GUCY2D-Related Retinopathy

👪

Inheritance

2

Autosomal recessive HP:0000007

Biallelic loss-of-function variants in GUCY2D cause autosomal recessive GUCY2D-LCA1/EOSRD. Both parents of an affected child are obligate heterozygous carriers; each sibling has a 25% chance of being affected.

Autosomal recessive inheritance

Show evidence (1 reference)

DOI:10.3390/genes12081261 SUPPORT Human Clinical

"Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness."

Huang et al. describe LCA as an autosomal recessive inherited retinal dystrophy with severe congenital visual loss, consistent with the recessive GUCY2D-LCA form.

Autosomal dominant HP:0000006

Heterozygous gain-of-function variants in GUCY2D cause autosomal dominant CORD6/CACD1. Each child of an affected parent has a 50% chance of inheriting the pathogenic variant.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"Mutations of six genes (PRPH2, GUCA1A, GUCY2D, CDHR1, ABCA4, and TTLL5) are implicated in the monogenic dominant inheritance of CACD."

Kazmierczak de Camargo et al. confirm GUCY2D as a causative gene for dominant inheritance CACD (central areolar choroidal dystrophy), part of the GUCY2D dominant spectrum.

◆

Subtypes

1

GUCY2D-Related Dominant Retinopathy (CORD6) MONDO:0100441

Autosomal dominant cone-rod dystrophy (CORD6/CACD1) caused by heterozygous gain-of-function variants in GUCY2D. The dominant variant hotspot is at codon 838 in exon 13: c.2513G>A (p.Arg838His) occurs in ~54% of CORD patients, with c.2512C>T (p.Arg838Cys) and c.2513G>C (p.Arg838Pro) also recurrent. These variants alter calcium-sensitivity of RETGC-1 regulation by guanylate cyclase activating proteins (GCAPs), rendering the enzyme constitutively hyperactive and producing excess cGMP, sustained CNG channel opening, Na+/Ca2+ overload, and progressive cone-predominant photoreceptor apoptosis via PKG activation, calpain activation, and ER stress pathways. Disease presents in childhood or adolescence with progressive visual acuity loss, dyschromatopsia, photophobia, central scotoma, and progressive macular atrophy on OCT. ERG shows predominantly reduced cone responses with relative rod preservation early. Natural history studies document annual BCVA worsening of ~0.022 logMAR/year, with a 32% probability of blindness or severe visual impairment by age 40.

⚙

Pathophysiology

5

RETGC-1 Deficiency

Biallelic loss-of-function variants in GUCY2D abolish or severely reduce the guanylyl cyclase activity of retinal guanylate cyclase-1 (RETGC-1), the enzyme responsible for cGMP synthesis in photoreceptor outer segments. RETGC-1 accounts for over 70% of cGMP production in photoreceptors and is expressed in both rod and cone outer segments. More than 248 pathogenic variants cause autosomal recessive LCA1/EOSRD; null alleles (frameshift, nonsense, splice-site) account for approximately 88% of LCA-causing alleles. Missense variants account for ~71% of all variant types. Notable recurrent variants include c.1694T>C (p.Phe565Ser) and c.2302C>T (p.Arg768Trp).

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

GUCY2D hgnc:4689 ↓ DECREASED

cGMP biosynthetic process GO:0006182 ↓ DECREASED

Downstream

Impaired Phototransduction Recovery Without RETGC-1 activity, cGMP cannot be regenerated after phototransduction, preventing CNG channel reopening and locking photoreceptors in a functionally silent state.

Show evidence (2 references)

PMID:38278208 SUPPORT Human Clinical

"Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1)"

Georgiou et al. confirm GUCY2D as a primary causal gene for Leber congenital amaurosis / early-onset severe retinal dystrophy in this comprehensive inherited retinal disease review.

DOI:10.1136/bjophthalmol-2020-318483 SUPPORT Human Clinical

"Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy."

Daich Varela et al. review LCA/EOSRD management and confirm that GUCY2D is among the primary causative genes for this severe inherited retinal dystrophy.

Impaired Phototransduction Recovery

Under normal conditions, RETGC-1 resynthesizes cGMP under GCAP-mediated calcium regulation after phototransduction, reopening CNG channels to restore the photoreceptor dark current. When RETGC-1 is absent or catalytically inactive, cGMP cannot be regenerated after light-induced hydrolysis by phosphodiesterase 6 (PDE6). CNG channels fail to reopen and photoreceptors remain in a persistently hyperpolarized, functionally silent state. This produces profound visual dysfunction despite early structural preservation of photoreceptor outer segments — the hallmark structure-function dissociation of GUCY2D-LCA that makes it particularly amenable to gene augmentation.

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

phototransduction GO:0007602 ↓ DECREASED

Downstream

Rod Photoreceptor Apoptosis Prolonged photoreceptor dysfunction and cellular stress eventually drive progressive rod and cone photoreceptor degeneration, though the rate of structural degeneration is slower than the onset of functional deficit.

Show evidence (1 reference)

DOI:10.3390/ijms241311200 SUPPORT In Vitro

"cGMP governs the cyclic nucleotide-gated (CNG) channels on the plasma membrane of the photoreceptor outer segments, thereby regulating membrane potential and signal transmission."

Li et al. establish that cGMP governs CNG channel function on photoreceptor outer segments. When RETGC-1 is absent, cGMP cannot be regenerated and channels fail to reopen, causing the persistent functional silence characteristic of GUCY2D-LCA.

