the lower half of the cyst where the vitelliform material settles. At the stage of vitelliform content resorption, the autofluorescence becomes mottled with areas of hypoautofluorescence. At the resorption/scrambled-egg and cyst rupture stages of BV, mottled autofluorescence is visualized. At the atrophic stage, a decreased autofluorescence signal is observed. A peripheral ring / small peripheral foci of hyper-autofluorescence may be noted at the cyst rupture stage [19]. In late stages, central hypoautofluorescence and peripheral hyperautofluorescence are typically observed. [20]

FAF Autofluorescence depends on the subtype.

Comments: The necessity and frequency of FAG are determined by an ophthalmologist depending on the specific course of the disease.

Table 1. Main diagnostic criteria for establishing the diagnosis of IRD

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.2. Etiopathogenetic gene replacement therapy.

Comments: Voretigene neparvovec is a gene transfer vector in which the capsid of adeno-associated viral vector serotype 2 (AAV2) is used as a delivery vehicle for the complementary DNA of human retinal pigment epithelium-specific 65 kDa protein (hRPE65, molecular weight 65 kDa). The drug was registered in the Russian Federation on 20.04.2022. Administration is carried out in specialized centers in specially equipped operating rooms under general anesthesia.

Comments: ophthalmological examination after administration of voretigene neparvovec should be performed in the medical facility where the treatment was carried out and should include the full range of diagnostic examinations to assess the state of the organ of vision.

Complications are possible after administration of the drug: chorioretinal atrophy at the injection site, episcleritis at the injection site, macular hole, ocular hypertension, cataract, endophthalmitis, which indicates the need for dynamic follow-up at scheduled intervals.

3.3. Surgical treatment

Not indicated

3.4. Prescription of medical nutrition in diseases of the organ of vision

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: if the child does not have photophobia, spectacle correction can be prescribed with initially clear lenses that nevertheless block blue light rays (L400) and photochromic lenses [85].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments. Since different assistive devices for rehabilitation (ADR) are intended for various situations—enabling the perception of distant large objects or small near objects, reading, writing—it is advisable for the patient to have multiple ADRs. The optimal combination can be selected by considering which ADRs are suitable for specific activities:

o Reading: glasses, including those with additional magnification and built-in monoculars (not medical devices), manual (not medical devices) or stationary magnifiers (not medical devices), electronic video magnifiers (portable, stationary, wearable), text-to-speech recognition devices, including wearable ones

o Writing: glasses, including those with additional magnification and built-in monoculars, stationary or portable electronic video magnifiers (portable ones are especially recommended for middle and high school students), as well as wearable ones

o Spatial orientation: optical devices (monocular (not medical devices) or binoculars (not medical devices)), wearable electronic devices (video magnifiers and environment text-to-speech recognition devices).

As balneotherapy, the use of iodine-bromine and gas baths (oxygen, carbon dioxide, nitrogen), dry-air baths is indicated [87].

Climatic and balneological resorts: Essentuki, Pyatigorsk, Zheleznovodsk, Krasnodar Krai (Gelendzhik)

GDR CLE 5Grade of recommendation C (level of evidence – 5)

5. Prevention and Dispensary Observation

Prognosis

The prognosis for patients with IRD in the absence of pathogenetic therapy is unfavorable. However, there are specific features in certain nosological entities; in particular, patients with Best disease often maintain high visual acuity or nearly normal vision for many decades. Conversely, Stargardt disease often leads to low vision with visual acuity of 0.1 and lower.

Comments: Some studies suggest that the rate of progression, age of onset, and potential vision loss are related to the inheritance type of RP. Autosomal dominant RP has a better prognosis: the majority of patients younger than 30 years have a visual acuity of 0.6 or higher. The X-linked form is the most severe form with a marked decrease in central visual acuity to 0.1 or less by the fifth decade of life. Autosomal recessive and sporadic cases are intermediate in severity [84,85].

6. Organization of Medical Care

Primary specialized health care is provided by an ophthalmologist in the outpatient department of a medical organization. Treatment (laser intervention to prevent neovascularization, conservative medical treatment, or physiotherapy) is carried out by an ophthalmologist on an outpatient basis, in a day hospital, or in an inpatient setting.

