PDE6A-Related Retinopathy

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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

PDE6A-related retinopathy is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in PDE6A.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:7493036 SUPPORT Human Clinical

"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."

This original gene-discovery paper establishes autosomal recessive inheritance for PDE6A-related retinitis pigmentosa.

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Pathophysiology

4

PDE6 Alpha Subunit Loss-of-Function

Biallelic pathogenic PDE6A variants alter essential functional domains of the alpha catalytic subunit of rod cGMP phosphodiesterase and are therefore inferred to disrupt its catalytic function; the gene-discovery study made that inference from the domain location of the variants rather than from a functional assay. PDE6A mutations affecting the catalytic domain produce variable biochemical outcomes and degeneration rates, indicating allelic heterogeneity.

retinal rod cell CL:0000604

PDE6A hgnc:8785 ↓ DECREASED

3',5'-cyclic-GMP phosphodiesterase activity GO:0047555 ↓ DECREASED

Downstream

Impaired PDE6 Holoenzyme Assembly and cGMP Hydrolysis Loss of functional PDE6A destabilizes the entire heterotetrameric PDE6 holoenzyme, not only its own catalytic contribution.

Show evidence (2 references)

PMID:7493036 SUPPORT Other

"Each mutation alters an essential functional domain of the encoded protein and likely disrupts its catalytic function."

This original gene-discovery paper proposes the loss-of-function mechanism of PDE6A pathogenic variants. The catalytic consequence is the authors' inference from domain location ("likely disrupts") -- no functional assay was performed in this study.

PMID:18849587 SUPPORT Model Organism

"significantly different biochemical outcomes and rates of degeneration of murine photoreceptor cells were observed, indicating allelic variation and previously unrecognized structure-function relationships"

This mouse model study of two distinct Pde6a catalytic-domain missense alleles establishes an allelic severity gradient.

Impaired PDE6 Holoenzyme Assembly and cGMP Hydrolysis

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.

retinal rod cell CL:0000604

Downstream

cGMP Accumulation and CNG Channel Constitutive Opening 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.

Show evidence (2 references)

PMID:18849587 SUPPORT Other

"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..."

This establishes the PDE6 holoenzyme composition and its role in cGMP hydrolysis during phototransduction.

PMID:18775863 SUPPORT Model Organism

"Affected retinas lacked PDE6 enzymatic activity."

This canine model directly confirms complete loss of PDE6 enzymatic activity as the biochemical consequence of the PDE6A mutation.

cGMP Accumulation and CNG Channel Constitutive Opening

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 into the outer segment; protein kinase G is the other proposed extra-phototransduction target of excess cGMP in photoreceptor death, and this entry models the CNG-channel arm only. Plasma cGMP was about twice control levels in one PDE6A family, which the authors report as indicating a possible role for cGMP as a diagnostic measure, not as a measurement of retinal cGMP: it is a single pedigree (seven homozygous siblings), seven family members also carry an ABCA4 variant, and no cited source proposes a route by which photoreceptor cGMP would raise plasma levels. It is treated here as a candidate biomarker observation rather than human confirmation of the retinal mechanism.

retinal rod cell CL:0000604

Downstream

Rod Photoreceptor Apoptosis and Progressive Retinal Degeneration Sustained ion influx and excessive cGMP-dependent signaling in rods drives rod photoreceptor apoptosis and halts photoreceptor outer segment development.

Show evidence (4 references)

PMID:31207907 SUPPORT Other

"Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations."

This review establishes cGMP accumulation as a shared final mechanistic step across many inherited retinal degeneration genes, including PDE6A.

PMID:31207907 SUPPORT Other

"The CNGC opening allows for an influx of Na+ and Ca2+ into the OS, yet, at the same time K+ and Ca2+ ions are constantly extruded via the Na+/Ca2+/K+ exchanger (NCKX)."

Sources the CNG-channel opening and Na+/Ca2+ influx step named in this node, which neither of the node's other evidence items mentions. The preceding sentence of the same review states that cGMP binds to and opens the CNG channel in the photoreceptor outer segment.

PMID:27820873 SUPPORT INDIRECT Human Clinical

"Additionally, patients showed increased plasma levels of cGMP, indicating a possible role for cGMP measurements as part of the clinical tests for this and, after further investigations, maybe other forms of RP."

