PRPH2-Related Retinopathies

The peripherin-2 allelic family: pattern dystrophies of the pigment epithelium (butterfly-shaped dystrophy, adult-onset foveomacular vitelliform dystrophy, multifocal pattern dystrophy simulating fundus flavimaculatus or "pseudo-Stargardt"), central areolar choroidal dystrophy (CACD2), autosomal dominant retinitis pigmentosa (RP7) and digenic RP with ROM1, retinitis punctata albescens, cone and cone-rod dystrophies, and the rare recessive forms (Leber congenital amaurosis 18 and early-onset dystrophies).

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview and clinical descriptions

The disorders now grouped under the PRPH2 gene were described, over several decades, as separate clinical entities with no apparent relationship. Central areolar choroidal atrophy was described by Sandvig in 1955, in a Norwegian family with 13 cases across four generations and autosomal dominant transmission [5]. In the 1970s and 1980s, Hsieh, Marmor and Byers, Watzke, and de Jong and Delleman described the pattern dystrophies of the retinal pigment epithelium and observed, in the same family, the coexistence of reticular, macroreticular and butterfly-shaped dystrophy and fundus pulverulentus, which led them to question the autonomy of each form and to propose that they were expressions of a single pigment epithelium dystrophy [1]. In 1974, Gass described the adult "peculiar foveomacular dystrophy", with subfoveal vitelliform lesions one third of a disc diameter in size and onset between 30 and 50 years, later called adult-onset foveomacular vitelliform dystrophy [2].

1.2. Milestones of molecular discovery

The link between these disorders and a single gene began with the retinal degeneration slow (rds) mouse model, a semidominant null allele in which photoreceptor outer segments fail to develop and rods and cones degenerate slowly; the gene, cloned by Travis and colleagues in 1989, encodes a 346-amino-acid protein, peripherin/rds [10]. In 1991, Farrar and colleagues identified, in a large Irish family with late-onset autosomal dominant retinitis pigmentosa linked to the short arm of chromosome 6, a three-base-pair deletion that removes one of the conserved cysteines of the third transmembrane domain of peripherin [34]; in the same issue of Nature, Kajiwara and colleagues described three mutations of the human homologue that cosegregated with the disease in different families [35]. In 1993, three papers published in the same issue of Nature Genetics broadened the spectrum: Wells and colleagues showed that substitutions at codon 172 cause macular dystrophy and that a stop codon at codon 258 causes adult vitelliform dystrophy, concluding that the same gene can cause retinitis pigmentosa or macular dystrophy [36]; Nichols and colleagues identified the codon 167 substitution in butterfly-shaped dystrophy of the fovea [37]; and Kajiwara and colleagues described a null allele in a family with autosomal dominant retinitis punctata albescens, which they proposed as the human phenotype equivalent to that of the rds mouse [15]. Also in 1993, Weleber and colleagues documented, in a single family with a one-codon deletion (153 or 154), retinitis pigmentosa, pattern dystrophy and a fundus flavimaculatus picture, the most cited demonstration of intrafamilial variability [38]. In 1994, Kajiwara, Berson and Dryja showed that retinitis pigmentosa could result from the combination of a PRPH2 p.(Leu185Pro) variant with a null allele of ROM1, an unlinked gene, only in double heterozygotes, one of the first examples of digenic inheritance documented at the molecular level [10, 13]. In 1996, Hoyng and colleagues identified the p.(Arg142Trp) variant in seven Dutch families with central areolar choroidal atrophy [39], and Boon and colleagues showed in 2009, in 103 patients, that this variant is a founder variant in the south-east of the Netherlands [20].

1.3. Nomenclature and reclassifications

The gene symbol changed from RDS to PRPH2, and the protein is called peripherin-2 to distinguish it from the neuronal peripherin encoded by PRPH [9, 10]. The form of retinitis pigmentosa linked to 6p was first designated RP6 and later corrected to RP7, because the symbol RP6 belongs to an X-linked form [6]. Adult-onset foveomacular vitelliform dystrophy has received several synonymous designations (adult vitelliform macular dystrophy, pseudovitelliform macular degeneration, adult foveomacular pigment epithelial dystrophy) and, in OMIM, is vitelliform macular dystrophy 3 (VMD3) [2]. In the recent literature, the disorders of the gene are collectively called "PRPH2-associated retinopathy", "peripherinopathy" or PRPH2-associated retinal degeneration (PARD) [40, 41]. For phenotypic classification with multimodal imaging, the largest international cohort uses six groups based on fundus autofluorescence: normal, vitelliform dystrophy (VMD), butterfly-shaped pattern dystrophy (BPD), central areolar choroidal atrophy (CACD), pseudo-Stargardt pattern dystrophy (PSPD) and retinitis pigmentosa [4]. The French National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé (HAS) groups the macular phenotypes of the gene under four names: pseudo-Stargardt, adult pseudovitelliform dystrophies with small-sized material, pattern dystrophies with variably arranged hyperautofluorescent deposits, and dominant central areolar atrophy [19].

1.4. Definition of the entities within scope

Pattern dystrophies are a heterogeneous group of macular disorders characterised by abnormal accumulation of lipofuscin in the pigment epithelium, most evident in the macula, with variable distribution of sizes and shapes; three main varieties are described (reticular, macroreticular and butterfly-shaped), and the group also includes fundus pulverulentus and, according to Orphanet, multifocal pattern dystrophy simulating fundus flavimaculatus [1, 3, 21, 42]. Adult-onset foveomacular vitelliform dystrophy is defined by an oval, yellow, slightly elevated subfoveal lesion, one third to one disc diameter in size, with symptoms in the fourth or fifth decade and a normal or slightly reduced electro-oculogram [2, 23]. Central areolar choroidal atrophy is a hereditary macular dystrophy with a well-defined area of atrophy of the pigment epithelium and choriocapillaris in the centre of the macula and loss of acuity generally between 30 and 60 years [5, 12]. Retinitis pigmentosa 7 is the autosomal dominant form of rod-cone dystrophy caused by PRPH2, which includes the digenic form with ROM1 [6]. Retinitis punctata albescens is characterised by scattered white dots in the fundus, night blindness and significant visual loss in the fifth and sixth decades [25]. The rare recessive forms comprise Leber congenital amaurosis 18 and early-onset dystrophies due to biallelic variants, as well as an autosomal recessive macular and cone dystrophy described in two families from Calabria [16, 18]. These entities are treated as a single allelic family, with a common description and subsections by phenotype; Stargardt disease, Best disease and the other vitelliform dystrophies, retinitis pigmentosa in general, cone and cone-rod dystrophies and Leber congenital amaurosis are part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The PRPH2 gene and peripherin-2

PRPH2 is located at 6p21.1 (GRCh38 coordinates 6:42,696,598–42,722,597) and the MANE Select reference transcript is NM_000322.5, which encodes the protein NP_000313.2 [10, 11]. The described variants are distributed across three exons and introns 1 and 2, where recurrent splicing variants such as c.582-1G>A, c.828+1G>A and c.828+3A>T are located [4]. The protein has 346 amino acids, 92% homology with the mouse protein, four hydrophobic transmembrane domains, two possible N-glycosylation sites and two intradiscal loops, D1 and D2, the latter between the third and fourth transmembrane domains [10, 32]. It belongs to the tetraspanin family and is located at the rim of the outer segment discs of rods and cones [9, 32]. The D2 loop contains conserved cysteines (Cys165, Cys213, Cys214 and Cys222, among others) that form intramolecular and intermolecular disulphide bonds, required for correct folding and subunit assembly; the C-terminal region is involved in targeting to the outer segment, membrane fusion and generation of curvature [17, 32]. The atomic structure of peripherin-2 and ROM1 was solved by cryo-electron microscopy in 2022 [43].

2.2. Function: disc morphogenesis and maintenance

Peripherin-2 and its homologue ROM1 associate into non-covalent tetramers, which in turn form higher-order oligomers linked by disulphide bonds; these complexes reinforce the highly curved rims of the flattened outer segment discs and are required for their formation and correct diameter [10, 14]. Peripherin-2 also suppresses the release of ectosomes from the photoreceptor ciliary membrane, allowing their retention and incorporation into discs; in its absence, discs do not form and outer segment structure is lost [32]. Complete absence of Prph2 prevents formation of rod outer segments, whereas cone outer segments form, albeit abnormally, indicating different requirements in the two photoreceptor types; with only one functional allele, rod and cone outer segments are shortened and disorganised [32]. Because it is present in both rods and cones, a defect of the same protein can manifest as rod-driven peripheral degeneration or as cone-driven maculopathy, which constitutes the structural basis of the phenotypic breadth [9].

2.3. Molecular mechanisms

The most frequent mechanism is haploinsufficiency: photoreceptors are sensitive to the total amount of functional peripherin-2 [32]. In mouse models of digenic and dominant RP, degeneration resulted from a simple deficiency of RDS and ROM1, with a critical threshold of combined abundance of about 60% of normal, below which outer segment disorganisation causes photoreceptor degeneration [10]. Some variants act through gain-of-function or dominant-negative mechanisms: in the transgenic mouse with p.(Arg172Trp), cone and rod structure and function declined in the presence of the normal allele, with a preferential effect on cones, and the mutant protein showed a conformational change [10]. In the p.(Tyr141Cys) knock-in mouse, the mutant and normal proteins formed abnormal disulphide complexes that localised to the outer segment and compromised its structure, with late hyperfluorescent spots and defects of the scotopic and photopic electroretinogram, supporting a model in which the primary photoreceptor defect produces secondary consequences in the pigment epithelium and choroid [10]. The p.(Pro210Arg) variant retains binding to Rom1 but accumulates in the endoplasmic reticulum, indicating misfolding [44]; p.(Leu254Gln), recurrent in France, causes protein aggregation [29]; and loss of disulphide bonds in p.(Cys165Tyr) and p.(Cys213Tyr) reduces protein stability [32]. The c.828+1G>A splicing variants activate a cryptic site with intron retention, documented in induced pluripotent stem cells and retinal organoids [45]. Accumulation of lipofuscin in the pigment epithelium, characteristic of pattern dystrophies, has been documented histopathologically in adult-onset foveomacular vitelliform dystrophy, with focal atrophy of the outer nuclear layer and photoreceptor degeneration [1, 2].

