Retinitis Pigmentosa and Inherited Retinal Dystrophies: General Approach

Non-syndromic and syndromic retinitis pigmentosa (rod–cone dystrophy); a shared clinical, genetic and therapeutic strategy for inherited retinal dystrophies.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Retinitis pigmentosa is the most frequent inherited retinal dystrophy and serves as a model for understanding a broader group of diseases in which a genetic defect progressively impairs photoreceptor function bilaterally [1, 4]. Its defining feature is chronological: rod dysfunction precedes cone dysfunction, explaining the clinical sequence of night blindness, visual field constriction and, only in advanced stages, loss of central vision. The term “rod–cone dystrophy” describes this sequence more precisely than the historical name, which suggests an inflammatory process that does not exist [1, 2].

The history of the condition parallels that of ophthalmoscopy. Hermann von Helmholtz introduced the ophthalmoscope in 1850 and, in 1853, Adrien Christophe van Trigt, a doctoral student of Franciscus Cornelis Donders in Utrecht, published the first colour illustrations of the ocular fundus. These included that of a 42-year-old man with progressive visual loss over 20 years and tunnel vision, described as having “a retina with pronounced pigment development” [24]. Four years later, in 1857, Donders coined the term retinitis pigmentosa [2, 24]. The designation has persisted despite being recognised as a misnomer [2].

The molecular era began in 1990, when the first RP gene was identified [21]. In that year, Dryja and colleagues described three mutations in the rhodopsin gene that segregated exclusively with the disease in families with autosomal dominant RP; together with the previously described codon 23 mutation, they accounted for 27 of 150 unrelated patients (18%) [25]. Since then, RP has become an example of locus and allelic heterogeneity: more than 80 genes have been implicated in the non-syndromic form and more than 200 in retinal receptor dystrophies as a whole [1, 26].

The clinical value of a general approach derives from three facts. First, RP may be isolated or form part of a systemic disease, and some of these, such as adult Refsum disease, abetalipoproteinaemia and ataxia with vitamin E deficiency, have specific treatment [4, 26]. Second, molecular diagnosis is no longer merely informative: eligibility for voretigene neparvovec and clinical trials depends on identifying the gene [6]. Third, ophthalmic follow-up allows treatment of complications that impair vision independently of degeneration, such as cataract and cystoid macular oedema [4]. This article addresses RP as a general finding; Leber congenital amaurosis, Usher syndrome and Stargardt disease enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Photoreceptors, sequence of degeneration and clinical consequences

The outer retinal layer contains two types of photoreceptors. Cones function in bright illumination and support visual acuity and colour discrimination; rods function at low luminance and provide the peripheral visual field and motion detection [26]. Inherited dystrophies are classified by the affected cell population (rods, cones or both) and by macular involvement. In RP, early rod loss causes nyctalopia and mid-peripheral field defects; secondary cone loss enlarges the defect and ultimately affects the foveal cones [1, 26]. Secondary cone death in diseases caused by genes expressed only in rods, such as RHO, remains incompletely explained; proposed mechanisms include loss of trophic factors such as rod-derived cone viability factor, nutrient deprivation, oxidative stress and microglial activation [2].

2.2. Functional groups of genes

RP genes are grouped by function: components of the phototransduction cascade, proteins involved in retinol metabolism (the visual cycle, which produces and recycles the rhodopsin chromophore), cell–cell interaction proteins, photoreceptor structural proteins, transcription factors, intracellular transport proteins and splicing factors [1, 4]. The function of many genes remains unknown [4]. A substantial proportion of the proteins localise to the photoreceptor connecting cilium; RP1, TULP1, ARL6, TTC8 and RPGR are among the ciliary proteins associated with RP, linking RP to systemic ciliopathies [27].

2.3. Locus heterogeneity, allelic heterogeneity and allelic diseases

The complexity of RP is expressed at three levels [4]. In locus heterogeneity, variants in different genes produce the same phenotype. In allelic heterogeneity, many different variants occur in the same gene, although some are recurrent. In allelic diseases, variants in the same gene cause distinct phenotypes: RHO variants cause autosomal dominant RP, autosomal dominant congenital stationary night blindness and, rarely, autosomal recessive RP; PRPH2 (formerly RDS) variants cause autosomal dominant RP, autosomal dominant macular degeneration and, together with a ROM1 variant, digenic RP [4]. The French PNDS for genetic maculopathies describes the macular phenotypes of PRPH2, mainly in adults (pseudo-Stargardt, pattern dystrophies, adult-onset pseudovitelliform dystrophy and central areolar atrophy), and stresses that some variants are always associated with maculopathy, whereas others produce, within the same family, pictures ranging from pseudovitelliform dystrophy, with a better prognosis, to RP; the existence of asymptomatic carriers makes dominant inheritance hard to discern in the pedigree [22]. In addition to RP, RPGR variants may cause cone–rod dystrophy or broader ciliary dysfunction with deafness and recurrent sinopulmonary infections [1, 27]. Severity and phenotype often differ between carriers of the same variant because of genetic or environmental modifiers [4].

2.4. Distribution by mode of inheritance and principal genes

The Oxford Desk Reference (2017), drawing on earlier series, attributes 25–30% of adRP to RHO, 5–10% to RDS (PRPH2) and 5–10% to RP1, and estimates, in an overall assessment, approximately 20% autosomal recessive cases, 20% dominant cases, 15% X-linked cases and 50% without a family history [1]. Differences from GeneReviews reflect different cohorts and methods; GeneReviews, revised in 2023, is the reference adopted for the proportions [4].

2.5. Gene-specific distinctions with clinical implications

RHO. Rhodopsin is the G protein-coupled receptor that initiates phototransduction in rods. A study of heterozygotes with 18 different variants identified two allele-specific expression classes: in class A, rod function is severely impaired throughout the retina from an early stage and the alleles behave as cytotoxic alleles; in class B, rods may remain normal in some regions into adulthood, outer segment loss occurs in microscopic patches that coalesce, cone function remains normal until more than 75% of rod outer segments have been lost, and most variants show an inferonasal–superotemporal vulnerability gradient [29]. The variant NM_000539.3:c.68C>A, p.(Pro23His), in the MANE Select transcript, causes disease with a sectoral distribution and accounts for 12–14% of all adRP in Americans of European ancestry, while being rare in other populations [4, 28].

PRPF31. The mechanism is haploinsufficiency of a spliceosome factor. Incomplete penetrance depends on expression of the normal allele: asymptomatic carriers express more non-mutated PRPF31, and the principal modifier is CNOT3 (19q13.4), which represses the PRPF31 promoter and whose expression varies with a common intronic polymorphism [30]. “Asymptomatic” does not mean a normal eye: in a phenotyping study of 21 carriers (16 symptomatic and 5 asymptomatic), asymptomatic individuals had normal acuity and fields, but reduced full-field ERG amplitudes, borderline sensitivity on full-field stimulus threshold testing (FST), and structural changes on OCT and fundoscopy [31]. Approximately 2.5% of adRP results from PRPF31 rearrangements not detected by sequencing, and non-coding variants undetectable by exome sequencing have been described [4].

RPGR and RP2. The alternative ORF15 exon of RPGR, essential for retinal function, contains most variants; in a series of 47 patients with xlRP, it contained 80% of mutations, most of which predict premature termination of translation and are private to each family [1]. In 1,033 clinical tests that included RPGR, 78 pathogenic or likely pathogenic variants were identified, 87% frameshift or nonsense and 67% located in exon 15 (ORF15); no de novo variants were found in 16 mother/affected son pairs, supporting the predominant origin of mutations in the male germline [32]. The MANE Select transcript of RPGR is NM_001034853.2, the isoform that includes ORF15 [28]. RPGR-associated RP accompanied by deafness and sinopulmonary infections is an allelic form, and RPGR is among the genes associated with X-linked primary ciliary dyskinesia [1, 27].

USH2A and EYS. These are the most frequent arRP genes in several series. USH2A causes 10–15% of arRP and also Usher syndrome type 2 [4]. EYS accounts for 10–30% of arRP in Spain and is common in China [4]. In a Portuguese cohort of 58 patients from 48 families with biallelic EYS variants, 57 had RP and one had cone–rod dystrophy, 25% of RP cases were atypical (crescent-shaped inferior macular atrophy with superior mid-peripheral preservation), and mean acuity loss was 1.45 letters per year [33].

CERKL. Despite its name (ceramide kinase-like), neither the substrate nor the function of the protein is known, and the disease does not belong to disorders of sphingolipid synthesis [34]. In the largest series (47 patients from 37 families), the most frequent initial symptom was loss of central vision (40%) and the most common finding was well-demarcated macular atrophy (57%); more than half lost 15 or more ETDRS letters in at least one eye within the first five years of follow-up [35].

CNGB1. The cyclic GMP-gated channel subunit is expressed in rods and olfactory neurones. In nine patients, nyctalopia began early, but diagnosis was usually made only in the fourth decade because of slow progression, and all but one had olfactory function in the lowest age-adjusted quartile, constituting an RP–olfactory dysfunction syndrome [36].

MAK. The 353 bp Alu insertion in exon 9 (c.1297_8ins353, p.K433Rins31*, in the publication's nomenclature) was the most frequent cause of RP in Ashkenazi Jews [37]. This type of structural variant escaped standard exome variant-calling algorithms, illustrating a relevant technical limitation [38].

2.6. Syndromic and systemic forms: mechanisms

Syndromic forms account for 20–30% of cases and are mostly divided into inborn errors of metabolism and ciliopathies [2]. Primary ciliopathies (Usher, Bardet-Biedl, Alström, Joubert and Senior-Løken, among others) affect the primary cilium, a sensory organelle that coordinates signalling pathways such as Sonic Hedgehog and Wnt; retinal degeneration is a core manifestation of these diseases [2, 27]. In inborn errors of metabolism, retinopathy results from toxic accumulation or deficiency of complex molecules, as in Refsum disease (phytanic acid), peroxisomal diseases, defects of long-chain β-oxidation (LCHAD and trifunctional protein), abetalipoproteinaemia and vitamin E deficiency [39]. In the mitochondrial disorder NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa), the m.8993T>G variant in MT-ATP6 replaces a conserved hydrophobic leucine with arginine at position 156 of ATP synthase subunit 6, interfering with the proton channel and ATP synthesis; the m.8993T>C variant replaces leucine with proline and tends to cause less severe disease [40].