The authors' own conclusion: raised plasma cGMP in this single family indicates a "possible role" for cGMP as a clinical measure, pending further investigation. Plasma is a systemic proxy, not retinal outer segment cGMP, and no cited source proposes a route by which photoreceptor cGMP would raise plasma levels, so the node's retinal claim is reached only through that proxy inference. Seven family members also carried an ABCA4 variant.

+ 1 more reference

Rod Photoreceptor Apoptosis and Progressive Retinal Degeneration

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.

retinal rod cell CL:0000604 retinal cone cell CL:0000573

Show evidence (2 references)

PMID:33057649 SUPPORT Human Clinical

"Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%)."

This 57-patient natural history cohort quantifies the frequency of non-recordable ERG responses at time of clinical assessment.

PMID:18775863 SUPPORT Model Organism

"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."

This canine model confirms the rod-predominant functional deficit with relative cone preservation early in the disease course.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Reduced visual acuity VERY_FREQUENT Ophthalmological HP:0007663

Show evidence (2 references)

PMID:33057649 SUPPORT Human Clinical

"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."

This 57-patient natural history cohort gives the severity distribution: impairment was mild or moderate in 90% of patients. It describes how severe the impairment is, not how often it occurs -- see the next item for the basis of the frequency band.

PMID:33057649 SUPPORT Human Clinical

"The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50)."

A cohort mean best-corrected acuity of 0.43 logMAR (20/50) implies reduced acuity across most of the 57 patients, which is the basis for the VERY_FREQUENT band; no source reports an explicit proportion of patients with reduced acuity, so the band remains a clinical estimate under docs/frequency-evidence-guidelines.md.

Constriction of peripheral visual field FREQUENT Ophthalmological HP:0001133

Show evidence (2 references)

PMID:27820873 SUPPORT Human Clinical

"Visual fields were constricted with mere central remnants in older subjects and additional temporal crescents in younger subjects."

This single-family case series (seven homozygous siblings, seven of whom also carry an ABCA4 variant) documents the pattern of visual field constriction with age-dependent severity. It supports the disease-phenotype association only; a single pedigree cannot fix a disease-level frequency band.

PMID:33057649 SUPPORT Human Clinical

"The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees)."

Cohort-level kinetic perimetry in 57 patients. The cohort reports no proportion of patients with constricted fields, so the FREQUENT band remains a clinical estimate rather than a reported figure; this item replaces the single family as its cohort-scale basis.

Undetectable electroretinogram VERY_FREQUENT Ophthalmological HP:0000550

Show evidence (2 references)

PMID:33057649 SUPPORT Human Clinical

"Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%)."

This large natural history cohort quantifies the high frequency of non-recordable ERG responses.

PMID:27820873 SUPPORT Human Clinical

"Full-field ERGs showed extinguished rod responses and minimal cone responses."

This family case series confirms extinguished rod ERG responses with only minimal residual cone responses.

Cystoid macular edema FREQUENT Ophthalmological HP:0011505

Show evidence (1 reference)

PMID:39218074 SUPPORT Human Clinical

"Eighteen eyes exhibited cystoid macular edema at baseline (56%), and 17 eyes (53%) at follow-up."

This longitudinal cohort quantifies cystoid macular edema as a common finding present in over half of eyes.

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Genetic Associations

1

PDE6A pathogenic variants (Causative)

Gene: PDE6A hgnc:8785

Autosomal recessive

Show evidence (2 references)

PMID:33057649 SUPPORT Human Clinical

"The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S)."

This 57-patient cohort directly compares the clinical severity of the two most common PDE6A alleles.

PMID:18849587 SUPPORT Model Organism

"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"

This mouse model study confirms that distinct PDE6A catalytic-domain alleles have secondary effects on PDE6B levels, supporting an allelic severity gradient.

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Medical Actions

3

AAV8.hPDE6A Gene Supplementation Therapy

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

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.

Show evidence (3 references)

PMID:29212391 SUPPORT Model Organism

"the ERG analysis confirmed a restoration of retinal function in a group of treated mice"

This mouse model study demonstrates preclinical proof-of-concept for AAV-mediated PDE6A gene supplementation.

