Central Areolar Choroidal Dystrophy

👪

Inheritance

1

Autosomal dominant

CACD is mostly autosomal dominant; rare autosomal recessive inheritance has been reported.

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"Being part of congenital retinal dystrophies, it may have an autosomal dominant or recessive inheritance and, until now, has no effective treatment."

The systematic review states CACD is predominantly autosomal dominant with rarer recessive inheritance.

◆

Subtypes

3

CACD1 (17p13 locus) MONDO:0024539

Autosomal dominant central areolar choroidal dystrophy historically mapped to chromosome 17p13 (OMIM 215500); the causative gene at this locus has not been definitively identified, and the locus is historically distinct from the PRPH2 form.

CACD2 (GUCY2D) MONDO:0013137

Central areolar choroidal dystrophy (OMIM 613105) associated with the GUCY2D gene encoding retinal guanylate cyclase-1 (retGC1), a phototransduction enzyme; on the cone-rod dystrophy / CACD spectrum.

CACD3 (PRPH2) MONDO:0013151

The most common, genetically solved autosomal dominant form (OMIM 613144) caused by PRPH2 (peripherin-2) missense variants (e.g., codons Arg142, Arg172, Arg195, Ile196, Arg203, Gly208), affecting photoreceptor outer-segment disc structure.

⚙

Pathophysiology

6

PRPH2 Outer-Segment Structural Defect

Pathogenic PRPH2 (peripherin-2) variants disrupt the photoreceptor outer-segment disc rim. Peripherin-2 is a tetraspanin that oligomerizes with ROM1 to maintain disc morphogenesis and rim curvature; defective outer-segment structure compromises rod and cone photoreceptor homeostasis in the central macula. This is the initiating lesion in the most common (CACD3) form.

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

photoreceptor cell outer segment organization GO:0035845 ↓ DECREASED

Downstream

RPE and Photoreceptor Degeneration

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"They are functionally related to photoreceptors (either in the phototransduction process, as in the case of GUCY2D, or the recovery of retinal photodegradation in photoreceptors for GUCA1A, or the formation and maintenance of specific structures within photoreceptors for PRPH2)."

The systematic review links PRPH2 to the formation and maintenance of photoreceptor outer-segment structures, the initiating molecular lesion in the dominant PRPH2 form of CACD.

Phototransduction Recovery Dysregulation

In the GUCY2D (CACD2) and GUCA1A CACD-spectrum forms, the primary defect is in the calcium-dependent recovery phase of phototransduction. GUCY2D encodes retinal guanylate cyclase-1 (retGC1) and GUCA1A encodes its calcium sensor GCAP1; pathogenic variants dysregulate cGMP/Ca2+ homeostasis in photoreceptors, producing photoreceptor stress and degeneration that converges on the same macular RPE/choriocapillaris atrophy.

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

phototransduction GO:0007602 ⚠ ABNORMAL

Downstream

RPE and Photoreceptor Degeneration

Show evidence (1 reference)

PMID:28125083 SUPPORT Model Organism

"The mutation was shown in zebrafish to cause significant disruptions in photoreceptors and retinal pigment epithelium, together with atrophies of retinal vessels and choriocapillaris."

A GUCA1A p.R120L variant disrupting the GCAP1/retGC1 phototransduction recovery axis recapitulated photoreceptor, RPE, and choriocapillaris damage in zebrafish, supporting phototransduction-recovery dysregulation as an alternative initiating mechanism in CACD-spectrum maculopathy.

RPE and Photoreceptor Degeneration

Progressive dysfunction and loss of the central macular retinal pigment epithelium and overlying photoreceptors, the primary degenerative event in CACD, preceding clinically apparent choriocapillaris loss. Reported CACD-causing genes are photoreceptor-expressed, supporting a photoreceptor/RPE-first cascade.

retinal pigment epithelial cell CL:0002586 eye photoreceptor cell CL:0000287

Downstream

Neuroinflammation and Glial Activation

Choriocapillaris Atrophy

Retinal pigment epithelial atrophy Degeneration of central RPE and photoreceptors produces RPE atrophy.

Abnormal electroretinogram Photoreceptor degeneration causes reduced ERG amplitudes and delayed responses.

Show evidence (1 reference)

PMID:37914688 SUPPORT Model Organism

"We corroborated the alteration of the outer segment structure, and we found changes in the synaptic connectivity in the outer plexiform layer as well as gliosis and signs of microglial activation."

The PRPH2 p.Arg195Leu knock-in mouse demonstrates outer-segment structural disruption and progressive retinal degeneration, supporting photoreceptor degeneration as a core CACD mechanism.

Neuroinflammation and Glial Activation

Secondary microglial activation, reactive gliosis, and aberrant synaptic remodeling accompany photoreceptor degeneration, as demonstrated in the PRPH2 knock-in CACD mouse model. This neuroinflammatory response is a downstream amplifier of retinal degeneration rather than the primary lesion.

microglial cell CL:0000129 Mueller cell CL:0000636

microglial cell activation GO:0001774 ↑ INCREASED

Downstream

Central Macular Geographic Atrophy

Show evidence (1 reference)

PMID:37914688 SUPPORT Model Organism

"Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation."

The CACD knock-in mouse model exhibits aberrant synaptic remodeling and microglial activation as part of the degenerative cascade. As model-organism evidence, this should not be the sole support for human neuroinflammation claims.

Choriocapillaris Atrophy

Secondary atrophy of the choriocapillaris and underlying choroidal vasculature beneath the degenerating central RPE, producing the characteristic well-demarcated areolar lesion of the central macula. OCT angiography can show choriocapillaris flow deficits extending beyond the clinically atrophic RPE.

endothelial cell CL:0000115

Downstream

Central Macular Geographic Atrophy

Central areolar chorioretinal atrophy Choriocapillaris atrophy contributes directly to the areolar chorioretinal atrophic lesion.

Show evidence (1 reference)

PMID:37914688 SUPPORT Model Organism

"Central areolar choroidal dystrophy is an inherited disorder characterized by progressive choriocapillaris atrophy and retinal degeneration and is usually associated with mutations in the PRPH2 gene."

Progressive choriocapillaris atrophy is a defining downstream feature of CACD, occurring beneath the degenerating central macular RPE.

Central Macular Geographic Atrophy

The end-stage, sharply bordered ("areolar") geographic atrophic lesion of the central macula encompassing RPE, choriocapillaris, and photoreceptor loss, causing irreversible central visual field loss while sparing the peripheral retina.

retinal pigment epithelial cell CL:0002586

Downstream

Macular degeneration Central macular geographic atrophy is the structural basis for progressive macular degeneration.

Reduced visual acuity Central macular atrophy causes progressive loss of central visual acuity.

Central scotoma The fovea-centered atrophic lesion produces a central visual field defect.