2.7. RLBP1-associated retinal dystrophy: retinitis punctata albescens, Bothnia dystrophy and Newfoundland rod–cone dystrophy

Gene and protein. The RLBP1 gene (15q26.1; OMIM 180090; MANE transcript NM_000326.5, with coding exons 3 to 9) encodes cellular retinaldehyde-binding protein (CRALBP), of 317 amino acids and 36 kDa, a member of the CRAL-TRIO superfamily [15, 41]. CRALBP is not expressed in photoreceptors but in the RPE and in the Müller cells of the neurosensory retina, where it carries 11-cis-retinol and 11-cis-retinaldehyde [42]. In the RPE, binding of 11-cis-retinol increases the activity of the isomerohydrolase RPE65 and facilitates the oxidation of 11-cis-retinol to 11-cis-retinal; in Müller cells, the protein supports a cone-specific visual cycle that allows rapid adaptation to widely differing light intensities [18, 43]. Loss of function makes chromophore regeneration very slow, which explains the extremely prolonged dark adaptation, the retinal deposits and the degeneration of rods followed by that of cones [18, 43].

Discovery and recognition of the entities. In 1997, in a consanguineous family with non-syndromic arRP, the affected siblings were homozygous by descent for a substitution in RLBP1; the recombinant mutant protein was less soluble than the normal protein and did not bind 11-cis-retinaldehyde [42]. The variant was published as R150Q, a numbering that does not count the initiator methionine; on the MANE transcript it corresponds to NM_000326.5:c.452G>A, p.(Arg151Gln), classified as pathogenic in ClinVar (VCV000013097, with several submitters and no conflicts) [42, 44]. In 1999, screening of the coding exons in 324 unrelated patients with recessive or isolated RP, RPA (retinitis punctata albescens), Leber congenital amaurosis and allied diseases found four novel variants, all in three patients with recessive RPA, and the authors concluded that RLBP1 is an infrequent cause of retinal degeneration and that the corresponding phenotype is a form of RPA [45]. Bothnia dystrophy, described in northern Sweden, was associated with the p.(Arg234Trp) variant in the homozygous state [17], and Newfoundland rod–cone dystrophy (NFRCD) was mapped by genetic linkage to 15q in an extended pedigree from this Canadian island, with two splicing variants in RLBP1 that segregated with the disease [46]. GeneReviews attributes 1% or less of non-syndromic arRP to RLBP1 [4].

Variant spectrum. By April 2021, the literature and the HGMD database had compiled 42 pathogenic variants: 18 insertions or deletions, 17 missense, 3 nonsense and 4 splicing variants, in addition to recurrent deletions with a founder effect, mainly in Mediterranean populations; the French series of that year added three novel variants [41]. The density of Alu elements in the gene favours large deletions, so that, in a phenotype compatible with the disease and only one allele or no point-variant allele identified, RLBP1 deletions should be sought [47]. The variants of greatest clinical weight are listed in the following table; the HGVS descriptions were confirmed in VariantValidator on the MANE transcript [28].

Genotype–phenotype correlation. The 2021 French series proposed an algorithm linking the combination of the two alleles to the phenotype [41]. Two null alleles (large deletions, nonsense and frameshift variants and certain splicing variants, probably subject to nonsense-mediated mRNA decay) are associated with NFRCD, with predictable absence of CRALBP [41, 46]. A Bothnia variant, p.(Arg234Trp) or p.(Met226Lys), in the homozygous state or in trans with a null allele, is associated with Bothnia dystrophy; Bothnia variants reorganise the ligand-binding cavity, increase binding to 11-cis-retinal and reduce the rate of photoisomerisation, which the authors interpret as a toxic effect of the mutant protein [41]. Combinations of two missense variants, even when one of them is a Bothnia variant, produce milder RPA, as in a patient with p.(Met226Lys) in trans with p.(Arg121Trp) [41]. Splicing variants must be interpreted individually: c.684+1del (published designation, with no transcript stated in the source consulted), which would be expected to be null, was found in patients with moderate RPA and preserved acuity at 60 and 68 years, a discrepancy the authors explain by the use of a cryptic site that generates a stop codon in the penultimate exon, where mRNA decay no longer operates and a truncated protein may arise [41]. In a Paris series, three unrelated patients homozygous for p.(Arg121Trp) had minimal changes in rod and cone responses and no macular atrophy, indicating a hypomorphic allele [49]. The Swedish and Canadian natural history cohort identified seven variants in eight allelic combinations, with p.(Arg234Trp) homozygosity in 24 of 29 Swedish patients (83%) and the c.141G>A/c.141+2T>C combination in 8 of 15 Canadian patients (53%) [18].

3. Clinical Spectrum and Manifestations by System

3.1. Visual symptoms and natural history

The first symptom is usually poor dark adaptation. When patients do not report it spontaneously, targeted questions about activities at dusk or in dim light often reveal nyctalopia beginning in childhood or adolescence; the earlier the onset, the more severe the course tends to be [4]. Mid-peripheral field loss occurs early but is rarely noticed by the patient, who may be considered “clumsy” before tunnel vision is documented [4]. On perimetry, a ring scotoma develops approximately 20–25 degrees from fixation; its outer border expands towards the periphery and its inner border slowly contracts towards the centre, sometimes leaving temporal and inferior islands in the far periphery and, for a long time, a small central island [4]. Sensitive tests document early cone involvement, but central acuity is usually preserved until the final stages [4]. Photopsia is frequent, and photophobia and loss of colour vision may accompany advanced disease [2].

At the group level, severity is related to the mode of inheritance. In a classic series cited by GeneReviews, most patients with adRP younger than 30 years retained acuity of 20/30 or better, whereas all men with xlRP older than 50 years had acuity below 20/200; recessive and simplex forms occupied an intermediate position [4]. Orphanet describes the same gradient [3]. Total blindness is uncommon: in series cited by Nguyen and colleagues, 7–8% of patients with generalised RP reached counting-fingers acuity or worse in the fourth or fifth decade, and fewer than 1% progressed to no light perception [2]. High myopia may be associated with faster progression, for example in RPGR-associated xlRP [2]. The Spanish clinical practice guideline summarises a mean annual loss of 4–5% of the visual field and 16–18.5% of ERG amplitude, with very low-quality evidence [21].

3.2. Ocular signs

Fundus appearance depends on the stage. In the earliest stages, when ERG already shows abnormal rod responses, the fundus may be normal (“RP sine pigmento”). The first changes are arteriolar narrowing, fine “dust-like” intraretinal pigmentation and RPE depigmentation; with progression, melanin collects in clumps with a “bone-spicule” configuration, and advanced disease features marked vascular attenuation and waxy pallor of the optic disc [4]. Pigmentation may also be nummular, “salt-and-pepper” or granular [2].

3.3. Atypical forms

Sectoral RP affects one quadrant or half of each fundus, most frequently the inferior and nasal quadrants symmetrically, with corresponding, less severe field defects; ERG usually shows diffuse abnormalities, and many forms that begin as sectoral disease become diffuse over decades [4]. It has been observed in adRP, for example with RHO p.(Pro23His), and in women heterozygous for xlRP [4]. Unilateral RP has an unknown aetiology; many non-genetic causes may mimic it and must be excluded, and when other family members are affected they usually have bilateral disease [4].

3.4. Extraocular manifestations

Non-syndromic RP does not involve other organs. In syndromic forms, the most frequent combination is RP with hearing loss in Usher syndrome [2]. In the Danish national registry of 1,301 prevalent patients in 1988, Usher syndrome accounted for 12% and Bardet-Biedl syndrome for 5% of all RP cases, and 11% had intellectual disability, mainly associated with atypical RP [51]. Section 6 summarises the systemic signs that point to each disease.

3.5. RLBP1-associated dystrophy: phenotypes and natural history

The clinical spectrum comprises three forms, all with nyctalopia from early childhood and very prolonged dark adaptation, which differ in the age of macular involvement and the rate of progression [18, 41]. Classic RPA is characterised by numerous small, round white dots in the posterior pole and periphery, which give way to peripheral atrophic areas in late stages, and spares the macula and acuity for longer [41]. Bothnia dystrophy adds an early atrophic maculopathy, in the second or third decade, and NFRCD is a rod–cone dystrophy of earlier onset and faster progression, leading to legal blindness in the third decade [41, 46].

Bothnia dystrophy in Sweden. In the series of 24 patients homozygous for p.(Arg234Trp), nyctalopia began in early childhood, RPA was visible in young adulthood and was followed by macular degeneration with loss of acuity to legal blindness in early adulthood; dark adaptometry and electrophysiology showed initial loss of rod function and progressive reduction of cone responses with age [17]. In 12 patients with the genotypes p.(Met226Lys)/p.(Arg234Trp) (10 patients, 7 to 84 years) and homozygous p.(Met226Lys) (2 patients, 63 and 73 years), loss of acuity and of field area was age-dependent, OCT showed early foveal and parafoveal thinning with homogeneous hyperreflective changes adjacent to the RPE and choriocapillaris, and dark adaptation and the ERG were abnormal at all ages, with phenotypic expression similar to that of p.(Arg234Trp) homozygosity [48].

French series. At the Montpellier reference centre, 11 patients from 7 families with RPA (mean age 24 years, range 3 to 39) all had nyctalopia, in 10 before 6 years of age; acuity ranged from 1.2 (decimal) to counting fingers with no correlation with age, ERG responses were markedly reduced with rod predominance, and mean central foveal thickness was 122 µm, compared with 187 µm in controls, irrespective of age [50]. On adaptive optics imaging, foveal cone counts were normal in a 13-year-old patient and fell to values between 5,833 and 10,500 per mm² in three patients aged 29 to 39 years, showing foveal cone death even in early stages [50]. The series extended to 21 patients from 15 families (mean age 26.4 years at the first visit, range 3 to 57) found NFRCD in 17, Bothnia dystrophy in 2 and classic RPA in 2; nyctalopia appeared in early childhood, and all patients with acuity below 20/200 had an ellipsoid line width below 1,000 µm and mean foveal thickness below 130–150 µm, with loss of the ellipsoid and interdigitation lines [41].