2.4. Inheritance

The great majority of PRPH2 retinopathies have autosomal dominant inheritance, with incomplete penetrance and highly variable expressivity [19, 32]. OMIM records autosomal dominant, autosomal recessive and digenic forms for the same gene, and the sources confirm both monogenic patterns: in the Spanish cohort, 102 of 103 families had heterozygous variants and one had homozygous p.(Gly208Asp), and in the Coimbra series inheritance was predominantly dominant, with a single recessive case, homozygous for NM_000322.5:c.622G>T p.(Gly208Cys) [10, 17, 46]. The GeneReviews overview of LCA classifies PRPH2 in this disease as mainly recessive in inheritance, with rare dominant cases, generally de novo [8]. The digenic form requires simultaneous heterozygosity for a PRPH2 variant and a ROM1 variant; in all published digenic cases the PRPH2 variant was the same, NM_000322.5:c.554T>C p.(Leu185Pro), associated with three different ROM1 variants, and no RP caused by a heterozygous ROM1 variant alone has been identified [14, 28, 47].

2.5. Variant spectrum

More than 200 pathogenic variants have been described, 318 to 352 variants in the Human Gene Mutation Database depending on the version, and about 70% of causal variants lie in the D2 loop [4, 17, 32]. In the international cohort of 241 patients, the 91 unique variants included 46 missense, 21 frameshift, 12 nonsense, five in-frame deletions, four splicing, two exonic deletions and one start-loss variant; 45 of the 51 variants altering the protein sequence were located in the D2 loop [4]. In the Spanish cohort, missense variants accounted for 64% of proband alleles and truncating variants for 28% [17]. The variants of greatest clinical relevance are normalised in the following table; historical nomenclature, based on other numbering origins of the complementary DNA, differs in some cases from current HGVS.

Normalisation was performed in VariantValidator for the MANE Select transcript [11]. The c.582-1G>A variant, described in a family with a benign concentric annular macular dystrophy phenotype and in patients with PSPD, and deletions of exon 1 and exon 3, identified by CNV analysis, complete the spectrum of non-missense variants [4, 57]. In two families with butterfly-shaped dystrophy and vitelliform dystrophy (Finland and USA), panels suggested a heterozygous 482 bp duplication of exon 2, and long-read nanopore sequencing showed duplications of almost 4 kb with breakpoints in intronic Alu elements, absent from gnomAD; the true size and structure of these variants could not be resolved by short-read sequencing [58].

2.6. Founder variants and geographical distribution

p.(Arg142Trp) was found in 98 of 103 Dutch patients with CACD, from 45 families, 96 of whom originated from the south-east of the Netherlands, with a shared chromosomal segment of about 519 kb; in a screen of 57 asymptomatic controls over 70 years of age from the same region, a 76-year-old man was a carrier and had early stage II CACD [10, 20]. p.(Arg172Trp) was identified in 11 British families with a common haplotype absent from 50 controls from the same population [48]. p.(Tyr141Cys) showed a common ancestral haplotype in three North American families [52]. In the US eyeGENE registry (187 participants, 161 families), the most frequent variant was c.828+3A>T, in 28 families (17.4%) [55]. In the Spanish cohort of 103 families, the most recurrent variants were p.(Gly167Ser), p.(Gly208Asp) and p.(Pro221_Cys222del), and p.(Leu41Pro) (five families from the Basque Country, 4.8% of alleles) and p.(Pro221_Cys222del) (5.8% of alleles) shared haplotypes, suggesting a founder effect; by contrast, c.828+3A>T was not found and p.(Arg142Trp) accounted for 3.9% of alleles [17]. The same comparison recorded p.(Gly305AlafsTer19) in 33.3% of alleles in a Chinese cohort and p.(Arg142Trp), p.(Arg172Trp) (13.3% each) and p.(Val200Glu) (10.0%) in a Japanese cohort [17]. A novel variant shared by five carriers from the Cook Islands, in the Pacific, has been proposed as a founder variant in an isolated population [59].

2.7. Genotype-phenotype correlations

Correlations are partial. Keen and Inglehearn observed, in 1996, that variants associated with dominant RP and severe macular degeneration were mainly missense or small deletions in the D2 loop, whereas those associated with the milder pattern dystrophies and digenic RP were distributed throughout the gene and were often nonsense [60]. In the 2024 international cohort, the most robust correlation was that of CACD, observed in 71 patients with 13 missense variants at 10 codons (Arg142, Arg172, Asp186, Arg195, Ile196, Val200, Gly208, Pro219, Thr228 and Ala232), with no case of CACD among the 85 patients with truncating, splicing or start-loss variants, who were distributed across PSPD (58%), butterfly or vitelliform (21%), RP (16%) and normal autofluorescence (5%) [4]. In an Italian series of 19 patients, D2 loop missense variants were associated with cone-rod dystrophy and a poor visual prognosis, and loss-of-function alleles with pattern dystrophies with good visual function in adulthood [40]. Among CACD variants, p.(Arg172Trp) was associated with earlier onset and significantly worse acuity than p.(Arg142Trp) (p<0.001) and p.(Arg172Gln) (p=0.04) up to 60 years, the age from which most had acuity below 6/60 [5, 49]; in the eyeGENE registry, p.(Arg172Trp) was also associated with younger onset [55]. In a North American cohort followed for a mean of 14 years, p.(Leu185Pro) carriers had pattern dystrophy in the fourth and fifth decades and better acuity, and c.828+3A>T carriers had fundus flavimaculatus-like flecks with diffuse CACD-like atrophy in the fifth decade, with worse acuity [54]. By contrast, the Oxford (36 patients) and Spanish cohorts found no clear correlations, and the same variant may give different phenotypes in the same family [17, 61, 62].

2.8. Penetrance and expressivity

In the international cohort of 241 carriers, 13 (about 6%) had no macular changes on fundus photography or autofluorescence, an observation recorded up to 71 years of age; 20 patients were asymptomatic at the last visit [4]. In the Dutch CACD cohort with p.(Arg142Trp), non-penetrance reached up to 21% of carriers, up to 64 years of age [20], and in the original Hoyng family a 65-year-old female carrier with 20/20 acuity had no posterior pole changes [39]. For p.(Arg172Trp), non-penetrance up to 24 years has been described and, in a Spanish family, asymptomatic carriers with irregular pigmentation of the pigment epithelium [4, 10]. In the Spanish cohort, 9% of carriers were asymptomatic at the last visit [17]. In the Portuguese Coimbra series, a heterozygous carrier of c.594C>A p.(Ser198Arg) had normal widefield autofluorescence, whereas other carriers of the same variant in the series had extensive macular atrophy or diffuse macular and peripheral changes [46]. The French PNDS stresses that dominant inheritance may not be evident because there are asymptomatic carriers and phenotypic variation [19]. These values are proportions from cohorts recruited at tertiary centres and not estimates of lifetime penetrance in the population.

2.9. Genetic modifiers

The variability is attributed to genetic and environmental modifiers, but few have been demonstrated [32]. In a study cited by the 2024 cohort, patients with isolated p.(Arg172Trp) had macular dystrophy, whereas those who also had ROM1 or ABCA4 variants had a more severe phenotype; another study excluded ROM1 as a modifier of the RP phenotype [4]. In mouse models, removal of Rom1 shifted the p.(Tyr141Cys) phenotype from pattern dystrophy to RP, and its reduction improved rod function in p.(Lys154del), without altering other variants, so the modifying effect of ROM1 depends on the variant [32]. Homozygosity for a ROM1 loss-of-function variant, c.712delC, caused in a 63-year-old woman a late-onset macular pattern dystrophy mimicking ABCA4- or PRPH2-related disease, a molecular differential diagnosis [63].

2.10. Allelic disorders

The same gene causes, in decreasing order of frequency in the cohorts, pseudo-Stargardt pattern dystrophy, CACD, butterfly-shaped and adult vitelliform dystrophies and RP, as well as cone and cone-rod dystrophies, retinitis punctata albescens and, when homozygous, LCA18 and juvenile RP [4, 6, 10]. Wang and colleagues identified three homozygous probands with early-onset dystrophy: two with p.(Leu185Pro), a 66-year-old woman with LCA from birth and a 30-year-old woman with juvenile RP from nine months of age, and a 29-year-old woman with LCA from eight months of age homozygous for p.(Cys213Arg); the asymptomatic heterozygous parents had macular pattern dystrophy [6, 16]. In two Calabrian families, the first autosomal recessive macular and cone dystrophy due to a homozygous variant was described [18]. PRPH2 maculopathies are strictly ocular disorders, without systemic manifestations [19]; a PRPH2 variant associated with RP has been described as a secondary exome finding in a patient with pseudoxanthoma elasticum [64].

3. Clinical Spectrum and Manifestations by Organ System

3.1. Overview: an adult disease with a continuous spectrum

PRPH2 retinopathies are strictly ocular disorders and, in most patients, disorders of adulthood [19]. In the international cohort of 241 patients from 168 families, recruited at 15 centres in nine countries (including the Portuguese IRD-PT registry, in Coimbra), the median age at symptom onset was 40 years (interquartile range 30–50; extremes 4–78), median visual acuity was 0.18 logMAR (about 20/30) in each eye, and the distribution of autofluorescence phenotypes was as follows: PSPD 41%, CACD 28%, RP 15%, butterfly-shaped or vitelliform dystrophy 11% and normal autofluorescence 5% [4]. The abstract of the same article gives 25% for RP, a value that does not match the 35 of 241 patients in the results table (15%). Acuity remained stable on average until the fifth decade and declined thereafter, and 22.8% of patients had interocular asymmetry greater than 0.3 logMAR [4]. In the Spanish cohort (182 patients with a known phenotype), the distribution was different, with macular dystrophy in 57%, cone or cone-rod dystrophy in 15%, RP in 19% and asymptomatic carriers in 9% [17]. In Oxford (36 patients), PSPD (47.2%), pattern dystrophy (25.0%) and adult vitelliform dystrophy (22.2%) predominated, with RP in 2.8% [61]. The differences reflect different classification criteria and referral pathways (medical retina, genetics or electrophysiology centres) and not demonstrated population differences. In a widefield imaging analysis of 144 eyes of 72 North American patients, 61.8% of eyes had combined macular and peripheral phenotypes, 30.6% macular only and 7.6% peripheral only, and 49.3% had concomitant outer retinal atrophy [65]. PRPH2 is the fourth most frequent cause of inherited retinal dystrophy in the United Kingdom (5.2%), and PRPH2 pattern dystrophies are often confused with age-related macular degeneration (AMD), Stargardt disease or Best disease [4, 32].