PMID:28676737 SUPPORT Model Organism

"Treatment resulted in improvement in dim light vision and evidence of rod function on electroretinographic examination."

This canine large-animal model further supported preclinical efficacy of PDE6A gene supplementation prior to human trials.

PMID:40825661 SUPPORT Human Clinical

"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."

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.

Avoidance of PDE5 Inhibitors (Counseling Caution)

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

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.

Show evidence (3 references)

PMID:33809319 SUPPORT Other

"Sildenafil and vardenafil, for example, have shown only 10 and 15 times lower specificity for PDE6 than for PDE5, respectively"

This review quantifies the structural cross-reactivity between PDE5 inhibitors and retinal PDE6, the mechanistic basis for the counseling caution.

PMID:33809319 SUPPORT Other

"Important regulatory agencies such as the U.S. Food and Drug Administration (FDA, www.fda.gov, accessed on 20 December 2020) and the European Medicines Agency (EMA, www.ema.europa.eu, accessed on 20 December 2020), and associations of eye physicians and surgeons such as the American Academy of..."

Sources the regulatory-caution claim in this treatment's description, which the other two snippets did not cover.

PMID:33809319 SUPPORT Other

"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"

This directly supports the clinical counseling recommendation for patients and carriers of PDE6A and other recessive retinal dystrophy alleles.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Genetic counseling is indicated given the autosomal recessive inheritance pattern, and molecular allele classification is prognostically relevant given the demonstrated allelic severity gradient.

Show evidence (1 reference)

PMID:7493036 SUPPORT Human Clinical

"We found three point mutations in PDEA in affected members of two pedigrees with recessive RP."

Confirms the autosomal recessive inheritance pattern underlying genetic counseling recommendations.

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Diagnosis

3

Molecular genetic testing

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.

diagnostic procedure NCIT:C18020

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.

Show evidence (1 reference)

PMID:33057649 SUPPORT Human Clinical

"The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S)."

This natural history cohort establishes molecular genotyping as informative for prognosis in PDE6A-RP.

Full-field electroretinography

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.

diagnostic procedure NCIT:C18020

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.

Show evidence (1 reference)

PMID:33057649 SUPPORT Human Clinical

"Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%)."

This directly quantifies the high frequency of non-recordable ERG responses at time of clinical assessment.

Multimodal retinal imaging

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.

diagnostic procedure NCIT:C18020

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.

Show evidence (1 reference)

PMID:39218074 SUPPORT Human Clinical

"There were statistically significant changes during the follow-up period in terms of BCVA, hyperautofluorescent ring area, and the EZW."

This longitudinal cohort establishes multimodal imaging biomarkers as sensitive to disease progression over time.

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Progression

2

Presentation with established visual impairment

Age: Adulthood (cohort mean baseline age approximately 35 years)

Natural history cohorts of PDE6A-RP patients (mean baseline age approximately 35 years in the longitudinal cohort cited below) show disease highly symmetrical between the two eyes, with mild or moderate visual impairment in the great majority of patients at baseline.

Show evidence (3 references)

PMID:39218074 SUPPORT Human Clinical

"The mean age (± standard deviation, range) was 34.8 years (± 17.4, 12-76) at baseline, with a mean follow-up time of 4.8 years."

Sources the baseline age of this phase: mean 34.8 years (range 12-76) at first assessment in the longitudinal cohort.

PMID:33057649 SUPPORT Human Clinical

"Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each."

Gives the size of the other natural history cohort drawn on in this phase: 30 homozygous plus 27 compound heterozygous = 57 patients. (The abstract's "Fifty-seven patients ... from 44 families were included" sentence carries an inline bracketed standard deviation that this repository's snippet matcher strips, so it cannot be quoted verbatim.)

PMID:33057649 SUPPORT Human Clinical

"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."

Sources the interocular symmetry and mild-to-moderate severity claims in this phase's notes.

Slow progressive decline

Age: Adulthood, over multi-year follow-up

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.

Show evidence (3 references)

PMID:39218074 SUPPORT Human Clinical

"There were statistically significant changes during the follow-up period in terms of BCVA, hyperautofluorescent ring area, and the EZW."