Prospective natural history. The five-year study (September 2013 to June 2019) enrolled 45 patients with biallelic variants in Västerbotten (Sweden) and Newfoundland (Canada); 44 had the genotype confirmed, with a mean age of 45.2 years (17 to 69), and 38 completed the five years [18]. At baseline, approximately 25% were legally blind (acuity of 1.0 logMAR or worse in both eyes), mean acuity was 1.00 logMAR in the right eye, mean central retinal thickness was 170 µm and the mean deviation of the Humphrey field was approximately −23 dB; approximately 15% had no measurable contrast sensitivity [18]. All had very delayed recovery of dark sensitivity, with minimal or no recovery at 30 minutes and at 1 hour after bleaching (times at which healthy volunteers recover fully) and full recovery only at around 6 hours [18]. Cross-sectionally, acuity was worse and the mean deviation of the field lower in older patients (correlation coefficients of around 0.6 in absolute value, p < 0.001), but over five years there were no relevant mean changes in functional or structural measures, although some patients worsened; test–retest reproducibility was high [18]. These data describe adults with advanced disease, without targeted treatment, and indicate that five years is a short horizon for detecting mean progression in this population.

Structural correlations and mild forms. In a retrospective Paris series of 22 patients with RLBP1-associated retinopathy (median age 36.9 years) and 5 with RDH5-associated retinopathy, approximately 80% of eyes in both cohorts had macular atrophy; the RLBP1 genotype was associated with a 0.28 mm³ lower macular volume (95% CI 0.11 to 0.46), and the annual macular volume loss of 0.007 mm³ did not differ between genes [49]. Three unrelated patients homozygous for p.(Arg121Trp) had minimal changes in the rod and cone systems and no macular atrophy [49]. A 25-year-old man with fundus flecks and a multimodal and electroretinographic picture compatible with benign familial fleck retina had a novel RLBP1 variant, which extends the spectrum to fleck phenotypes without apparent progressive dystrophy [52].

4. Clinical Recognition and Warning Signs

RP should be considered in the presence of nyctalopia with concentric visual field reduction, reduced or absent scotopic ERG responses, and the triad of peripheral pigment, vascular attenuation and optic disc pallor [21]. Bilateral and approximately symmetrical abnormalities strengthen suspicion of inherited disease and should prompt genetic testing [20, 21]. The Spanish clinical practice guideline recommends that primary care physicians refer to ophthalmology patients with night blindness and concentric field reduction, and children with age-inappropriate vision, bilateral deafness or the combination of obesity, polydactyly and hypogonadism [21].

Some findings suggest that the diagnosis is another retinal disease rather than RP: photopsia as the initial symptom, early impairment of central or colour vision, and marked asymmetry between the eyes [4]. The AAO recommends considering and excluding non-genetic diseases and actively looking for other organ involvement in syndromic forms [6].

The French PNDS for genetic maculopathies organises the first consultation around three pictures that share reduced vision and require different management [22]. Inherited maculopathy presents with uncorrectable loss of acuity, usually bilateral and symmetrical (vitelliform dystrophies are the exception and may be unilateral or asymmetrical), central scotoma and dyschromatopsia proportional to the loss of acuity; photophobia appears late, and metamorphopsia is rare in the absence of atrophy or neovascularisation. Cone dystrophy shares the central loss and dyschromatopsia but, for the same acuity, the colour vision defect is more severe and photophobia may be the presenting symptom. Nyctalopia and constriction of the peripheral field argue against isolated maculopathy and point to a mixed dystrophy (cone–rod or rod–cone, the latter corresponding to RP); the slowness in adapting to changes in luminance reported by patients with Stargardt disease does not have the same significance [22]. The distinction between the three pictures rests on the full-field ERG (section 5.3). The same document recommends that the history cover all medication, from dietary supplements to synthetic antimalarials, and look for obesity, deafness, polydactyly, abnormalities on magnetic resonance imaging, intellectual disability, epilepsy, developmental regression, neurological signs and diabetes, and notes that the absence of a family history does not exclude an inherited disease [22].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

A 1983 consensus conference cited by GeneReviews established that RP diagnosis rests on four elements: rod dysfunction demonstrated by dark adaptation (elevated final rod threshold) or ERG (undetectable or markedly reduced rod responses with prolonged implicit time, frequently with a lesser reduction in cone responses); progressive loss of photoreceptor function; loss of peripheral vision, often greater superiorly; and bilateral involvement with highly symmetrical severity and pattern of abnormalities [4]. Advanced funduscopic changes are not required for diagnosis, but fundoscopy is decisive in distinguishing RP from other dystrophies with a characteristic appearance [4].

5.2. Assessment recommended by the AAO (2022)

The 2022 AAO clinical statement defines four objectives: establishing the clinical diagnosis, providing information about the genetic nature and family implications, providing information about trials and new treatments, and supporting patients facing progressive visual loss [6]. It recommends an ocular and medical history including current medication and exposure to retinotoxic drugs, a pedigree, attention to signs of depression, ETDRS visual acuity measurement, slit-lamp examination, intraocular pressure and ophthalmoscopy [6].

In children younger than 2 years, ERG with skin electrodes or handheld OCT may be performed with the infant swaddled in the dark, but sedation usually provides more reliable results; between 2 and 6 years, sedation allows a more complete examination, with consideration of its risks, and may influence the ERG waveform; perimetry before 7 years is unreliable, improving with repetition [6]. The Portuguese guideline adds that, under sedation, ERG should be performed immediately after anaesthetic induction and proposes handheld OCT as a child-adapted alternative [20]. The French PNDS for maculopathies proposes an age-adapted initial assessment: in young children, rapid OCT scans of the macula and, if possible, of the temporal retina, to recognise an incipient mixed dystrophy behind the appearance of a simple maculopathy, combined with full-field ERG; in older children and adults, distance and near acuity, visual field, colour fundus photography, multimodal imaging with macular OCT, temporal scans and ganglion cell fibre analysis, macular and wide-field autofluorescence, full-field ERG and, if this is normal, electro-oculography (EOG) in deposit diseases or when a toxic cause is suspected [22].

5.3. Electroretinography and other functional tests

ERG measures the electrical potential generated by the retina after light stimulation. Dark-adapted responses to dim or blue stimuli predominantly reflect rods; light-adapted responses or responses to 30 Hz flicker reflect cones [4]. The 2022 ISCEV standard requires at least 20 minutes of dark adaptation and defines six standard responses: DA 0.01 (rod bipolar cells, rod-dependent), DA 3 and DA 10 (mixed responses dominated by rods), oscillatory potentials, LA 3 and LA 30 Hz (cone system) [7]. In RP, scotopic responses show reduced a- and b-waves and, in end-stage disease, scotopic and photopic responses are extinguished; ERG therefore ceases to be useful for monitoring progression, and perimetry and multimodal imaging assume that role [2]. Delayed cone b-wave implicit time is an early sign of diffuse disease [6]. Multifocal ERG records local macular responses and, together with full-field ERG, helps distinguish rod–cone from cone–rod degeneration [4]. The Spanish clinical practice guideline suggests following the ISCEV standard, supervision of testing by a physician trained in electrophysiology, requesting visual evoked potentials when optic nerve or visual pathway involvement is suspected, and electro-oculography when the RPE is the target [21].

In maculopathy, the French PNDS considers full-field ERG according to the ISCEV standard indispensable at any age, with a single exception, the typical picture of Best disease (characteristic vitelliform material and autosomal dominant transmission), and assigns it three functions: to measure severity and progression, to separate maculopathies (preserved cone and rod responses) from cone dystrophies (reduced or abolished cone responses with preserved rods) and from mixed dystrophies, and to estimate the risk of future loss of the peripheral field [22]. In Stargardt disease, the Lois electrophysiological classification distinguishes group 1 (preserved cone and rod responses), group 2 (reduced cone responses) and group 3 (reduced cone and rod responses), the last with a higher risk of peripheral field loss in adulthood, which brings its prognosis closer to that of a generalised dystrophy [22]. A pure cone dystrophy and a cone–rod dystrophy can be distinguished only clinically, because they share the same genes and differ in the severity of the variants [22]. EOG, with a reduced Arden ratio, is the characteristic test for Best disease and, together with testing for the familial variant, serves to identify asymptomatic carriers; a normal EOG does not exclude the diagnosis [22]. In maculopathies with a preserved full-field ERG, such as occult macular dystrophy, OCT and multifocal ERG are the tests that reveal the dysfunction [22].

FST measures the stimulus threshold seen 50% of the time using red, blue and white stimuli, distinguishing rod, cone or mixed responses without spatial information; it has become a central endpoint in gene therapy trials [2]. Static scotopic perimetry with cyan and red stimuli separates rod and cone function over extensive areas [2].

5.4. Multimodal imaging

On autofluorescence, a hyperautofluorescent macular ring marks the transition between preserved and degenerated retina and is accompanied on OCT by thinning of the ellipsoid zone, external limiting membrane and outer nuclear layer; in RP, the ring progressively contracts towards the centre, whereas in cone–rod dystrophies it expands, and extensive areas of hypoautofluorescence predominate in advanced disease [2]. Ellipsoid zone width and central retinal thickness are structural markers of progression, and OCT detects CMO and epiretinal membranes [2].

The French PNDS for maculopathies considers autofluorescence indispensable for the diagnosis of IRDs and states that it has completely replaced fluorescein angiography, which is no longer indicated in this setting [22]. The document proposes a decision tree based on the autofluorescence pattern, summarised in the following table; several patterns are shared by more than one entity, so the tree guides the ERG and genetic testing but does not replace them [22].

Source: decision tree of the French PNDS for genetic maculopathies [22].

5.5. Targeted laboratory testing

In isolated cases and in children, assessment should exclude systemic disease [1]. The Oxford Desk Reference proposes electrolytes, renal and liver function and fasting blood glucose; phytanic acid (Refsum); very-long-chain fatty acids; apolipoprotein B; plasma amino acids (elevated ornithine in gyrate atrophy); vitamins A and E; neutrophil count (low in Cohen syndrome), testing for acanthocytes and vacuolated lymphocytes; renal ultrasound; ECG and echocardiography; mitochondrial DNA and SCA7 testing when indicated [26]. These specialised examinations are not usually required in isolated dystrophy with dominant or X-linked inheritance [26]. Plasma phytanic acid is a robust biomarker of Refsum disease, with no reported false negatives and values that may exceed 1,000 µmol/L (normal below 10 µmol/L) [53].

5.6. Genetic testing strategy

Genetic testing is appropriate for most patients with presumed genetic retinal degeneration [6]. The 2012 AAO task force recommended offering testing when the Mendelian cause has already been identified, using a certified laboratory, providing the patient with a copy of the report and avoiding direct-to-consumer tests; it also emphasised that qualified counselling should accompany all testing because results may affect reproductive decisions, cause anxiety or guilt and disrupt family relationships [4, 19]. The 2025 Portuguese guideline recommends testing all patients with IRDs [20].

