Pigmented Paravenous Retinochoroidal Atrophy (PPRCA) is a rare hereditary retinal disease characterized by pigmentation and retinochoroidal atrophy along the retinal veins. It was first described by Hewitson-Brown in 1937.
In a systematic review by Antropoli et al. (2024), the mean age of 23 reported cases was 35 years (range 10–67 years). 3) Most cases are sporadic, but familial cases have also been reported. There is no consistent gender predilection.
The clinical course is considered non-progressive or slowly progressive, but some cases progress to RP. Fukushima et al. (2023) reported that 1 of 5 cases (20%) had combined PPRCA and RP, with CRB1 and RPGRIP1 mutations. 2) This observation suggests that PPRCA and RP may represent a genetic continuum.
PPRCA is often asymptomatic. The main subjective symptoms are as follows.
Characteristic findings on fundus examination are pigmentation along the retinal veins and chorioretinal atrophy. Antropoli et al. (2024) classified the lesion morphology into three types. 3)
The classification of PPRCA lesion morphology is shown below.
| Classification | Features |
|---|---|
| Paravenous type | Continuous atrophy and pigmentation along the veins |
| Focal type | Isolated atrophic lesions |
| Confluent type | Widespread confluent atrophy |
Other major clinical findings are as follows:
In most cases, lesions occur in both eyes. However, asymmetric cases with different degrees of progression between the two eyes have also been reported. 1) Rarely, it occurs in only one eye, with retinitis pigmentosa in the fellow eye. 2)
The exact etiology of PPRCA remains unknown. A hereditary predisposition is strongly suggested, and multiple gene mutations have been identified.
The four major associated genes identified in the review by Antropoli et al. (2024) are as follows: 3)
| Gene | Inheritance Pattern | Associated Disease |
|---|---|---|
| CRB1 | Autosomal recessive | Shared with RP and Leber congenital amaurosis |
| CRX | Autosomal dominant | Shared with cone-rod dystrophy |
| HK1 | — | Reported specifically in PPRCA |
| RPGRIP1 | Autosomal recessive | Shared with RP and Leber congenital amaurosis |
Specific reports of each gene mutation are as follows.
There are also reports suggesting the involvement of inflammatory predisposition. Mente et al. (2022) suggested the presence of an occult inflammatory mechanism in a 7-year-old girl with cystoid macular edema complicating PPRCA, as cystoid macular edema occurred without inflammatory findings. 7) However, the mainstream view is that cases with an association with inflammatory diseases (sarcoidosis, syphilis, etc.) are distinguished from true PPRCA as “pseudo-PPRCA.” 3)
The diagnosis of PPRCA is made by a combination of characteristic fundus findings and various imaging findings.
Fundus autofluorescence
Low autofluorescence: Areas of RPE loss show hypofluorescence due to decreased lipofuscin.
High autofluorescence band: A band-like hyperautofluorescence is seen at the edge of atrophy, indicating active lesions. 3)
Ultra-widefield FAF: Useful for assessing the overall extent of peripheral lesions. 3)
OCT / OCTA
Loss of outer retinal layers: Loss of the photoreceptor layer is observed in atrophic areas. 3)
OCTA choriocapillaris flow void: Choriocapillaris perfusion defect in the lesion area. 3)
En face OCT hyalocytes: Ramified (quiescent) type in advanced eyes and amoeboid (active) type in mild eyes were observed. 1)
Electrophysiology
Full-field electroretinography (ffERG): Shows various findings ranging from normal to severely impaired. 3)
Rod and cone dysfunction: Both rod and cone dysfunction have been confirmed in cases with CRX mutations. 6)
EOG: Some cases show a reduced Arden ratio.
Kitahara et al. (2022) reported the reverse shadowing sign on OCT. 4) In areas where the outer retina and RPE are absent, the usual shadowing effect is reversed, serving as an auxiliary diagnostic finding.
PPRCA must be differentiated from the following diseases. 3)
There is currently no specific treatment for PPRCA. The treatment strategy is determined by the presence or absence of complications.
For asymptomatic and non-progressive cases, regular follow-up is the mainstay. Kitahara et al. (2022) recommended regular examinations every 6 months using visual acuity tests, visual field tests, OCT, and FAF. 4)
For stable asymptomatic cases, follow-up every 6 months is recommended. 4) If visual acuity decreases, visual field defects worsen, or new symptoms appear, it is important to shorten the interval between visits.
The pathogenesis of PPRCA remains largely unknown, but the photoreceptor-first model is a leading hypothesis.
Antropoli et al. (2024) proposed a model in which genetic mutations cause primary photoreceptor damage, followed by retinal thinning and RPE atrophy. 3) This model is consistent with the following observations:
The involvement of hyalocytes (vitreous-resident macrophage-like cells) has attracted attention.
Fallon et al. (2023) first reported that in asymmetric PPRCA cases using en face OCT, ramified hyalocytes were observed in the more advanced eye, while amoeboid hyalocytes were observed in the milder eye. 1) Amoeboid hyalocytes are interpreted as inflammatory markers, suggesting a link between lesion activity and inflammation.
The fact that cystoid macular edema occurred without inflammatory findings in the pediatric case with cystoid macular edema reported by Mente et al. (2022) suggests the existence of a potential inflammatory pathway. 7)
OCTA shows flow voids in the choriocapillaris of the lesion area, suggesting that choroidal blood flow impairment may contribute to atrophy. 3) However, whether choroidal damage precedes or follows photoreceptor damage remains unknown.
Liu et al. (2023) reported a case of a 2-year-old boy in whom compound heterozygous mutations in the RPGRIP1 gene (c.2592T>G: p.Y864*, c.154C>T: p.R52*) were identified by whole-exome sequencing. 8) RPGRIP1 is an essential gene for rod photoreceptor outer segment formation, and this is the earliest confirmed report of such mutations causing autosomal recessive PPRCA.
With the spread of ultra-wide-field FAF (UWF-FAF) and OCTA, more detailed evaluation of the lesion extent and choroidal blood flow changes in PPRCA is becoming possible. 3) These techniques are expected to enable identification of peripheral lesions not captured by conventional examinations and quantification of activity indicators.
Fallon et al. (2023) reported the first in vivo visualization of hyalocytes in the vitreous cortex of PPRCA patients using en face OCT. 1) In advanced eyes, ramified hyalocytes were predominant, while in mild eyes, amoeboid hyalocytes were observed. Whether the activation state of hyalocytes can serve as a biomarker for disease progression awaits verification in future longitudinal studies.
Currently, four genes (CRB1, CRX, HK1, RPGRIP1) have been reported as associated with PPRCA, but in many cases, the genetic mutation remains unidentified. 3)
The identification of compound heterozygous RPGRIP1 mutations in a 2-year-old boy by Liu et al. (2023) is notable as the youngest reported case of PPRCA. 8) The RPGRIP1 gene is also involved in Leber congenital amaurosis and RP, and elucidating the genetic continuum between PPRCA and these diseases may lead to future gene therapy strategies.
Fukushima et al. (2023) reported a series of 5 cases including PPRCA+RP combined cases, noting that 20% had both diseases. 2) Electroretinography showed different patterns in each eye (attenuated type on the PPRCA side, negative type on the RP side). Long-term longitudinal studies are needed to investigate whether PPRCA is a precursor stage or subtype of RP.
This is currently at the research stage. The causative genes of PPRCA (such as CRB1 and RPGRIP1) are shared with RP and Leber congenital amaurosis, and progress in gene therapy research for these diseases may lead to applications for PPRCA. 3, 8)