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"Central areolar choroidal dystrophy (CACD) is a rare hereditary disease that mainly affects the macula, resulting in progressive and usually profound visual loss."

The terminal lesion is a macula-confined geographic atrophy producing progressive, often profound, central visual loss.

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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

6

Eye 4

Retinal pigment epithelial atrophy Retinal pigment epithelial atrophy HP:0007722

Show evidence (1 reference)

PMID:39693084 SUPPORT Human Clinical

"diffuse RPE atrophy consistent with central areolar chorioretinal dystrophy (CACD) in the fifth decade of life"

Diffuse central RPE atrophy is a defining structural feature of CACD, documented in PRPH2 c.828+3A>T carriers.

Reduced visual acuity Reduced visual acuity HP:0007663

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"Central areolar choroidal dystrophy (CACD) is a rare hereditary disease that mainly affects the macula, resulting in progressive and usually profound visual loss."

CACD causes progressive and often profound loss of central visual acuity.

Central scotoma Central scotoma HP:0000603

Show evidence (1 reference)

PMID:20306439 SUPPORT Human Clinical

"HVF revealed central scotoma in 6 of 7 eyes (85.7%), whereas a paracentral scotoma extending to fixation point was detected in 1 eye."

Humphrey visual field testing in CACD patients demonstrated a central scotoma in the great majority of affected eyes, corresponding to the atrophic macular lesion.

Abnormal electroretinogram Abnormal electroretinogram HP:0000512

Show evidence (1 reference)

PMID:38743414 SUPPORT Human Clinical

"ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001)."

The 241-patient PRPH2 cohort (28% CACD phenotype) documented significantly reduced ERG amplitudes and delayed peak times.

Other 2

Central areolar chorioretinal atrophy Chorioretinal atrophy HP:0000533

Course: PROGRESSIVE

Show evidence (2 references)

PMID:37914688 SUPPORT Model Organism

"Central areolar choroidal dystrophy is an inherited disorder characterized by progressive choriocapillaris atrophy and retinal degeneration and is usually associated with mutations in the PRPH2 gene."

Progressive choriocapillaris and retinal atrophy is the hallmark chorioretinal lesion of CACD.

PMID:39693084 SUPPORT Human Clinical

"diffuse RPE atrophy consistent with central areolar chorioretinal dystrophy (CACD) in the fifth decade of life"

In a human longitudinal PRPH2 cohort, carriers developed diffuse central RPE/chorioretinal atrophy diagnostic of CACD, providing human clinical support for the defining lesion.

Macular degeneration Macular degeneration HP:0000608

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"Central areolar choroidal dystrophy (CACD) is a rare hereditary disease that mainly affects the macula, resulting in progressive and usually profound visual loss."

CACD is a macula-predominant dystrophy causing progressive macular degeneration.

🧬

Genetic Associations

3

PRPH2 pathogenic variants (Causative)

Gene: PRPH2 hgnc:9942

Autosomal dominant

Show evidence (1 reference)

PMID:38743414 SUPPORT Human Clinical

"The central areolar choroidal dystrophy phenotype was associated with 13 missense variants."

In the multicenter PRPH2 cohort the CACD phenotype was specifically associated with PRPH2 missense variants.

GUCY2D pathogenic variants (Causative)

Gene: GUCY2D hgnc:4689

Autosomal dominant

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."

The systematic review lists GUCY2D among the genes implicated in monogenic dominant CACD.

GUCA1A pathogenic variants (Causative)

Gene: GUCA1A hgnc:4678

Autosomal dominant

Show evidence (1 reference)

PMID:28125083 SUPPORT Human Clinical

"We conclude that GUCA1A mutations could cause significant variability in maculopathies, including central areolar choroidal dystrophy, which represents a severe pattern of maculopathy."

GUCA1A variants can produce a CACD-spectrum maculopathy, representing a severe end of the GUCA1A phenotypic range.

💊

Medical Actions

3

Low Vision Rehabilitation and Supportive Care

Action: supportive care MAXO:0000950

No disease-modifying therapy currently prevents CACD progression; management is supportive, including low-vision aids and rehabilitation for central vision loss, with monitoring for complications such as macular neovascularization.

Show evidence (1 reference)

PMID:35656327 SUPPORT Human Clinical

"Being part of congenital retinal dystrophies, it may have an autosomal dominant or recessive inheritance and, until now, has no effective treatment."

No effective disease-modifying treatment exists; care is supportive.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling for affected families given the predominantly autosomal dominant inheritance and the value of molecular diagnosis for risk assessment and clinical-trial eligibility.

Investigational Gene-Directed Therapy

Action: gene therapy MAXO:0001001

Experimental, not yet approved. A 2024 PRPH2 workshop report described candidate gene-specific and gene-agnostic strategies for PRPH2-associated retinal disease (including CACD), spanning gene augmentation, allele-specific knockdown, knockdown-and-replace, and genome/prime editing, with the approach depending on the loss-of-function vs gain-of-function mechanism.

Show evidence (1 reference)

PMID:39382871 SUPPORT Other

"possible therapeutic approaches for autosomal dominant PRPH2-associated IRDs, including gene-specific therapies and gene-agnostic approaches."

A stakeholder workshop report (expert consensus, not a clinical trial) outlines candidate gene-directed therapeutic approaches under development for PRPH2-associated IRDs including CACD.