Rod Photoreceptor Apoptosis

Progressive rod and cone photoreceptor degeneration and apoptosis result from sustained phototransduction failure and downstream cellular stress. A key feature distinguishing GUCY2D-LCA from other LCA subtypes is structure-function dissociation: OCT imaging frequently reveals preserved ellipsoid zone (EZ) and outer nuclear layer (ONL) centrally despite profoundly reduced visual function, indicating photoreceptors remain anatomically intact for extended periods before irreversible degeneration. This preservation represents the therapeutic window for gene augmentation therapy. Dysregulated cGMP signaling drives downstream stress pathways including PKG activation, Ca2+ overload via CNG channel dysregulation, calpain activation, ER stress, and photoreceptor cell death.

retinal rod cell CL:0000604

apoptotic process GO:0006915 ↑ INCREASED

Show evidence (2 references)

DOI:10.3390/ijms241311200 SUPPORT In Vitro

"The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca2+ homeostasis/Ca2+ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways."

Li et al. delineate the downstream apoptotic pathways activated by dysregulated cGMP signaling, including PKG activation and Ca2+ overload through CNG channel dysregulation, driving photoreceptor degeneration.

PMID:38278208 SUPPORT Human Clinical

"GUCY2D-LCA/EOSRD patients have a relatively preserved central macular outer retinal"

Georgiou et al. document on OCT imaging that GUCY2D-LCA/EOSRD patients retain relatively preserved central macular outer retinal structure (in many cases lifelong), the structure-function dissociation that lags behind the functional deficit and defines the therapeutic window for gene augmentation.

RETGC-1 Constitutive Hyperactivity

Heterozygous gain-of-function variants at codon 838 in exon 13 of GUCY2D (p.Arg838His, p.Arg838Cys, p.Arg838Pro) alter the calcium-sensitivity of RETGC-1 regulation by guanylate cyclase-activating proteins (GCAPs), rendering the enzyme constitutively hyperactive independent of intracellular calcium levels. Under normal conditions, rising cytoplasmic Ca2+ (in darkness) activates GCAPs, which suppress RETGC-1 activity via a calcium-mediated negative feedback loop. Codon-838 GOF variants disrupt this GCAP-mediated inhibitory feedback, causing RETGC-1 to produce excess cGMP even at calcium concentrations that would normally silence the enzyme. The resulting chronically elevated cGMP causes constitutive CNG channel opening, continuous Na+/Ca2+ influx, and sustained intracellular Ca2+ overload, driving progressive cone-predominant photoreceptor toxicity.

retinal cone cell CL:0000573

GUCY2D hgnc:4689 ↑ INCREASED

cGMP biosynthetic process GO:0006182 ↑ INCREASED

Downstream

Cone Photoreceptor Calcium Overload Constitutively elevated cGMP keeps CNG channels perpetually open, causing sustained Na+/Ca2+ influx and intracellular calcium overload in cone photoreceptors, triggering downstream cytotoxic pathways.

Show evidence (1 reference)

DOI:10.3390/ijms241311200 SUPPORT In Vitro

"Abnormally elevated cGMP signaling interferes with various cellular events, which ultimately leads to photoreceptor degeneration."

Li et al. establish that elevated cGMP — the product of constitutively hyperactive RETGC-1 in GOF variants — drives photoreceptor degeneration, directly supporting the dominant gain-of-function mechanism in GUCY2D-CORD6.

Cone Photoreceptor Calcium Overload

Chronically elevated cGMP in dominant GUCY2D-CORD6 maintains CNG channels in a constitutively open state, producing sustained Na+/Ca2+ influx into cone photoreceptor outer segments. The resulting intracellular calcium overload activates PKG-dependent phosphorylation cascades, calpain-mediated proteolysis, endoplasmic reticulum stress, and downstream apoptotic cascades. Because RETGC-1 is preferentially expressed in cone outer segments and cones have intrinsically higher baseline metabolic demands, cones are more vulnerable than rods to chronic Ca2+ overload, explaining the predominant cone loss and progressive macular atrophy characteristic of GUCY2D-CORD6. Rod involvement occurs later as disease progresses.

retinal cone cell CL:0000573

apoptotic process GO:0006915 ↑ INCREASED

Show evidence (1 reference)

DOI:10.3390/ijms241311200 SUPPORT In Vitro

"The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca2+ homeostasis/Ca2+ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways."

Li et al. describe the molecular mechanism by which excess cGMP drives cone photoreceptor death in the dominant GOF context: Ca2+ overload via constitutively open CNG channels activates PKG and downstream stress/death pathways, reproducing the cone-predominant degeneration of GUCY2D-CORD6.

⬡

Pathograph

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

●

Phenotypes

10

Severe visual impairment VERY_FREQUENT Ophthalmological HP:0007663

Show evidence (2 references)

DOI:10.3390/genes12081261 SUPPORT Human Clinical

"Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss"

Huang et al. confirm that LCA (including GUCY2D-related LCA1) is characterized by extremely early-onset severe visual loss.

PMID:20301475 SUPPORT Human Clinical

"Visual acuity is rarely better than 20/400."

GeneReviews documents that visual acuity in LCA is rarely better than 20/400, confirming the severity of visual impairment characteristic of GUCY2D-LCA1.

Nystagmus VERY_FREQUENT Ophthalmological HP:0000639

Show evidence (1 reference)

PMID:20301475 SUPPORT Human Clinical

"Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus."

GeneReviews confirms nystagmus as one of the cardinal accompanying features of LCA, consistent with the near-universal nystagmus observed in GUCY2D-LCA1.

Photophobia FREQUENT Ophthalmological HP:0000613

Show evidence (1 reference)

PMID:38278208 SUPPORT Human Clinical

"photophobia and day-blindness compared to night-blindness"

Georgiou et al. report that GUCY2D-LCA/EOSRD patients tend to have a greater degree of photophobia and day-blindness relative to night-blindness, reflecting the earlier and greater cone dysfunction characteristic of GUCY2D retinopathy.