Technical limitations that change interpretation. A negative result does not mean absence of genetic disease, because it depends on the method [6]. Exome sequencing covers more than 95% of coding regions and may detect splicing variants near exons, but does not comprehensively detect structural variants, CNVs and rearrangements [2]. Three examples have direct implications: the repetitive, purine-rich ORF15 region of RPGR is technically difficult to sequence using next-generation sequencing and may not be included in panels [4, 56]; 2.5% of adRP results from PRPF31 rearrangements detected only by deletion/duplication analysis [4]; and the founder Alu insertion in MAK was not recognised by standard variant-calling algorithms [38]. The Portuguese guideline emphasises that CNV annotation is not standard in exome data and that screening for CNVs is highly relevant given their frequency in IRD genes [20]. Furthermore, proportions of variants in a gene or region (for example, 67% of pathogenic RPGR variants in ORF15) describe the mutational spectrum and do not equate to the clinical sensitivity of a test [32]. The French PNDS applies the same reasoning to ABCA4: of the more than 1,300 pathogenic variants recorded in HGMD, 82% lie in coding regions, 15% in non-coding regions and 3% are structural, so a panel limited to exons misses some alleles; null variants are associated with earlier onset, some missense variants with later onset, and the hypomorphic variant NM_000350.3:c.5603A>T, p.(Asn1868Ile) has a high carrier frequency in the general population [22, 28]. The same document stresses that a negative result does not exclude the clinical diagnosis (variants in unexplored regions, in genes outside the panel or in genes not yet described), that detection of variants in an unexpected gene requires the clinical diagnosis to be revisited, and that results must be compared with the examination and with the pedigree drawn at the start of the consultation [22].

Interpretation and reporting. Classification should follow ACMG/AMP criteria (pathogenic, likely pathogenic, uncertain significance, likely benign, benign), in laboratories with quality accreditation; variants of uncertain significance consistent with the phenotype warrant family studies and referral to medical genetics, and inconclusive results should be reviewed in the light of new information (“reverse phenotyping”) [20]. The report should state the gene, transcript with version, HGVS nomenclature, zygosity, classification and methodological limitations. The MANE Select transcripts confirmed in VariantValidator for the genes most frequently cited in this article are: RHO NM_000539.3; RPGR NM_001034853.2; PRPF31 NM_015629.4; USH2A NM_206933.4; EYS NM_001142800.2; PRPH2 NM_000322.5; CERKL NM_201548.5; MAK NM_001242957.3; RP2 NM_006915.3; RP1 NM_006269.2 [28]. In older literature, PRPH2 is designated RDS and RPGR as the RP3 locus [1, 4]; variants described in publications using earlier transcripts (for example, NM_000322.4 for PRPH2) should be normalised before comparison [28].

5.7. Practical algorithm

1. Confirm rod–cone dystrophy (symptoms, fundus, fields, ISCEV ERG, OCT and autofluorescence) and exclude acquired causes and mimicking disorders [4, 6].
2. Construct a three-generation pedigree (more if X-linked inheritance is suspected), record consanguinity and examine relatives, particularly the mother of a boy who is the only affected family member [1, 26].
3. Look for systemic signs; in simplex and autosomal recessive cases and in children, request phytanic acid and the other targeted tests [26].
4. Request a broad IRD panel with CNV analysis, including syndromic genes; ensure RPGR ORF15 coverage when X-linked inheritance is suspected [4, 6, 20].
5. If negative or inconclusive: exome or genome, segregation studies as research, periodic reanalysis [6, 20].
6. Communicate the result during genetic counselling and plan follow-up [20].

5.8. RLBP1-associated dystrophy: diagnostic particularities

Suspicion arises from the combination of nyctalopia from early childhood, white dots in the fundus and disproportionately slow dark adaptation [18, 41]. Dark adaptometry quantifies the delay: in the prospective study, all patients, aged 17 to 69 years, had minimal or no recovery of sensitivity at 30 minutes and at 1 hour after bleaching and recovered it only at around 6 hours, and a difference of 2 or more log units between the 450 and 632 nm stimuli at 1 hour reflects the rod contribution [18]. In the Bothnia series, prolonged dark adaptation and ERG (recording after 24 hours in the dark) were used to document the elevated final threshold and the rod and mixed responses [48]. Full-field ERG according to the ISCEV standard shows markedly reduced responses with rod predominance, and spectral-domain OCT quantifies ellipsoid zone width and foveal thickness, which serve as staging markers and as eligibility criteria in trials [7, 41, 50].

The first-line test is an IRD panel with CNV analysis, because the recurrent deletion of exons 7 to 9 and other deletions linked to Alu elements escape point-variant sequencing; when only one allele is found, or none in a typical phenotype, deletions should be sought by CNV analysis or by long-range PCR, the method with which the Moroccan deletion was characterised [41, 47]. The report should state both variants on transcript NM_000326.5, the phase confirmed by segregation and the ACMG/AMP class; the historical designation R150Q, for example, corresponds to p.(Arg151Gln) [42, 44]. As the combination of the two alleles predicts the clinical form (two null alleles for NFRCD, a Bothnia variant with a null allele or another Bothnia variant for Bothnia dystrophy, two missense variants for milder RPA), classifying each allele as null or hypomorphic has prognostic value and enters the inclusion criteria for gene therapy trials [41]. Splicing variants require individual interpretation, because some generate a truncated protein and a moderate phenotype [41].

6. Differential Diagnosis

The differential diagnosis has two aspects. On the one hand, other inherited retinal dystrophies, often caused by the same genes, differ in their functional pattern, age at onset and fundus appearance [4]. On the other, treatable systemic diseases and acquired causes may produce a similar pigmentary retinopathy, requiring an active search before accepting a diagnosis of isolated RP [2, 4, 26].

6.1. Other inherited retinal dystrophies and diseases

Deep white dots in the fundus are not specific: they occur in RLBP1-associated dystrophy, in RDH5-associated fundus albipunctatus and, as a manifestation of RPE degeneration, in other forms of RP [4, 47]. In the Paris series, macular atrophy affected approximately 80% of eyes with both RLBP1 and RDH5, so the presence of maculopathy does not distinguish the two genes in adults; genetic testing is the discriminator, and RLBP1 forms with hypomorphic alleles, such as homozygous p.(Arg121Trp), may approach the milder picture associated with RDH5 [49]. A benign familial fleck retina phenotype with an RLBP1 variant has been described in a young adult [52].

Inherited maculopathies. In a French reference centre specialised in retinal disease, genetic maculopathies account for approximately 15% of IRDs; they are strictly ocular in the three main forms (Stargardt, Best and PRPH2), but some reveal syndromic diseases [22]. The French PNDS lists 21 genes for inherited maculopathies, excluding cone dystrophies, and summarises in the following table the features that distinguish them [22].

Source: diagnostic criteria and appendix 3 of the French PNDS for genetic maculopathies [22]. AD, autosomal dominant; AR, autosomal recessive; MIDD, maternally inherited diabetes and deafness.

The same document lists as differential diagnoses of maculopathies the cone and cone–rod dystrophies, associated with CERKL (AR), CRB1, CRX, GUCA1A, GUCA1B and GUCY2D (AD) and, with X-linked inheritance, with RPGR and juvenile retinoschisis; syndromic mixed dystrophies, such as SCA7 and Bardet-Biedl syndrome, which in children may mimic an atrophic maculopathy but has an abnormal ERG and is accompanied by truncal obesity, polydactyly and slowed ideation, and CLN3; dome-shaped macula in adults, with a preserved ERG and diagnosis by OCT; occult macular dystrophy, unmasked by OCT and multifocal ERG; age-related macular degeneration after 50 years, which is more asymmetrical and sequential between the eyes; and extensive macular atrophy with pseudodrusen (EMAP), with onset at around 50 years, atrophy with a long vertical axis and legal blindness within 5–10 years [22]. Early macular or peripheral chorioretinal atrophy and narrowing of vessel calibre weigh against Stargardt disease and point to other dystrophies; flavimaculate flecks, although highly suggestive, also occur in pseudo-Stargardt and in mitochondrial diseases [22].

6.2. Pigmentary retinopathy in systemic diseases

In NARP, Holt and colleagues described the m.8993T>G variant in a family with maternally transmitted neurodegenerative disease over three generations; the proband developed nyctalopia at 12 years and was almost blind at 30. The proportion of mutated mitochondrial DNA correlates with severity: loads above 95% are usually associated with Leigh syndrome, 70–90% with NARP, and 3–6% may be asymptomatic; analysis should not be restricted to m.8993T>G/C, because other MT-ATP6 variants have been described [40].

6.3. Acquired causes and phenocopies

Congenital rubella causes pigmentary retinopathy and sensorineural deafness, the only defects that frequently occur in isolation in this embryopathy [58]. Infections (syphilis, congenital rubella), drugs (chloroquine, thioridazine), iatrogenic injury (photocoagulation), nutritional deficiencies (vitamin A, zinc), trauma and autoimmune retinopathy must be excluded [2, 4]. In an isolated case with the appearance of a maculopathy, the French PNDS adds to the list synthetic antimalarials and antiretrovirals, use of poppers, exposure to recreational lasers and to sunlight, diabetes, vascular occlusions and inflammatory and infectious diseases (toxoplasmosis, multifocal choroiditis, placoid epitheliopathies, cat-scratch disease) [22]. Some forms of uveitis, such as acute zonal occult outer retinopathy and advanced birdshot chorioretinopathy, may mimic RP with pigment clumps and vascular attenuation [2].

7. Treatments and Risk Management Strategies

7.1. General principles

No treatment halts degeneration in most RP genotypes. Management includes aetiological confirmation, treatment of treatable systemic diseases, treatment of ocular complications, visual and psychological rehabilitation, information about clinical trials and, for biallelic RPE65 variants, authorised gene therapy [2, 4, 6]. The Spanish clinical practice guideline does not suggest using deflazacort, valproic acid, raubasine, isopropyl unoprostone, “encad” or brimonidine tartrate in IRDs, and makes no recommendation for or against neuroprotection based on the evidence available in 2017 [21]. The 2021 French PNDS recognises, for inherited maculopathies, the same absence of validated pharmacological treatment and defines as objectives treating low vision and complications, reiterating protective measures and ensuring comprehensive care of the patient and family; at the time, pharmacological therapies (molecules that slow the visual cycle and lipofuscin accumulation, in phase 1/2 and 3 trials), gene and cell therapies and retinal implants belonged to the research domain [22].