3.2. Pattern dystrophies: butterfly-shaped, reticular and fundus pulverulentus

Butterfly-shaped dystrophy is characterised by bilateral accumulation of yellowish or pigmented material at the level of the pigment epithelium, with a butterfly-wing distribution at the fovea; it shares clinical and histopathological features with AMD [22, 37]. Watzke and colleagues reported usual onset in the second or third decade, with great variability [1]. Many carriers are asymptomatic: in a family with six affected members across two generations, only two had unilateral visual loss, due to a disciform scar, and all those tested had a tritan defect in chromatic contrast sensitivity [1]. In the North American family of Yang and colleagues, the 31-year-old proband had mild metamorphopsia and 20/25 acuity, and his 69-year-old father and a 30-year-old sister had the same findings without complaints and with 20/20 [1, 52]. Orphanet describes slowly progressive visual loss that often becomes apparent only at an advanced age [22]. The reticular form (a hyperpigmented "knotted fishnet" pattern) and fundus pulverulentus (a granular appearance of the macula) belong to the same group; reticular dystrophy of the pigment epithelium is associated mainly with RCBTB1 and not with PRPH2 [42, 66]. In the 2024 cohort, the 27 patients with butterfly-shaped or vitelliform dystrophy had a median onset at 44 years and the best acuity of all groups (median 0.02 logMAR in the better eye), and most had a normal ERG or isolated macular dysfunction [4].

3.3. Adult-onset foveomacular vitelliform dystrophy

The typical lesion is single, oval, slightly elevated, yellow and subfoveal, one third to one disc diameter in size, sometimes initially unilateral, with small yellow paracentral spots [2]. Patients become symptomatic in the fourth or fifth decade with a prolonged decrease in acuity and mild metamorphopsia, and most retain reading vision throughout life [2]. In Gass's original series, onset was between 30 and 50 years, with normal ERG and colour vision [2]. Optical coherence tomography (OCT) shows the material between the neurosensory retina and the pigment epithelium, corresponding to late staining on angiography, and foveal thinning that explains the progressive visual loss and possible progression to a full-thickness macular hole [2]. Among 28 German patients with adult vitelliform dystrophy, 18% had PRPH2 variants [2], and in a French series patients with onset after 40 years had PRPH2 variants in 10.5% and no BEST1 variant [67]. The French PNDS describes PRPH2 pseudovitelliform dystrophies as those with the best prognosis within the spectrum of the gene and reports a genetic test yield of 70% in pseudovitelliform dystrophies [19]. Most adult vitelliform dystrophies remain without an identified genetic cause, and the IMPG1, IMPG2 and BEST1 genes explain another part [23].

3.4. Multifocal pattern dystrophy simulating fundus flavimaculatus (pseudo-Stargardt)

In ten unrelated families with multifocal pattern dystrophy with yellow-white flecks at the posterior pole, identical to those of Stargardt disease on ophthalmoscopy, autofluorescence and OCT, all probands had PRPH2 variants, and relatives with the same variant ranged from no changes to RP [62]. The authors concluded that PRPH2 is the main cause of this phenotype and that it should be distinguished from autosomal recessive Stargardt disease by its inheritance and better visual prognosis [62]. PSPD was the most frequent phenotype in the 2024 cohort (98 of 241 patients, median onset at 40 years) and showed the greatest electrophysiological heterogeneity: macular dysfunction in 21%, cone dystrophy in 11%, cone-rod dystrophy in 34% and rod-cone dystrophy in 34% of patients with an ERG [4]. In the widefield series, the fundus flavimaculatus type was the most frequent combined phenotype (37.5% of eyes) and the one most associated with atrophy (80.3%) [65]. In c.828+3A>T carriers, adult fundus flavimaculatus-like flecks progressed, in the fifth decade, to diffuse CACD-like atrophy and, from the sixth to the eighth, to extensive atrophy [54].

3.5. Central areolar choroidal dystrophy (CACD2)

CACD caused by PRPH2 mainly affects the macula, with a well-defined area of atrophy of the pigment epithelium and choriocapillaris at the centre and loss of acuity generally between 30 and 60 years [5]. The Hoyng staging classification ranges from subtle parafoveal changes to the well-demarcated atrophy of the final stage, and the 2024 cohort included in this category only stages 2 to 4, because stage 1 is difficult to distinguish from the vitelliform and butterfly-shaped forms [4]. In the Dutch cohort of 103 patients, the mean age at onset of visual loss was 46 years, followed by gradual deterioration, electrophysiology was compatible with central cone dystrophy and there were substantial changes in autofluorescence after a mean follow-up of 11 months; the age at onset and clinical appearance overlap with those of atrophic AMD, but the drusen-like lesions at the CACD margin show intense autofluorescence, unlike the basal laminar drusen of AMD [5, 20]. In the Hoyng families with p.(Arg142Trp), the lesions were smaller and did not connect to the optic disc, and disabling visual loss generally appeared only in the seventh decade, when atrophy reached the fovea [5]. With p.(Arg172Trp), symptoms (blurred central vision and photophobia) began in the third decade and acuity was below 6/60 by 40 years in the Wells families, with central atrophy and absolute central scotomas up to 20 degrees, without night blindness or loss of peripheral field [5, 10]. In 12 British families with codon 172 variants, referred with diagnoses as diverse as CACD, cone dystrophy, RP, Sorsby dystrophy and Stargardt disease, 17 of 19 patients had a common phenotype: a granular appearance of the pigment epithelium from the third decade, central macular dystrophy reaching the arcades by 50 years and peripapillary extension with age, an abnormal (generally extinguished) pattern ERG with a normal full-field ERG, and autofluorescence and pattern ERG abnormalities even in asymptomatic individuals [5, 68]. In the Swiss Zermatt family, with p.(Arg172Trp), adolescents had central pigmentary changes, young adults drusen-like deposits, and central geographic atrophy led to severe visual loss in the fifth decade [5]. In the 2024 cohort, the CACD group (68 patients) had the worst acuity in the better eye (median 0.2 logMAR), and the ERG ranged from normal to macular dysfunction, cone dystrophy and cone-rod dystrophy [4]. In a prospective study of seven p.(Gly208Asp) carriers, all with a CACD phenotype (four at stage IV and three at stage II), retinal thickness decreased significantly over one year and the area of decreased autofluorescence increased in atrophic eyes, with no significant change in microperimetric sensitivity [50].

3.6. Retinitis pigmentosa 7 and peripheral forms

In the original Irish family, RP was of late onset, with pigment deposits mainly in the inferior mid-periphery, initial loss of the superior field, reduction of rod responses on ERG from five years of age, night blindness in the fourth decade and loss of rod and cone responses in the fifth or sixth decade [6]. In 32 French families with PRPH2 adRP, severity was generally moderate: 78% of eyes had acuity between 1.0 and 0.5 (20/20–20/40) and 52% retained more than 50% of the visual field; some patients had vitelliform deposits or macular involvement, and pericentral RP, macular dystrophy and diffuse RP coexisted within the same family [6, 29]. A Japanese family with p.(Asn244Lys) had night blindness from early adolescence, reduced acuity and bull's-eye maculopathy at the end of the fourth decade, and almost extinguished rod responses on the ERG from nine years of age, with no complaints at that age [6]. RP was associated with the earliest onset in all cohorts: median of 33 years in the 2024 cohort and 24.5 years in the Spanish cohort, with median night blindness at 24 years [4, 17]. GeneReviews describes the typical course of RP in general: initial night blindness, mid-peripheral ring scotoma, field constriction, preservation of central acuity until late stages, posterior subcapsular cataract and cystoid macular oedema in 10–50% of patients [28]. Digenic PRPH2–ROM1 RP was found in one of 215 families with apparent adRP (0.5%) [28].

3.7. Retinitis punctata albescens

In the family described by Kajiwara and colleagues, a 59-year-old man with advanced retinal degeneration with macular involvement and peripheral subretinal spots had a two-base-pair deletion at codon 25; his 33-year-old daughter, a carrier, had no symptoms but showed attenuated vessels, subretinal spots and an ERG compatible with progressive degeneration [10, 15]. The OMIM entry groups fundus albipunctatus and retinitis punctata albescens and attributes the autosomal dominant form to PRPH2, distinct from the recessive forms due to RDH5 and RLBP1 [7]. The worldwide prevalence validated by Orphanet (0.125/100,000) refers to retinitis punctata albescens of all causes, mainly RLBP1 [9, 25].

3.8. Cone and cone-rod dystrophies

In the Spanish cohort, 15% of patients had cone or cone-rod dystrophy, with median onset at 41 years [17]. In the Italian series of 19 patients, D2 loop missense variants were associated with this phenotype and a worse prognosis [40]. With p.(Pro210Arg), in 11 patients, acuity ranged from 20/15 to 20/80, cone function was more impaired than rod function and the scotomas corresponded to atrophic lesions formed after regression of drusen [44].

3.9. Recessive and early-onset forms

The three homozygous probands of Wang and colleagues had onset between birth and nine months of age, constricted visual fields and a reduced to undetectable ERG; fundus examination showed multilobulated central atrophic maculopathy, sometimes with concentric rings of yellow deposits, vascular narrowing and salt-and-pepper or bone-spicule peripheral changes [6, 16]. In the Spanish family with homozygous p.(Gly208Asp), symptoms began in the second decade, earlier than in heterozygotes in the same cohort (third to sixth decade) [17]. In the Portuguese series, the only recessive patient, homozygous for c.622G>T p.(Gly208Cys), a substitution at the same codon 208 as p.(Gly208Asp), had on widefield autofluorescence a mottling of hypo- and hyperautofluorescence occupying the posterior pole and surrounding the optic disc; the publication does not state the age or visual function [46].