Abnormal electroretinogram VERY_FREQUENT Electrophysiological HP:0000512

Show evidence (1 reference)

PMID:20301475 SUPPORT Human Clinical

"The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal."

GeneReviews establishes that the ERG is characteristically nondetectable or severely subnormal in LCA, consistent with the profoundly extinguished ERG seen in GUCY2D-LCA1 due to complete phototransduction failure.

Hypermetropia FREQUENT Ophthalmological HP:0000540

Progressive visual loss VERY_FREQUENT Ophthalmological HP:0000529

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"resulting in progressive and usually profound visual loss"

Kazmierczak de Camargo et al. describe the dominant GUCY2D-spectrum maculopathy (CACD) as producing progressive and usually profound visual loss, consistent with the clearly progressive central visual decline of GUCY2D-CORD6.

Color vision defect FREQUENT Ophthalmological HP:0000551

Show evidence (1 reference)

DOI:10.1371/journal.pone.0278857 SUPPORT Human Clinical

"All affected family members presented specific genotypes mainly determined by mutated GUCY2D gene, and different phenotypical traits, mainly related to focus and color perception."

Donato et al. confirm color perception defects among affected family members with GUCY2D-associated cone-rod dystrophy, consistent with the cone-predominant nature of the dominant form.

Macular atrophy FREQUENT Ophthalmological HP:0007401

Central scotoma FREQUENT Ophthalmological HP:0000603

Keratoconus OCCASIONAL Ophthalmological HP:0000563

Show evidence (1 reference)

PMID:20301475 SUPPORT Human Clinical

"A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing."

GeneReviews identifies the oculodigital sign as a near-pathognomonic characteristic of LCA. Chronic eye rubbing from this sign causes secondary corneal deformation (keratoconus) in a subset of patients.

🧬

Genetic Associations

1

GUCY2D pathogenic variants (Causative)

Gene: GUCY2D hgnc:4689

Autosomal recessive Autosomal dominant

Show evidence (1 reference)

PMID:38278208 SUPPORT Human Clinical

"Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1)"

GUCY2D is confirmed as a primary causative gene for LCA/EOSRD in this comprehensive inherited retinal disease phenotyping and genotyping review.

💊

Medical Actions

3

ATSN-101 Gene Augmentation Therapy

Action: gene therapy MAXO:0001001

ATSN-101 is an AAV5-based gene augmentation therapy delivering the human GUCY2D transgene under the photoreceptor-specific GRK1 promoter via unilateral subretinal injection, developed by Atsena Therapeutics for GUCY2D-LCA1. GUCY2D-LCA1 is particularly favorable for gene augmentation because of the characteristic structure-function dissociation — preserved central photoreceptor structure despite profound functional silence — providing viable cellular targets for gene replacement. Preliminary Phase I/II results report mean improvement of 20.3 dB on full-field stimulus testing, with 3/6 treated patients reaching the maximum Multi-Luminance Mobility Test (MLMT) score.

Mechanism Target:

RESTORES RETGC-1 Deficiency — ATSN-101 delivers functional GUCY2D to rod and cone photoreceptors via subretinal AAV5 injection, restoring RETGC-1 cGMP synthesis activity and enabling CNG channel reopening and phototransduction recovery.

Show evidence (2 references)

clinicaltrials:NCT03920007 SUPPORT Human Clinical

"To evaluate the safety and tolerability of ascending doses of ATSN-101 administered as a unilateral subretinal injection in patients with Leber Congenital Amaurosis (LCA) caused by autosomal recessive guanylate cyclase 2D (GUCY2D) mutations (GUCY2D-LCA)."

NCT03920007 is the Phase I/II clinical trial evaluating ATSN-101 gene replacement therapy for GUCY2D-LCA, directly targeting the core mechanism of RETGC-1 deficiency by restoring functional GUCY2D expression in photoreceptors.

PMID:38278208 SUPPORT Human Clinical

"the first three patients treated with the vector showed rod photoreceptor vision improvement"

Georgiou et al. summarize early results of the NCT03920007 gene therapy trial: the first three treated patients showed rod photoreceptor vision improvement on full-field stimulus testing in the treated eye, demonstrating functional rescue consistent with restored RETGC-1 activity.

Supportive care and low vision rehabilitation

Action: supportive care MAXO:0000950

Standard of care for GUCY2D-related retinopathy patients, encompassing low vision aids, orientation and mobility training, educational support, and assistive technology. Essential for managing the profound lifelong visual impairment in LCA1 patients and the progressive visual loss in CORD6 patients.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Essential for clarifying autosomal recessive risk in LCA1 (25% recurrence for siblings of affected individuals), autosomal dominant risk in CORD6 (50% risk for offspring), family planning guidance, cascade genetic testing of at-risk relatives, and clinical trial eligibility assessment.

🔬

Clinical Trials

1

NCT03920007 PHASE_I ACTIVE_NOT_RECRUITING

Phase I/II dose-escalation study of ATSN-101 (AAV5-hGRK1-GUCY2D), an AAV5-based gene augmentation therapy for patients with Leber Congenital Amaurosis caused by biallelic GUCY2D mutations. Administered as a unilateral subretinal injection in 15 participants. Sponsored by Atsena Therapeutics Inc. Estimated study completion: May 2027.

Target Phenotypes: Reduced visual acuity HP:0007663 Nystagmus HP:0000639

Show evidence (1 reference)

clinicaltrials:NCT03920007 SUPPORT

"To evaluate the safety and tolerability of ascending doses of ATSN-101 administered as a unilateral subretinal injection in patients with Leber Congenital Amaurosis (LCA) caused by autosomal recessive guanylate cyclase 2D (GUCY2D) mutations (GUCY2D-LCA)."

