PDE6A-related retinopathy is an autosomal recessive retinitis pigmentosa (historically RP43) caused by biallelic pathogenic variants in PDE6A, encoding the alpha catalytic subunit of rod cGMP phosphodiesterase-6 (PDE6). PDE6 is a heterotetramer of alpha (PDE6A), beta (PDE6B), and two gamma (PDE6G) subunits that hydrolyzes cGMP during phototransduction; this entry is the direct mechanistic complement to AIPL1-Related_Retinopathy, whose chaperone product folds and assembles this same holoenzyme rather than forming part of it. PDE6A mutations disrupt the catalytic domain directly and also destabilize the entire PDE6 holoenzyme (loss of PDE6A secondarily depletes PDE6B and PDE6G), abolishing cGMP hydrolysis. The resulting cGMP accumulation keeps cyclic-nucleotide-gated channels open, sustaining Na+/Ca2+ influx and driving rod photoreceptor apoptosis, followed by progressive outer retinal degeneration. PDE6A accounts for roughly 3-4% of autosomal recessive RP families in North America. Unlike AIPL1, where a first-in-human gene therapy trial showed substantial benefit, a completed PDE6A gene supplementation trial did not improve visual function and showed a safety signal (central retinal thinning), despite favorable preclinical mouse and canine data -- a notably more cautionary translational story.
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name: PDE6A-Related Retinopathy
creation_date: "2026-07-22T22:10:00Z"
category: Mendelian
description: >-
PDE6A-related retinopathy is an autosomal recessive retinitis pigmentosa
(historically RP43) caused by biallelic pathogenic variants in PDE6A, encoding
the alpha catalytic subunit of rod cGMP phosphodiesterase-6 (PDE6). PDE6 is a
heterotetramer of alpha (PDE6A), beta (PDE6B), and two gamma (PDE6G) subunits
that hydrolyzes cGMP during phototransduction; this entry is the direct
mechanistic complement to AIPL1-Related_Retinopathy, whose chaperone product
folds and assembles this same holoenzyme rather than forming part of it. PDE6A
mutations disrupt the catalytic domain directly and also destabilize the
entire PDE6 holoenzyme (loss of PDE6A secondarily depletes PDE6B and PDE6G),
abolishing cGMP hydrolysis. The resulting cGMP accumulation keeps
cyclic-nucleotide-gated channels open, sustaining Na+/Ca2+ influx and driving
rod photoreceptor apoptosis, followed by progressive outer retinal
degeneration. PDE6A accounts for roughly 3-4% of autosomal recessive RP
families in North America. Unlike AIPL1, where a first-in-human gene therapy
trial showed substantial benefit, a completed PDE6A gene supplementation trial
did not improve visual function and showed a safety signal (central retinal
thinning), despite favorable preclinical mouse and canine data -- a notably
more cautionary translational story.
disease_term:
preferred_term: PDE6A-related retinopathy
term:
id: MONDO:0700224
label: PDE6A-related retinopathy
synonyms:
- Retinitis pigmentosa 43
- RP43
- PDE6A-related retinitis pigmentosa
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
notes: >-
Do not conflate PDE6A with the classic naturally-occurring rd1 ("retinal
degeneration 1") mouse, one of the oldest and most widely used inherited
retinal degeneration models -- rd1 is caused by a defect in PDE6B (the beta
subunit), not PDE6A. PDE6A and PDE6B are homologous genes encoding the two
distinct catalytic subunits of the same rod PDE6 holoenzyme and both cause
clinically similar autosomal recessive RP, but they are genetically distinct
loci; this entry covers PDE6A specifically. No gene-specific citable evidence
was found for nyctalopia (night blindness) or spicular/bone-spicule fundus
pigmentation in PDE6A-RP despite these being classic hallmarks of RP as a
disease class generally -- rather than support these phenotypes with a
non-gene-specific citation, they are omitted here; the phenotypes below are
restricted to findings with direct PDE6A-cohort quantitative support.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
PDE6A-related retinopathy is caused by biallelic (homozygous or compound
heterozygous) pathogenic variants in PDE6A.