3.10. Complications

Macular neovascularisation is the most important treatable complication. It was found in five of 28 Italian patients [69], in 2 of 33 patients with adult-onset foveomacular vitelliform dystrophy (3 of 58 eyes) [2] and in two of seven members of a family with c.828+3A>T [56]. In a multicentre series of six patients with unilateral neovascularisation (median age 55 years), all had pattern dystrophy with multifocal flecks [31]. In Sorsby disease and Best disease, neovascularisation is more frequent (constant by around 50 years in the former and in 15% in the latter), and in Stargardt disease it is very rare [19]. In forms with an RP component, cystoid macular oedema and posterior subcapsular cataract follow the natural history of RP [28]. Progression to macular hole has been described in adult vitelliform dystrophy [2], and inferior retinoschisis developed in a patient with c.828+3A>T [56].

3.11. Visual function, quality of life and disease burden

In a 2023 Foundation Fighting Blindness survey (117 responses, 78% from the USA, mean age 57.8 years), symptoms began on average at 35.9 years and the diagnosis was established only at 44.2 years; 79% had more than one affected relative and 83% of those who knew the acuity of their better eye had 20/63 or better [32]. In a cross-sectional study with the NEI VFQ-25 questionnaire (22 patients), the median composite score was 76.9, and the lowest domain was vision-related mental health (59.4), followed by driving and distance activities (75.0 each) [70]. In Oxford, mean acuity went from 0.20 and 0.14 logMAR to 0.33 and 0.32 logMAR over a mean follow-up of six years [61]. In 12 patients followed for a mean of 4.7 years, the lesion radius on autofluorescence increased by 0.14 mm per year, and total macular volume decreased by 0.071 mm³ per year [71]. These data describe the natural history without targeted treatment, with short follow-up and small samples.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion arises mainly in an adult between the third and fifth decades with non-correctable, bilateral and generally symmetrical loss of central acuity, a central or paracentral scotoma (difficulty recognising faces and reading) and dyschromatopsia proportional to the loss of acuity, signs that the French PNDS regards as favouring a hereditary maculopathy [19]. The fundus findings that should prompt consideration of PRPH2 are yellowish or pigmented deposits at the level of the pigment epithelium in a butterfly, reticular or multifocal arrangement, a small subfoveal vitelliform lesion in an adult, fundus flavimaculatus-like flecks in an adult without confirmed Stargardt disease, and well-demarcated central atrophy of the pigment epithelium and choriocapillaris between 30 and 60 years of age [5, 19, 62]. A family history of "macular degeneration" in several relatives across successive generations, especially if some have received diagnoses of early AMD, Stargardt disease or RP, is a warning sign: in the family of Elhusseiny and colleagues, the seven members had been referred with diagnoses of retinal dystrophy, rod-cone dystrophy, macular degeneration and rod dysfunction, and the index patient had received diagnoses of presumed ocular histoplasmosis and Stargardt disease [56]. In Seddon's North American cohort, several patients were initially diagnosed as having geographic atrophy due to AMD, and had low genetic susceptibility to AMD and younger onset [54]. The absence of a family history does not exclude the diagnosis, because penetrance is incomplete and carriers may not know that they are affected [19].

4.2. Contexts by age

In childhood and adolescence, PRPH2 is rarely the cause; a severe dystrophy in the first months of life, with nystagmus and an undetectable ERG, in a consanguineous family, should prompt inclusion of PRPH2 in LCA panels [8, 16]. In autosomal dominant RP due to PRPH2, night blindness may appear in early adolescence and the ERG may be abnormal before any complaint [6]. In asymptomatic children of patients, miniature foveal lesions may be present at school age, such as the butterfly-shaped form in a seven-year-old child of a patient with LCA18 [1]. In adults aged 40 to 60 years, PRPH2 becomes the main hypothesis in the presence of a vitelliform lesion, and BEST1 analysis is more cost-effective when onset is before 40 years [67]. After 50 years, distinguishing it from AMD is the main problem: AMD is generally more asymmetrical, affecting one eye and then the other [19].

4.3. Signs against the diagnosis and non-genetic causes to exclude

Marked photophobia at onset points to cone dystrophy; reduction of the peripheral field or night blindness points to a mixed dystrophy, although in PRPH2 both may coexist with maculopathy [19, 65]. In an isolated case, the PNDS recommends excluding drug-related causes (synthetic antimalarials, antiretrovirals), recreational drugs (poppers), recreational lasers, diabetes, vascular occlusions and inflammatory diseases (toxoplasmosis, multifocal choroiditis, placoid epitheliopathies, cat-scratch disease) [19]. Extraocular signs should prompt a search for a syndromic form: polydactyly, obesity, intellectual disability and renal abnormalities (Bardet-Biedl syndrome), developmental regression and epilepsy (neuronal ceroid lipofuscinosis), ataxia and dysarthria (spinocerebellar ataxia 7), maternally inherited deafness and diabetes (MIDD) [19, 72].

4.4. Warning and emergency signs

New-onset metamorphopsia, rapid visual loss or macular haemorrhage or exudation in a patient with known pattern dystrophy suggest macular neovascularisation, which requires rapid assessment with OCT and OCT angiography, because early anti-VEGF treatment is associated with a good long-term outcome [19, 31, 69]. The PNDS notes that metamorphopsia is very rare in genetic maculopathies in the absence of atrophy or neovascular complications and that, when it appears, it points to a neovascular complication [19].

4.5. Newborn and population screening

There is no newborn or population screening for PRPH2 retinopathies, and no treatment that would justify it; screening is directed at relatives of patients with an identified variant, with ophthalmological examination and, in adults who wish it, cascade genetic testing [19, 28].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal consensus diagnostic criteria published for the PRPH2 family; the diagnosis is clinico-molecular and rests on the identification of a pathogenic or likely pathogenic variant in the context of a compatible phenotype [19, 41]. The French PNDS defines the macular phenotypes of the gene as typical of mainly adult patients, with autosomal dominant transmission, and lists the four pictures: pseudo-Stargardt, adult pseudovitelliform dystrophies with small-sized material, pattern dystrophies with hyperautofluorescent deposits of highly variable arrangement, and dominant central areolar atrophy [19]. For RP, the 1983 consensus criteria cited by GeneReviews remain: rod dysfunction (dark adaptation or ERG), progressive loss of photoreceptor function, loss of peripheral vision and bilateral symmetrical involvement [28]. The 2025 systematic review recommends revising the phenotypic criteria with recent imaging techniques and always confirming the diagnosis by genetic testing [41]. The autofluorescence-based phenotypic classification of the 2024 cohort is useful in practice and in trial selection [4].

5.2. Clinical and functional assessment

The PNDS recommends, in children and adults, measurement of distance and near acuity, visual field, colour fundus photographs, multimodal imaging with macular and temporal OCT scans and study of the ganglion cell fibres, macular and widefield autofluorescence, full-field ERG according to the standards of the International Society for Clinical Electrophysiology of Vision (ISCEV) and, possibly, an electro-oculogram (EOG) if the ERG is normal in a deposit disease or if toxicity is suspected [19]. Autofluorescence is indispensable and has replaced fluorescein angiography, which the PNDS considers not indicated in hereditary dystrophies [19]. The American Academy of Ophthalmology (AAO), in its 2022 recommendations, includes a history of retinotoxic medication, the pedigree, acuity with the ETDRS protocol, biomicroscopy, intraocular pressure, dilated fundus examination, high-density OCT as the follow-up baseline, short-wavelength autofluorescence with reduced illumination, infrared imaging, kinetic and static perimetry, microperimetry and, where appropriate, full-field, multifocal or pattern ERG, and recommends sparing use of fundus photographs in maculopathies because of the risk of phototoxicity [30]. The AAO considers full-field ERG unnecessary in pattern dystrophy confined to the macula, but useful in young patients with macular disease, because delayed cone b-wave implicit time is an early sign of diffuse involvement [30]. The PNDS considers it indispensable at any age for any maculopathy, except in the typical picture of Best disease [19]. Cohort data support caution: among 29 patients in the 2024 cohort with a normal full-field ERG, 21 had localised macular dysfunction on pattern or multifocal ERG, and in PSPD 68% of patients had combined cone and rod dysfunction [4].

5.3. Electrophysiology and imaging biomarkers

In the 2024 cohort (ERG in 100 patients, median age 52 years), 29% had no generalised dysfunction, 16% had cone dystrophy, 17% cone-rod dystrophy and 38% rod-cone dystrophy; the pattern ERG was subnormal in 8 of 26 patients with a normal full-field ERG and the multifocal ERG was reduced in all 16 in whom it was performed; the EOG was reduced (Arden ratio below 1.7) in 2 of 12 patients without generalised dysfunction [4]. Compared with controls from the same centre (25 patients and 44 controls), patients had reduced median amplitudes in all responses (for example, DA 0.01 b-wave 81 versus 162 µV; 30 Hz flicker 39 versus 81 µV) and delayed peak time of the 30 Hz flicker (30 versus 27 ms) and of the LA 3.0 b-wave (33 versus 30 ms) [4]. In a case-control study of 133 PRPH2 patients, 155 ABCA4 patients and 52 controls, in the subgroup with a CACD-like phenotype the peak times of the 30 Hz flicker and of the LA 3.0 b-wave distinguished PRPH2 from ABCA4 (area under the curve 0.78 and 0.76; thresholds of 27.8 and 31.7 ms with sensitivities of 77% and 85%), and in the subgroup with flecks the amplitude of the DA 0.01 b-wave and of the DA 3 a-wave did so (area under the curve 0.88; thresholds of 85 and 109 µV with sensitivities of 93% and 88%) [73]. On OCT, a thickened ellipsoid zone was found in 34 of 36 Oxford patients (mean thickness 44.3 and 42.7 µm) and has been proposed as a biomarker to distinguish PRPH2 from phenocopies [61]; the ratio between the thicknesses of outer retinal bands 2 and 4 also distinguishes PRPH2-related disease from ABCA4-related disease [32]. In adult vitelliform dystrophy, the normal or slightly reduced EOG contrasts with the markedly abnormal EOG of Best disease, but in a French series the EOG was reduced in the three patients with a PRPH2 variant and normal in 3 of 15 with a BEST1 variant, so it is not discriminating on its own [2, 67]. OCT angiography is useful for detecting neovascularisation, even in the extensive chorioretinal atrophy phenotype [69]. These biomarkers do not replace genetic testing.

