RDH5-related retinopathy is an autosomal recessive inherited retinal disease caused by biallelic pathogenic variants in RDH5, encoding 11-cis-retinol dehydrogenase, a microsomal short-chain dehydrogenase/reductase abundant in the retinal pigment epithelium (RPE) that catalyzes the oxidation of 11-cis-retinol to 11-cis-retinal, the chromophore shared by rod and cone opsins. Loss of this enzymatic activity delays regeneration of both rod and cone photopigments and causes accumulation of cis-retinoid intermediates in the RPE. The classic clinical presentation, fundus albipunctatus, is a congenital, largely stationary form of night blindness with numerous small yellow-white deep retinal flecks sparing the fovea and a characteristic negative-configuration electroretinogram (ERG) that normalizes after prolonged (2-3 hour) dark adaptation. A subset of patients, more often after age 40 and with variable expressivity even among relatives sharing an identical genotype, develop a distinct, progressive course of cone dysfunction and macular atrophy superimposed on the flecked-retina background.
Ask a research question about RDH5-Related Retinopathy. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: RDH5-Related Retinopathy
creation_date: "2026-07-21T22:25:59Z"
category: Mendelian
description: >-
RDH5-related retinopathy is an autosomal recessive inherited retinal disease caused
by biallelic pathogenic variants in RDH5, encoding 11-cis-retinol dehydrogenase, a
microsomal short-chain dehydrogenase/reductase abundant in the retinal pigment
epithelium (RPE) that catalyzes the oxidation of 11-cis-retinol to 11-cis-retinal,
the chromophore shared by rod and cone opsins. Loss of this enzymatic activity
delays regeneration of both rod and cone photopigments and causes accumulation of
cis-retinoid intermediates in the RPE. The classic clinical presentation, fundus
albipunctatus, is a congenital, largely stationary form of night blindness with
numerous small yellow-white deep retinal flecks sparing the fovea and a
characteristic negative-configuration electroretinogram (ERG) that normalizes after
prolonged (2-3 hour) dark adaptation. A subset of patients, more often after age 40
and with variable expressivity even among relatives sharing an identical genotype,
develop a distinct, progressive course of cone dysfunction and macular atrophy
superimposed on the flecked-retina background.
disease_term:
preferred_term: RDH5-related retinopathy
term:
id: MONDO:0100443
label: RDH5-related retinopathy
synonyms:
- Fundus albipunctatus
- RDH5 retinopathy
- Pigmentary retinal dystrophy
- Retinitis punctata albescens
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
notes: >-
"Retinitis punctata albescens" is included as a historical synonym because MONDO
lists it as a narrow synonym of MONDO:0100443, but the term is genetically
heterogeneous in the broader literature and can also arise from RLBP1 or PRPH2
variants; a curator encountering that label alone should not assume an RDH5 cause
without confirmatory genetic testing. RPE65 mutations are a separate, non-allelic
phenocopy of the fundus albipunctatus phenotype (a distinct disease mechanism, not
a modifier or digenic interaction with RDH5) — no literature was found supporting a
true RDH5+RPE65 digenic or modifier mechanism despite this being a plausible a
priori hypothesis given both genes act in the same visual cycle. Reported fundus
autofluorescence findings at the fleck lesions are inconsistent across studies
(decreased in some series, small hyperautofluorescent dots in others), likely
reflecting different lesion maturity/stage rather than a single characteristic FAF
signature. The disease is part of the broader "flecked retina syndrome" group
(which also includes Stargardt disease/fundus flavimaculatus, familial drusen, and
fleck retina of Kandori) and must be distinguished from unrelated "white dot
syndromes" of inflammatory/uveitic origin.
has_subtypes:
- name: Stationary
display_name: Stationary Fundus Albipunctatus
description: >-
The classic, typically non-progressive presentation: congenital night blindness
with numerous yellow-white retinal flecks sparing the fovea and a negative
dark-adapted ERG that normalizes to typical amplitudes after prolonged (2-3 hour)
dark adaptation. Long-term follow-up usually shows no progression of the rod
dysfunction in this form.
evidence:
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: OTHER
snippet: "Although long-term follow-up usually shows no progression in rods dysfunction in patients with this form of night blindness, some patients, especially the elderly, reveal progressive cone dystrophy"
explanation: >-
This review confirms that the rod-dominant night blindness of fundus
albipunctatus is typically stationary over long-term follow-up, distinguishing
this subtype from the progressive cone dystrophy subset.