{ }

Source YAML

click to show

name: Central Areolar Choroidal Dystrophy
creation_date: "2026-06-16T00:00:00Z"
category: Mendelian
description: >-
  Central areolar choroidal dystrophy (CACD) is a rare inherited macular
  dystrophy characterized by a slowly progressive, bilateral, symmetric,
  well-demarcated ("areolar") area of retinal pigment epithelium (RPE) and
  choriocapillaris atrophy centered on the fovea, producing central vision loss
  in mid-adult life. It evolves through stages from subtle parafoveal RPE
  mottling, through a sharply bordered patch of RPE atrophy outside the fovea,
  to an end-stage geographic atrophic lesion of the central macula with loss of
  the choriocapillaris and underlying choroidal vessels and severe visual acuity
  loss (commonly <20/200). Most genetically solved cases are autosomal dominant
  and caused by PRPH2 (peripherin-2) variants (CACD3), with a historically
  defined autosomal dominant 17p13 locus (CACD1) of unknown gene and
  GUCY2D-associated disease (CACD2) also described; GUCA1A variants can produce
  a CACD-spectrum maculopathy. The reported genes are photoreceptor-expressed,
  supporting a model of primary photoreceptor/RPE dysfunction with secondary
  choriocapillaris degeneration restricted to the central macula, distinguishing
  CACD from generalized choroideremia and the panretinal rod-cone degenerations.
disease_term:
  preferred_term: central areolar choroidal dystrophy
  term:
    id: MONDO:0008982
    label: central areolar choroidal dystrophy
synonyms:
- CACD
- central areolar chorioretinal dystrophy
- central areolar choroidal sclerosis
- central areolar choroidal atrophy
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
notes: >-
  CACD overlaps the broader PRPH2-Related Retinopathy entry: CACD is one of
  several fundus-autofluorescence phenotypes within the PRPH2 disease spectrum
  (about 28% of a 241-patient PRPH2 cohort) and is kept as a distinct disease
  entry because it is an etiologically heterogeneous, clinically defined macular
  dystrophy (PRPH2, GUCY2D, GUCA1A, plus a gene-undefined 17p13 locus) rather
  than a single-gene disorder. It is distinct from Fuchs (corneal) dystrophy and
  from generalized choroideremia in being confined to the central macula with a
  photoreceptor-first, RPE/choriocapillaris-second mechanism. CACD cases are
  sometimes initially misdiagnosed as geographic atrophy secondary to age-related
  macular degeneration; multimodal imaging and genetic testing improve the
  distinction. CACD is deliberately NOT mapped with conforms_to to the
  photoreceptor_degeneration module: although PRPH2/peripherin is listed there as
  a gene-class substitution, that module encodes the panretinal rod-first /
  cone-second apoptotic cascade of classic retinitis pigmentosa / rod-cone
  dystrophy, whereas CACD is a macula-confined, central (cone-region)-predominant
  dystrophy with a primary RPE/choriocapillaris atrophic lesion that does not
  follow the rod-first sequence; forcing conformance would misrepresent the
  CACD mechanism.
has_subtypes:
- name: CACD1
  display_name: CACD1 (17p13 locus)
  classification: mondo_direct_subclass
  subtype_term:
    preferred_term: choroidal dystrophy, central areolar, 1
    term:
      id: MONDO:0024539
      label: choroidal dystrophy, central areolar, 1
  description: >-
    Autosomal dominant central areolar choroidal dystrophy historically mapped
    to chromosome 17p13 (OMIM 215500); the causative gene at this locus has not
    been definitively identified, and the locus is historically distinct from
    the PRPH2 form.
- name: CACD2
  display_name: CACD2 (GUCY2D)
  classification: mondo_direct_subclass
  subtype_term:
    preferred_term: choroidal dystrophy, central areolar 2
    term:
      id: MONDO:0013137
      label: choroidal dystrophy, central areolar 2
  description: >-
    Central areolar choroidal dystrophy (OMIM 613105) associated with the GUCY2D
    gene encoding retinal guanylate cyclase-1 (retGC1), a phototransduction
    enzyme; on the cone-rod dystrophy / CACD spectrum.
- name: CACD3
  display_name: CACD3 (PRPH2)
  classification: mondo_direct_subclass
  subtype_term:
    preferred_term: choroidal dystrophy, central areolar, 3
    term:
      id: MONDO:0013151
      label: choroidal dystrophy, central areolar, 3
  description: >-
    The most common, genetically solved autosomal dominant form (OMIM 613144)
    caused by PRPH2 (peripherin-2) missense variants (e.g., codons Arg142,
    Arg172, Arg195, Ile196, Arg203, Gly208), affecting photoreceptor
    outer-segment disc structure.
pathophysiology:
- name: PRPH2 Outer-Segment Structural Defect
  description: >-
    Pathogenic PRPH2 (peripherin-2) variants disrupt the photoreceptor
    outer-segment disc rim. Peripherin-2 is a tetraspanin that oligomerizes with
    ROM1 to maintain disc morphogenesis and rim curvature; defective
    outer-segment structure compromises rod and cone photoreceptor homeostasis
    in the central macula. This is the initiating lesion in the most common
    (CACD3) form.
  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: photoreceptor cell outer segment organization
    term:
      id: GO:0035845
      label: photoreceptor cell outer segment organization
    modifier: DECREASED
  evidence:
  - reference: PMID:35656327
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They are functionally related to photoreceptors (either in the
      phototransduction process, as in the case of GUCY2D, or the recovery of
      retinal photodegradation in photoreceptors for GUCA1A, or the formation and
      maintenance of specific structures within photoreceptors for PRPH2).
    explanation: >-
      The systematic review links PRPH2 to the formation and maintenance of
      photoreceptor outer-segment structures, the initiating molecular lesion in
      the dominant PRPH2 form of CACD.
  downstream:
  - target: RPE and Photoreceptor Degeneration
- name: Phototransduction Recovery Dysregulation
  description: >-
    In the GUCY2D (CACD2) and GUCA1A CACD-spectrum forms, the primary defect is
    in the calcium-dependent recovery phase of phototransduction. GUCY2D
    encodes retinal guanylate cyclase-1 (retGC1) and GUCA1A encodes its calcium
    sensor GCAP1; pathogenic variants dysregulate cGMP/Ca2+ homeostasis in
    photoreceptors, producing photoreceptor stress and degeneration that
    converges on the same macular RPE/choriocapillaris atrophy.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: phototransduction
    term:
      id: GO:0007602
      label: phototransduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28125083
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The mutation was shown in zebrafish to cause significant disruptions in
      photoreceptors and retinal pigment epithelium, together with atrophies of
      retinal vessels and choriocapillaris.
    explanation: >-
      A GUCA1A p.R120L variant disrupting the GCAP1/retGC1 phototransduction
      recovery axis recapitulated photoreceptor, RPE, and choriocapillaris
      damage in zebrafish, supporting phototransduction-recovery dysregulation as
      an alternative initiating mechanism in CACD-spectrum maculopathy.
  downstream:
  - target: RPE and Photoreceptor Degeneration
- name: RPE and Photoreceptor Degeneration
  description: >-
    Progressive dysfunction and loss of the central macular retinal pigment
    epithelium and overlying photoreceptors, the primary degenerative event in
    CACD, preceding clinically apparent choriocapillaris loss. Reported
    CACD-causing genes are photoreceptor-expressed, supporting a
    photoreceptor/RPE-first cascade.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  - preferred_term: eye photoreceptor cell
    term:
      id: CL:0000287
      label: eye photoreceptor cell
  evidence:
  - reference: PMID:37914688
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We corroborated the alteration of the outer segment structure, and we
      found changes in the synaptic connectivity in the outer plexiform layer as
      well as gliosis and signs of microglial activation.
    explanation: >-
      The PRPH2 p.Arg195Leu knock-in mouse demonstrates outer-segment structural
      disruption and progressive retinal degeneration, supporting photoreceptor
      degeneration as a core CACD mechanism.
  downstream:
  - target: Neuroinflammation and Glial Activation
  - target: Choriocapillaris Atrophy
  - target: Retinal pigment epithelial atrophy
    description: Degeneration of central RPE and photoreceptors produces RPE atrophy.
  - target: Abnormal electroretinogram
    description: Photoreceptor degeneration causes reduced ERG amplitudes and delayed responses.
- name: Neuroinflammation and Glial Activation
  description: >-
    Secondary microglial activation, reactive gliosis, and aberrant synaptic
    remodeling accompany photoreceptor degeneration, as demonstrated in the
    PRPH2 knock-in CACD mouse model. This neuroinflammatory response is a
    downstream amplifier of retinal degeneration rather than the primary lesion.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: Mueller cell
    term:
      id: CL:0000636
      label: Mueller cell
  biological_processes:
  - preferred_term: microglial cell activation
    term:
      id: GO:0001774
      label: microglial cell activation
    modifier: INCREASED
  evidence:
  - reference: PMID:37914688
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy
      retinal degeneration and exhibit aberrant synaptic remodeling and
      microglial activation.
    explanation: >-
      The CACD knock-in mouse model exhibits aberrant synaptic remodeling and
      microglial activation as part of the degenerative cascade. As model-organism
      evidence, this should not be the sole support for human neuroinflammation
      claims.
  downstream:
  - target: Central Macular Geographic Atrophy
- name: Choriocapillaris Atrophy
  description: >-
    Secondary atrophy of the choriocapillaris and underlying choroidal
    vasculature beneath the degenerating central RPE, producing the
    characteristic well-demarcated areolar lesion of the central macula. OCT
    angiography can show choriocapillaris flow deficits extending beyond the
    clinically atrophic RPE.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:37914688
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Central areolar choroidal dystrophy is an inherited disorder characterized
      by progressive choriocapillaris atrophy and retinal degeneration and is
      usually associated with mutations in the PRPH2 gene.
    explanation: >-
      Progressive choriocapillaris atrophy is a defining downstream feature of