Choroidal neovascularisation in macular dystrophies. It may occur in any inherited maculopathy; it is frequent in Best disease (approximately 15% of cases), virtually constant by around 50 years in Sorsby dystrophy and exceptional in Stargardt disease [22]. The French PNDS accepts intravitreal anti-VEGF injections in the active phase and considers them without indication and ineffective in the fibrotic phase; it does not specify the drug or the regimen [22]. In the absence of a dose specific to macular dystrophies, the reference regimen is that of the European SmPC for ranibizumab (Lucentis®), authorised in adults for visual impairment due to choroidal neovascularisation without restriction as to cause: 0.5 mg (0.05 ml) given as a single intravitreal injection, which is the dose per administration, with a minimum interval of four weeks in the same eye, starting with one injection per month until maximum acuity is reached and/or there are no signs of disease activity and then adjusting the intervals to activity; below 18 years, outside retinopathy of prematurity, safety and efficacy have not been established, and the SmPC makes no posology recommendation for adolescents aged 12–17 years with choroidal neovascularisation [59]. Its application to inherited macular dystrophies is an extrapolation from other causes of choroidal neovascularisation. Recent-onset metamorphopsia in an inherited maculopathy suggests this complication, because it is rare in the absence of neovascularisation or atrophy [22].

7.2. Cystoid macular oedema

Carbonic anhydrase inhibitors (CAIs) are first-line treatment. GeneReviews reports therapeutic success with oral acetazolamide and topical dorzolamide, with possible recurrence (“rebound”) during continued use [4]. In eight patients treated with 2% dorzolamide three times daily, all had a significant reduction in foveal thickness in at least one eye after 1–2 months; two had bilateral recurrence during treatment and three gained 7 or more letters in at least one eye [60]. In the synthesis by Nguyen and colleagues, oral acetazolamide reduced central macular thickness in up to 80% of patients in small studies, topical CAIs reduced CMO in 30–81% of eyes, acuity benefit was limited, and recurrence after withdrawal was common [2].

The review by Nguyen and colleagues considers that anti-VEGF is not indicated for uncomplicated RP-associated CMO and that evidence for the dexamethasone implant is limited, although a prospective study with 30 eyes per arm showed greater thickness reduction and greater letter gain than acetazolamide [2]. This divergence from the Spanish guideline, which permits ranibizumab in refractory cases, reflects the scarcity of comparative trials and should be explained to the patient [2, 21].

7.3. Cataract

Approximately 50% of patients develop cataract that eventually requires extraction, with visual improvement in most [4]. Patients with a field greater than 10 degrees are rarely substantially limited by mild subcapsular cataracts, whereas those with a field below 10 degrees generally report significant improvement after surgery [4]. The risk of postoperative inflammation and CMO is higher than usual, so iris manipulation should be avoided and anti-inflammatory therapy prolonged [4]. New or worsened CMO in up to 32%, zonular dehiscence in up to 13%, posterior capsule opacification at a median of 12–15 months and anterior capsular phimosis have been described; combining topical non-steroidal anti-inflammatory drugs and CAIs for at least 3 months and assessing ellipsoid zone and external limiting membrane integrity as outcome predictors have been proposed [2]. The Spanish guideline suggests surgery when some macular function remains and consideration of a capsular tension ring [21].

7.4. Protection, lifestyle and supplements

GeneReviews recommends glasses blocking UV-A and UV-B and avoidance of intense light because it accelerates degeneration in animal models (particularly rhodopsin models), and avoidance of tobacco; prolonged light deprivation does not alter progression [4]. CPF 550 filters eliminate 97–99% of energy below 550 nm and aim to reduce glare, improve contrast and shorten adaptation [4]; the Spanish guideline suggests selective absorption filters in RP, visual field-expanding aids and the best possible refractive correction [21]. The French PNDS for maculopathies recommends a varied diet rich in fruit, vegetables and antioxidants, fish three times a week, abstinence from smoking and regular physical activity, even if moderate (approximately one hour a day); in ABCA4-associated disease, it considers glasses with suitable protective filters and a peaked cap mandatory, advises against sun exposure without these protections and proposes blue-light filters in glasses or suppression of blue light on computer and mobile phone screens [22]. The same document advises against violent or combat sports with a risk of head trauma in Stargardt disease, because these patients may have dense retinal haemorrhages that progress to subretinal fibrosis [22].

Vitamin A and vitamin E. In the randomised trial by Berson and colleagues (601 patients aged 18–49 years, 4–6 years of follow-up, factorial design), groups receiving vitamin A (palmitate) 15,000 IU/day had slower cone ERG amplitude decline (p = 0.01) and, among 354 patients with higher baseline amplitudes, a lower annual probability of losing 50% of amplitude (32% lower); groups receiving vitamin E 400 IU/day had a 42% higher probability of this decline (p = 0.03); acuity decreased by approximately one letter per year in all groups [63]. GeneReviews considers that vitamin A may delay ERG changes, without demonstrated effects on acuity or field, advises against its use before 18 years, contraindicates it in ABCA4 disease (it increases the toxic by-product A2E), recommends monitoring serum vitamin A, liver function and bone density, and warns of teratogenicity; patients should avoid high-dose vitamin E supplements (for example, 400 IU/day) [4]. The Spanish guideline is more restrictive: a strong recommendation against vitamin A supplements in pregnant women or women of childbearing potential who may become pregnant and in ABCA4 disease, a conditional recommendation against use in those younger than 19 years, syndromic patients with neuronal deficits, osteoporosis, and liver or renal disease, a strong recommendation against vitamin E, and a suggestion of clinical toxicity surveillance rather than serum vitamin A measurement, considered unreliable [21]. The French PNDS brings the restriction forward to the moment of clinical suspicion: when Stargardt disease is suspected, before genetic confirmation, vitamin A supplementation is strongly discouraged, so as not to increase the accumulation of toxic derivatives, and retinotoxic drugs, such as quinine derivatives, should be avoided [22]. This precaution has a practical consequence in RP: as ABCA4 is also among the arRP genes and Stargardt disease may progress to generalised involvement, vitamin A should be considered only after genetic testing has excluded ABCA4 disease [4, 22]. In any case, this is supplementation without a specific medicinal authorisation for RP.

Other supplements. Docosahexaenoic acid (DHA) 1,200 mg/day did not alter the course in patients already treated with vitamin A, and 400 mg/day did not alter acuity or field in men with xlRP; lutein (a four-year trial in patients receiving vitamin A) was associated with slower mid-peripheral field loss [4]. The Spanish guideline suggests lutein and β-carotene 20 mg in RP, strongly advises against β-carotene in smokers and those exposed to asbestos, and suggests an omega-3-rich diet in adults treated with vitamin A 15,000 IU/day [21]. The 2014 Orphanet summary mentions vitamin A and lutein-DHA as protective antioxidants [3]. These divergences reflect low-quality evidence and do not justify presenting any supplement as an established disease-modifying treatment.

7.5. Visual rehabilitation and psychological and social support

The AAO recommends low vision assessment at baseline and every 1–2 years, mobility training, liaison with schools, emotional assessment and referral to rehabilitation services and associations [6]. Magnifiers, closed-circuit television, wide-beam torches for night-time mobility and portable electronic devices are examples of described aids [2, 4]. Visual loss is associated with depression, isolation, anxiety and fear, and multidisciplinary rehabilitation services improve quality of life [2]. The Spanish guideline suggests considering psychological interventions, such as cognitive behavioural therapy, and providing guidance on registration as legally blind when acuity is below 20/200 and/or the field below 10 degrees [21]. A patient with RP may meet the visual field criterion for legal blindness (horizontal diameter of 20 degrees or less with the III4e target in the better eye, in the USA) before acuity falls to 20/200 [4].

The French PNDS for maculopathies details the rehabilitation of people who lose central vision, complementary to that for the peripheral losses of RP [22]. It begins with the best possible optical correction; in Best disease, the frequent hypermetropia should be corrected early to reduce the risk of amblyopia. Low-vision rehabilitation should be early, led by an orthoptist trained in low vision in liaison with the ophthalmologist and the specialised optician, close to home or in a multidisciplinary centre, with possible movement between the two settings. Therapeutic education focuses on eccentric fixation (use of the unaffected retina, usually above the fovea, once acuity stabilises) and on the use of optical aids (magnifying spectacles, magnifiers, telescopes), non-optical aids (large-print books, talking clocks, large-character telephone keypads) and electronic aids (reading systems); the input of the various professionals should be coordinated and may be individual or in groups. For photophobia, contrast-enhancing filters in a wraparound frame with wide sides are recommended. Mini-cameras attached to glasses that read text pointed at with the finger, and voice and character recognition software, are available. In maculopathies, Braille or placement in an institution for people with visual impairment is rarely needed; assessment by a mobility instructor may be useful, and a guide dog may help in severe impairment. Occupational therapy for activities of daily living is useful mainly in syndromic forms, physiotherapy treats musculoskeletal pain caused by compensatory postures, and the team may intervene at home to apply safety rules and, with occupational medicine, to adapt the workstation [22].

Psychological support should be offered to the patient and family to screen for and treat anxiety and depression, whose risk should be reassessed regularly, particularly in the initial phase of declining acuity [22]. At school, a child with non-syndromic maculopathy attends mainstream education with adaptations: a seat facing the board, adequate lighting, a computer with magnification and audio reading, a tablet to photograph the board and documents, materials in digital format, a school support assistant if needed, extra time in examinations and, depending on symptoms, an individualised reception plan [22]. In adults, the PNDS states that, in France, driving is no longer permitted with acuity below 5/10 and/or with a central scotoma, recommends assessment of fitness to drive (acuity and binocular visual field) and fitness for the workstation during follow-up, the involvement of the occupational physician and social worker in vocational redeployment, and rehabilitation in a specialised institute when the impairment is disabling [22]. Legal driving criteria differ between countries, and fitness should be assessed according to the applicable national regulations.

7.6. Treatable systemic diseases

Early treatment of Refsum disease (restriction of phytanic acid from dairy products, meats and certain fish, without a need to restrict green vegetables) [53], abetalipoproteinaemia and ataxia with vitamin E deficiency (vitamins A and E) [4, 26], and gyrate atrophy (arginine-restricted diet and a therapeutic trial of pyridoxine) [21, 55] may alter the course, justifying the targeted tests in section 5.5.

7.7. Voretigene neparvovec (Luxturna®) for RPE65-associated retinal dystrophy

Voretigene neparvovec is an adeno-associated virus vector (AAV2) carrying human RPE65 cDNA, administered by subretinal injection after vitrectomy. It is the first approved retinal gene therapy; the AAO emphasises that genetic testing is required to determine eligibility [6, 68]. The clinical spectrum of RPE65 includes Leber congenital amaurosis, severe early-onset retinal dystrophy and juvenile RP; the labels and their application to RP are summarised here.