- name: Progressive Cone Dystrophy
display_name: Progressive Cone Dystrophy and Macular Atrophy
description: >-
A subset of RDH5 patients, most frequently over age 40, develop progressive cone
dysfunction and/or macular atrophy superimposed on the flecked fundus, with
declining photopic ERG amplitudes, reduced visual acuity, and in some cases
fading of the classic white dots over decades. Genotype-phenotype correlation is
incomplete: siblings homozygous for the identical RDH5 variant have been reported
with discordant macular involvement, suggesting unidentified genetic or
environmental modifiers.
evidence:
- reference: PMID:11053295
reference_title: A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cone dystrophy was most frequently seen in patients over 40 years old."
explanation: >-
This case series establishes the age-associated onset of the progressive
cone dystrophy subtype among RDH5 patients.
- reference: PMID:12788147
reference_title: Macular dystrophy in a Japanese family with fundus albipunctatus.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He also had bull's-eye maculopathy and prepappillary arterial loops, whereas she did not, and his best-corrected visual acuity was impaired, whereas hers was normal."
explanation: >-
A sibling pair homozygous for the identical Gly107Arg RDH5 mutation showed
discordant macular phenotypes, demonstrating incomplete genotype-phenotype
correlation for the progressive subtype.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
RDH5-related retinopathy is caused by biallelic (homozygous or compound
heterozygous) loss-of-function variants in RDH5.
evidence:
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: OTHER
snippet: "This disorder shows autosomal recessive inheritance and is caused mostly by mutations in the RDH5 gene."
explanation: >-
This review confirms autosomal recessive inheritance as the primary mode for
RDH5-related retinopathy.
pathophysiology:
- name: RDH5 11-cis-Retinol Dehydrogenase Deficiency
conforms_to: "retinoid_visual_cycle_disruption#Visual Cycle Enzyme or Transporter Defect"
biological_scale: MOLECULAR
description: >-
Biallelic pathogenic RDH5 variants reduce or abolish the enzymatic activity of
11-cis-retinol dehydrogenase, a microsomal enzyme abundant in the RPE proposed
to catalyze the oxidation of 11-cis-retinol to 11-cis-retinal. Recombinant mutant
enzyme shows directly reduced activity compared with wild-type enzyme.
gene:
preferred_term: RDH5
modifier: DECREASED
term:
id: hgnc:9940
label: RDH5
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
biological_processes:
- preferred_term: retinol metabolic process
modifier: DECREASED
term:
id: GO:0042572
label: retinol metabolic process
- preferred_term: retinoid metabolic process
modifier: DECREASED
term:
id: GO:0001523
label: retinoid metabolic process
downstream:
- target: Delayed Chromophore Regeneration and Retinoid Intermediate Accumulation
description: >-
Loss of 11-cis-retinol dehydrogenase activity blocks the final oxidation step
of the visual cycle, preventing efficient regeneration of the 11-cis-retinal
chromophore.
evidence:
- reference: PMID:10369264
reference_title: Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.
supports: SUPPORT
evidence_source: OTHER
snippet: "This microsomal enzyme is abundant in the retinal pigment epithelium, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal."
explanation: >-
This original genetic-discovery paper establishes RDH5's proposed enzymatic
role in the RPE, the proximal step disrupted by pathogenic variants.
evidence:
- reference: PMID:10369264
reference_title: Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence."
explanation: >-
This biochemical comparison of recombinant mutant versus wild-type enzyme
directly demonstrates the loss-of-function mechanism of RDH5 pathogenic
variants.