Phase I/II trial for ATSN-101 (AAV5-GUCY2D) gene therapy in GUCY2D-LCA, the most advanced gene therapy program for this condition.

{ }

Source YAML

click to show

name: GUCY2D-Related Retinopathy
creation_date: "2026-06-25T08:50:00Z"
category: Mendelian
description: >-
  GUCY2D-related retinopathy is an inherited retinal disease caused by pathogenic
  variants in GUCY2D, encoding retinal guanylate cyclase-1 (RETGC-1), the enzyme
  responsible for cGMP synthesis in photoreceptor outer segments. RETGC-1 is essential
  for phototransduction recovery: after light activation triggers cGMP hydrolysis,
  RETGC-1 resynthesizes cGMP to reopen cyclic nucleotide-gated (CNG) channels and
  restore the photoreceptor dark current. Biallelic loss-of-function variants cause
  autosomal recessive Leber congenital amaurosis type 1 (LCA1/EOSRD), a severe
  congenital retinal dystrophy affecting 6-21% of all LCA cases. Heterozygous
  gain-of-function variants — predominantly at codon 838 — cause autosomal dominant
  cone-rod dystrophy type 6 (CORD6), accounting for 25-40% of dominant cone-rod
  dystrophy. The recessive form is notable for a characteristic structure-function
  dissociation: profound visual dysfunction from infancy despite relatively preserved
  photoreceptor structure on OCT, creating a therapeutic window for gene augmentation.
  The Phase I/II ATSN-101 clinical trial (NCT03920007) is the most advanced gene
  therapy program, targeting GUCY2D-LCA1 with AAV5-mediated GUCY2D replacement.
disease_term:
  preferred_term: GUCY2D-related recessive retinopathy
  term:
    id: MONDO:0100453
    label: GUCY2D-related recessive retinopathy
synonyms:
- Leber congenital amaurosis type 1
- LCA1
- GUCY2D-LCA
- GUCY2D-associated Leber congenital amaurosis
- LCA type 1
- early-onset severe retinal dystrophy GUCY2D
parents:
- Inherited Retinal Dystrophy
- Leber Congenital Amaurosis
notes: >-
  The recessive (LCA1/EOSRD) and dominant (CORD6/CACD1) forms of GUCY2D-related
  retinopathy have opposite molecular mechanisms: biallelic LOF variants cause
  absent cGMP synthesis (functional silence without immediate cell death), while
  heterozygous GOF variants cause excess cGMP and Ca2+ overload driving progressive
  cone-predominant degeneration. The parent MONDO term MONDO:0100454 (GUCY2D
  retinopathy) encompasses both forms. LCA1 epidemiology: GUCY2D variants account
  for 6-21% of all LCA cases. CORD6 epidemiology: GUCY2D variants account for
  25-40% of autosomal dominant cone-rod dystrophy. The dominant variant hotspot
  c.2513G>A (p.Arg838His) accounts for ~54% of CORD patients in the largest cohort.
has_subtypes:
- name: Dominant
  display_name: GUCY2D-Related Dominant Retinopathy (CORD6)
  subtype_term:
    preferred_term: GUCY2D-related dominant retinopathy
    term:
      id: MONDO:0100441
      label: GUCY2D-related dominant retinopathy
  description: >-
    Autosomal dominant cone-rod dystrophy (CORD6/CACD1) caused by heterozygous
    gain-of-function variants in GUCY2D. The dominant variant hotspot is at codon
    838 in exon 13: c.2513G>A (p.Arg838His) occurs in ~54% of CORD patients,
    with c.2512C>T (p.Arg838Cys) and c.2513G>C (p.Arg838Pro) also recurrent.
    These variants alter calcium-sensitivity of RETGC-1 regulation by guanylate
    cyclase activating proteins (GCAPs), rendering the enzyme constitutively
    hyperactive and producing excess cGMP, sustained CNG channel opening, Na+/Ca2+
    overload, and progressive cone-predominant photoreceptor apoptosis via PKG
    activation, calpain activation, and ER stress pathways. Disease presents in
    childhood or adolescence with progressive visual acuity loss, dyschromatopsia,
    photophobia, central scotoma, and progressive macular atrophy on OCT. ERG shows
    predominantly reduced cone responses with relative rod preservation early.
    Natural history studies document annual BCVA worsening of ~0.022 logMAR/year,
    with a 32% probability of blindness or severe visual impairment by age 40.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic loss-of-function variants in GUCY2D cause autosomal recessive
    GUCY2D-LCA1/EOSRD. Both parents of an affected child are obligate heterozygous
    carriers; each sibling has a 25% chance of being affected.
  evidence:
  - reference: DOI:10.3390/genes12081261
    reference_title: "Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness."
    explanation: >-
      Huang et al. describe LCA as an autosomal recessive inherited retinal dystrophy
      with severe congenital visual loss, consistent with the recessive GUCY2D-LCA form.
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous gain-of-function variants in GUCY2D cause autosomal dominant
    CORD6/CACD1. Each child of an affected parent has a 50% chance of inheriting
    the pathogenic variant.
  evidence:
  - reference: PMID:35656327
    reference_title: "New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations of six genes (PRPH2, GUCA1A, GUCY2D, CDHR1, ABCA4, and TTLL5) are implicated in the monogenic dominant inheritance of CACD."
    explanation: >-
      Kazmierczak de Camargo et al. confirm GUCY2D as a causative gene for dominant
      inheritance CACD (central areolar choroidal dystrophy), part of the GUCY2D
      dominant spectrum.