      CACD, occurring beneath the degenerating central macular RPE.
  downstream:
  - target: Central Macular Geographic Atrophy
  - target: Central areolar chorioretinal atrophy
    description: Choriocapillaris atrophy contributes directly to the areolar chorioretinal atrophic lesion.
- name: Central Macular Geographic Atrophy
  description: >-
    The end-stage, sharply bordered ("areolar") geographic atrophic lesion of
    the central macula encompassing RPE, choriocapillaris, and photoreceptor
    loss, causing irreversible central visual field loss while sparing the
    peripheral retina.
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  evidence:
  - reference: PMID:35656327
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central areolar choroidal dystrophy (CACD) is a rare hereditary disease
      that mainly affects the macula, resulting in progressive and usually
      profound visual loss.
    explanation: >-
      The terminal lesion is a macula-confined geographic atrophy producing
      progressive, often profound, central visual loss.
  downstream:
  - target: Macular degeneration
    description: Central macular geographic atrophy is the structural basis for progressive macular degeneration.
  - target: Reduced visual acuity
    description: Central macular atrophy causes progressive loss of central visual acuity.
  - target: Central scotoma
    description: The fovea-centered atrophic lesion produces a central visual field defect.
phenotypes:
- name: Central areolar chorioretinal atrophy
  description: >-
    Well-demarcated bilateral atrophy of the RPE and choriocapillaris centered
    on the fovea, the defining lesion of CACD.
  phenotype_term:
    preferred_term: Chorioretinal atrophy
    term:
      id: HP:0000533
      label: Chorioretinal atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37914688
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Central areolar choroidal dystrophy is an inherited disorder characterized
      by progressive choriocapillaris atrophy and retinal degeneration and is
      usually associated with mutations in the PRPH2 gene.
    explanation: >-
      Progressive choriocapillaris and retinal atrophy is the hallmark
      chorioretinal lesion of CACD.
  - reference: PMID:39693084
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diffuse RPE atrophy consistent with
      central areolar chorioretinal dystrophy (CACD) in the fifth decade of life
    explanation: >-
      In a human longitudinal PRPH2 cohort, carriers developed diffuse central
      RPE/chorioretinal atrophy diagnostic of CACD, providing human clinical
      support for the defining lesion.
- name: Macular degeneration
  description: Progressive degeneration of the central macula.
  phenotype_term:
    preferred_term: Macular degeneration
    term:
      id: HP:0000608
      label: Macular degeneration
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35656327
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central areolar choroidal dystrophy (CACD) is a rare hereditary disease
      that mainly affects the macula, resulting in progressive and usually
      profound visual loss.
    explanation: >-
      CACD is a macula-predominant dystrophy causing progressive macular
      degeneration.
- name: Retinal pigment epithelial atrophy
  description: Atrophy of the central macular retinal pigment epithelium.
  phenotype_term:
    preferred_term: Retinal pigment epithelial atrophy
    term:
      id: HP:0007722
      label: Retinal pigment epithelial atrophy
  evidence:
  - reference: PMID:39693084
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diffuse RPE atrophy consistent with
      central areolar chorioretinal dystrophy (CACD) in the fifth decade of life
    explanation: >-
      Diffuse central RPE atrophy is a defining structural feature of CACD,
      documented in PRPH2 c.828+3A>T carriers.
- name: Reduced visual acuity
  description: Progressive loss of central visual acuity in mid-adult life.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35656327
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central areolar choroidal dystrophy (CACD) is a rare hereditary disease
      that mainly affects the macula, resulting in progressive and usually
      profound visual loss.
    explanation: >-
      CACD causes progressive and often profound loss of central visual acuity.
- name: Central scotoma
  description: Central visual field defect corresponding to the atrophic lesion.
  phenotype_term:
    preferred_term: Central scotoma
    term:
      id: HP:0000603
      label: Central scotoma
  evidence:
  - reference: PMID:20306439
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HVF revealed central scotoma in 6 of 7 eyes (85.7%), whereas a paracentral
      scotoma extending to fixation point was detected in 1 eye.
    explanation: >-
      Humphrey visual field testing in CACD patients demonstrated a central
      scotoma in the great majority of affected eyes, corresponding to the
      atrophic macular lesion.
- name: Abnormal electroretinogram
  description: >-
    Full-field ERG abnormalities in PRPH2-associated disease, including reduced
    amplitudes and delayed peak times, reflecting generalized photoreceptor
    dysfunction beyond the visible macular lesion.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:38743414
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ERG showed a significantly reduced amplitude across all components
      (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and
      single-flash b-wave (P < 0.001).
    explanation: >-
      The 241-patient PRPH2 cohort (28% CACD phenotype) documented significantly
      reduced ERG amplitudes and delayed peak times.
genetic:
- name: PRPH2 pathogenic variants
  subtype: CACD3
  gene_term:
    preferred_term: PRPH2
    term:
      id: hgnc:9942
      label: PRPH2
  association: Causative
  features: >-
    PRPH2 (peripherin-2) missense variants are the most common cause of
    autosomal dominant CACD (CACD3), recurrently at codons Arg142, Arg172,
    Arg195, Ile196, Arg203, and Gly208, disrupting photoreceptor outer-segment
    disc structure. The CACD fundus-autofluorescence phenotype was associated
    with 13 missense variants in a large PRPH2 cohort.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:38743414
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The central areolar choroidal dystrophy phenotype was associated with 13
      missense variants.
    explanation: >-
      In the multicenter PRPH2 cohort the CACD phenotype was specifically
      associated with PRPH2 missense variants.
- name: GUCY2D pathogenic variants
  subtype: CACD2
  gene_term:
    preferred_term: GUCY2D
    term:
      id: hgnc:4689
      label: GUCY2D
  association: Causative
  features: >-
    GUCY2D, encoding retinal guanylate cyclase-1 (retGC1), is an established
    CACD gene (CACD2; OMIM 613105), with reported variants such as p.Val933Ala,
    acting through dysregulated phototransduction recovery.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:35656327
    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: >-
      The systematic review lists GUCY2D among the genes implicated in monogenic
      dominant CACD.
- name: GUCA1A pathogenic variants
  gene_term:
    preferred_term: GUCA1A
    term:
      id: hgnc:4678
      label: GUCA1A
  association: Causative
  features: >-
    GUCA1A encodes GCAP1, the calcium sensor regulating retGC1 in
    phototransduction recovery. A p.Arg120Leu variant caused a five-generation
    maculopathy spanning mild photoreceptor degeneration to a severe
    CACD-pattern lesion, likely via a gain-of-function mechanism.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:28125083
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that GUCA1A mutations could cause significant
      variability in maculopathies, including central areolar choroidal
      dystrophy, which represents a severe pattern of maculopathy.
    explanation: >-
      GUCA1A variants can produce a CACD-spectrum maculopathy, representing a
      severe end of the GUCA1A phenotypic range.
inheritance:
- name: Autosomal dominant
  description: >-
    CACD is mostly autosomal dominant; rare autosomal recessive inheritance has
    been reported.
  evidence:
  - reference: PMID:35656327
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Being part of congenital retinal dystrophies, it may have an autosomal
      dominant or recessive inheritance and, until now, has no effective
      treatment.
    explanation: >-
      The systematic review states CACD is predominantly autosomal dominant with
      rarer recessive inheritance.
treatments:
- name: Low Vision Rehabilitation and Supportive Care
  description: >-
    No disease-modifying therapy currently prevents CACD progression; management
    is supportive, including low-vision aids and rehabilitation for central
    vision loss, with monitoring for complications such as macular
    neovascularization.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:35656327
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Being part of congenital retinal dystrophies, it may have an autosomal
      dominant or recessive inheritance and, until now, has no effective
      treatment.
    explanation: >-
      No effective disease-modifying treatment exists; care is supportive.
- name: Genetic Counseling
  description: >-
    Genetic counseling for affected families given the predominantly autosomal
    dominant inheritance and the value of molecular diagnosis for risk
    assessment and clinical-trial eligibility.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Investigational Gene-Directed Therapy
  description: >-
    Experimental, not yet approved. A 2024 PRPH2 workshop report described
    candidate gene-specific and gene-agnostic strategies for PRPH2-associated
    retinal disease (including CACD), spanning gene augmentation, allele-specific
    knockdown, knockdown-and-replace, and genome/prime editing, with the
    approach depending on the loss-of-function vs gain-of-function mechanism.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  evidence:
  - reference: PMID:39382871
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      possible therapeutic approaches for autosomal
      dominant PRPH2-associated IRDs, including gene-specific therapies and
      gene-agnostic approaches.
    explanation: >-
      A stakeholder workshop report (expert consensus, not a clinical trial)
      outlines candidate gene-directed therapeutic approaches under development
      for PRPH2-associated IRDs including CACD.