evidence:
- reference: PMID:7493036
reference_title: Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we examined the gene encoding the alpha subunit of cGMP phosphodiesterase (PDEA) in 340 unrelated patients with RP. We found three point mutations in PDEA in affected members of two pedigrees with recessive RP."
explanation: >-
This original gene-discovery paper establishes autosomal recessive
inheritance for PDE6A-related retinitis pigmentosa.
pathophysiology:
- name: PDE6 Alpha Subunit Loss-of-Function
conforms_to: "phototransduction_cascade_dysfunction#Phototransduction Cascade Component Defect"
biological_scale: MOLECULAR
description: >-
Biallelic pathogenic PDE6A variants alter essential functional domains of
the alpha catalytic subunit of rod cGMP phosphodiesterase, directly
disrupting its catalytic function. PDE6A mutations affecting the catalytic
domain produce variable biochemical outcomes and degeneration rates,
indicating allelic heterogeneity.
gene:
preferred_term: PDE6A
modifier: DECREASED
term:
id: hgnc:8785
label: PDE6A
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
molecular_functions:
- preferred_term: 3',5'-cyclic-GMP phosphodiesterase activity
modifier: DECREASED
term:
id: GO:0047555
label: 3',5'-cyclic-GMP phosphodiesterase activity
downstream:
- target: Impaired PDE6 Holoenzyme Assembly and cGMP Hydrolysis
description: >-
Loss of functional PDE6A destabilizes the entire heterotetrameric PDE6
holoenzyme, not only its own catalytic contribution.
evidence:
- reference: PMID:18775863
reference_title: Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the affected retinas also lacked the other PDE6 subunits, suggesting expression of PDE6A is essential for normal expression of PDE6B and PDE6G"
explanation: >-
This canine model directly demonstrates that PDE6A loss secondarily
depletes the other PDE6 holoenzyme subunits.
evidence:
- reference: PMID:7493036
reference_title: Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase.
supports: SUPPORT
evidence_source: OTHER
snippet: "Each mutation alters an essential functional domain of the encoded protein and likely disrupts its catalytic function."
explanation: >-
This original gene-discovery paper establishes the loss-of-function
mechanism of PDE6A pathogenic variants.
- reference: PMID:18849587
reference_title: New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "significantly different biochemical outcomes and rates of degeneration of murine photoreceptor cells were observed, indicating allelic variation and previously unrecognized structure-function relationships"
explanation: >-
This mouse model study of two distinct Pde6a catalytic-domain missense
alleles establishes an allelic severity gradient.
- name: Impaired PDE6 Holoenzyme Assembly and cGMP Hydrolysis
biological_scale: MOLECULAR
description: >-
The heterotetrameric PDE6 complex (alpha, beta, and two gamma subunits)
hydrolyzes cGMP in response to light activation of the phototransduction
cascade. Loss of PDE6A prevents assembly of a functional holoenzyme, and
affected retinas lack PDE6 enzymatic activity entirely, not merely a
partial reduction.
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
downstream:
- target: cGMP Accumulation and CNG Channel Constitutive Opening
description: >-
Absent PDE6 catalytic activity prevents light-triggered cGMP hydrolysis,
causing cGMP to accumulate in rod outer segments instead of falling as
it normally would upon light exposure.
evidence:
- reference: PMID:31207907
reference_title: "The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers."
supports: SUPPORT
evidence_source: OTHER
snippet: "provided an explanation for excessive photoreceptor cGMP levels"
explanation: >-
This review directly links PDE6 subunit loss-of-function mutations to
excessive photoreceptor cGMP accumulation.
evidence:
- reference: PMID:18849587
reference_title: New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene.
supports: SUPPORT
evidence_source: OTHER
snippet: "The heterotetrameric phosphodiesterase (PDE) 6 complex, made up of alpha, beta and two gamma subunits, regulates intracellular cGMP levels by hydrolyzing cGMP in response to light activation of G protein coupled receptors in cones and rods, making it an essential component of the visual phototransduction cascade"
explanation: >-
This establishes the PDE6 holoenzyme composition and its role in cGMP
hydrolysis during phototransduction.