5.4. Genetic testing

The PNDS recommends sequencing of a retinal dystrophy gene panel by next-generation sequencing (NGS) on the patient's DNA and, whenever possible, that of the parents, with exon copy number analysis to detect deletions and duplications; the panels include the main maculopathy genes, ABCA4, BEST1 and PRPH2 [19]. In France, maculopathies are a pre-indication of the France Genomic Medicine Plan 2025, and genome sequencing, preferably as a trio, may be offered as first line [19]. GeneReviews and the AAO consider the multigene panel the most effective approach, with exome or genome sequencing when the phenotype does not point to a panel, and the genome able to detect non-coding variants [28, 30]. The 2012 AAO recommendations remain valid: offer testing when the findings suggest a Mendelian disorder with a known gene, use certified laboratories, give the patient a copy of the report and avoid direct-to-consumer tests [74]. In a family with a PRPH2 or ROM1 variant in which inheritance appears non-Mendelian, digenic inheritance should be considered and the other gene tested [28].

5.5. Yield and limitations of the tests

The PNDS reports a positive result in more than 62% of Stargardt disease cases, 70% of pseudovitelliform dystrophies and more than one in two patients with maculopathy in general, but only 30% in autosomal recessive maculopathies other than Stargardt disease [19]. In the United Kingdom, with a good phenotype and family history, the probability of a genetic diagnosis in retinal dystrophies was about 55% in 2012 [72], and in RP the yield of panels reaches about 80% in the autosomal dominant form [75]. These rates are proportions of patients with an identified variant in centre series and not clinical sensitivities of the test for PRPH2. A negative result does not exclude the diagnosis: the variant may lie in unexplored regions of the panel genes, in genes not included or in genes still unknown [19]. Some PRPH2 structural variants have been resolved only by long-read sequencing, and exonic deletions require CNV analysis [4, 58]. Interpretation of missense variants benefits from gene-specific cohorts: in the eyeGENE registry, evidence of a hotspot in the D2 loop and of enrichment in patients changed the classification of 16.5% of variants according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [55]. A variant in an unexpected gene should prompt reconsideration of the clinical diagnosis, and novel variants may require functional studies [19].

5.6. Report content and interpretation

The report should state the gene, the transcript with version (NM_000322.5), the variant in HGVS nomenclature at complementary DNA and protein level, the zygosity and the ACMG/AMP classification [11, 19]. Because the same variant may correspond to different phenotypes within the same family, the report does not allow prediction of the phenotype, age at onset or severity [9, 28]. Two decisions depend on the molecular result and not on imaging: distinction from ABCA4, with therapeutic implications (high-dose vitamin A is discouraged in ABCA4-related disease), and demonstration of digenic inheritance [9, 28]. Novel variants may require functional studies to be classified as pathogenic, and the PNDS stresses the limits of knowledge about the distinction between rare non-pathogenic variants and pathogenic variants when reproductive decisions are discussed; the segregation study in the pedigree, requested from the first consultation, contributes to this classification [19].

5.7. Practical algorithm

In an adult with a suggestive bilateral maculopathy, the first step is to exclude toxic, inflammatory and syndromic causes and to document the phenotype with acuity, visual field, widefield autofluorescence, OCT and full-field, pattern or multifocal ERG [19, 30]. The second step is the retinal dystrophy panel with CNV analysis, including the maculopathy and cone dystrophy genes listed by the PNDS (ABCA4, BEST1, PRPH2, ELOVL4, PROM1, TIMP3, EFEMP1, PRDM13, CRX, GUCA1A, GUCY2D, CERKL, CRB1, RPGR), the adult vitelliform dystrophy genes (IMPG1, IMPG2) and ROM1, or the genome where available [19, 23, 28]. If a pathogenic PRPH2 variant is identified, a genetics clinic appointment with segregation study and examination of relatives follows; if the result is negative and suspicion persists, exome or genome sequencing may follow and, in selected cases, long-read sequencing [19, 58]. For a vitelliform lesion, the age at onset guides the order: BEST1 before 40 years, PRPH2 after 40, and between 30 and 40 years PRPH2 if BEST1 is negative, when a panel is not used [67].

5.8. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible once the familial variant has been identified, but the phenotype and severity cannot be predicted from the molecular result [28]. The PNDS considers these requests possible within a tightly regulated framework, with numerous restrictions, given the nature of the disease and the limits of knowledge about rare variants [19].

6. Differential Diagnosis

6.1. Comparative table

6.2. Stargardt disease

Stargardt disease is the most important differential, because fundus flavimaculatus-like flecks are not pathognomonic and also occur in pseudo-Stargardt forms and in mitochondrial disorders [19]. In adults, a Stargardt picture may be autosomal recessive due to ABCA4, with a small risk to offspring, or autosomal dominant due to a heterozygous PRPH2 variant, with a 50% risk for each child, and only genetic testing distinguishes them reliably [19]. The distinction has therapeutic consequences, because vitamin A supplementation is discouraged in ABCA4-related disease [9, 19], and prognostic consequences, because PRPH2 multifocal pattern dystrophy generally has a better visual prognosis [62]. Electrophysiology helps when testing is not available: in the subgroup with flecks, lower scotopic amplitudes favoured PRPH2, and in the CACD-like subgroup longer photopic peak times did so [73].

6.3. Best disease and other vitelliform dystrophies

The adult vitelliform lesion due to PRPH2 is generally smaller and appears later than that of Best disease, and an age at onset of 40 years is the most useful criterion for choosing which gene to study when a panel is not used [19, 67]. The EOG, classically markedly abnormal in Best disease and normal or slightly reduced in adult vitelliform dystrophy, is not discriminating on its own [2, 67]. Adult vitelliform dystrophy due to PRPH2 is also part of the differential of the vitelliform dystrophies.

6.4. Age-related macular degeneration

Patients with CACD or pattern dystrophy after 50 years are often diagnosed with AMD, especially when penetrance is reduced and the family history appears negative [20, 32, 54]. Factors favouring PRPH2 are symmetry, younger age at onset, a family history of vertical transmission, drusen-like lesions with intense autofluorescence at the margin of the atrophy and low genetic susceptibility to AMD [20, 54]. AMD tends to affect one eye and then the other [19].

6.5. Retinitis pigmentosa and generalised dystrophies

In families with dominant RP, PRPH2 accounts for 5–10% of cases in North American and British series and for 10.3% in France, after RHO [28, 29, 75]. A pedigree with vertical transmission and affected individuals of both sexes may correspond to X-linked RP with expression in heterozygous women, a possibility excluded by male-to-male transmission [28]. The coexistence of maculopathy and generalised RP in the same family is highly suggestive of PRPH2 [29, 38].

7. Treatments and Risk Management Strategies

7.1. General principles and framework of recommendations

There is no approved pharmacological, gene or cell therapy for any of the PRPH2 retinopathies, and in 2023 no company was developing a gene-specific therapy [9, 19, 32]. Management has four objectives, set out by the PNDS: treating low vision, treating complications, applying the general recommendations for maculopathies (no smoking, a varied and balanced diet, light protection and no vitamin A supplementation when Stargardt disease is suspected) and ensuring a global approach to the patient and family [19]. The central guideline is the HAS PNDS "Maculopathies génétiques" (2021), prepared by the MAOLYA reference centre and validated by the coordinators of the CARGO, REFERET and Lille centres, which covers PRPH2 maculopathies together with Stargardt and Best diseases [19]. For forms with RP, the management section of the GeneReviews overview applies, which is expert opinion and not trial evidence [9, 28]. The AAO published recommendations in 2022 on the clinical assessment of inherited retinal degenerations and, in 2012, on genetic testing [30, 74]. ClinGen has not issued an actionability assertion for PRPH2 in adults or children [9].

7.2. Macular neovascularisation

Macular neovascularisation is the main treatable complication of pattern dystrophies and adult vitelliform dystrophy [2, 31, 69]. The PNDS recommends discussing intravitreal injections of anti-VEGF (vascular endothelial growth factor) in the active phase and considers them not indicated and ineffective in fibrotic phases [19]. The specific evidence comes from small series, without controlled trials. In a retrospective multicentre series of six patients with unilateral neovascularisation, median acuity at entry was 0.2 logMAR (20/32) and central thickness 320 µm; after a median of 6.2 years and 5.5 injections per patient, five eyes (83%) maintained 20/32 or better, central thickness decreased by a median of 69 µm with no additional thinning relative to the fellow eye, and in four eyes (67%) OCT angiography showed persistent sub-RPE neovascular networks after resolution of exudation [31]. In a Swiss family with p.(Tyr141Cys), subfoveal neovascularisation regressed after four injections of ranibizumab, with acuity improving from 0.8 to 1.0 and complete anatomical restoration on OCT [1, 53]. In the family with c.828+3A>T, the index patient had complete resolution without recurrence after two injections of bevacizumab over two months, off-label use of a drug without an ophthalmic authorisation [56].

There is no published dose specific to neovascularisation in PRPH2-related disease; the label dose for choroidal neovascularisation is used, which in the European Union covers neovascularisation of any cause and in the USA does not cover this aetiology, so in the USA the use is off-label and constitutes an extrapolation from myopic neovascularisation and neovascular AMD [77, 78]. Ranibizumab (Lucentis®, centrally authorised in the EU and valid in Portugal, and approved in the USA; active ranibizumab registrations in Brazil, including the biosimilar Amelivu®) is given by intravitreal injection, by an experienced ophthalmologist, at a dose of 0.5 mg (0.05 mL of a 10 mg/mL solution), with a minimum interval of four weeks between doses in the same eye; in choroidal neovascularisation the European SmPC determines treatment individually, according to disease activity, and states that some patients need a single injection in the first 12 months and others monthly injections, and that in myopic neovascularisation many patients need one or two injections in the first year; monitoring of activity includes clinical examination, functional tests and imaging (OCT or angiography) [77, 79]. The FDA label for myopic neovascularisation indicates 0.5 mg monthly for up to three months, with retreatment if needed [78]. Aflibercept (Eylea®) has, in neovascular AMD, a dose of 2 mg (0.05 mL of 40 mg/mL) every four weeks for the first three months and then every eight weeks [80]. The contraindications of ranibizumab are hypersensitivity, active or suspected ocular or periocular infection and active severe intraocular inflammation; serious adverse effects include endophthalmitis, intraocular inflammation, rhegmatogenous detachment, retinal tear and iatrogenic traumatic cataract, which requires aseptic technique and monitoring in the week following injection, and there are transient rises in intraocular pressure within 60 minutes of injection and sustained rises, which require monitoring of pressure and optic disc perfusion [77]. Injection of bone marrow cells given to one of the patients at another institution produced no improvement and is not a validated therapy [56].