📚

References & Deep Research

Deep Research

1

Falcon ▸

1. Disease Information

Edison Scientific Literature 33 citations 2026-06-16T17:25:16.196120

1. Disease Information

1.1 Definition and current understanding

CACD is a rare hereditary macular dystrophy characterized by bilateral, symmetric, well-circumscribed macular loss of retinal pigment epithelium (RPE), choriocapillaris, and overlying retina, leading to progressive—often profound—central vision loss. (camargo2022newinsightson pages 1-2)

A 2022 systematic review summarizes CACD as a macula-predominant dystrophy with typical onset “between the third and fifth decades,” and emphasizes that there is no effective treatment that prevents progression. (camargo2022newinsightson pages 1-2)

Direct abstract quote (definition): “Central areolar choroidal dystrophy is an inherited disorder characterized by progressive choriocapillaris atrophy and retinal degeneration…” (Ruiz-Pastor et al., 2023; Cell Death & Disease; published Nov 2023; https://doi.org/10.1038/s41419-023-06243-8). (ruizpastor2023prph2knockinmice pages 1-2)

1.2 Key identifiers

OMIM/MIM: CACD has been cited as MIM 215500 in CACD literature summaries. (abeshi2017genetictestingfor pages 3-3, chiang2023electrophysiologicalevaluationof pages 18-18)
OMIM phenotype reference in PRPH2 retinopathy cohort: CACD phenotype within PRPH2-associated disease referenced as OMIM #613105 in a 2024 PRPH2 cohort paper. (jeffery2024retinaldystrophiesassociated pages 2-3)
MONDO ID / Orphanet / ICD-10/ICD-11 / MeSH: Not retrievable from the available tool context in this run; should be added by direct lookup in MONDO/Orphanet/ICD/MeSH resources.

1.3 Synonyms and alternative names

“CACD” (abbreviation) and “central areolar chorioretinal dystrophy” appear in recent PRPH2 longitudinal phenotyping work describing diffuse RPE atrophy “consistent with central areolar chorioretinal dystrophy (CACD).” (seddon2024clinicalandimaging pages 1-2)

2. Etiology

2.1 Disease causal factors

CACD is primarily genetic (Mendelian), with both autosomal dominant and rarer recessive inheritance reported. (camargo2022newinsightson pages 1-2, abeshi2017genetictestingfor pages 3-3)

A 2022 systematic review identified mutations in six genes as implicated in monogenic CACD in the literature it reviewed: PRPH2, GUCA1A, GUCY2D, CDHR1, ABCA4, and TTLL5. (camargo2022newinsightson pages 1-2)

2.2 Risk factors

Genetic risk factors - PRPH2 is highlighted as the main gene in most published CACD studies. (camargo2022newinsightson pages 6-8, camargo2022newinsightson pages 8-9) - CACD has been associated with variants in genes involved in photoreceptor structure (PRPH2), phototransduction recovery/Ca2+ feedback (GUCA1A, GUCY2D), and other retinal dystrophy genes (CDHR1, ABCA4, TTLL5) with variable strength of evidence depending on the gene/variant. (camargo2022newinsightson pages 1-2, camargo2022newinsightson pages 8-9)

Environmental risk factors / lifestyle risk factors No CACD-specific environmental or lifestyle risk factors were identified in the retrieved evidence set for this run.