- reference: PMID:18775863
reference_title: Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Affected retinas lacked PDE6 enzymatic activity."
explanation: >-
This canine model directly confirms complete loss of PDE6 enzymatic
activity as the biochemical consequence of the PDE6A mutation.
- name: cGMP Accumulation and CNG Channel Constitutive Opening
conforms_to: "phototransduction_cascade_dysfunction#Loss of Outer-Segment cGMP and Calcium Set-Point Control"
biological_scale: CELLULAR
description: >-
Excessive accumulation of cGMP in photoreceptors is a common downstream
mechanism shared by many inherited retinal degeneration genes, including
PDE6A. Elevated cGMP keeps cyclic-nucleotide-gated channels open, sustaining
Na+/Ca2+ influx. Directly measured plasma cGMP is elevated in PDE6A-RP
patients, providing human biomarker evidence for this mechanism in vivo,
not just in animal models.
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
downstream:
- target: Rod Photoreceptor Apoptosis and Progressive Retinal Degeneration
description: >-
Sustained ion influx and excessive cGMP-dependent signaling in rods
drives rod photoreceptor apoptosis and halts photoreceptor outer segment
development.
evidence:
- reference: PMID:18775863
reference_title: Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Development of photoreceptor outer segments stopped, and rod cells were lost by apoptosis."
explanation: >-
This canine model directly demonstrates rod photoreceptor apoptosis
and arrested outer segment development as the consequence of PDE6A
loss.
evidence:
- reference: PMID:31207907
reference_title: "The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers."
supports: SUPPORT
evidence_source: OTHER
snippet: "Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations."
explanation: >-
This review establishes cGMP accumulation as a shared final mechanistic
step across many inherited retinal degeneration genes, including PDE6A.
- reference: PMID:27820873
reference_title: Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mean plasma cGMP in patients was approximately twice that in controls."
explanation: >-
This is direct human biomarker evidence of cGMP elevation in PDE6A-RP
patients, confirming the mechanism proposed from animal models applies
in vivo in humans.
- name: Rod Photoreceptor Apoptosis and Progressive Retinal Degeneration
biological_scale: TISSUE
conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
description: >-
Rod photoreceptor apoptosis begins early and produces progressive,
rod-predominant retinal degeneration with secondary cone dysfunction,
consistent with typical retinitis pigmentosa. Full-field electroretinography
is frequently non-recordable at the time of clinical assessment, and
cystoid macular edema is a common secondary structural finding.
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:33057649
reference_title: Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%)."
explanation: >-
This 57-patient natural history cohort quantifies the frequency of
non-recordable ERG responses at time of clinical assessment.
- reference: PMID:18775863
reference_title: Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The mutant puppies failed to develop normal rod-mediated ERG responses and had reduced light-adapted a-wave amplitudes from an early age. The residual ERG waveforms originated primarily from cone-driven responses."
explanation: >-
This canine model confirms the rod-predominant functional deficit with
relative cone preservation early in the disease course.
phenotypes:
- category: Ophthalmological
name: Reduced visual acuity
frequency: VERY_FREQUENT
description: >-
Visual acuity impairment is present in nearly all patients, though most
have mild or moderate loss rather than severe impairment.
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:33057649
reference_title: Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy."
explanation: >-
This 57-patient natural history cohort quantifies visual acuity
impairment as present in the great majority of patients, mostly at a
mild-to-moderate severity.