- reference: PMID:11418621
reference_title: Characterization of a dehydrogenase activity responsible for oxidation of 11-cis-retinol in the retinal pigment epithelium of mice with a disrupted RDH5 gene. A model for the human hereditary disease fundus albipunctatus.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The RDH5 gene encodes a dehydrogenase that is responsible for the majority of RDH activity."
explanation: >-
This Rdh5-knockout mouse study confirms RDH5 accounts for the majority of
11-cis-retinol dehydrogenase activity in the RPE.
- name: Delayed Chromophore Regeneration and Retinoid Intermediate Accumulation
conforms_to: "retinoid_visual_cycle_disruption#Chromophore Insufficiency and Retinoid Intermediate Accumulation"
biological_scale: MOLECULAR
description: >-
Loss of RDH5 activity delays regeneration of 11-cis-retinal for both rod and
cone photopigments and causes accumulation of cis-retinoid intermediates
(particularly 13-cis-isomers) in the RPE, directly demonstrated in an
Rdh5-knockout mouse model of the human disease.
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
downstream:
- target: Prolonged Rod and Cone Photopigment Regeneration Kinetics
description: >-
The core stationary-phenotype consequence: both rod and cone photopigment
regeneration is delayed but ultimately complete, producing a reversible
dark-adaptation defect rather than permanent photoreceptor signaling loss.
evidence:
- reference: PMID:10369264
reference_title: Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.
supports: SUPPORT
evidence_source: OTHER
snippet: "a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments"
explanation: >-
This defines the core mechanistic consequence of RDH5 loss: delayed, not
absent, regeneration of both rod and cone photopigments.
- target: Age-Associated Chronic Retinoid Stress and Cone Photoreceptor Vulnerability
description: >-
In a subset of patients, ongoing impaired chromophore supply and/or retinoid
intermediate accumulation produces cumulative cone photoreceptor and RPE
stress that becomes clinically apparent with age, diverging from the typical
stationary course.
evidence:
- reference: PMID:11053295
reference_title: A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the mutations of the RDH5 gene caused a progressive cone dystrophy as well as night blindness"
explanation: >-
This case series establishes that a subset of RDH5 mutations produce
progressive cone dystrophy in addition to the stationary night blindness,
diverging from the purely stationary mechanistic path.
evidence:
- reference: PMID:11418621
reference_title: Characterization of a dehydrogenase activity responsible for oxidation of 11-cis-retinol in the retinal pigment epithelium of mice with a disrupted RDH5 gene. A model for the human hereditary disease fundus albipunctatus.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Lack of 11-cis-RDH leads to an accumulation of cis-retinoids, particularly 13-cis-isomers."
explanation: >-
This Rdh5-knockout mouse study directly demonstrates retinoid intermediate
accumulation as the biochemical consequence of RDH5 loss.
- name: Prolonged Rod and Cone Photopigment Regeneration Kinetics
conforms_to: "retinoid_visual_cycle_disruption#Delayed Dark Adaptation and Night Blindness"
biological_scale: TISSUE
description: >-
Clinically, delayed but ultimately complete photopigment regeneration produces
the classic reversible dark-adaptation defect of fundus albipunctatus: a
negative-configuration, reduced-amplitude ERG after a short (20-30 minute)
dark-adaptation period that normalizes to typical amplitudes after prolonged
(2-3 hour) dark adaptation in patients without macular involvement. This
recoverable pattern distinguishes stationary fundus albipunctatus from other
congenital stationary night blindness disorders with permanently subnormal ERGs.
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
evidence:
- reference: PMID:12906118
reference_title: "RDH5 gene mutations and electroretinogram in fundus albipunctatus with or without macular dystrophy: RDH5 mutations and ERG in fundus albipunctatus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The bright-flash, mixed rod-cone ERG had a negative configuration with reduced a-wave amplitudes after a short period of dark-adaptation (20 or 30 min). After a prolonged dark-adaptation period (2 or 3 h), the waveform attained normal amplitudes in patients without macular dystrophy but the a-waves were still subnormal in patients with macular dystrophy."
explanation: >-
This cohort study of 21 patients establishes the diagnostic ERG recovery
pattern that defines the stationary form and distinguishes it electrophysiologically
from the progressive/macular subtype.