The 2026 international consensus concludes that, in most reports, chorioretinal atrophy does not compromise visual and functional outcomes, but longer follow-up is needed [68]. The Portuguese guideline states that treatment is administered in several countries, including Portugal [20]. Regulatory authorisation does not itself guarantee reimbursement or access in each country; no information about the situation in Brazil was found in the consulted sources.

7.8. RPGR gene therapy: results, including negative findings

RPGR-associated xlRP is the principal target of gene augmentation therapy beyond RPE65. Four subretinal AAV programmes reached clinical trials: cotoretigene toliparvovec (AAV8-coRPGR, Biogen; XIRIUS), botaretigene sparoparvovec (AAV5-hRKp.RPGR, Janssen/MeiraGTx), AGTC-501 or laruparetigene zovaparvovec (rAAV2tYF-GRK1-RPGR, Beacon), and 4D-125 [10, 70].

The 2026 meta-analysis, with 128 participants from four trials, found a mesopic sensitivity difference of +1.11 dB at 6 months (95% CI −0.88 to 3.09) and +0.97 dB at 12 months (95% CI −3.99 to 5.94), and an acuity difference of +0.94 letters (95% CI −4.97 to 6.85), none statistically significant; certainty was very low for functional outcomes and low for safety. Among eyes with central injection, intraocular inflammation occurred in 80.8%, serious ocular adverse events in 17.0% and retinal detachment in 4.3% [10]. The authors conclude that the evidence does not establish a clinically actionable functional benefit, although a modest effect cannot be excluded [10].

Developments in the last 12 months (evidence hierarchy). In April–May 2026, MeiraGTx acquired all rights to botaretigene from Johnson & Johnson and announced its intention to submit applications for authorisation globally in 2026, with a possible first commercial launch in 2027; the product has Fast Track and orphan designations in the USA and PRIME, advanced therapy and orphan designations in the EU [11, 72]. This is the sponsor's intention, rather than an accepted application, opinion or authorisation. Up to 6-10-2026, no regulatory acceptance of an application for RPGR gene therapy was identified in the consulted sources.

7.9. Optogenetics and other gene-independent approaches

Optogenetics makes surviving inner retinal cells photosensitive and is applicable in advanced stages independently of the causative gene [2]. Results are heterogeneous and include negative studies.

Other approaches in advanced phases: OCU400 modifier gene therapy (AAV5-NR2E3) is in a phase 3 trial (liMeliGhT, NCT06388200) with 140 patients aged 3 years or older, a RHO arm and a gene-independent arm, 2.5 × 10^10 vg per eye, and a primary visual function endpoint at 52 weeks; the sponsor expects topline results in the first quarter of 2027 [13, 81]. Oral N-acetylcysteine (in the protocol, 1,800 mg — three 600 mg effervescent tablets — twice daily for 45 months) is in phase 3 (NAC Attack, NCT05537220; 485 patients aged 18–65 years; primary endpoint ellipsoid zone width at 45 months), following a phase 1 trial with good tolerability and dose-dependent improvement in acuity and macular sensitivity [14, 82]; it should not be prescribed outside a trial as an established treatment. The intraocular implant of encapsulated cells releasing ciliary neurotrophic factor (CNTF) was safe in phase 1 but showed no benefit in phase 2 in RP [4]; the same platform (revakinagene taroretcel-lwey, Encelto®) was approved by the FDA in March 2025 for idiopathic macular telangiectasia type 2, rather than RP [82]. A gene therapy trial for MERTK-associated RP was mentioned by GeneReviews, and the 2017 Spanish guideline suggested offering gene therapy for MERTK and RPE65 only in clinical trials, a recommendation preceding the authorisation of voretigene [4, 21].

7.10. Retinal prostheses and cell transplantation

GeneReviews (2017 revision, partially updated in 2023) describes Argus II as the first FDA-approved therapy for RP in patients with light perception or worse [4]. However, a 2023 review identified four discontinued devices, including Alpha IMS, Alpha AMS, IRIS II and Argus II, which had FDA approval and CE marking, with the company shifting its focus to a cortical implant [83]. The Spanish guideline suggests prostheses only in a research setting after shared decision-making, and makes no recommendation on cell transplantation outside trials [21]. GeneReviews does not mention trials of stem cell-derived RPE cells in RP [4].

7.11. Limitations of trial interpretation

Indirect comparisons between programmes do not allow products to be ranked: vectors, doses, injection sites, corticosteroid regimens, endpoints and observation windows differ [10]. In patients with RP, acuity is preserved until late and has a ceiling effect, favouring endpoints such as microperimetry, low-luminance acuity, FST and mobility tests, whose relevance to patients has not been validated in every case; no validated minimal clinically important difference exists for mean 68-point sensitivity in RPGR-associated xlRP [10]. Failure to meet a primary endpoint (XIRIUS part 2, LUMEOS) is not overturned by favourable secondary endpoints, which generate hypotheses. Sponsor-reported results (LUMEOS, RESTORE, OCU400) do not replace peer-reviewed publication, and acceptance of a regulatory application does not equate to authorisation [12, 13, 71].

7.12. RLBP1-associated dystrophy: current management and investigational gene therapy

There is no authorised therapy for RLBP1-associated dystrophy; management follows the general principles of sections 7.1 to 7.5 (treatment of CMO and cataract, protection, visual rehabilitation and psychosocial support) [4, 18]. Dark adaptation lasting several hours has its own practical consequences, such as difficulty in low-luminance environments for a long time after exposure to bright light, which justify orientation and mobility training and lighting aids, although the sources consulted do not describe interventions evaluated specifically in this disease [18, 43].

Phase 1/2 trial with AAV8-RLBP1 (CPK850). The first-in-human trial (NCT03374657, sponsor Novartis) administered a single subretinal injection of an AAV8 vector carrying RLBP1 to 12 Caucasian patients (4 men and 8 women, aged 31 to 66 years, acuity between light perception and 64 ETDRS letters), in four ascending-dose cohorts, in the worse-seeing eye, with 1 to 3 years of follow-up [43, 84]. Ten patients were homozygous for p.(Arg234Trp) and two had p.(Met226Lys)/p.(Arg234Trp); the first cohort deliberately included advanced disease, with extensive chorioretinal atrophy [43]. All patients received prophylactic corticosteroids per protocol, extended in later cohorts, because intraocular inflammation had been dose-limiting in the primate toxicology study [43]. The doses below are experimental and do not constitute clinical posology.

Source: Kvanta 2024 [43]. vg, vector genomes.

The primary efficacy endpoint was dark adaptation kinetics, designed on the basis of the natural history study; improvement was defined as a value outside the one-sided 75% prediction interval (based on three pre-treatment curves) at 1, 2 or 3 hours after bleaching, and a responder as a patient with improvement at at least two consecutive visits in the first year [18, 43]. Among the 12 treated eyes there were 8, 11 and 9 responders at 1, 2 and 3 hours, compared with 2, 1 and 2 in untreated eyes; at cohort level, there was efficacy in all four cohorts at 2 and 3 hours and in no cohort of untreated eyes [43]. No patient improved in acuity, low-luminance acuity, microperimetry or the Humphrey field, which the authors attribute to the advanced stage or to the unsuitability of these tests [43]. The only non-responder had a smaller subretinal bleb than planned, confined to the macula [43].

There were 108 adverse events (65 ocular) and four serious events: two fractures unrelated to treatment; ocular hypertension of 43 mmHg on the first postoperative day, due to anterior displacement of the intraocular lens caused by gas tamponade, resolved by surgical evacuation of the air on the third day; and a drug-related severe loss of vision in a patient in the highest-dose cohort (from 64 to 5 letters at 2 months and 13 letters after 1 year), with partial recovery and normal ancillary investigations [43]. Two patients had inferior subretinal exudates with focal serous detachment, which regressed within 3 months without changes in corticosteroids, and three had intraocular inflammation attributed to the drug [43].

The CPK850 results come from an open-label interim analysis, with no randomised control group other than the fellow eye, with a primary endpoint created for the trial and response criteria derived from the variability observed in the natural history; they do not allow functional benefit for the patient to be estimated or comparison with other programmes [43]. The authors of the French series propose, for gene therapy eligibility, prior classification of the allelic combination, treatment within the first two decades in severe forms (NFRCD and Bothnia), before acuity falls below 20/200, and OCT criteria of an ellipsoid zone wider than 1,100–1,200 µm and central thickness above 130–150 µm [41]. No FDA or EMA opinions or authorisations for therapies targeting RLBP1 were identified in the sources consulted.

8. Reproductive Options and Family Counselling

8.1. Determining the mode of inheritance

Pedigree analysis may be unreliable for determining the mode of inheritance: xlRP and arRP families may appear autosomal dominant [4]. In families with vertical transmission and affected men and women, xlRP with expression in heterozygous women should be considered; only male-to-male transmission excludes this possibility [4]. In a cohort of 258 families with a provisional diagnosis of adRP and no male-to-male transmission, 22 (8.5%) actually had xlRP, 19 due to RPGR and two due to RP2, with an additional ORF15 variant found by subcloning in women [56]. Simplex cases are not necessarily autosomal recessive: they may result from recessive inheritance without affected siblings, a dominant or X-linked de novo variant, reduced penetrance in previous generations or incomplete family history, so recurrence risk should be estimated cautiously when molecular testing is inconclusive [4]. For isolated cases without a definitive diagnosis after complete investigation, the Oxford Desk Reference considers autosomal recessive inheritance the most likely and notes a high recurrence risk [26].

8.2. Risks by mode of inheritance

8.3. Female xlRP carriers

Women heterozygous for xlRP show a spectrum from a normal fundus to extensive degeneration, and approximately 90% have fundus and/or ERG abnormalities [1]. The mother of a boy with RP who is the only affected family member should therefore undergo careful fundoscopy and ERG [26]. In a cohort of 77 RPGR carriers from 41 families, most were mildly affected or unaffected at all ages, and those progressing to moderate or severe visual loss were older than 30 years; RPGR genotype was not associated with severity, but X-inactivation skewed against the normal allele was: with extreme skewing of 80:20 or more, 57% were severely affected versus 8% with less skewing (p = 0.002) [86]. In PRPF31 families, the observation that asymptomatic carriers have objective ERG, FST and OCT abnormalities indicates that assessment of at-risk relatives should include objective examinations, rather than acuity and fields alone [31].