- category: Ophthalmological
name: Constriction of peripheral visual field
frequency: FREQUENT
description: >-
Kinetic visual fields are constricted, with only central remnants
persisting in older patients and additional temporal crescents in younger
patients.
phenotype_term:
preferred_term: Constriction of peripheral visual field
term:
id: HP:0001133
label: Constriction of peripheral visual field
evidence:
- reference: PMID:27820873
reference_title: Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Visual fields were constricted with mere central remnants in older subjects and additional temporal crescents in younger subjects."
explanation: >-
This family case series documents the characteristic pattern of visual
field constriction with age-dependent severity.
- category: Ophthalmological
name: Undetectable electroretinogram
frequency: VERY_FREQUENT
description: >-
Full-field electroretinography (both dark- and light-adapted) shows no
recordable responses in the great majority of eyes at the time of clinical
assessment.
phenotype_term:
preferred_term: Undetectable electroretinogram
term:
id: HP:0000550
label: Undetectable electroretinogram
reports_on:
- target: cGMP Accumulation and CNG Channel Constitutive Opening
relationship: READOUT_OF
endpoint_context: DIAGNOSTIC
interpretation: >-
Non-recordable ERG responses reflect the near-complete loss of
light-triggered phototransduction signaling caused by absent PDE6
catalytic activity and consequent cGMP dysregulation.
evidence:
- reference: PMID:33057649
reference_title: Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%)."
explanation: >-
This large natural history cohort quantifies the high frequency of
non-recordable ERG responses.
- reference: PMID:27820873
reference_title: Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Full-field ERGs showed extinguished rod responses and minimal cone responses."
explanation: >-
This family case series confirms extinguished rod ERG responses with
only minimal residual cone responses.
- category: Ophthalmological
name: Cystoid macular edema
frequency: FREQUENT
description: >-
Cystoid macular edema is a common secondary structural finding on OCT,
present in over half of eyes at baseline in one longitudinal cohort.
phenotype_term:
preferred_term: Cystoid macular edema
term:
id: HP:0011505
label: Cystoid macular edema
evidence:
- reference: PMID:39218074
reference_title: PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Eighteen eyes exhibited cystoid macular edema at baseline (56%), and 17 eyes (53%) at follow-up."
explanation: >-
This longitudinal cohort quantifies cystoid macular edema as a common
finding present in over half of eyes.
genetic:
- name: PDE6A pathogenic variants
gene_term:
preferred_term: PDE6A
term:
id: hgnc:8785
label: PDE6A
association: Causative
features: >-
Biallelic PDE6A variants include missense, nonsense, and splice-site
changes affecting the catalytic and cGMP-binding domains. In the largest
reported cohort the most frequently observed alleles were c.304C>A
(p.R102S), c.998+1G>A (a splice-donor variant), and c.2053G>A (p.V685M);
the c.998+1G>A splice variant produces a more severe phenotype than
c.304C>A when homozygous, indicating an allelic severity gradient
consistent with mouse model data showing variable biochemical outcomes
across different catalytic-domain alleles.
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:7493036
reference_title: Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found three point mutations in PDEA in affected members of two pedigrees with recessive RP."
explanation: >-
Confirms autosomal recessive inheritance for PDE6A-related RP.
evidence:
- reference: PMID:33057649
reference_title: Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S)."
explanation: >-
This 57-patient cohort directly compares the clinical severity of the
two most common PDE6A alleles.
- reference: PMID:18849587
reference_title: New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "these new models reveal that the mutations not only affect the function of the PDE6A protein itself, but also the level of PDE6B within the retina"
explanation: >-
This mouse model study confirms that distinct PDE6A catalytic-domain
alleles have secondary effects on PDE6B levels, supporting an allelic
severity gradient.