Sources the three progression measures asserted in this phase's notes: best-corrected visual acuity, hyperautofluorescent ring area, and ellipsoid zone width all changed significantly over follow-up.

PMID:39218074 SUPPORT Human Clinical

"The mean age (± standard deviation, range) was 34.8 years (± 17.4, 12-76) at baseline, with a mean follow-up time of 4.8 years."

Sources the baseline age and the approximately 5-year mean follow-up duration quoted in this phase.

PMID:39218074 SUPPORT Human Clinical

"Most patients in this cohort had mild BCVA loss, and slowly progressive disease, based on FAF and OCT measurements."

The authors' own characterization of the course as slowly progressive, which is the basis for this phase's name and notes.

🌍

Epidemiology

1

Contribution to autosomal recessive retinitis pigmentosa

PDE6A accounts for approximately 3% to 4% of families with autosomal recessive retinitis pigmentosa in North America.

Show evidence (1 reference)

PMID:10393062 SUPPORT Human Clinical

"The PDE6A gene appears to account for roughly 3% to 4% of families with recessive RP in North America."

This mutation-screening study of 164 unrelated arRP patients establishes the population contribution of PDE6A to recessive RP.

{ }

Source YAML

click to show

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. 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 than those preclinical results predicted.
  (For the chaperone-defect counterpart see AIPL1-Related_Retinopathy; this
  entry cites no AIPL1 trial and makes no claim about its outcome.)
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 and are therefore
    inferred to disrupt its catalytic function; the gene-discovery study made
    that inference from the domain location of the variants rather than from a
    functional assay. 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 proposes the loss-of-function
      mechanism of PDE6A pathogenic variants. The catalytic consequence is the
      authors' inference from domain location ("likely disrupts") -- no
      functional assay was performed in this study.
  - 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: "PDE6, which is located to the membranous disks within photoreceptor OS, hydrolyses cGMP, leading to the closure of CNGC and a hyperpolarization of the OS due to continued activity of NCKX."
      explanation: >-
        Establishes the normal step this edge removes: PDE6 hydrolyzes outer
        segment cGMP on light activation, so absent PDE6 catalytic activity
        leaves cGMP unhydrolyzed. The same review states elsewhere that
        disease-causing mutations in the PDE6 alpha and beta genes explain
        excessive photoreceptor cGMP levels (that sentence spans an inline
        citation marker and so cannot be quoted verbatim under this
        repository's snippet matcher).
  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 into the outer segment; protein kinase G is the other
    proposed extra-phototransduction target of excess cGMP in photoreceptor
    death, and this entry models the CNG-channel arm only. Plasma cGMP was
    about twice control levels in one PDE6A family, which the authors report as
    indicating a possible role for cGMP as a diagnostic measure, not as a
    measurement of retinal cGMP: it is a single pedigree (seven homozygous
    siblings), seven family members also carry an ABCA4 variant, and no cited
    source proposes a route by which photoreceptor cGMP would raise plasma
    levels. It is treated here as a candidate biomarker observation rather than
    human confirmation of the retinal mechanism.
  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:31207907
    reference_title: "The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The CNGC opening allows for an influx of Na+ and Ca2+ into the OS, yet, at the same time K+ and Ca2+ ions are constantly extruded via the Na+/Ca2+/K+ exchanger (NCKX)."
    explanation: >-
      Sources the CNG-channel opening and Na+/Ca2+ influx step named in this
      node, which neither of the node's other evidence items mentions. The
      preceding sentence of the same review states that cGMP binds to and opens
      the CNG channel in the photoreceptor outer segment.
  - 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
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, patients showed increased plasma levels of cGMP, indicating a possible role for cGMP measurements as part of the clinical tests for this and, after further investigations, maybe other forms of RP."
    explanation: >-
      The authors' own conclusion: raised plasma cGMP in this single family
      indicates a "possible role" for cGMP as a clinical measure, pending
      further investigation. Plasma is a systemic proxy, not retinal outer
      segment cGMP, and no cited source proposes a route by which photoreceptor
      cGMP would raise plasma levels, so the node's retinal claim is reached
      only through that proxy inference. Seven family members also carried an
      ABCA4 variant.
  - 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
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mean plasma cGMP in patients was approximately twice that in controls."
    explanation: >-
      The measurement itself: plasma cGMP roughly doubled in the seven affected
      siblings of one PDE6A family relative to controls. It is a systemic