7.3. Cystoid macular oedema

In patients with an RP phenotype, cystoid macular oedema may respond to systemic or topical carbonic anhydrase inhibitors (oral acetazolamide or topical dorzolamide), with the possibility of rebound oedema during continued use; GeneReviews does not give doses [9, 28]. In the absence of a dose for this indication, the reference doses are those of the glaucoma labels, used off-label: oral acetazolamide 250 mg to 1 g per 24 hours, in divided doses above 250 mg, with no additional effect above 1 g per day; dorzolamide 2% eye drops, one drop in the affected eye three times daily [81, 82]. Acetazolamide is a sulphonamide and is contraindicated in sulphonamide hypersensitivity, hyponatraemia or hypokalaemia, marked renal or hepatic disease, adrenal insufficiency, hyperchloraemic acidosis and cirrhosis; it was teratogenic in several animal species, and prolonged use in children caused growth retardation attributed to chronic acidosis [81]. Dorzolamide is contraindicated in hypersensitivity to its components and, in pregnancy, there are no adequate studies [82]. In Brazil, dorzolamide has several active registrations (for example, Andrum® and generics), and the acetazolamide registrations listed in the ANVISA open data are inactive [79]. Intravitreal triamcinolone had short-lived benefit and anti-VEGF agents preliminary data in RP oedema [28].

7.4. Cataract and surgery

About half of patients with RP develop cataract that eventually requires extraction, with visual improvement in most; patients with a visual field greater than 10 degrees tolerate mild cataracts well, and those with less than 10 degrees report clear improvement after surgery [28]. In the presence of macular disease, early extraction may not improve the quality of vision, especially in young patients who retain accommodation, and it is difficult to distinguish the contribution of cataract and maculopathy to the loss of acuity [28]. Patients with RP have a higher risk of postoperative inflammation and cystoid macular oedema, so unnecessary manipulation of the iris should be avoided and anti-inflammatory drugs continued for longer than usual [28].

7.5. Supplements and diet

There is no supplement with demonstrated benefit in PRPH2 maculopathies [9, 19]. In RP in general, retinyl palmitate (vitamin A) at a dose of 15,000 IU per day was associated with a possible slowing of the loss of ERG amplitude, with no effect on acuity or visual field; it is not recommended before 18 years, requires monitoring of serum vitamin A, liver function and bone density, is teratogenic at high doses and is contraindicated in ABCA4-related disease, because it increases accumulation of the bisretinoid A2E [28]. Because PRPH2 PSPD cannot be reliably distinguished from Stargardt disease without genetic testing, and because the PNDS prohibits vitamin A supplementation when Stargardt disease is suspected, vitamin A should not be started before the molecular diagnosis; even afterwards, its usefulness in the PRPH2 RP phenotype is extrapolated from studies in RP of various causes [9, 19, 28]. Docosahexaenoic acid (DHA) had no effect on the course of the disease in patients already taking vitamin A (1200 mg per day) or in men with X-linked RP (400 mg per day), and lutein (20 mg per day) increased macular pigment in about half of patients without altering central vision, with slower loss of the mid-peripheral field in a four-year trial in combination with vitamin A [28]. The PNDS recommends a varied and balanced diet, rich in fruit, vegetables and antioxidants, fish three times a week, regular physical activity of about one hour per day and abstinence from smoking [19].

7.6. Light protection

The PNDS recommends light protection (filter lenses and a hat) in all maculopathies and makes it mandatory in ABCA4-related Stargardt disease [19]. GeneReviews recommends UV-A- and UV-B-blocking glasses and avoidance of intense light in all patients with RP, based on animal models (mainly of rhodopsin variants), and states that filters blocking 97–99% of energy below 550 nm improve comfort, glare and adaptation [28]. The AAO advises sparing use of fundus photographs in maculopathies because of the risk of phototoxicity and preferring long or infrared wavelengths where possible [30].

7.7. Visual rehabilitation, school, work and driving

Low vision rehabilitation should be early and carried out by specialised teams (low vision orthoptist, specialised optician, occupational therapist, mobility instructor), with the best possible optical correction, optical aids (magnifiers, telescopes, magnifying spectacles), non-optical aids (large-print books, talking watches) and electronic aids (reading systems, spectacle-mounted mini-cameras, voice or character recognition software), and with training in the use of eccentric fixation [19]. Braille and referral to specialised institutions are rarely needed in maculopathies, and a guide dog may be useful in severe visual loss [19]. In forms with RP and a constricted field, wide-angle torches and devices that reduce the visible field or magnify images in real time are described options, and retinal prostheses have been used in end-stage disease with light perception or worse [28]. Children with maculopathy attend mainstream education with adaptations (seat facing the board, adapted lighting, computer and tablet with magnification, digital materials, extra time in examinations) [19]. In adults, the PNDS states that in France driving is no longer permitted with acuity below 5/10 or a central scotoma, and recommends regular assessment of fitness to drive and for the workplace, with involvement of the occupational physician and social worker; the legal driving criteria are national and should be checked in each country [19]. The AAO includes in the assessment preparation for progressive visual impairment, workplace adaptations and emotional support [30].

7.8. Psychological support

The PNDS recommends regular assessment of depressive risk, especially during the phase of loss of acuity, and offering psychological support to the patient and family; when acuity stabilises, the patient learns to use the unaffected retina [19]. The AAO recommends monitoring mood and depression associated with progressive visual loss [30]. Vision-related mental health was the domain with the worst score on the NEI VFQ-25 in patients with PRPH2 [70].

7.9. Agents and circumstances to avoid

Smoking [19, 28], high-dose vitamin E (for example, 400 IU per day), which may adversely affect the course of RP [28], vitamin A until ABCA4-related disease is excluded [19], intense unprotected light exposure [19, 28] and retinotoxic drugs, such as quinine derivatives, listed by the PNDS for Stargardt disease [19], should be avoided. Prolonged light deprivation does not alter the progression of RP [28]. The contraindication of violent and combat sports is stated by the PNDS for Stargardt disease, because of the risk of retinal haemorrhages [19].

7.10. Pregnancy and lactation

Between 5% and 10% of women with RP report decreased vision during pregnancy, often without recovery after delivery, with no objective data to confirm it; pregnancy increases the risk of central serous chorioretinopathy and alters refraction [28]. High-dose vitamin A is teratogenic and should be discussed with women of childbearing age [28]. With ranibizumab, women of childbearing potential should use effective contraception, the drug should not be used in pregnancy unless the expected benefit outweighs the risk, waiting at least three months after the last dose before conceiving is recommended and breastfeeding is not recommended [77]. Acetazolamide was teratogenic in animals and should be used in pregnancy only if the benefit justifies the risk [81].

7.11. Transition to adult care

In the rare childhood-onset forms, the PNDS recommends organising, at the end of adolescence, the transition to adult services so as to avoid interruption of follow-up, and anticipating in educational guidance the needs of the future adult with visual impairment [19].

7.12. Gene and molecular therapies under investigation

Gene-directed strategies are divided according to the variant mechanism [32]. For loss-of-function and haploinsufficiency variants, the strategy is gene augmentation, which consists of delivering a normal copy of PRPH2 to the photoreceptors by a viral or non-viral vector; the gene is about 1.1 kb and fits easily into an adeno-associated virus (AAV) vector, administered by subretinal injection in mouse studies [32]. The preclinical results are the proof of concept and, at the same time, show the limits: in the rds mouse, subretinal injection of recombinant AAV carrying Prph2 generated outer segments with new discs containing peripherin-2 and rhodopsin and partially corrected the electroretinogram, but the benefit depended on age at treatment and did not reduce photoreceptor loss [10]. Because photoreceptors are sensitive to the amount of protein, the response is dose-dependent, and even 80% of the normal level did not rescue all the degeneration; the authors of the mouse studies concluded that success in patients may depend on early intervention and precise control of transgene expression [10, 32]. Non-viral vectors (DNA vectors and DNA nanoparticles) have been developed for intravitreal injection, with hyaluronic acid nanospheres and co-injection of sulfotyrosine to cross the inner limiting membrane, tested in animals with minimal toxicity [32]. For gain-of-function or dominant-negative variants, such as p.(Arg172Trp), gene augmentation alone is not sufficient: a two-step "knockdown and replace" strategy has been proposed, which eliminates the mutant allele and reintroduces a normal copy, so far theoretical [32]. RNase H-mediated allele-specific antisense oligonucleotides (ASOs) were able to degrade p.(Arg142Trp) mutant RNA without affecting the normal allele, in unpublished data presented at an expert meeting [32]. Rhodopsin reduction is a variant-independent strategy: in p.(Lys154del) and p.(Tyr141Cys) knock-in mice, reducing rhodopsin improved photoreceptor function and reduced disc abnormalities and gliosis, and an intravitreal ASO against rhodopsin improved function and disc ultrastructure [83]. Prime editing allowed the c.828+1G>A variant to be installed and corrected in human induced pluripotent stem cells, restoring the canonical transcript, with no detectable off-target mutations or karyotype changes [45]. All these approaches are preclinical, with the exception of a phase 1/2 trial of a personalised ASO (nL-PRPH2-001) in a single participant heterozygous for p.(Gly208Asp), started on 28 August 2025, open-label and without a control group, with primary safety and tolerability endpoints at 24 months and no published results [84]. The risks of these therapies include those of the intraocular route of administration, which for intravitreal injections comprise endophthalmitis, intraocular inflammation, retinal detachment and raised intraocular pressure [77], and those of an insufficient or dysregulated protein dose, to which photoreceptors are sensitive [32].