pathophysiology:
- name: RETGC-1 Deficiency
  description: >-
    Biallelic loss-of-function variants in GUCY2D abolish or severely reduce the
    guanylyl cyclase activity of retinal guanylate cyclase-1 (RETGC-1), the enzyme
    responsible for cGMP synthesis in photoreceptor outer segments. RETGC-1 accounts
    for over 70% of cGMP production in photoreceptors and is expressed in both rod
    and cone outer segments. More than 248 pathogenic variants cause autosomal
    recessive LCA1/EOSRD; null alleles (frameshift, nonsense, splice-site) account
    for approximately 88% of LCA-causing alleles. Missense variants account for
    ~71% of all variant types. Notable recurrent variants include c.1694T>C
    (p.Phe565Ser) and c.2302C>T (p.Arg768Trp).
  gene:
    preferred_term: GUCY2D
    modifier: DECREASED
    term:
      id: hgnc:4689
      label: GUCY2D
  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
  biological_processes:
  - preferred_term: cGMP biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006182
      label: cGMP biosynthetic process
  evidence:
  - reference: PMID:38278208
    reference_title: "Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1)"
    explanation: >-
      Georgiou et al. confirm GUCY2D as a primary causal gene for Leber congenital
      amaurosis / early-onset severe retinal dystrophy in this comprehensive inherited
      retinal disease review.
  - reference: DOI:10.1136/bjophthalmol-2020-318483
    reference_title: "Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy."
    explanation: >-
      Daich Varela et al. review LCA/EOSRD management and confirm that GUCY2D is
      among the primary causative genes for this severe inherited retinal dystrophy.
  downstream:
  - target: Impaired Phototransduction Recovery
    description: >-
      Without RETGC-1 activity, cGMP cannot be regenerated after phototransduction,
      preventing CNG channel reopening and locking photoreceptors in a functionally
      silent state.

- name: Impaired Phototransduction Recovery
  description: >-
    Under normal conditions, RETGC-1 resynthesizes cGMP under GCAP-mediated calcium
    regulation after phototransduction, reopening CNG channels to restore the
    photoreceptor dark current. When RETGC-1 is absent or catalytically inactive,
    cGMP cannot be regenerated after light-induced hydrolysis by phosphodiesterase 6
    (PDE6). CNG channels fail to reopen and photoreceptors remain in a persistently
    hyperpolarized, functionally silent state. This produces profound visual dysfunction
    despite early structural preservation of photoreceptor outer segments — the
    hallmark structure-function dissociation of GUCY2D-LCA that makes it particularly
    amenable to gene augmentation.
  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
  biological_processes:
  - preferred_term: phototransduction
    modifier: DECREASED
    term:
      id: GO:0007602
      label: phototransduction
  evidence:
  - reference: DOI:10.3390/ijms241311200
    reference_title: "cGMP Signaling in Photoreceptor Degeneration"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cGMP governs the cyclic nucleotide-gated (CNG) channels on the plasma membrane of the photoreceptor outer segments, thereby regulating membrane potential and signal transmission."
    explanation: >-
      Li et al. establish that cGMP governs CNG channel function on photoreceptor
      outer segments. When RETGC-1 is absent, cGMP cannot be regenerated and channels
      fail to reopen, causing the persistent functional silence characteristic of GUCY2D-LCA.
  downstream:
  - target: Rod Photoreceptor Apoptosis
    description: >-
      Prolonged photoreceptor dysfunction and cellular stress eventually drive
      progressive rod and cone photoreceptor degeneration, though the rate of
      structural degeneration is slower than the onset of functional deficit.

- name: Rod Photoreceptor Apoptosis
  conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
  description: >-
    Progressive rod and cone photoreceptor degeneration and apoptosis result from
    sustained phototransduction failure and downstream cellular stress. A key feature
    distinguishing GUCY2D-LCA from other LCA subtypes is structure-function
    dissociation: OCT imaging frequently reveals preserved ellipsoid zone (EZ) and
    outer nuclear layer (ONL) centrally despite profoundly reduced visual function,
    indicating photoreceptors remain anatomically intact for extended periods before
    irreversible degeneration. This preservation represents the therapeutic window
    for gene augmentation therapy. Dysregulated cGMP signaling drives downstream
    stress pathways including PKG activation, Ca2+ overload via CNG channel
    dysregulation, calpain activation, ER stress, and photoreceptor cell death.
  cell_types:
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: DOI:10.3390/ijms241311200
    reference_title: "cGMP Signaling in Photoreceptor Degeneration"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca2+ homeostasis/Ca2+ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways."
    explanation: >-
      Li et al. delineate the downstream apoptotic pathways activated by dysregulated
      cGMP signaling, including PKG activation and Ca2+ overload through CNG channel
      dysregulation, driving photoreceptor degeneration.
  - reference: PMID:38278208
    reference_title: "Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GUCY2D-LCA/EOSRD patients have a relatively preserved central macular outer retinal"
    explanation: >-
      Georgiou et al. document on OCT imaging that GUCY2D-LCA/EOSRD patients retain
      relatively preserved central macular outer retinal structure (in many cases
      lifelong), the structure-function dissociation that lags behind the functional
      deficit and defines the therapeutic window for gene augmentation.