Indication for scheduled hospitalization in a medical organization: laser treatment and/or drug therapy and/or physical therapy when outpatient treatment is not feasible.

Indication for emergency hospitalization in a medical organization: − retinal tear or detachment due to inherited retinal dystrophies.

Indication for patient discharge from a medical organization:

1) completion of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour or day hospital, provided there are no complications of treatment requiring medical correction and/or inpatient medical interventions;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-care setting;

3) need to transfer the patient to another medical organization.

7. Additional Information

Overall, in the absence of pathogenetic therapy for inherited retinal dystrophies, the visual prognosis is unfavorable.

Factors influencing the outcome of the disease include:

• Late diagnosis of inherited retinal dystrophies in the clinical practice of an ophthalmologist

• Incomplete functional and instrumental examination of a patient with suspected inherited retinal dystrophy, including mandatory OCT, FA, ERG, and other high-tech methods;

• Lack of medical genetic counseling for the patient and family with the establishment of a clinical and genetic diagnosis;

• Lack of mandatory molecular genetic testing of the patient and referral for genetic diagnostics;

• Lack of interdisciplinary interaction – coordination of efforts between ophthalmologists and geneticists at the regional and federal levels in working with patients with inherited retinal dystrophies.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lyudmila Anatolyevna Katargina – Head of the Group, Chief freelance pediatric ophthalmologist of the Russian Ministry of Health, Deputy Director for Research at the National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Professor, MD, Moscow; member of the Presidium of the All-Russian Public Organization "Association of Ophthalmologists", member of the Presidium of the Ophthalmological Society of Russia, Chief freelance pediatric ophthalmologist of the Ministry of Health of the Russian Federation, Chairman of the Profile Commission on Pediatric Ophthalmology of the Ministry of Health of the Russian Federation, Deputy Chairman of the Profile Commission on Ophthalmology of the Ministry of Health of the Russian Federation, Honored Doctor of the Russian Federation, Honored Worker of Science, Moscow;

2. Sergey Ivanovich Kutsev – Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences (RAS), Director of the Research Centre for Medical Genetics (RCMG), Chief freelance medical geneticist of the Russian Ministry of Health, Chairman of the Profile Commission on Medical Genetics of the Russian Ministry of Health, Chairman of the Ethics Committee of the Russian Ministry of Health, President of the Association of Medical Geneticists of Russia, Moscow.

3. Vitaly Viktorovich Kadyshev – Candidate of Medical Sciences, Senior Researcher at the Laboratory of Genetic Epidemiology, Head of the Department of Ophthalmic Genetics at the Institute of Higher and Additional Professional Education, physician-geneticist-ophthalmologist of the highest qualification category at the Research Centre for Medical Genetics (RCMG), Coordinator for Hereditary Eye Diseases of the Russian Federation, member of the All-Russian Public Organization "Association of Ophthalmologists", member of the Association of Medical Geneticists of Russia, member of the "Russian Society of Medical Geneticists", member of the European Retina Specialists Association (Euretina), Moscow.

4. Rena Abulfazovna Zinchenko – Doctor of Medical Sciences, Professor, Deputy Director for Scientific and Clinical Work, Head of the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics (RCMG), member of the Russian Society of Medical Geneticists, member of the Association of Medical Geneticists, Honored Worker of Science, Moscow.

5. Inna Vladimirovna Zolnikova – Doctor of Medical Sciences, Senior Researcher at the S.V. Kravkov Department of Clinical Physiology of Vision at the National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation (Helmholtz NMRC Eye Diseases of the Ministry of Health of Russia), Professor of the Department of Ophthalmic Genetics at the Institute of Higher and Additional Professional Education of the RCMG, member of the All-Russian Public Organization "Association of Ophthalmologists", Moscow

6. Kogoleva Lyudmila Viktorovna – Doctor of Medical Sciences, Head of the Pediatric Consultative and Polyclinic Department, National Medical Research Center of Eye Diseases named after Academician V.N. Helmholtz of the Russian Ministry of Health, Chief freelance pediatric ophthalmologist of the Central Federal District of the Russian Federation, member of the All-Russian Public Organization "Association of Ophthalmologists", Moscow.