7.13. Gene-independent therapies

Optogenetics confers light sensitivity on inner retinal cells that survive photoreceptor loss and may, in principle, serve patients with end-stage disease regardless of the gene [32]. Sonpiretigene isteparvovec (MCO-010, Mogenry®) is an AAV2 encoding a multi-characteristic opsin, administered by a single intravitreal injection targeting bipolar cells [32, 85]. According to September 2026 reports from two independent specialist publications, the FDA accepted the biologics licence application (BLA) for RP with severe visual loss, with a target decision date in the first half of 2027, based on a phase 1/2a study and the RESTORE trial, a phase 2b/3, randomised, double-masked, sham-controlled trial, which according to the sponsor met its primary and key secondary endpoints with improvement in acuity at 52 and 76 weeks and no serious treatment-related adverse events; the numerical values were not disclosed in the sources consulted [85, 86]. This is an accepted application, not an authorisation; the product has FDA fast track and orphan drug designations, and in Japan an application with priority review was accepted for a broader indication of inherited retinal dystrophies [86]. If approved with a gene-independent indication, it could apply to end-stage PRPH2 RP, but not to most patients, who have maculopathy with preserved peripheral vision. Other approaches are at earlier stages: cGMP analogues inhibiting protein kinase G protected photoreceptors in several mouse models (preclinical); rod-derived cone viability factor (RdCVF) is in a trial in patients with RHO and PDE6 variants, without inclusion of PRPH2 patients; and a gene therapy with the GIRK potassium channel for dormant cones was planned [32]. No cell therapy has been tested in patients with RP, and bone marrow cell injections have no demonstrated efficacy [28, 56]. Voretigene neparvovec (Luxturna®) is restricted to dystrophy due to biallelic RPE65 variants and does not apply [14, 30].

7.14. Regulatory table

7.15. Trials and clinical studies

There is no controlled efficacy trial with published results in patients with PRPH2. The RESTORE results come from press releases and news reports, without peer-reviewed publication in the sources consulted, and include patients with RP of various causes, so they cannot be transposed to PRPH2 patients without subgroup analysis. Natural history studies have shown that acuity and microperimetric sensitivity are unreliable endpoints in one- to two-year trials, that expansion of lesions on autofluorescence is slow and that total macular volume may be a more sensitive structural endpoint; a change of 15 or more letters of acuity is one of the few endpoints accepted by the FDA for retinal diseases [32, 71]. The absence of large animal models, phenotypic variability and the lack of natural history studies with many participants are the main obstacles identified, and the Foundation Fighting Blindness and the Nixon Visions Foundation set up a PRPH2-specific funding programme in 2024 [32].

7.16. Developments in the last 12 months

Between November 2025 and November 2026 the following were recorded: the start, in August 2025, of the first trial of a molecular therapy targeting a PRPH2 variant (personalised ASO, n=1, no results) [84]; FDA acceptance of the MCO-010 BLA for advanced RP regardless of gene (accepted application, not authorisation) [85, 86]; publication of preclinical base editing studies (c.828+1G>A in pluripotent cells) [45]; the description of exon 2 duplications resolved by long-read sequencing [58]; the identification of electrophysiological biomarkers distinguishing PRPH2 from ABCA4 [73]; the first prospective natural history data for p.(Gly208Asp) [50]; a founder variant in the Cook Islands [59]; and the first patient-reported outcome study with the NEI VFQ-25 [70]. A search that found no other trials does not demonstrate that none exist.

8. Reproductive Options and Family Counselling

8.1. Genetics clinic and disclosure of the diagnosis

The PNDS recommends a dedicated appointment to disclose the diagnosis, explaining the disease, its course and the possible therapies or their absence, introducing the team and the patient associations, and a genetics clinic appointment as early as possible to establish the mode of transmission and the recurrence risk for the couple and the siblings [19]. The AAO considers genetic testing and counselling essential components of management and recommends providing information on the inheritance pattern and the implications for relatives [30]. Testing requires written consent [19].

8.2. Recurrence risks in autosomal dominant inheritance

Each child of a carrier of a heterozygous PRPH2 variant has a 50% probability of inheriting it, in each pregnancy [19, 28]. The presence of the variant does not mean that the disease will manifest, nor with what phenotype or severity: the PNDS expressly mentions healthy carriers and variation in penetrance, and a relative's phenotype may differ from that of the proband, from vitelliform dystrophy with a better prognosis to RP [19]. The observed proportions of non-penetrance (about 6% in the international cohort, up to 21% with p.(Arg142Trp) up to 64 years) should be presented as cohort data and not as individual probabilities [4, 20]. The parents of a proband are generally affected or carriers; a de novo variant is possible, and if the variant is not found in the blood of either parent, the risk to siblings is slightly higher than that of the population, though below 1%, because of the possibility of germline mosaicism [28]. Isolated cases are not necessarily recessive: they may result from a de novo variant, reduced penetrance in previous generations or an incomplete family history, and examination of the parents may reveal asymptomatic changes [19, 28]. In the North American survey, 79% of patients had more than one affected relative [32].

8.3. Digenic and recessive inheritance

In digenic RP, the patient is heterozygous for PRPH2 p.(Leu185Pro) and for a ROM1 variant; each child has a 25% probability of inheriting both variants, if the genes segregate independently, and 50% of inheriting only one, in which case the carrier does not develop RP, although p.(Leu185Pro) heterozygotes may have macular pattern dystrophy [1, 13, 28, 54]. In recessive forms, the parents are heterozygous carriers, who may have asymptomatic macular pattern dystrophy, and the risk for each sibling is 25% of being affected [16, 28]. In a family with a PRPH2 or ROM1 variant and apparently non-Mendelian inheritance, the other gene should be studied [28].

8.4. Cascade testing, predictive testing and minors

Testing of adult relatives requires prior identification of the variant in the proband and should be accompanied by ophthalmological examination, because carriers may have subclinical changes on autofluorescence, OCT or pattern ERG [5, 19]. In risk assessment, the age at onset in the family is relevant: a normal examination at 20 years is more reassuring when the familial disease begins in childhood than when it is an adult-onset disease [75]. The PNDS stipulates that a minor may be tested only with the parents' agreement and if there are clinical signs, so that, in a dominant disease, an unaffected minor is not tested, and recommends discussing with the parents the psychological impact of systematic examination of siblings [19]. The 2012 AAO recommendations also discourage testing of asymptomatic minors for untreatable diseases [74].

8.5. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible once the familial variant has been identified [28]. The PNDS considers these requests within a tightly regulated framework and with numerous restrictions, given the variable severity, incomplete penetrance and the limits of knowledge about rare variants [19]. Severity and age at onset cannot be predicted from the molecular result, and views on the use of these tests may differ between professionals and families [28].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Relative frequency in retinal dystrophy cohorts

There is no measured population prevalence of PRPH2 retinopathies; the available data are proportions in cohorts of patients with retinal dystrophies [9]. PRPH2 accounted for 5.2% of diagnoses in the United Kingdom (fourth most frequent cause), 4.6% of families in a British cohort, 3.4% of patients in Japan, 3% in the USA and Canada and about 4% of families with non-syndromic retinal dystrophy in Spain (cohort of 5124 families) [4, 17]. Among pattern dystrophies, the systematic review attributes about 25% of cases to PRPH2 [41]. In autosomal dominant RP, PRPH2 explained 5–10% of cases in North American and British series and 10.3% in 310 French families, making it the second most frequent gene after RHO in that series; in 300 British patients with dominant macular dystrophies, the proportion was 7.3% [10, 28, 29, 75]. In adult vitelliform dystrophy, the proportions were 18% in Germany and 10.5% in France [2, 67]. From the proportion of 3% to 5% of pathogenic variants in large cohorts, the authors of an expert report estimated 6000 to 22,000 affected people in the USA and up to 200,000 worldwide, an extrapolation rather than a measurement [32]. About 1000 families with PRPH2 retinopathy had been described worldwide by 2023, according to the Spanish cohort [17].

9.2. Prevalence of the clinical entities

Orphanet prevalences refer to the clinical entities of all genetic causes and cannot be attributed to PRPH2 or summed without double counting [9]. RP has a validated point prevalence of 26.7/100,000 worldwide, 30.0/100,000 in Europe, 21.0/100,000 in the USA, 25.4/100,000 in Denmark, 22.5/100,000 in Norway and 20.5/100,000 in the United Kingdom [24]. CACD has an estimate of 3.33/100,000 in France, not validated, and of 1–9/100,000 in Europe, with contributions also from the GUCA1A and GUCY2D genes [12]. Butterfly-shaped dystrophy has a prevalence below 1/1,000,000, with 33 published cases, retinitis punctata albescens 0.125/100,000 worldwide and 0.175/100,000 in Europe, and the prevalences of adult-onset foveomacular vitelliform dystrophy and multifocal pattern dystrophy are unknown [3, 22, 23, 25]. The PNDS estimates that genetic maculopathies represent about 15% of retinal dystrophies in a reference centre and places PRPH2 maculopathies third, after Stargardt disease (1/10,000) and Best disease (1/10,000 to 1/20,000) [19].

9.3. Populations with founder variants

The Netherlands (p.(Arg142Trp), south-east of the country), the United Kingdom (p.(Arg172Trp)), the USA (c.828+3A>T, 17.4% of families in eyeGENE; p.(Tyr141Cys) in three families), Spain (p.(Leu41Pro) in the Basque Country and p.(Pro221_Cys222del)), Switzerland (p.(Arg172Trp) in the Zermatt family), Japan (p.(Arg142Trp), p.(Arg172Trp), p.(Val200Glu)), China (p.(Gly305AlafsTer19)) and the Cook Islands have documented recurrent or founder variants [5, 17, 20, 48, 52, 55, 59]. The Spanish cohort stressed the relevance of these data for the Spanish diaspora in Latin America [17].