8.4. Predictive testing, prenatal diagnosis and preimplantation testing

Once familial variants have been identified, carrier testing, prenatal diagnosis and preimplantation genetic testing are possible; however, severity and age at onset cannot be predicted from genotype because they differ between carriers of the same variant [4]. Ophthalmic examination of at-risk individuals, including ERG, may detect early stages; if disease in the family began in childhood, a normal examination at 20 years is more reassuring than if the disease is adult-onset [1]. In mitochondrial diseases such as NARP, the random distribution of mutated DNA makes prenatal diagnosis and carrier detection unreliable, although it has been performed on chorionic villi and risk calculations based on 56 families exist [40].

Reproductive options include natural conception, gamete or embryo donation, adoption or choosing not to have children; invasive prenatal diagnosis (chorionic villus sampling or amniocentesis) is possible when the variants are known, whereas non-invasive prenatal testing is not yet available for RP; preimplantation genetic testing for monogenic disorders (PGT-M) avoids selective termination but retains a small risk of error due to allele dropout, contamination or mosaicism [2]. Differences in perspective between professionals and families regarding these tests should be discussed as a personal decision [4].

8.5. Counselling framework: Portugal, Spain and France

The Portuguese guideline recommends at least two genetic counselling consultations, before and after testing; counselling may be provided by a trained ophthalmologist for the index case and affected relatives, but for healthy relatives it should be provided by a medical geneticist, and under Portuguese law testing in healthy individuals may only be performed by a clinical geneticist [20]. The same guideline describes the legal framework: predictive tests in minors are permitted only for the child's direct benefit and are restricted for diseases with onset up to young adulthood without effective prevention or treatment; termination of pregnancy for severe incurable disease is regulated by Law No. 16/2007 (up to 24 weeks, with a technical committee) and preimplantation testing by Law No. 32/2006, under the supervision of the National Council for Medically Assisted Procreation; it also recommends a specific consultation on reproductive options between 16 and 18 years for those tested in childhood [20]. The Spanish guideline suggests genetic counselling in all monogenic IRDs, before and after testing, in prenatal diagnosis and predictive and carrier testing, and providing information about transmission risk and alternatives before reproductive decisions [21].

The French PNDS for genetic maculopathies requires written consent for genetic testing and permits testing of a minor only with the agreement of the parents or guardian and in the presence of clinical signs; in a dominant disease, an unaffected minor cannot be tested to learn his or her status, and the psychological impact of systematic clinical examination of the siblings of an affected child should be discussed with the parents [22]. In recessive forms, parental DNA is needed to confirm by segregation that the patient’s two altered alleles come one from each parent [22]. The document makes genetic testing the prerequisite for counselling, because isolated cases due to variants in dominant genes, with a risk of transmission to the next generation, are frequent; in an adult, the same Stargardt-like picture may be recessive, due to ABCA4, with a low risk to offspring, or dominant, due to PRPH2, with a 50% risk [22]. The diagnosis is disclosed in a dedicated consultation that explains the disease, its course and the therapies that are or are not available, introduces the multidisciplinary team and patient associations and initiates genetic counselling, to be carried out as early as possible; the information should include the natural history, aids and treatments with their adverse effects, the risks of recurrence and transmission, and the surveillance plan [22]. Regarding risks, the PNDS gives a 25% recurrence risk for a couple with a child affected by an autosomal recessive disease and 50% per pregnancy when a parent has a dominant disease with an identified variant, with no guarantee that the disease will manifest in the carrier, given variable expressivity and penetrance [22]. When a patient with Stargardt disease plans to have children, testing of the partner may be offered, bearing in mind that the PNDS estimates the frequency of heterozygotes for a pathogenic ABCA4 variant in the general population at approximately 1 in 50 [22], whereas molecular series estimate approximately 1 in 20 carriers of a potentially pathogenic allele when frequent hypomorphic alleles, such as c.5603A>T p.(Asn1868Ile), are included [87], and that the test does not exclude variants not yet known, particularly intronic ones, limits that the geneticist should explain to the couple; prenatal diagnosis and preimplantation genetic diagnosis are possible in France within a very restricted framework, conditioned by the limited knowledge of the pathogenicity of rare variants [22].

8.6. Pregnancy

Five to 10% of women with RP report decreased vision during pregnancy that often does not recover postpartum, without objective data confirming this; pregnancy changes refraction and increases the risk of central serous chorioretinopathy and progression of pre-existing diabetic retinopathy [4]. Based on the evidence it reviewed, the Spanish guideline suggests not discouraging pregnancy because it does not increase progression risk, and proposes more frequent ophthalmic examinations during pregnancy and breastfeeding [21]. Both sources agree in warning about the teratogenicity of high-dose vitamin A [4, 21], and the acetazolamide label states teratogenicity in animals and use during pregnancy only if the benefit justifies the risk [61]. There are no studies of voretigene neparvovec in pregnant women [8].

8.7. RLBP1-associated dystrophy

Inheritance is autosomal recessive: the parents of a patient are obligate heterozygotes, usually asymptomatic, and each sibling has a 25% risk of being affected and a 50% risk of being a carrier [4, 15]. In populations with founder variants, such as Västerbotten (p.(Arg234Trp)), Newfoundland (splicing variants NM_000326.5:c.141G>A and c.141+2T>C) and Moroccan families with the deletion of exons 7 to 9, the probability that the partner is a carrier is higher than in the general population and justifies, once the familial variants have been identified, carrier testing of the partner and cascade testing of relatives [17, 41, 46]. The allelic combination guides the prognosis conveyed to the family, but intrafamilial variability with the same genotype, documented in sisters with Bothnia dystrophy, prevents accurate prediction of severity in an affected sibling [41]. Prenatal diagnosis and preimplantation genetic testing are technically possible when both familial variants have been identified, as set out in section 8.4 [4].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence

GeneReviews estimates a prevalence of 1:3,000 to 1:7,000 (14–33 per 100,000), approximately 1:3,500 to 1:4,000 in the USA and Europe, and a lifetime risk of 1:2,500 in Denmark [4]. Orphanet describes 1:3,000 to 1:5,000 without ethnic specificity, but with possible founder effects [3]. The Portuguese guideline estimates IRDs as a whole at approximately 1 in 2,000–3,000 people, more than 2 million worldwide [20]. Nguyen and colleagues cite ranges from 1 in 750 to 1 in 9,000 depending on the region, higher in consanguineous or isolated populations [2].

In Spain, the PREVARET study estimated a prevalence of identified IRD cases of 1 per 19,000 inhabitants, well below genetic population estimates, with more than 15,000 affected individuals and approximately 500,000 estimated carriers [21]. The discrepancy illustrates the difference between cases identified in services and population prevalence. In France, the PNDS for genetic maculopathies states that these account for approximately 15% of the IRDs seen in a reference centre specialised in retinal disease, a proportion of the hospital caseload and not of the population, and cites prevalences of approximately 1 in 10,000 for Stargardt disease and 1 in 10,000 to 1 in 20,000 for Best disease, without stating the primary source or the population of origin [22].

Distribution by mode of inheritance varies with population and method. In Maine, 19% of families were autosomal dominant, 65% recessive or isolated, and 8% X-linked [88]; in Denmark, among non-systemic cases, 14.3% were X-linked, 8.4% dominant and 42.9% simplex [51]; in the United Kingdom, approximately 15% of patients have xlRP [1].

9.2. Founder variants and genes

The CERKL c.238+1G>A variant was described by the authors without a transcript in the abstract; VariantValidator confirms that the description is valid in the MANE transcript NM_201548.5, but correspondence with the original transcript was not checked in the full article [28, 90]. The absence of broader Brazilian population data in the consulted sources does not mean that none exist.

RLBP1-associated dystrophy illustrates the difference between regional and global prevalence. Approximately 160 cases had been published by 2023, mainly from Sweden and Canada, concentrated in Västerbotten and Newfoundland [18]. The estimate of 1:4,500 refers to the area studied in northern Sweden and not to the Swedish population [17]. For RPA, Orphanet records a point prevalence of 1–9 per 1,000,000 (mean value of 0.125 per 100,000 worldwide and 0.175 per 100,000 in Europe), and the French series cites approximately 1% of autosomal recessive rod–cone dystrophy; for Bothnia dystrophy Orphanet has no estimate [16, 41]. In southern France, NFRCD was the most frequent form (17 of 21 patients) and classic RPA the least frequent (2 of 21), in a cohort in which 12 patients were of Moroccan and 1 of Algerian origin [41]. A Russian registry of 2,425 patients with IRDs from 83 regions, set up between 2022 and 2025 to estimate the prevalence of RPE65- and RLBP1-associated forms, presents no quantitative data on RLBP1 in the abstract [92]. The sources consulted contain no data from Portugal or Brazil for this gene.

9.3. Special populations

Children: diagnosis requires adaptations (sedation, handheld OCT, repeated fields), and multigene panels have a high yield in children; surveillance is more frequent [6, 20]. Female xlRP carriers: see section 8.3. Deafblind patients (Usher): the Spanish guideline suggests communication facilitators (lighting, an interpreter, sign language, adapted tests) and adapted sexual education programmes [21]. Consent: the Portuguese guideline proposes audio recordings, Braille versions, large-print and high-contrast documents, impartial witnesses and assistive technologies to ensure accessible informed consent [20].

10. Illustrative Clinical Case

10.1. Portuguese family with RHO p.(Gly182Asp): typical and sectoral RP in the same family

Teixeira-Martins and colleagues, from the São João Local Health Unit (Porto), described in 2026 four patients over three generations of a Portuguese family, all with nyctalopia of varying degree and no systemic disease [93]. The index case, a 17-year-old young woman, underwent a next-generation sequencing panel of 124 RP genes, which identified the heterozygous RHO variant NM_000539.3:c.545G>A, p.(Gly182Asp), located in the extracellular/intradiscal domain of rhodopsin and registered in ClinVar (ID 1038982); targeted Sanger sequencing confirmed the variant in her father and a paternal aunt, and no other pathogenic or likely pathogenic variants were found in retinal dystrophy genes, including ABCA4, PRPH2, ROM1 and CNGB1 [93]. The variant description was confirmed in VariantValidator using the MANE Select transcript [28]. The 71-year-old grandfather was not tested in the published sources, and his diagnosis is presumed from the clinical presentation [93].

All patients underwent acuity testing (ETDRS), slit-lamp examination, fundus photography, blue-light autofluorescence, spectral-domain OCT, Goldmann kinetic perimetry, and full-field and multifocal ERG according to the ISCEV standard [93]. The pedigree is in Figure 1 and multimodal imaging in Figure 2 of the original article.