- reference: PMID:22669287
reference_title: "Multimodal fundus imaging in fundus albipunctatus with RDH5 mutation: a newly identified compound heterozygous mutation and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Electroretinography (ERG) showed improved dark-adapted responses after a prolonged 2.5-h dark adaptation."
explanation: >-
This case confirms the characteristic ERG recovery after prolonged dark
adaptation in a genetically confirmed RDH5 patient.
- name: Age-Associated Chronic Retinoid Stress and Cone Photoreceptor Vulnerability
biological_scale: CELLULAR
description: >-
In a subset of patients, more frequently after age 40 and with variable
expressivity even among relatives sharing an identical RDH5 genotype, chronic
impairment of chromophore supply produces cumulative cone photoreceptor stress
that diverges from the typical stationary course.
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
downstream:
- target: Progressive Cone Dystrophy and Macular Atrophy
description: >-
Sustained cone photoreceptor and RPE stress in the vulnerable subset
progresses to measurable macular atrophy and declining cone-mediated visual
function.
evidence:
- reference: PMID:38945349
reference_title: "RDH5 and RLBP1-Associated Inherited Retinal Diseases: Refining the Spectrum of Stationary and Progressive Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Progressive MA in addition to congenital night blindness can be identified in adult patients with RDH5-associated retinopathy."
explanation: >-
This retrospective cohort study directly documents progressive macular
atrophy as a distinct clinical trajectory in adult RDH5 patients.
evidence:
- reference: PMID:12788147
reference_title: Macular dystrophy in a Japanese family with fundus albipunctatus.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A homozygous Gly107Arg mutation in the RDH5 gene was detected in both siblings."
explanation: >-
Despite an identical homozygous genotype, this sibling pair showed discordant
macular involvement, supporting variable expressivity of the progressive
cone/macular subtype rather than strict genotype-determined severity.
- name: Progressive Cone Dystrophy and Macular Atrophy
biological_scale: TISSUE
description: >-
In the vulnerable subset, cone dysfunction and macular atrophy progress over
years to decades, with significant measurable macular volume loss, declining
photopic (cone) ERG amplitudes, and in the most advanced cases fading of the
classic white flecks and reduced central visual acuity. This represents a
materially different prognosis and monitoring need than the typical stationary
course. Unlike the photoreceptor_degeneration module's rod-first apoptosis
followed by non-cell-autonomous secondary cone loss, RDH5 cone dysfunction
arises directly from the same chronic RPE chromophore-supply defect that
affects rods, not as a bystander effect of rod death, so this node does not
declare conforms_to either module node.
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
evidence:
- reference: PMID:38945349
reference_title: "RDH5 and RLBP1-Associated Inherited Retinal Diseases: Refining the Spectrum of Stationary and Progressive Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we found a significant annual rate of macular volume loss, estimated at -0.007 mm3/y (95% CI, -0.012 to -0.001; P = .02), without any significant difference between the two genotypes"
explanation: >-
This retrospective cohort quantifies the annual rate of macular volume loss
in RDH5-associated retinopathy, confirming a measurable progressive
trajectory in adult patients.
- reference: PMID:32232344
reference_title: RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "macular involvement was observed in 12 patients (24 eyes)"
explanation: >-
This large Japanese cohort (25 patients) quantifies the proportion of
patients with OCT-confirmed macular involvement.
- reference: PMID:32232344
reference_title: RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "decreased cone responses were seen in 17 patients (73.9%)"
explanation: >-
This confirms decreased cone (photopic) ERG responses as a common finding
in this large RDH5 cohort, consistent with the progressive cone dystrophy
mechanism.