2.3 Protective factors and gene–environment interactions

No CACD-specific protective factors or gene–environment interactions were identified in the retrieved evidence set for this run.

3. Phenotypes

3.1 Core clinical phenotype and staging

A disease-staging framework described in a 2022 systematic review includes four clinical stages: - Stage 1: subtle parafoveal RPE changes - Stage 2: oval/round mildly atrophic hypopigmented area with a “speckled” fundus autofluorescence (FAF) pattern - Stage 3: well-demarcated RPE atrophy patches outside the fovea - Stage 4: foveal involvement with markedly decreased visual acuity, commonly <20/200. (camargo2022newinsightson pages 1-2)

3.2 Frequency and quantitative phenotype statistics (recent cohorts)

In the largest recent multicenter PRPH2 cohort (241 patients, 168 families; Investigative Ophthalmology & Visual Science; May 2024; https://doi.org/10.1167/iovs.65.5.22): - Median age at symptom onset: 40 years (range 4–78). (jeffery2024retinaldystrophiesassociated pages 1-2) - FAF phenotype distribution included CACD: 28% classified as CACD. (jeffery2024retinaldystrophiesassociated pages 1-2) - Median visual acuity: 0.18 logMAR in each eye (IQRs provided in the abstract). (jeffery2024retinaldystrophiesassociated pages 1-2) - ERG: significantly reduced amplitudes across components and delayed peak times in light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). (jeffery2024retinaldystrophiesassociated pages 1-2)

3.3 Representative symptoms/signs (suggested HPO terms)

Evidence in this run supports the following clinical manifestations and corresponding suggested HPO terms (examples): - Progressive central vision loss / reduced visual acuity → HP:0007663 (Reduced visual acuity) (stage 4 often <20/200). (camargo2022newinsightson pages 1-2) - Macular atrophy / chorioretinal atrophy → HP:0000608 (Macular degeneration) / HP:0000556 (Chorioretinal atrophy) (phenotype described as central macular RPE/choriocapillaris atrophy). (camargo2022newinsightson pages 1-2, corradetti2024retinalimagingfindings pages 13-15) - Central scotoma (reported in a 2023 CACD case report abstract, but not deeply extracted here) → HP:0000603 (Central scotoma) (limited evidence in retrieved set; primarily case-report level). (paper retrieved but not evidence-extracted)

3.4 Quality of life impact

No CACD-specific quality-of-life instrument results (e.g., NEI VFQ-25, EQ-5D) were found in the retrieved evidence set for this run; however, the disease is described as “usually profound visual loss” at later stages, which is expected to substantially impact daily functioning. (camargo2022newinsightson pages 1-2)

4. Genetic / Molecular Information

4.1 Causal genes (with disease context)

A 2022 systematic review of CACD-causing genes reports that variants in PRPH2, GUCA1A, GUCY2D, CDHR1, ABCA4, TTLL5 have been implicated in monogenic CACD in the literature, with functional connections to photoreceptors. (camargo2022newinsightson pages 1-2, camargo2022newinsightson pages 8-9)

Functional grouping (from review synthesis): - Photoreceptor outer segment structure: PRPH2 (peripherin-2) required for outer segment disc morphogenesis and rim curvature. (camargo2022newinsightson pages 8-9) - Phototransduction recovery / Ca2+ feedback: GUCY2D encodes retinal guanylyl cyclase; GUCA1A encodes GCAP1 regulating GUCY2D in Ca2+-dependent feedback. (camargo2022newinsightson pages 8-9)

4.2 Pathogenic variants (examples explicitly supported here)

PRPH2 - p.Arg195Leu (R195L): used to generate a CRISPR knock-in model that “recapitulate[s] human central areolar choroidal dystrophy.” (Ruiz-Pastor et al., 2023; published Nov 2023; https://doi.org/10.1038/s41419-023-06243-8). (ruizpastor2023prph2knockinmice pages 1-2, ruizpastor2023prph2knockinmice pages 3-5) - c.828+3A>T (splice-site): associated with a more severe CACD-like phenotype in a longitudinal PRPH2 cohort, presenting with diffuse RPE atrophy consistent with CACD and progressing to extensive atrophy. (Seddon et al., 2024; IOVS; published Dec 2024; https://doi.org/10.1167/iovs.65.14.31). (seddon2024clinicalandimaging pages 1-2)

GUCY2D - p.Val933Ala / V933A: cited as a CACD-causative variant in summaries and systematic review context. (camargo2022newinsightson pages 6-8, abeshi2017genetictestingfor pages 3-3)

GUCA1A - Variants including p.Arg120Leu are discussed as disrupting photoreceptors/RPE in mechanistic work and are included in CACD gene lists in the systematic review. (camargo2022newinsightson pages 8-9, chen2017guca1amutationcauses pages 9-10)

Important limitation: This run did not retrieve ClinVar/gnomAD allele frequencies or ACMG per-variant classifications directly; variant classification statements here are limited to what the retrieved papers explicitly state.

4.3 Genotype–phenotype correlations

A 2024 longitudinal cohort found PRPH2 c.828+3A>T associated with more advanced disease compatible with CACD and worse visual outcomes versus PRPH2 L185P associated with pattern dystrophy phenotypes and better visual acuity over follow-up. (seddon2024clinicalandimaging pages 1-2)

In a large 2024 PRPH2 cohort, the CACD phenotype was associated with missense variants, and specific codons were highlighted as repeatedly reported for CACD (Arg142, Arg172, Arg195, Ile196, Arg203, Gly208). (jeffery2024retinaldystrophiesassociated pages 2-3)

5. Environmental Information

No CACD-specific environmental, lifestyle, or infectious contributors were identified in the retrieved evidence set for this run.

6. Mechanism / Pathophysiology

6.1 Causal chain (gene to phenotype)

Photoreceptor-first with secondary RPE/choriocapillaris involvement (proposed): - CACD is often recognized clinically by RPE and choriocapillaris defects, but mechanistic discussion notes that genes reported to cause CACD are photoreceptor-expressed, supporting a model where primary photoreceptor dysfunction can precede and drive secondary RPE/choriocapillaris degeneration. (chen2017guca1amutationcauses pages 9-10) - In imaging-based characterization, CACD is described as “well-demarcated central macular atrophy of the RPE and choriocapillaris,” consistent with downstream tissue loss. (corradetti2024retinalimagingfindings pages 13-15)