9.4. Portugal and Brazil

Patients from the Portuguese registry of inherited retinal dystrophies (IRD-PT, Coimbra) are part of the international cohort of 241 patients, without data separated by country [4]. The series from the Ophthalmology Department of the Unidade Local de Saúde de Coimbra, published in 2026 in captioned-image format, brings together 24 widefield autofluorescence images (Optomap, green autofluorescence) of carriers of PRPH2 variants, without stating the number of patients, ages or acuity [46]. The phenotypes represented are RP, CACD, multifocal pattern dystrophy simulating fundus flavimaculatus, butterfly-shaped dystrophy and adult vitelliform dystrophy, as well as a carrier without disease. The annotated variants (transcript NM_000322.5) are c.623G>A p.(Gly208Asp), the most represented (six images), c.515G>C p.(Arg172Pro), c.594C>A p.(Ser198Arg) and c.695C>T p.(Ala232Val) (three images each), c.424C>T p.(Arg142Trp), c.568A>G p.(Lys190Glu), c.112G>A p.(Gly38Arg) and c.602_615del p.(Asp201GlyfsTer12) (one image each), c.73_74del (two images), a genomic interval chr6:42689492-42690072 (three images) and homozygous c.622G>T p.(Gly208Cys) [11, 46]. The figure writes c.73_74del as p.(Trp25Valfs*18), whereas VariantValidator, on NM_000322.5, returns p.(Trp25ValfsTer19). The genomic interval is presented without assembly or type of change; only in GRCh37 coordinates does it fall within PRPH2, where it corresponds to 581 bp contained in exon 1. Inheritance was predominantly autosomal dominant, with a single recessive case [46]. The series does not allow frequencies or penetrance to be calculated, but it shows in Portugal the Dutch variant p.(Arg142Trp), the recurrence of p.(Gly208Asp), also frequent in Spain, and structural changes detectable only with CNV analysis. In the sources consulted there are no Brazilian epidemiological data on PRPH2; a Spanish family with c.582-1G>A was described in a Brazilian ophthalmology journal [57]. The absence of data in the sources consulted does not demonstrate the absence of published data.

9.5. Special populations

Elderly patients with CACD or pattern dystrophy and reduced penetrance may be misdiagnosed as having AMD, which has consequences for counselling of their descendants [20, 54]. In patients with variants in two genes (for example, PRPH2 and IMPG2) or homozygous variants, the phenotype and recurrence risks must be assessed case by case [17]. In pregnant women with RP, monitoring of vision and refraction should take account of the changes of pregnancy [28].

9.6. European network, reference centres and patient associations

The relevant European reference network is ERN-EYE (rare eye diseases) [33]. In France, the SENSGENE filière includes the reference centres REFERET (Quinze-Vingts, Paris), MAOLYA (Montpellier), CARGO (Strasbourg) and OPHTARA (Necker, Paris), and the PNDS lists patient associations such as Retina France, the Fédération des Aveugles de France, the Fondation Stargardt and the Association Valentin Haüy [19]. The Oxford Desk Reference lists, in the United Kingdom, the Royal National Institute for the Blind (RNIB), the Macular Society, RP Fighting Blindness UK and Fight for Sight [72]. Retina International brings together national associations of patients with retinal dystrophies, and the Foundation Fighting Blindness, in the USA, maintains the My Retina Tracker registry and held a PRPH2-specific workshop in 2023 [32, 90, 91].

10. Illustrative Clinical Case

10.1. An Arkansas family with the c.828+3A>T variant

Elhusseiny and colleagues described seven members of a Caucasian family from Arkansas (USA), five of whom had the confirmed splicing variant NM_000322.5:c.828+3A>T, followed at the Jones Eye Institute [56]. The index patient, a 49-year-old woman, presented in 2013 with scotomas in both eyes that had been enlarging for about 20 years; she had received from one physician a diagnosis of presumed ocular histoplasmosis and from another that of Stargardt disease, and several relatives had a diagnosis of macular degeneration [56]. Acuity was 20/25 in each eye; the fundus showed diffuse pisciform lesions at the posterior pole with speckled autofluorescence, OCT showed uniform thickening of the pigment epithelium with focal areas of loss, and full-field ERG showed reduced rod amplitudes with normal implicit times and normal cone responses; the Stargardt and macular dystrophy panel identified the PRPH2 variant [56]. The pedigree and images of the index patient are available at https://pmc.ncbi.nlm.nih.gov/articles/PMC11604250/figure/FIG1/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC11604250/figure/FIG2/ [56].

10.2. Course and complications

In 2014, the patient developed submacular neovascularisation in the left eye, confirmed by fluorescein angiography, treated with two intravitreal injections of bevacizumab over two months, with complete resolution and no recurrence [56]. In 2016 she received, at another institution, intravitreal injections of bone marrow-derived cells in both eyes, without visual improvement [56]. Over nine years, acuity fell from 20/25 to 20/200 in each eye, the pisciform lesions extended from the posterior pole to the periphery and OCT showed progressive focal atrophy of the pigment epithelium with gradual loss of the outer retinal layers [56].

10.3. Variability within the family

Her 53-year-old brother had 20/25 and hyperautofluorescent yellow subretinal macular lesions that enlarged over one year. A 58-year-old female cousin had patchy atrophy of the pigment epithelium at the posterior pole and along the arcades, peripheral deposits, an ERG compatible with rod-cone dysfunction that worsened over six years, stable acuity and inferior retinoschisis; the images are at https://pmc.ncbi.nlm.nih.gov/articles/PMC11604250/figure/FIG4/ [56]. Her 71-year-old mother, referred for bilateral macular degeneration, had 20/25 in one eye and counting fingers at 3 feet in the other, peripheral pigmented pisciform lesions and foveal atrophy, and also developed neovascularisation; a 79-year-old uncle and a 75-year-old male cousin had extensive chorioretinal atrophy with acuity from 20/200 to hand movements; another female cousin, diagnosed with AMD at 40 years, had bilateral pattern dystrophy and acuity of 20/50 and 20/40 after five years [56]. The family members had been referred with diagnoses of retinal dystrophy, rod-cone dystrophy, macular degeneration and rod dysfunction [56].

10.4. Lessons from the case

The case brings together the central features of the PRPH2 family: dominant inheritance with different clinical pictures in the same family, ranging from macular pattern dystrophy to generalised atrophy; misdiagnoses of Stargardt disease and AMD before genetic testing; a treatable neovascular complication; and slow progression over decades [4, 56]. The management of neovascularisation (anti-VEGF in the active phase) is consistent with the PNDS, but bevacizumab was used off-label, and bone marrow cell injections have no demonstrated efficacy and are not part of the recommendations [19, 56]. The authors did not study genetic modifiers, owing to financial constraints, and the imaging devices changed during follow-up [56].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The visual prognosis depends on the phenotype and, in part, on the variant, but is highly variable within families [4, 19]. In the international cohort, acuity remained stable on average until the fifth decade and declined thereafter, with age-related decline from the sixth decade in the CACD, PSPD and RP groups [4]. Adult vitelliform dystrophy and butterfly-shaped dystrophies have the best prognosis, and most patients with vitelliform dystrophy retain reading vision [2, 4, 19]. In CACD, disabling visual loss usually appears when atrophy reaches the fovea, in the seventh decade with p.(Arg142Trp) and earlier with p.(Arg172Trp), a variant with which most patients have acuity below 6/60 after 60 years [5, 49]. PRPH2 multifocal pattern dystrophy generally has a better visual prognosis than Stargardt disease [62]. PRPH2 RP is, in the French series, of moderate severity, with 78% of eyes having acuity between 1.0 and 0.5 [29]. Neovascularisation treated in time is associated with long-term maintenance of acuity [31]. As strictly ocular disorders without systemic manifestations, they mainly affect independence, driving, work and mental health [19, 70].

11.2. Surveillance

The PNDS recommends an annual ophthalmological examination by the treating ophthalmologist and an appointment at the reference or competence centre on request or every two to three years, with shorter intervals if there is loss of acuity or new complaints and longer ones if acuity stabilises [19]. The AAO proposes reassessment every one to two years, and GeneReviews, in RP, annual perimetry and dilated fundus examination, more frequently in the presence of active complications such as cystoid macular oedema [28, 30].

11.3. Follow-up of carrier relatives

Asymptomatic adult carriers should have a baseline ophthalmological examination with autofluorescence and OCT, because changes may be present without complaints, and should be informed that metamorphopsia or sudden loss of vision require prompt assessment [4, 5, 19]. Minor children of patients are not tested genetically without clinical signs, but an ophthalmological examination may be performed and discussed with the parents [19].

12. Summary and Final Considerations

PRPH2 encodes peripherin-2, a tetraspanin of the disc rims of rod and cone outer segments, and is one of the most frequent causes of inherited retinal dystrophy, with 3% to 5% of diagnoses in large cohorts. Its variants, almost always heterozygous, cause a continuous spectrum of disorders: pseudo-Stargardt pattern dystrophy, central areolar choroidal atrophy, butterfly-shaped and adult vitelliform dystrophies, retinitis pigmentosa 7, retinitis punctata albescens, cone and cone-rod dystrophies and, when homozygous, early-onset forms. The disease generally begins between the third and fifth decades, penetrance is incomplete and the same variant can produce different phenotypes in the same family, so the proband does not allow the disease in relatives to be predicted. Only a few correlations are consistent: central areolar atrophy is associated with specific missense variants of the D2 loop, truncating variants tend to produce pattern dystrophies and do not produce areolar atrophy, and p.(Arg172Trp) has a worse prognosis than p.(Arg142Trp). The diagnosis rests on multimodal imaging (autofluorescence and OCT), full-field, pattern and multifocal ERG and a gene panel with copy number variant analysis, which distinguishes PRPH2-related disease from ABCA4-related Stargardt disease, Best disease and AMD, diagnoses with which it is often confused and from which it differs in inheritance, prognosis and management. There is no targeted treatment: management includes early detection and treatment of neovascularisation with intravitreal anti-VEGF, avoidance of vitamin A until ABCA4 is excluded, light protection, smoking cessation, low vision rehabilitation, psychological support and annual follow-up. Genetic counselling should convey the 50% risk for each child and, at the same time, the uncertainty about expression of the disease, and predictive testing of asymptomatic minors is not recommended. Gene and molecular therapies (gene augmentation, knockdown and replacement, allele-specific antisense oligonucleotides, rhodopsin reduction and base editing) are at the preclinical stage or, in a single case, in a trial with one participant; gene-independent optogenetics awaits a regulatory decision for advanced RP and does not apply to most patients with maculopathy.

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