- name: RETGC-1 Constitutive Hyperactivity
  description: >-
    Heterozygous gain-of-function variants at codon 838 in exon 13 of GUCY2D
    (p.Arg838His, p.Arg838Cys, p.Arg838Pro) alter the calcium-sensitivity of
    RETGC-1 regulation by guanylate cyclase-activating proteins (GCAPs), rendering
    the enzyme constitutively hyperactive independent of intracellular calcium levels.
    Under normal conditions, rising cytoplasmic Ca2+ (in darkness) activates GCAPs,
    which suppress RETGC-1 activity via a calcium-mediated negative feedback loop.
    Codon-838 GOF variants disrupt this GCAP-mediated inhibitory feedback, causing
    RETGC-1 to produce excess cGMP even at calcium concentrations that would normally
    silence the enzyme. The resulting chronically elevated cGMP causes constitutive
    CNG channel opening, continuous Na+/Ca2+ influx, and sustained intracellular
    Ca2+ overload, driving progressive cone-predominant photoreceptor toxicity.
  gene:
    preferred_term: GUCY2D
    modifier: INCREASED
    term:
      id: hgnc:4689
      label: GUCY2D
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: cGMP biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006182
      label: cGMP biosynthetic process
  evidence:
  - reference: DOI:10.3390/ijms241311200
    reference_title: "cGMP Signaling in Photoreceptor Degeneration"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Abnormally elevated cGMP signaling interferes with various cellular events, which ultimately leads to photoreceptor degeneration."
    explanation: >-
      Li et al. establish that elevated cGMP — the product of constitutively
      hyperactive RETGC-1 in GOF variants — drives photoreceptor degeneration,
      directly supporting the dominant gain-of-function mechanism in GUCY2D-CORD6.
  downstream:
  - target: Cone Photoreceptor Calcium Overload
    description: >-
      Constitutively elevated cGMP keeps CNG channels perpetually open, causing
      sustained Na+/Ca2+ influx and intracellular calcium overload in cone
      photoreceptors, triggering downstream cytotoxic pathways.

- name: Cone Photoreceptor Calcium Overload
  description: >-
    Chronically elevated cGMP in dominant GUCY2D-CORD6 maintains CNG channels in
    a constitutively open state, producing sustained Na+/Ca2+ influx into cone
    photoreceptor outer segments. The resulting intracellular calcium overload
    activates PKG-dependent phosphorylation cascades, calpain-mediated proteolysis,
    endoplasmic reticulum stress, and downstream apoptotic cascades. Because RETGC-1
    is preferentially expressed in cone outer segments and cones have intrinsically
    higher baseline metabolic demands, cones are more vulnerable than rods to chronic
    Ca2+ overload, explaining the predominant cone loss and progressive macular
    atrophy characteristic of GUCY2D-CORD6. Rod involvement occurs later as disease
    progresses.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: DOI:10.3390/ijms241311200
    reference_title: "cGMP Signaling in Photoreceptor Degeneration"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca2+ homeostasis/Ca2+ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways."
    explanation: >-
      Li et al. describe the molecular mechanism by which excess cGMP drives
      cone photoreceptor death in the dominant GOF context: Ca2+ overload via
      constitutively open CNG channels activates PKG and downstream stress/death
      pathways, reproducing the cone-predominant degeneration of GUCY2D-CORD6.

phenotypes:
- category: Ophthalmological
  name: Severe visual impairment
  frequency: VERY_FREQUENT
  description: >-
    Profound visual impairment present from birth or early infancy in recessive
    GUCY2D-LCA1. Approximately 76% of patients are severely visually impaired
    (hand movements or worse); only ~24% achieve measurable Snellen visual acuity.
    Visual function is profoundly and relatively stably impaired over years to decades
    of follow-up, though some patients experience additional visual decline from
    complications such as keratoconus or early-onset cataract.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: DOI:10.3390/genes12081261
    reference_title: "Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss"
    explanation: >-
      Huang et al. confirm that LCA (including GUCY2D-related LCA1) is characterized
      by extremely early-onset severe visual loss.
  - reference: PMID:20301475
    reference_title: "Leber Congenital Amaurosis - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Visual acuity is rarely better than 20/400."
    explanation: >-
      GeneReviews documents that visual acuity in LCA is rarely better than 20/400,
      confirming the severity of visual impairment characteristic of GUCY2D-LCA1.

- category: Ophthalmological
  name: Nystagmus
  frequency: VERY_FREQUENT
  description: >-
    Infantile nystagmus is a near-universal presenting feature of GUCY2D-LCA1,
    developing within the first three years of life and typically present from
    birth. It reflects severe photoreceptor dysfunction impairing visual fixation
    from early infancy.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:20301475
    reference_title: "Leber Congenital Amaurosis - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus."
    explanation: >-
      GeneReviews confirms nystagmus as one of the cardinal accompanying features
      of LCA, consistent with the near-universal nystagmus observed in GUCY2D-LCA1.

- category: Ophthalmological
  name: Photophobia
  frequency: FREQUENT
  description: >-
    Light sensitivity is a prominent and characteristic feature of GUCY2D-related
    retinopathy occurring in both the recessive (LCA1) and dominant (CORD6) forms.
    In recessive disease, photophobia likely reflects cone photoreceptor dysfunction;
    in dominant CORD6 it results from abnormal cone sensitivity secondary to the
    gain-of-function mechanism.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:38278208
    reference_title: "Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "photophobia and day-blindness compared to night-blindness"
    explanation: >-
      Georgiou et al. report that GUCY2D-LCA/EOSRD patients tend to have a greater
      degree of photophobia and day-blindness relative to night-blindness, reflecting
      the earlier and greater cone dysfunction characteristic of GUCY2D retinopathy.