treatments:
- name: AAV8.hPDE6A Gene Supplementation Therapy
therapeutic_modality: GENE_THERAPY
description: >-
Subretinal delivery of an adeno-associated viral vector expressing human
PDE6A cDNA. Preclinical studies in a Pde6a-mutant mouse model and a
naturally-occurring PDE6A-null canine model both showed favorable
structural and functional rescue. However, a subsequent non-randomised
controlled Phase I/IIa human trial in adults with biallelic PDE6A variants
did NOT improve visual function over 1 year and showed a safety signal
(central retinal thinning and visual acuity decline in a subset of
treated eyes), a notably more cautionary outcome than the preclinical data
predicted -- a materially different translational story than the
contemporaneous AIPL1 gene therapy trial, which showed clear benefit.
treatment_term:
preferred_term: gene therapy
term:
id: NCIT:C15238
label: Gene Therapy
evidence:
- reference: PMID:29212391
reference_title: Gene Therapy Successfully Delays Degeneration in a Mouse Model of PDE6A-Linked Retinitis Pigmentosa (RP43).
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the ERG analysis confirmed a restoration of retinal function in a group of treated mice"
explanation: >-
This mouse model study demonstrates preclinical proof-of-concept for
AAV-mediated PDE6A gene supplementation.
- reference: PMID:28676737
reference_title: Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Treatment resulted in improvement in dim light vision and evidence of rod function on electroretinographic examination."
explanation: >-
This canine large-animal model further supported preclinical efficacy
of PDE6A gene supplementation prior to human trials.
- reference: PMID:40825661
reference_title: "Safety and vision outcomes of subretinal gene supplementation therapy in PDE6A-associated retinitis pigmentosa: a non-randomised controlled trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subretinal gene therapy with AAV8.hPDE6A did not improve visual function over 1 year and posed risks, including central retinal thinning and visual acuity decline. This is in contrast to the safety and efficacy profile established in preclinical models."
explanation: >-
This completed Phase I/IIa human trial (9 patients) directly reports
lack of efficacy and a safety signal, materially diverging from the
favorable preclinical results.
- name: Avoidance of PDE5 Inhibitors (Counseling Caution)
therapeutic_modality: OTHER
description: >-
PDE5 inhibitors (sildenafil, vardenafil) have only 10- to 15-fold lower
specificity for retinal PDE6 than for PDE5, owing to close structural and
kinetic similarity between the two enzyme families. This cross-reactivity
can cause transient visual disturbances in the general population, and
regulatory agencies including the FDA specifically caution about the lack
of controlled safety data for these drugs in patients with retinitis
pigmentosa or a family history of the disease. Animal evidence suggests
carriers of some recessive retinal-dystrophy alleles may be more sensitive
to sildenafil toxicity, making this a relevant counseling point for
PDE6A-RP patients and carriers.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:33809319
reference_title: "Visual Side Effects Linked to Sildenafil Consumption: An Update."
supports: SUPPORT
evidence_source: OTHER
snippet: "Sildenafil and vardenafil, for example, have shown only 10 and 15 times lower specificity for PDE6 than for PDE5, respectively"
explanation: >-
This review quantifies the structural cross-reactivity between PDE5
inhibitors and retinal PDE6, the mechanistic basis for the counseling
caution.
- reference: PMID:33809319
reference_title: "Visual Side Effects Linked to Sildenafil Consumption: An Update."
supports: SUPPORT
evidence_source: OTHER
snippet: "caution should be taken in patients with a family history of retinal dystrophy because available evidence in animal research supports the hypothesis that carriers of some recessive alleles are more sensitive to sildenafil toxicity"
explanation: >-
This directly supports the clinical counseling recommendation for
patients and carriers of PDE6A and other recessive retinal dystrophy
alleles.
- name: Genetic counseling
therapeutic_modality: OTHER
description: >-
Genetic counseling is indicated given the autosomal recessive inheritance
pattern, and molecular allele classification is prognostically relevant
given the demonstrated allelic severity gradient.
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:7493036
reference_title: Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found three point mutations in PDEA in affected members of two pedigrees with recessive RP."
explanation: >-
Confirms the autosomal recessive inheritance pattern underlying genetic
counseling recommendations.