- reference: PMID:12967826
reference_title: A novel RDH5 gene mutation in a patient with fundus albipunctatus presenting with macular atrophy and fading white dots.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fundoscopy revealed only macular atrophy with notable absence of white dots."
explanation: >-
This long-term case (76-year-old patient) documents the most advanced end
of the progressive trajectory: macular atrophy with disappearance of the
classic flecks.
phenotypes:
- category: Ophthalmological
name: Nyctalopia
frequency: VERY_FREQUENT
description: >-
Congenital or early-childhood-onset night blindness is the presenting symptom
in the stationary form, reflecting delayed rod photopigment regeneration.
phenotype_term:
preferred_term: Night blindness
term:
id: HP:0000662
label: Nyctalopia
evidence:
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: OTHER
snippet: "Fundus albipunctatus (FA) is a rare, congenital form of night blindness with rod system impairment, characterised by the presence of numerous small, white-yellow retinal lesions."
explanation: >-
This review confirms congenital night blindness as the defining presenting
feature of fundus albipunctatus.
- category: Ophthalmological
name: Retinal flecks
frequency: VERY_FREQUENT
description: >-
Numerous small, deep yellow-white retinal lesions distributed throughout the
fundus but sparing the fovea are the characteristic ophthalmoscopic finding.
phenotype_term:
preferred_term: Retinal flecks
term:
id: HP:0012045
label: Retinal flecks
evidence:
- reference: PMID:22669287
reference_title: "Multimodal fundus imaging in fundus albipunctatus with RDH5 mutation: a newly identified compound heterozygous mutation and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fundus examination revealed diffuse yellow flecks with foveal sparing."
explanation: >-
This genetically confirmed case documents the characteristic distribution
of retinal flecks with foveal sparing.
- category: Ophthalmological
name: Abnormal dark-adapted electroretinogram
frequency: VERY_FREQUENT
description: >-
A negative-configuration, reduced-amplitude ERG after a short dark-adaptation
period is the diagnostic electrophysiological hallmark; in the pure stationary
form the waveform normalizes after prolonged (2-3 hour) dark adaptation.
phenotype_term:
preferred_term: Abnormal dark-adapted electroretinogram
term:
id: HP:0030469
label: Abnormal dark-adapted electroretinogram
reports_on:
- target: Prolonged Rod and Cone Photopigment Regeneration Kinetics
relationship: READOUT_OF
endpoint_context: DIAGNOSTIC
interpretation: >-
The negative-configuration ERG and its recovery after prolonged dark
adaptation directly measure the delayed-but-recoverable rod and cone
photopigment regeneration kinetics caused by RDH5 loss.
evidence:
- reference: PMID:35250012
reference_title: "THE TARGET SIGN: A Near Infrared Feature and Multimodal Imaging in a Pluri-Ethnic Cohort with RDH5-Related Fundus Albipunctatus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Scotopic electroretinograms were significantly reduced in all cases with an electronegative pattern, 66.7% displayed cone dysfunction."
explanation: >-
This multicenter, multiethnic case series confirms the electronegative
scotopic ERG pattern as a consistent finding across genotypes and ethnicities.
- category: Ophthalmological
name: Cone dystrophy
subtype: Progressive Cone Dystrophy
frequency: FREQUENT
description: >-
A subset of patients, most often over age 40, develop progressive cone
dysfunction with reduced photopic ERG amplitudes, distinct from the typical
stationary rod-predominant course.
phenotype_term:
preferred_term: Cone dystrophy
term:
id: HP:0008020
label: Cone dystrophy
evidence:
- reference: PMID:11053295
reference_title: A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cone dystrophy was most frequently seen in patients over 40 years old."
explanation: >-
This case series of 14 patients directly quantifies the age-associated
onset of cone dystrophy in RDH5-related disease.
- reference: PMID:32232344
reference_title: RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "decreased cone responses were seen in 17 patients (73.9%)"
explanation: >-
This large cohort study confirms decreased cone ERG responses as a
frequent finding among RDH5 patients overall.
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Recently, it has been estimated that cone dysfunction can affect more than 30 % of patients with FA"
explanation: >-
A review estimate of cone dysfunction frequency across the FA
literature, corroborating the FREQUENT band alongside the two
cohort-specific counts above.