- category: Electrophysiological
  name: Abnormal electroretinogram
  frequency: VERY_FREQUENT
  description: >-
    Full-field ERG in GUCY2D-LCA1 shows severely reduced or extinguished rod and
    cone responses (panphotoreceptor dysfunction) consistent with profound
    phototransduction failure caused by RETGC-1 absence. In dominant CORD6, ERG
    shows predominantly reduced cone responses with relative rod preservation early,
    with later rod involvement as disease progresses.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:20301475
    reference_title: "Leber Congenital Amaurosis - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The electroretinogram (ERG) is characteristically \"nondetectable\" or severely subnormal."
    explanation: >-
      GeneReviews establishes that the ERG is characteristically nondetectable or
      severely subnormal in LCA, consistent with the profoundly extinguished ERG
      seen in GUCY2D-LCA1 due to complete phototransduction failure.

- category: Ophthalmological
  name: Hypermetropia
  frequency: FREQUENT
  description: >-
    High hyperopia is the most common refractive error in GUCY2D-LCA1, reported
    as a consistent finding across multiple natural history cohorts.
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia

- category: Ophthalmological
  name: Progressive visual loss
  subtype: Dominant
  frequency: VERY_FREQUENT
  description: >-
    Dominant CORD6 shows clearly progressive visual decline with annual BCVA
    worsening of approximately 0.022 logMAR/year. Natural history studies document
    a 32% probability of blindness or severe visual impairment by age 40.
    Structural degeneration on OCT becomes more apparent over time with progressive
    macular atrophy.
  phenotype_term:
    preferred_term: Progressive visual loss
    term:
      id: HP:0000529
      label: Progressive visual loss
  evidence:
  - reference: PMID:35656327
    reference_title: "New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in progressive and usually profound visual loss"
    explanation: >-
      Kazmierczak de Camargo et al. describe the dominant GUCY2D-spectrum maculopathy
      (CACD) as producing progressive and usually profound visual loss, consistent
      with the clearly progressive central visual decline of GUCY2D-CORD6.

- category: Ophthalmological
  name: Color vision defect
  subtype: Dominant
  frequency: FREQUENT
  description: >-
    Dyschromatopsia (color vision defect) is a characteristic finding in dominant
    GUCY2D-CORD6, reflecting early and preferential cone dysfunction. Color
    perception defects are reported across affected members of GUCY2D-CORD families.
  phenotype_term:
    preferred_term: Color vision defect
    term:
      id: HP:0000551
      label: Color vision defect
  evidence:
  - reference: DOI:10.1371/journal.pone.0278857
    reference_title: "The impact of modifier genes on cone-rod dystrophy heterogeneity: An explorative familial pilot study and a hypothesis on neurotransmission impairment"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected family members presented specific genotypes mainly determined by mutated GUCY2D gene, and different phenotypical traits, mainly related to focus and color perception."
    explanation: >-
      Donato et al. confirm color perception defects among affected family members
      with GUCY2D-associated cone-rod dystrophy, consistent with the cone-predominant
      nature of the dominant form.

- category: Ophthalmological
  name: Macular atrophy
  subtype: Dominant
  frequency: FREQUENT
  description: >-
    Progressive macular atrophy is a hallmark structural finding in dominant
    GUCY2D-CORD6. Early granular RPE changes in the macular region progress to
    frank macular atrophy in older patients. OCT demonstrates progressive loss
    of outer retinal bands and reduced retinal thickness over time.
  phenotype_term:
    preferred_term: Macular atrophy
    term:
      id: HP:0007401
      label: Macular atrophy

- category: Ophthalmological
  name: Central scotoma
  subtype: Dominant
  frequency: FREQUENT
  description: >-
    Central visual field loss corresponding to the zone of macular cone
    photoreceptor degeneration is a characteristic functional finding in dominant
    GUCY2D-CORD6. Visual field testing reveals a central scotoma reflecting the
    cone-predominant macular degeneration that defines this form of the disease.
    Central scotoma often precedes or accompanies measurable decline in Snellen
    visual acuity and provides a sensitive functional correlate of structural
    macular atrophy on OCT.
  phenotype_term:
    preferred_term: Central scotoma
    term:
      id: HP:0000603
      label: Central scotoma

- category: Ophthalmological
  name: Keratoconus
  frequency: OCCASIONAL
  description: >-
    Keratoconus is a recognized secondary complication in LCA patients, caused by
    chronic mechanical deformation of the cornea from the characteristic oculodigital
    sign (Franceschetti sign) — the habitual behavior of pressing, poking, and rubbing
    the eyes that is nearly pathognomonic of LCA. This repetitive pressure deforms the
    corneal apex over time, producing corneal thinning and cone-shaped ectasia that
    further reduces vision. GeneReviews notes that children with LCA should be
    discouraged from repeatedly poking and pressing on their eyes to limit this
    secondary corneal complication.
  phenotype_term:
    preferred_term: Keratoconus
    term:
      id: HP:0000563
      label: Keratoconus
  evidence:
  - reference: PMID:20301475
    reference_title: "Leber Congenital Amaurosis - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing."
    explanation: >-
      GeneReviews identifies the oculodigital sign as a near-pathognomonic
      characteristic of LCA. Chronic eye rubbing from this sign causes secondary
      corneal deformation (keratoconus) in a subset of patients.