6.2 Molecular pathways/processes implicated (suggested GO terms)

Evidence-supported processes include: - Photoreceptor outer segment organization/morphogenesis (PRPH2 structural role) → GO:0031644 (regulation of neurological system process) is too broad; more appropriate suggested terms include GO:0031638 (z-disc?) not correct. Given the evidence, suggested (curation) terms: GO:0030154 (cell differentiation) not right. Due to absence of explicit GO terms in evidence, provide conceptual mapping only: outer segment disc morphogenesis/organization (photoreceptor outer segment structure). (camargo2022newinsightson pages 8-9, ruizpastor2023prph2knockinmice pages 3-5) - Phototransduction recovery and cGMP/Ca2+ homeostasis (GUCY2D regulated by GUCA1A) → suggested conceptual GO: phototransduction, cGMP biosynthetic process, calcium ion homeostasis. (camargo2022newinsightson pages 8-9) - Neuroinflammation and glial activation (mouse model) → suggested conceptual GO: microglial cell activation, gliosis, synaptic remodeling. (ruizpastor2023prph2knockinmice pages 14-16, ruizpastor2023prph2knockinmice pages 8-11)

6.3 Cell types involved (suggested CL terms)

Photoreceptors (rods and cones) (PRPH2 expressed in photoreceptors; functional impairment in rod and cone pathways) → suggested CL: CL:0000018 (photoreceptor cell). (camargo2022newinsightson pages 8-9, ruizpastor2023prph2knockinmice pages 1-2)
Retinal pigment epithelial cells (RPE atrophy/irregularities) → suggested CL: CL:0002585 (retinal pigment epithelial cell). (seddon2024clinicalandimaging pages 1-2, corradetti2024retinalimagingfindings pages 13-15)
Microglia (activation/invasion of outer nuclear layer in knock-in mice) → suggested CL: CL:0000129 (microglial cell). (ruizpastor2023prph2knockinmice pages 14-16, ruizpastor2023prph2knockinmice pages 8-11)
Müller glia / retinal glia (gliosis) → suggested CL: CL:0000634 (Müller cell). (ruizpastor2023prph2knockinmice pages 14-16)

6.4 Key 2023 mechanistic advance: PRPH2 knock-in CACD model

Ruiz-Pastor et al. (Cell Death & Disease; Nov 2023; https://doi.org/10.1038/s41419-023-06243-8) created Prph2 p.Arg195Leu knock-in mice and reported: - ERG amplitudes reduced early in homozygotes (from 1 month) and later in heterozygotes (from 6 months). (ruizpastor2023prph2knockinmice pages 1-2) - Declining visual acuity from 3 months (homozygotes) and 6 months (heterozygotes). (ruizpastor2023prph2knockinmice pages 1-2) - Outer segment structural disruption plus synaptic remodeling and microglial activation / gliosis. (ruizpastor2023prph2knockinmice pages 14-16, ruizpastor2023prph2knockinmice pages 8-11)

Direct abstract quote (model utility): the mice “show a pattern of retinal degeneration similar to that described in human patients with central areolar choroidal dystrophy and appear to be good models to study the mechanisms involved…” (ruizpastor2023prph2knockinmice pages 1-2)

6.5 Molecular profiling / multi-omics

No CACD-specific transcriptomic/proteomic/metabolomic or single-cell/spatial studies were identified in the retrieved evidence set for this run.

7. Anatomical Structures Affected

7.1 Organ/tissue localization (suggested UBERON terms)

Eye → UBERON:0000970 (eye)
Retina (macula region) → UBERON:0000966 (retina); macula conceptual localization supported by macula-focused atrophy. (camargo2022newinsightson pages 1-2, corradetti2024retinalimagingfindings pages 13-15)
RPE and choriocapillaris / choroid → conceptual localization supported by “RPE and choriocapillaris” atrophy. (corradetti2024retinalimagingfindings pages 13-15)

7.2 Laterality

CACD is typically bilateral and symmetric by definition in the disease overview, though unilateral presentations have been reported (not evidence-extracted here). (camargo2022newinsightson pages 1-2)

8. Temporal Development

8.1 Onset

Typical onset is described as between the third and fifth decades in a 2022 systematic review. (camargo2022newinsightson pages 1-2)

In PRPH2-associated retinopathy cohorts (which include CACD as a major phenotype), median symptom onset across PRPH2 disease was 40 years (range 4–78). (jeffery2024retinaldystrophiesassociated pages 1-2)

8.2 Progression

The longitudinal PRPH2 cohort demonstrates multi-decade progression patterns: - PRPH2 L185P: adult-onset vitelliform/butterfly pattern dystrophy in 40s–50s evolving to central macular atrophy approximately 20 years later. (seddon2024clinicalandimaging pages 1-2) - PRPH2 c.828+3A>T: presentation in the fifth decade with CACD-like diffuse RPE atrophy progressing to extensive atrophy in later decades. (seddon2024clinicalandimaging pages 1-2)

9. Inheritance and Population

9.1 Inheritance pattern

CACD is described as mostly autosomal dominant, with rare autosomal recessive inheritance also reported. (camargo2022newinsightson pages 1-2, abeshi2017genetictestingfor pages 3-3)

9.2 Epidemiology

A genetic-testing-focused summary reported an “overall prevalence” estimate of 1–9 per 100,000; this estimate is older and should be validated against up-to-date registry data. (abeshi2017genetictestingfor pages 3-3)

No robust CACD incidence estimates were identified in the retrieved evidence set.

10. Diagnostics

10.1 Clinical and imaging diagnostics (2024 state-of-the-art)

A 2024 IRD imaging review states CACD shows “well-demarcated central macular atrophy of the RPE and choriocapillaris,” and that: - FAF helps identify accumulated lipofuscin and areas of RPE hypopigmentation. - Spectral-domain OCT can demonstrate “complete loss of all outer retinal layers in the atrophic region.” - OCTA can show “patchy choriocapillaris flow deficits not only within the area of RPE atrophy but also in surrounding regions.” (Corradetti et al., Journal of Clinical Medicine; Apr 2024; https://doi.org/10.3390/jcm13072079). (corradetti2024retinalimagingfindings pages 13-15)

10.2 Electrophysiology

The 2024 PRPH2 cohort reported full-field ERG abnormalities (reduced amplitudes and delayed peak times), supporting the role of ERG for characterization and differential diagnosis. (jeffery2024retinaldystrophiesassociated pages 1-2)

10.3 Genetic testing

Genetic testing is emphasized as clinically useful for confirming diagnosis and enabling counseling and research/trial access; a summary states CACD diagnosis may rely on ophthalmologic examination plus imaging and electrophysiology, and that genetic testing supports differential diagnosis and couple risk assessment. (abeshi2017genetictestingfor pages 3-3)

Panel limitations / diagnostic yield: In an IRD cohort context, CACD had low molecular diagnostic rate (example cited: 35% (7/20)). (camargo2022newinsightson pages 6-8)

10.4 Differential diagnosis

CACD can be confused with geographic atrophy due to age-related macular degeneration (AMD). A 2024 longitudinal PRPH2 cohort notes some individuals were initially misdiagnosed as geographic atrophy secondary to AMD, highlighting the value of multimodal imaging and genetic testing. (seddon2024clinicalandimaging pages 9-10, seddon2024clinicalandimaging pages 1-2)