- category: Ophthalmological
name: Macular atrophy
subtype: Progressive Cone Dystrophy
frequency: FREQUENT
description: >-
Progressive macular atrophy, sometimes with fading of the classic white
flecks over decades, occurs in a subset of adult patients.
phenotype_term:
preferred_term: Macular atrophy
term:
id: HP:0007401
label: Macular atrophy
evidence:
- reference: PMID:38945349
reference_title: "RDH5 and RLBP1-Associated Inherited Retinal Diseases: Refining the Spectrum of Stationary and Progressive Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Progressive MA in addition to congenital night blindness can be identified in adult patients with RDH5-associated retinopathy."
explanation: >-
This retrospective cohort establishes progressive macular atrophy as a
documented clinical trajectory distinct from the stationary form.
- reference: PMID:12967826
reference_title: A novel RDH5 gene mutation in a patient with fundus albipunctatus presenting with macular atrophy and fading white dots.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This is the first reported long-term case of fundus albipunctatus demonstrating macular atrophy with fading of the typical white dots."
explanation: >-
This long-term case report (76-year-old patient) demonstrates the most
advanced natural-history endpoint of the progressive subtype.
- category: Ophthalmological
name: Bull's eye maculopathy
subtype: Progressive Cone Dystrophy
frequency: OCCASIONAL
description: >-
A bull's-eye pattern of macular pigmentary change has been reported in some
patients with the progressive/macular subtype.
phenotype_term:
preferred_term: Bull's eye maculopathy
term:
id: HP:0011504
label: Bull's eye maculopathy
evidence:
- reference: PMID:12788147
reference_title: Macular dystrophy in a Japanese family with fundus albipunctatus.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He also had bull's-eye maculopathy and prepappillary arterial loops, whereas she did not"
explanation: >-
This case documents bull's-eye maculopathy in one of two siblings sharing
an identical homozygous RDH5 genotype.
- category: Ophthalmological
name: Reduced visual acuity
subtype: Progressive Cone Dystrophy
frequency: OCCASIONAL
description: >-
Central visual acuity is preserved in the typical stationary form but can
become impaired in patients who develop the progressive macular subtype.
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:32232344
reference_title: RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two patients (16.7%) exhibited diffuse disruption throughout the macula and decreased BCVA"
explanation: >-
This cohort study confirms that a minority of patients with macular
involvement have measurably decreased best-corrected visual acuity.
genetic:
- name: RDH5 pathogenic variants
gene_term:
preferred_term: RDH5
term:
id: hgnc:9940
label: RDH5
association: Causative
features: >-
Biallelic (homozygous or compound heterozygous) loss-of-function variants in
RDH5 cause the disease. In Japanese cohorts the recurrent variant
p.L310delinsEV accounts for a majority of disease alleles and has been
detected in patients both with and without the progressive cone dystrophy
subtype, indicating that this specific allele alone does not fully predict
progression.
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: OTHER
snippet: "This disorder shows autosomal recessive inheritance and is caused mostly by mutations in the RDH5 gene."
explanation: >-
Confirms autosomal recessive inheritance as the primary mode for
RDH5-related retinopathy.
evidence:
- reference: PMID:32232344
reference_title: RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most frequently observed variant was p.L310delinsEV (65.2%, 30/46 alleles)."
explanation: >-
This large Japanese cohort study establishes p.L310delinsEV as the
predominant recurrent RDH5 allele.
- reference: PMID:11053295
reference_title: A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The nt 928 C to GAAG mutation was detected in patients with and without cone dystrophy."
explanation: >-
This finding (the nt928 C-to-GAAG variant corresponds to p.L310delinsEV)
demonstrates that this single recurrent allele alone does not fully
determine progression to the cone dystrophy subtype.