genetic:
- name: GUCY2D pathogenic variants
  gene_term:
    preferred_term: GUCY2D
    term:
      id: hgnc:4689
      label: GUCY2D
  association: Causative
  features: >-
    Over 248 pathogenic variants in GUCY2D cause autosomal recessive LCA1/EOSRD;
    null alleles (frameshift, nonsense, splice-site) account for approximately 88%
    of LCA-causing alleles. Approximately 30 additional variants cause autosomal
    dominant CORD6, strongly enriched at codon 838 in exon 13 (c.2513G>A
    p.Arg838His accounting for ~54% of dominant cases). Variants in the extracellular
    domain (exon 2) are associated with milder LCA phenotypes and better-preserved
    visual acuity.
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: DOI:10.3390/genes12081261
      reference_title: "Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils"
      explanation: >-
        LCA from biallelic GUCY2D loss-of-function variants follows autosomal
        recessive inheritance.
  - name: Autosomal dominant
    evidence:
    - reference: PMID:35656327
      reference_title: "New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutations of six genes (PRPH2, GUCA1A, GUCY2D, CDHR1, ABCA4, and TTLL5) are implicated in the monogenic dominant inheritance of CACD."
      explanation: >-
        GUCY2D gain-of-function variants cause autosomal dominant CACD1/CORD6.
  evidence:
  - reference: PMID:38278208
    reference_title: "Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1)"
    explanation: >-
      GUCY2D is confirmed as a primary causative gene for LCA/EOSRD in this
      comprehensive inherited retinal disease phenotyping and genotyping review.

treatments:
- name: ATSN-101 Gene Augmentation Therapy
  therapeutic_modality: GENE_THERAPY
  description: >-
    ATSN-101 is an AAV5-based gene augmentation therapy delivering the human GUCY2D
    transgene under the photoreceptor-specific GRK1 promoter via unilateral subretinal
    injection, developed by Atsena Therapeutics for GUCY2D-LCA1. GUCY2D-LCA1 is
    particularly favorable for gene augmentation because of the characteristic
    structure-function dissociation — preserved central photoreceptor structure
    despite profound functional silence — providing viable cellular targets for
    gene replacement. Preliminary Phase I/II results report mean improvement of
    20.3 dB on full-field stimulus testing, with 3/6 treated patients reaching
    the maximum Multi-Luminance Mobility Test (MLMT) score.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: RETGC-1 Deficiency
    treatment_effect: RESTORES
    description: >-
      ATSN-101 delivers functional GUCY2D to rod and cone photoreceptors via
      subretinal AAV5 injection, restoring RETGC-1 cGMP synthesis activity and
      enabling CNG channel reopening and phototransduction recovery.
  evidence:
  - reference: clinicaltrials:NCT03920007
    reference_title: "A Phase 1/2 Dose Escalation Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To evaluate the safety and tolerability of ascending doses of ATSN-101 administered as a unilateral subretinal injection in patients with Leber Congenital Amaurosis (LCA) caused by autosomal recessive guanylate cyclase 2D (GUCY2D) mutations (GUCY2D-LCA)."
    explanation: >-
      NCT03920007 is the Phase I/II clinical trial evaluating ATSN-101 gene replacement
      therapy for GUCY2D-LCA, directly targeting the core mechanism of RETGC-1
      deficiency by restoring functional GUCY2D expression in photoreceptors.
  - reference: PMID:38278208
    reference_title: "Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the first three patients treated with the vector showed rod photoreceptor vision improvement"
    explanation: >-
      Georgiou et al. summarize early results of the NCT03920007 gene therapy trial:
      the first three treated patients showed rod photoreceptor vision improvement on
      full-field stimulus testing in the treated eye, demonstrating functional rescue
      consistent with restored RETGC-1 activity.

- name: Supportive care and low vision rehabilitation
  therapeutic_modality: OTHER
  description: >-
    Standard of care for GUCY2D-related retinopathy patients, encompassing low
    vision aids, orientation and mobility training, educational support, and assistive
    technology. Essential for managing the profound lifelong visual impairment in
    LCA1 patients and the progressive visual loss in CORD6 patients.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care

- name: Genetic counseling
  therapeutic_modality: OTHER
  description: >-
    Essential for clarifying autosomal recessive risk in LCA1 (25% recurrence for
    siblings of affected individuals), autosomal dominant risk in CORD6 (50% risk
    for offspring), family planning guidance, cascade genetic testing of at-risk
    relatives, and clinical trial eligibility assessment.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling

clinical_trials:
- name: NCT03920007
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Phase I/II dose-escalation study of ATSN-101 (AAV5-hGRK1-GUCY2D), an AAV5-based
    gene augmentation therapy for patients with Leber Congenital Amaurosis caused by
    biallelic GUCY2D mutations. Administered as a unilateral subretinal injection
    in 15 participants. Sponsored by Atsena Therapeutics Inc. Estimated study
    completion: May 2027.
  target_phenotypes:
  - preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  - preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: clinicaltrials:NCT03920007
    reference_title: "A Phase 1/2 Dose Escalation Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D"
    supports: SUPPORT
    snippet: "To evaluate the safety and tolerability of ascending doses of ATSN-101 administered as a unilateral subretinal injection in patients with Leber Congenital Amaurosis (LCA) caused by autosomal recessive guanylate cyclase 2D (GUCY2D) mutations (GUCY2D-LCA)."
    explanation: >-
      Phase I/II trial for ATSN-101 (AAV5-GUCY2D) gene therapy in GUCY2D-LCA,
      the most advanced gene therapy program for this condition.

references:
- reference: PMID:20301475
  title: "Leber Congenital Amaurosis - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
- reference: PMID:38278208
  title: "Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes."
- reference: PMID:35656327
  title: "New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates."
- reference: DOI:10.3390/ijms241311200
  title: "cGMP Signaling in Photoreceptor Degeneration"
- reference: DOI:10.1136/bjophthalmol-2020-318483
  title: "Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials"
- reference: DOI:10.3390/genes12081261
  title: "Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations"
- reference: DOI:10.1371/journal.pone.0278857
  title: "The impact of modifier genes on cone-rod dystrophy heterogeneity: An explorative familial pilot study and a hypothesis on neurotransmission impairment"
- reference: clinicaltrials:NCT03920007
  title: "A Phase 1/2 Dose Escalation Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D"

📚

References & Deep Research