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
- classification_value: NEUROLOGIC
diagnosis:
- name: Molecular genetic testing
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
description: >-
Sequencing of PDE6A confirms the diagnosis and classifies the allele as
a known severe (e.g., c.998+1G>A splice) or comparatively milder (e.g.,
c.304C>A) variant, informing prognosis and clinical trial eligibility.
results: >-
Identification of biallelic pathogenic PDE6A variants confirms the
diagnosis. Homozygosity for the c.998+1G>A splice variant predicts a more
severe course than homozygosity for c.304C>A.
evidence:
- reference: PMID:33057649
reference_title: Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S)."
explanation: >-
This natural history cohort establishes molecular genotyping as
informative for prognosis in PDE6A-RP.
- name: Full-field electroretinography
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
description: >-
Dark-adapted and light-adapted full-field ERG characterizes the severity
of rod and cone dysfunction and is frequently non-recordable at the time
of clinical presentation.
results: >-
No recordable responses in the majority of eyes tested; when present,
residual waveforms are predominantly cone-driven, reflecting relative
early preservation of cones over rods.
evidence:
- reference: PMID:33057649
reference_title: Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%)."
explanation: >-
This directly quantifies the high frequency of non-recordable ERG
responses at time of clinical assessment.
- name: Multimodal retinal imaging
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
description: >-
Fundus autofluorescence (FAF) and optical coherence tomography (OCT) track
hyperautofluorescent ring area, ellipsoid zone width, and cystoid macular
edema as structural progression biomarkers, used both diagnostically and
for clinical trial candidacy assessment.
results: >-
A hyperautofluorescent ring is commonly observed on FAF; ellipsoid zone
width and hyperautofluorescent ring area both decrease over follow-up,
tracking disease progression. Cystoid macular edema is a frequent
additional OCT finding.
evidence:
- reference: PMID:39218074
reference_title: PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were statistically significant changes during the follow-up period in terms of BCVA, hyperautofluorescent ring area, and the EZW."
explanation: >-
This longitudinal cohort establishes multimodal imaging biomarkers as
sensitive to disease progression over time.
epidemiology:
- name: Contribution to autosomal recessive retinitis pigmentosa
description: >-
PDE6A accounts for approximately 3% to 4% of families with autosomal
recessive retinitis pigmentosa in North America.
evidence:
- reference: PMID:10393062
reference_title: Frequency of mutations in the gene encoding the alpha subunit of rod cGMP-phosphodiesterase in autosomal recessive retinitis pigmentosa.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The PDE6A gene appears to account for roughly 3% to 4% of families with recessive RP in North America."
explanation: >-
This mutation-screening study of 164 unrelated arRP patients establishes
the population contribution of PDE6A to recessive RP.
progression:
- phase: Presentation with established visual impairment
age_range: Adulthood (cohort mean age 35-40 years)
notes: >-
Natural history cohorts of PDE6A-RP patients (mean baseline age
approximately 35-40 years) show disease highly symmetrical between the two
eyes, with mild or moderate visual impairment in the great majority of
patients at baseline.
evidence:
- reference: PMID:33057649
reference_title: Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "from 44 families were included"
explanation: >-
This establishes the largest reported PDE6A-RP natural history cohort
(57 patients, mean baseline age 40 years).
- phase: Slow progressive decline
age_range: Adulthood, over multi-year follow-up
notes: >-
Over a mean follow-up of approximately 5 years, best-corrected visual
acuity, hyperautofluorescent ring area, and ellipsoid zone width all show
statistically significant decline, confirming PDE6A-RP as slowly but
measurably progressive.
evidence:
- reference: PMID:39218074
reference_title: PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This study highlights the natural history of PDE6A-retinopathy."
explanation: >-
This longitudinal cohort study (mean follow-up 4.8 years) directly
characterizes the slow progressive natural history of PDE6A-RP.