      measurement standing in for the photoreceptor outer-segment cGMP this node
      is about, so it supports the node through that proxy step.
- 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 is reduced in the great majority of patients, with mild or
    moderate rather than severe loss in most: mean best-corrected visual acuity
    in a 57-patient cohort was 0.43 logMAR (Snellen 20/50), and impairment was
    mild or moderate in 90% of those patients.
  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 gives the severity distribution:
      impairment was mild or moderate in 90% of patients. It describes how
      severe the impairment is, not how often it occurs -- see the next item
      for the basis of the frequency band.
  - 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 mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50)."
    explanation: >-
      A cohort mean best-corrected acuity of 0.43 logMAR (20/50) implies
      reduced acuity across most of the 57 patients, which is the basis for the
      VERY_FREQUENT band; no source reports an explicit proportion of patients
      with reduced acuity, so the band remains a clinical estimate under
      docs/frequency-evidence-guidelines.md.
- 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 single-family case series (seven homozygous siblings, seven of whom
      also carry an ABCA4 variant) documents the pattern of visual field
      constriction with age-dependent severity. It supports the
      disease-phenotype association only; a single pedigree cannot fix a
      disease-level frequency band.
  - 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 median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees)."
    explanation: >-
      Cohort-level kinetic perimetry in 57 patients. The cohort reports no
      proportion of patients with constricted fields, so the FREQUENT band
      remains a clinical estimate rather than a reported figure; this item
      replaces the single family as its cohort-scale basis.
- 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.
  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: "Important regulatory agencies such as the U.S. Food and Drug Administration (FDA, www.fda.gov, accessed on 20 December 2020) and the European Medicines Agency (EMA, www.ema.europa.eu, accessed on 20 December 2020), and associations of eye physicians and surgeons such as the American Academy of Ophthalmology (www.aao.org, accessed on 20 December 2020) warn about the lack of controlled clinical data on the safety of sildenafil in patients with retinitis pigmentosa or with a family history of the disease."
    explanation: >-
      Sources the regulatory-caution claim in this treatment's description,
      which the other two snippets did not cover.
  - 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 baseline age approximately 35 years)
  notes: >-
    Natural history cohorts of PDE6A-RP patients (mean baseline age
    approximately 35 years in the longitudinal cohort cited below) 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:39218074
    reference_title: PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age (± standard deviation, range) was 34.8 years (± 17.4, 12-76) at baseline, with a mean follow-up time of 4.8 years."
    explanation: >-
      Sources the baseline age of this phase: mean 34.8 years (range 12-76) at
      first assessment in the longitudinal cohort.
  - 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: "Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each."
    explanation: >-
      Gives the size of the other natural history cohort drawn on in this
      phase: 30 homozygous plus 27 compound heterozygous = 57 patients. (The
      abstract's "Fifty-seven patients ... from 44 families were included"
      sentence carries an inline bracketed standard deviation that this
      repository's snippet matcher strips, so it cannot be quoted verbatim.)
  - 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: >-
      Sources the interocular symmetry and mild-to-moderate severity claims in
      this phase's notes.
- 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: "There were statistically significant changes during the follow-up period in terms of BCVA, hyperautofluorescent ring area, and the EZW."
    explanation: >-
      Sources the three progression measures asserted in this phase's notes:
      best-corrected visual acuity, hyperautofluorescent ring area, and
      ellipsoid zone width all changed significantly over follow-up.
  - reference: PMID:39218074
    reference_title: PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age (± standard deviation, range) was 34.8 years (± 17.4, 12-76) at baseline, with a mean follow-up time of 4.8 years."
    explanation: >-
      Sources the baseline age and the approximately 5-year mean follow-up
      duration quoted in this phase.
  - reference: PMID:39218074
    reference_title: PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients in this cohort had mild BCVA loss, and slowly progressive disease, based on FAF and OCT measurements."
    explanation: >-
      The authors' own characterization of the course as slowly progressive,
      which is the basis for this phase's name and notes.

PDE6A-Related Retinopathy

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