treatments:
- name: Oral 9-cis-beta-carotene supplementation
therapeutic_modality: SMALL_MOLECULE
description: >-
An investigational, non-FDA-approved chromophore-analog supplementation
strategy. In a small open-label phase I pilot study, daily oral high-dose
9-cis-beta-carotene for 90 days significantly improved peripheral visual
field and rod ERG recovery kinetics in patients with fundus albipunctatus,
with no reported complications. This is proof-of-concept evidence for
visual-cycle bypass supplementation rather than an established standard of
care.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: 9-cis-beta-carotene
term:
id: CHEBI:67188
label: 9-cis-beta-carotene
evidence:
- reference: PMID:19955196
reference_title: "Treatment of a retinal dystrophy, fundus albipunctatus, with oral 9-cis-{beta}-carotene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients showed significant improvements in peripheral visual field (mean deviation improved from -4.77+/-2.0 to -3.28+/-2.28, p=0.009, t test) and a highly significant improvement in rod recovery rates measured electroretinographically (maximal scotopic b-wave amplitude responses, improved from 197+/-49 muV to 292+/-48 muV, p<0.001, t test)."
explanation: >-
This phase I pilot study (n=7) provides the quantitative efficacy data for
the investigational chromophore-supplementation approach.
- reference: PMID:19955196
reference_title: "Treatment of a retinal dystrophy, fundus albipunctatus, with oral 9-cis-{beta}-carotene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Oral treatment with 9-cis-beta-carotene led to reversal of a human retinal dystrophy."
explanation: >-
This is the study's own summary conclusion characterizing the treatment
effect observed in the pilot trial.
- name: Supportive care and monitoring
therapeutic_modality: OTHER
description: >-
In the absence of an approved disease-modifying therapy, management for the
typical stationary form consists of reassurance and routine ophthalmological
follow-up given the generally favorable long-term prognosis. Patients who
develop the progressive cone/macular subtype warrant closer monitoring
(visual acuity, photopic ERG, OCT) and low vision support as needed.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:12906118
reference_title: "RDH5 gene mutations and electroretinogram in fundus albipunctatus with or without macular dystrophy: RDH5 mutations and ERG in fundus albipunctatus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The clinical phenotype including electrophysiological responses varied among patients with the RDH5 gene mutations."
explanation: >-
This variability in clinical course across patients supports individualized
monitoring rather than a uniform management pathway.
- name: Genetic counseling
therapeutic_modality: OTHER
description: >-
Genetic counseling is indicated given the autosomal recessive inheritance
pattern, the availability of molecular confirmation, and the incomplete
genotype-phenotype correlation for the progressive cone/macular subtype.
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: OTHER
snippet: "This disorder shows autosomal recessive inheritance and is caused mostly by mutations in the RDH5 gene."
explanation: >-
Confirms the autosomal recessive inheritance pattern that underlies
genetic counseling recommendations for affected families.
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
- classification_value: NEUROLOGIC
diagnosis:
- name: Molecular genetic testing
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
Sequencing of RDH5 (and, when negative, the phenocopy genes RLBP1 and RPE65)
confirms the diagnosis and distinguishes RDH5-related retinopathy from other
flecked-retina syndromes and phenocopies.
results: >-
Identification of biallelic pathogenic RDH5 variants confirms the diagnosis.
A negative RDH5 result in a patient with a fundus-albipunctatus-like
phenotype should prompt consideration of RLBP1 or RPE65 as phenocopy genes.
evidence:
- reference: PMID:22669287
reference_title: "Multimodal fundus imaging in fundus albipunctatus with RDH5 mutation: a newly identified compound heterozygous mutation and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ERG and genetic study remain the most reliable tests for making the diagnosis"
explanation: >-
This review confirms genetic testing alongside ERG as the most reliable
diagnostic standard, more definitive than retinal imaging alone.
- name: Prolonged dark-adaptation electroretinography
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
description: >-
Serial ERG testing after a short (20-30 minute) versus a prolonged (2-3 hour)
dark-adaptation period is the classic diagnostic maneuver for fundus
albipunctatus.
results: >-
Recovery of rod and cone ERG amplitudes to normal after prolonged dark
adaptation indicates the stationary form; persistent subnormal amplitudes
after prolonged dark adaptation indicate the progressive/macular subtype.
evidence:
- reference: PMID:12906118
reference_title: "RDH5 gene mutations and electroretinogram in fundus albipunctatus with or without macular dystrophy: RDH5 mutations and ERG in fundus albipunctatus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the waveform attained normal amplitudes in patients without macular dystrophy but the a-waves were still subnormal in patients with macular dystrophy"
explanation: >-
This directly establishes the ERG recovery pattern as a functional
differentiator between the stationary and progressive/macular subtypes.