7. Sheremet Natalia Leonidovna – Doctor of Medical Sciences, RAS Expert, Chief Researcher, Federal State Budgetary Scientific Institution "Research Institute of Eye Diseases" (FSBSI "NIIGB"), Moscow;

8. Pozdeeva Nadezhda Aleksandrovna – Doctor of Medical Sciences, Associate Professor, Director of the Cheboksary Branch, S.N. Fyodorov Eye Microsurgery Federal State Institution, Ministry of Health of the Russian Federation, member of the "Society of Ophthalmologists of Russia", Cheboksary;

9. Sydasheva Elvira Irekovna – Doctor of Medical Sciences, Professor at the Department of Ophthalmology, North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of the Russian Federation, Chief Pediatric Ophthalmologist of the Ministry of Health of the Russian Federation in the North-Western Federal District, member of the All-Russian Public Organization "Association of Ophthalmologists", Saint Petersburg;

10. Brzhesky Vladimir Vsevolodovich – Doctor of Medical Sciences, Professor, Head of the Department of Ophthalmology, Saint Petersburg State Pediatric Medical University (SPbGPMU), Saint Petersburg;

11. Konikova Olga Aleksandrovna, Candidate of Medical Sciences, Associate Professor at the Department of Ophthalmology, Saint Petersburg State Pediatric Medical University (SPbGPMU), Saint Petersburg;

12. Denisova Ekaterina Valerievna – Candidate of Medical Sciences, Senior Researcher at the Department of Eye Pathology in Children, National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, member of the All-Russian Public Organization "Association of Ophthalmologists", Moscow.

13. Ryabina Marina Vladimirovna – Candidate of Medical Sciences, Senior Researcher at the Department of Retinal Pathology, National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, member of the All-Russian Public Organization "Association of Ophthalmologists", Moscow.

14. Fesyun Anatoly Dmitrievich, Doctor of Medical Sciences, Acting Director of the National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation, President of the National Association of Experts in Sanatorium-Resort Treatment, Moscow.

15. Yurova Olga Valentinovna, Doctor of Medical Sciences, Professor at the National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation, National Association of Experts in Sanatorium-Resort Treatment, Moscow.

16. Nikitin Mikhail Vladimirovich, Doctor of Medical Sciences, Professor, Chief Freelance Specialist of the Russian Ministry of Health for Sanatorium-Resort Treatment, Director of the Vulan Sanatorium-Resort Complex, Scientific and Clinical Branch of the National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation, National Association of Experts in Sanatorium-Resort Treatment, Moscow.

No conflict of interest

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for evidence collection/selection: search in electronic databases; analysis of modern scientific developments on the problem of glaucoma in Russia and abroad, synthesis of practical experience of Russian and foreign colleagues.

The preliminary version of these guidelines was reviewed by independent experts who commented on the accessibility and interpretability of the evidence underlying the guidelines for practitioners and patients.

The comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and appropriate changes were made to the guidelines.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Target audience for these clinical guidelines:

1. Ophthalmologists

2. Geneticists

3. Pediatricians

4. Medical students, residents, and postgraduate students.

Table 2. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 3. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 4. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following documents:

1. "Procedure for Providing Medical Care to Children with Diseases of the Eye, Its Adnexa, and Orbit", approved by Order of the Ministry of Health of the Russian Federation No. 442n dated October 25, 2012.

2. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (World Health Organization) 1994.

3. Nomenclature of Medical Services (Ministry of Health and Social Development of the Russian Federation) 2011.

4. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."

5. Order of the Ministry of Health of the Russian Federation dated September 28, 2020, No. 1029n "On Approval of Lists of Medical Indications and Contraindications for Sanatorium-Resort Treatment".

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

IRD are characterized by a progressive decrease in vision. In infancy, in the absence of fixation and pupillary reactions, the presence of nystagmus, as well as a burdened family history, it is necessary to consult an ophthalmologist to rule out Leber congenital amaurosis. At an older age, the appearance of complaints of decreased vision, deterioration of vision in twilight and darkness, color vision disturbances, visual field defects, distortion of objects, and "sparks" requires an ophthalmological examination to rule out IRD. To verify the diagnosis of IRD and clarify the management strategy, a molecular genetic examination must be performed.

Following gene augmentation therapy, it is critical to strictly adhere to follow-up timelines and perform the prescribed treatment.