Full-field ERG was abnormal in all patients, most severely in the grandfather [93]. The aunt with cystoid changes was treated with 2% dorzolamide twice daily, with partial reduction of the cystoid spaces and stable acuity during follow-up; the grandfather was followed privately, with no further information [93]. The article text contains an inconsistency in patient numbering between the genetics section and Table 1; the description above follows the ages and family relationships in Table 1 and the Figure 1 legend.

Teaching points. The same variant produced sectoral RP in a 44-year-old man and typical RP in the others, with a severity gradient by age and generation [93]. Even in typical cases, degeneration predominated in the inferior retina, with a superior field defect, a pattern the authors relate to the greater light vulnerability described in extracellular RHO variants [93], consistent with the inferonasal gradient of class B variants [29]. Investigation of digenic modifiers was negative on the panel, but does not exclude deep intronic or structural variants [93]. The dorzolamide regimen used in the case is an individual clinical decision, different from the three-times-daily regimen cited in reference sources, and should not be generalised [21, 60, 93]. For counselling, each child of a carrier has a 50% probability of inheriting the variant, but age at onset and severity cannot be predicted from genotype [4].

10.2. Two French sisters with Bothnia dystrophy due to p.(Arg234Trp) in trans with a null allele

In the series from the Montpellier reference centre, two sisters were compound heterozygous for the Bothnia variant NM_000326.5:c.700C>T, p.(Arg234Trp), in exon 8, and for the nonsense variant c.333T>G, p.(Tyr111Ter), in exon 5, probably subject to nonsense-mediated mRNA decay, so that only the Bothnia allele would produce protein [41]. The sister examined at 23 years had had nyctalopia since the age of 2 and reading difficulties since childhood; the table records an initial acuity of 20/125 in the right eye and 20/40 in the left, and the figure legend gives 20/200 and 20/40 at 23 years and less than 20/200 in both eyes at 28 years [41]. Fundus photographs and infrared images showed a whitish retina, reduced vessel calibre, foveal and perifoveal atrophy in the right eye and bilateral optic disc drusen; on OCT, the ellipsoid and interdigitation zones were not visible and foveal thickness was markedly reduced in the right eye and reduced in the left (Figure 3) [41]. After 144 months of follow-up, at 35 years, acuity was 20/400 and counting fingers, and the visual field was classified as blindness [41]. Her sister, examined at 28 years, had had nyctalopia since the age of 3 and acuity of 20/32 and 20/25, which at 42 years, after 167 months, was 20/50 and 20/32, with no reading difficulties [41].

Teaching points. The family showed that Bothnia dystrophy may result from a Bothnia variant in trans with a null allele, and not only from homozygosity or compound heterozygosity for p.(Arg234Trp) and p.(Met226Lys), which broadens the genotype–phenotype correlation used to predict severity and select candidates for gene therapy [41]. The difference in course between sisters with the same genotype shows that the allelic combination defines a clinical form but does not fix the rate of progression of each patient [41].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

In general, earlier onset predicts a worse prognosis, and marked intrafamilial variability is common [1]. In most cases, except mild or sectoral forms, RP progresses to legal blindness [3]. Acuity loss correlates with macular lesions present at baseline, and a flat standard ERG is associated with a high probability of central acuity loss over the next five years [4, 21]. In EYS-associated RP in Portugal, atypical forms had better acuity, a wider ellipsoid zone and less annual letter loss than typical forms [33]. In CNGB1-associated RP, central vision is maintained for long periods [36]. No validated estimate of lifetime gene-specific blindness risk exists for most genotypes in the consulted sources.

In RLBP1-associated dystrophy, prognosis depends on the allelic combination: NFRCD leads to legal blindness in the third decade, Bothnia dystrophy to legal blindness in early adulthood through early maculopathy, and RPA with missense or hypomorphic alleles may retain useful acuity for decades [17, 41, 49]. In the prospective study of adults with established disease, functional and structural means did not change over five years, although some patients worsened [18].

11.2. Surveillance

The sources agree on annual to biennial assessments in adults and differ in the detail of examinations; selection should account for stage, gene, complications and trial eligibility. The French PNDS, written for maculopathies, separates the annual local consultation from periodic reassessment in a specialised centre and does not include the ERG in routine surveillance, unlike the AAO, which retains it when appropriate, and the Spanish guideline, which repeats it every 2–3 years while a response remains; the PNDS itself gives two intervals for the specialised centre (2–3 years in the summary, 3 years in the follow-up chapter) [6, 21, 22]. The same document includes among the objectives of follow-up the coordination of care, informing the treating physician about advances in knowledge, and the transition from paediatric to adult services at the end of adolescence, prepared so as to avoid interruption of follow-up [22]. In syndromic forms such as Usher syndrome, initial and ongoing ENT or audiological assessment should be added [6], and patients with RP or cone–rod dystrophy should be referred to ENT if hearing loss is suspected [21]. In patients treated with voretigene neparvovec, regular follow-up with multimodal imaging and efficacy measures is recommended to monitor chorioretinal atrophy [68].

11.3. Networks and resources

ERN-EYE (European Reference Network for Rare Eye Diseases) provides an online training programme on IRDs and the CPMS platform mentioned on its website; on the consensus page consulted, the only published consensus was that on Bardet-Biedl syndrome (2024) [23]. GeneReviews lists Foundation Fighting Blindness, the American Council of the Blind, the National Federation of the Blind, Retina International and the National Eye Institute eyeGENE registry [4]; the AAO adds the American Foundation for the Blind, Fighting Blindness Canada, CNIB Foundation and the National Council of State Agencies for the Blind [6]; the Oxford Desk Reference mentions RP Fighting Blindness, the Royal National Institute for the Blind, the Macular Society, Fight for Sight and SENSE [1, 26]. The Portuguese guideline values collaboration with patient associations [20].

In France, care for IRDs is organised within SENSGENE, the health network (filière de santé) for rare sensory diseases, which liaises with ERN-EYE [22]. The PNDS for genetic maculopathies recommends that follow-up be directed by an expert in a reference or competence centre, who builds the care network close to the patient’s home; the reference centres cited are REFERET (retinal and macular disorders of genetic origin, Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris), MAOLYA (genetic sensory disorders, CHU de Montpellier), CARGO (rare disorders in ophthalmic genetics, CHU de Strasbourg) and OPHTARA (rare ophthalmic diseases, Hôpital Necker-Enfants malades, Paris), in addition to the reference centre for genetic deafness (Necker), relevant to syndromic forms, and a network of competence centres in the regions, including the overseas territories (Saint-Denis, Réunion) [22]. The general practitioner and the treating ophthalmologist have four roles: to suspect the diagnosis and refer to a reference or competence centre; to ensure regular follow-up with teams trained in visual impairment and low-vision rehabilitation; to coordinate medico-social aspects (100% coverage by health insurance, as a condition outside the list of long-term illnesses, and an application to the Maison départementale des personnes handicapées, MDPH, which also supports requests such as that for a guide dog); and to direct patients to appropriate medico-social structures, including adult rehabilitation in specialised institutes, such as ARAMAV or the Centre André Mathis [22]. The social worker supports administrative procedures, school integration, vocational guidance and information on disability legislation, with the participation of the maternal and child health physician, the school physician and the occupational physician [22]. The patient associations listed (a non-exhaustive list) include Retina France, Information Recherche Rétinite Pigmentaire (IRRP), SOS Rétinite, the Fondation Stargardt, RETGEN, the Fédération des Aveugles de France, the Association Valentin Haüy and Histoire de voir un peu; referral to associations should always be offered, the choice remaining with the patient, and they may take part in therapeutic education [22].

12. Summary and Final Considerations

Retinitis pigmentosa is a group of inherited retinal dystrophies defined by primary rod loss and secondary cone loss, with a prevalence of 1:3,000 to 1:7,000, more than 80 genes in the non-syndromic form, and autosomal dominant, recessive, X-linked, digenic or mitochondrial inheritance [1, 4]. Nyctalopia, ring scotoma, arteriolar attenuation, bone-spicule pigment and ERG showing rod dysfunction support the clinical diagnosis, which should be supplemented by exclusion of treatable systemic diseases, particularly Refsum disease, abetalipoproteinaemia, vitamin E deficiency and gyrate atrophy [4, 26].

Multigene genetic testing, with copy number analysis and attention to difficult regions such as RPGR ORF15, resolves approximately half to four-fifths of cases and is now recommended for almost all patients by American and Portuguese guidance; a negative result does not exclude genetic disease [4, 6, 20]. Counselling should consider the possibility of xlRP in apparently dominant pedigrees, variable expression in female carriers and incomplete PRPF31 penetrance [31, 56, 86].

Current management treats complications (CMO with carbonic anhydrase inhibitors used off-label; cataract surgery with anti-inflammatory prophylaxis), avoids high-dose vitamin E and tobacco, offers visual rehabilitation and psychological support, and maintains surveillance every 1–2 years [4, 6, 21]. Voretigene neparvovec remains the only authorised gene therapy, restricted to biallelic RPE65 disease [8, 9]. In RPGR-associated xlRP, two randomised trials failed to meet their primary endpoint and the 2026 meta-analysis did not demonstrate an actionable functional benefit, although the botaretigene sponsor is preparing regulatory submissions [10, 11, 71]. In optogenetics, the sponsor reported in September 2026 that the FDA had accepted an application for authorisation of MCO-010 based on data not yet published in a peer-reviewed journal, whereas AGN-151597 showed no efficacy [12, 80]. Interpreting these developments requires distinguishing published results, sponsor press releases, accepted applications and actual authorisations.

The French PNDS for genetic maculopathies (2021) adds to the common IRD care pathway autofluorescence as a guiding test, replacing fluorescein angiography, full-field ERG as the mandatory discriminator between maculopathy, cone dystrophy and mixed dystrophy, first-line access to genome sequencing under the national genomic medicine plan, avoidance of vitamin A from the moment Stargardt disease is suspected, rehabilitation centred on eccentric fixation, and annual surveillance with reassessment in a specialised centre every 2–3 years, organised within the SENSGENE network [22].

In RLBP1-associated dystrophy, the combination of the two alleles separates classic RPA, Bothnia dystrophy and NFRCD, dark adaptation of approximately 6 hours is the constant functional feature, testing for deletions is part of genetic testing, and subretinal gene therapy improved dark adaptation kinetics in a phase 1/2 trial without gains in measures of central vision [18, 41, 43].

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