- name: Multimodal retinal imaging
diagnosis_term:
preferred_term: multimodal retinal imaging
term:
id: NCIT:C17369
label: Imaging Procedure
description: >-
Near-infrared reflectance imaging, fundus autofluorescence, and optical
coherence tomography (OCT) characterize the retinal flecks and detect
macular involvement.
results: >-
Near-infrared imaging shows a characteristic "target sign" corresponding to
the yellow flecks in nearly all patients regardless of ethnicity or specific
RDH5 variant; SD-OCT localizes lesions to the level between the external
limiting membrane and retinal pigment epithelium.
evidence:
- reference: PMID:35250012
reference_title: "THE TARGET SIGN: A Near Infrared Feature and Multimodal Imaging in a Pluri-Ethnic Cohort with RDH5-Related Fundus Albipunctatus."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All eyes (n = 36, 100%) showed small circular findings seen on near-infrared images, termed as the \"target sign,\" correlating to the yellowish dots seen clinically"
explanation: >-
This multicenter, multiethnic cohort establishes the target sign as a
consistent near-infrared imaging finding across genetic and ethnic
backgrounds.
epidemiology:
- name: Rarity and variant spectrum
description: >-
RDH5-related retinopathy is rare without an established population
prevalence estimate. The RDH5 variant spectrum is enriched for a small
number of recurrent alleles in specific populations; in Japanese cohorts the
p.L310delinsEV variant accounts for the majority of disease alleles.
evidence:
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: OTHER
snippet: "Fundus albipunctatus (FA) is a rare, congenital form of night blindness with rod system impairment"
explanation: >-
This review characterizes fundus albipunctatus as a rare disease without
a precise population prevalence figure in the literature.
- reference: PMID:32232344
reference_title: RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most frequently observed variant was p.L310delinsEV (65.2%, 30/46 alleles)."
explanation: >-
This is the largest reported single-population cohort and quantifies the
dominant recurrent allele in the Japanese RDH5 variant spectrum.
progression:
- phase: Congenital stationary night blindness with flecked fundus
age_range: Childhood through early adulthood
notes: >-
Night blindness is typically apparent from childhood. ERG demonstrates
delayed but recoverable dark adaptation. Long-term follow-up in this form
usually shows no progression of rod dysfunction.
evidence:
- reference: PMID:25820994
reference_title: "Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe)."
supports: SUPPORT
evidence_source: OTHER
snippet: "Although long-term follow-up usually shows no progression in rods dysfunction in patients with this form of night blindness, some patients, especially the elderly, reveal progressive cone dystrophy"
explanation: >-
This establishes the typical stationary natural history through
adulthood in the majority of patients.
- phase: Age-associated progressive cone dystrophy and macular atrophy in a subset
age_range: Typically after age 40
notes: >-
A minority of patients, more often after age 40, develop progressive cone
dysfunction and/or macular atrophy with declining visual acuity; in the most
advanced reported case (a 76-year-old patient) the classic white dots had
faded entirely, leaving only macular atrophy.
evidence:
- reference: PMID:11053295
reference_title: A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cone dystrophy was most frequently seen in patients over 40 years old."
explanation: >-
This directly documents the age-associated onset of the progressive
cone dystrophy phase.
- reference: PMID:12967826
reference_title: A novel RDH5 gene mutation in a patient with fundus albipunctatus presenting with macular atrophy and fading white dots.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This is the first reported long-term case of fundus albipunctatus demonstrating macular atrophy with fading of the typical white dots."
explanation: >-
This 76-year-old case represents the most advanced documented endpoint of
the progressive natural history trajectory.