11. Outcome / Prognosis

11.1 Visual outcomes

The 2022 systematic review notes that late-stage CACD (foveal involvement) often results in severe acuity reduction (commonly <20/200). (camargo2022newinsightson pages 1-2)

In PRPH2-associated disease (where CACD is common), median VA was 0.18 logMAR in a 241-patient cohort, but this includes multiple PRPH2 phenotypes; CACD-specific VA distributions were not extracted from the available abstract evidence. (jeffery2024retinaldystrophiesassociated pages 1-2)

11.2 Prognostic factors

Variant-specific prognosis is suggested in PRPH2 cohorts: c.828+3A>T is associated with more severe CACD-like disease and worse VA than L185P, with different trajectories over decades. (seddon2024clinicalandimaging pages 1-2)

12. Treatment

12.1 Current standard of care

No disease-modifying treatment preventing CACD progression is established in the retrieved evidence set; management is currently supportive and focused on diagnosis, monitoring, and counseling. (camargo2022newinsightson pages 1-2)

12.2 Advanced therapeutics and experimental directions (2023–2024 priority)

A 2024 PRPH2 workshop report (TVST; Oct 2024; https://doi.org/10.1167/tvst.13.10.16) highlights therapeutic directions for PRPH2-associated IRDs, including gene-specific and gene-agnostic strategies and the need for larger natural-history studies. (ayyagari2024currentandfuture pages 1-2)

Direct abstract quote (expert consensus framing): the workshop highlighted “possible therapeutic approaches…including gene-specific therapies and gene-agnostic approaches.” (ayyagari2024currentandfuture pages 1-2)

The workshop report details gene-specific approaches including gene augmentation, allele-specific knockdown (ASO/RNase H concepts), knockdown-and-replace strategies, and genome editing/prime editing as potential routes depending on PRPH2 mechanism (loss-of-function vs gain-of-function). (ayyagari2024currentandfuture pages 6-8)

A 2023 review of genetic treatments for autosomal dominant IRDs emphasizes that gain-of-function variants “will require gene or RNA editing/knockdown to suppress the mutant allele,” while dominant-negative mechanisms may be more amenable to augmentation. (British Journal of Ophthalmology; Aug 2023; https://doi.org/10.1136/bjo-2022-321903). (varela2023genetictreatmentfor pages 13-19)

12.3 Clinical trials relevant to CACD genes / IRD endpoints

NCT03920007 (ATSN-101; Atsena Therapeutics; Phase 1/2; started 2019) targets biallelic GUCY2D Leber congenital amaurosis (not CACD), but is relevant as a proof-of-concept for retinal gene therapy targeting a CACD-associated gene. Primary endpoint: adverse events; secondary endpoints include BCVA and full-field stimulus testing sensitivity. (NCT03920007 chunk 1)
NCT07265895 (IRCCS San Raffaele; observational; NOT_YET_RECRUITING; start 2026-01-01) is a natural-history/genotype–phenotype study for IRDs (including PRPH2) and explicitly lists imaging/functional endpoints that could be used in CACD: BCVA, microperimetry sensitivity, total macular volume, central subfield thickness, preserved ellipsoid zone area, decreased autofluorescence area, etc. (NCT07265895 chunk 1)

12.4 Suggested MAXO terms (treatments/actions)

Evidence-supported interventions and actions (as ontology suggestions) include: - Genetic testing / molecular diagnosis → MAXO:0000127 (genetic testing) (conceptual; exact MAXO ID should be verified) - Optical coherence tomography → MAXO (diagnostic imaging procedure) (verify exact MAXO term) - Fundus autofluorescence imaging → MAXO (retinal imaging) (verify) - Low-vision rehabilitation/support → MAXO (vision rehabilitation) (verify) - Gene therapy / gene augmentation / genome editing / antisense therapy → MAXO (gene therapy) / MAXO (genome editing therapy) / MAXO (antisense oligonucleotide therapy) (verify)

13. Prevention

No primary prevention strategies specific to CACD onset were identified in the retrieved evidence set. Secondary/tertiary prevention is currently centered on early diagnosis (genetic testing + multimodal imaging), monitoring for complications such as macular neovascularization described in PRPH2 longitudinal follow-up, and supportive interventions for visual disability. (seddon2024clinicalandimaging pages 9-10, seddon2024clinicalandimaging pages 1-2)

14. Other Species / Natural Disease

No naturally occurring CACD in non-human species was identified in the retrieved evidence set for this run.

15. Model Organisms

A 2023 CRISPR/Cas9 Prph2 p.Arg195Leu knock-in mouse model recapitulates key CACD features and is positioned as a platform for mechanistic studies and therapeutic testing. (ruizpastor2023prph2knockinmice pages 1-2, ruizpastor2023prph2knockinmice pages 8-11)

Evidence Gaps / Not Available in Retrieved Corpus (explicit)

MONDO/Orphanet/ICD/MeSH identifiers for CACD were not retrievable via the available tool outputs in this run.
CACD-specific, instrumented quality-of-life outcomes (NEI VFQ-25/EQ-5D/PROMIS) were not found in the retrieved evidence set.
Variant allele frequencies (gnomAD) and formal ClinVar/ClinGen assertions were not directly retrieved.
CACD-specific omics (bulk RNA-seq, single-cell, spatial transcriptomics, proteomics, metabolomics) were not identified in the retrieved evidence set.

References

(camargo2022newinsightson pages 1-2): João Paulo Kazmierczak de Camargo, Giovanna Nazaré de Barros Prezia, Naoye Shiokawa, Mario Teruo Sato, Roberto Rosati, and Angelica Beate Winter Boldt. New insights on the regulatory gene network disturbed in central areolar choroidal dystrophy—beyond classical gene candidates. Frontiers in Genetics, May 2022. URL: https://doi.org/10.3389/fgene.2022.886461, doi:10.3389/fgene.2022.886461. This article has 5 citations and is from a peer-reviewed journal.
(jeffery2024retinaldystrophiesassociated pages 1-2): Rachael C. Heath Jeffery, Jennifer A. Thompson, Johnny Lo, Enid S. Chelva, Sean Armstrong, Jose S. Pulido, Rebecca Procopio, Andrea L. Vincent, Lorenzo Bianco, Maurizio Battaglia Parodi, Lucia Ziccardi, Giulio Antonelli, Lucilla Barbano, João P. Marques, Sara Geada, Ana L. Carvalho, Wei C. Tang, Choi M. Chan, Camiel J. F. Boon, Jonathan Hensman, Ta-Ching Chen, Chien-Yu Lin, Pei-Lung Chen, Ajoy Vincent, Anupreet Tumber, Elise Heon, John R. Grigg, Robyn V. Jamieson, Elisa E. Cornish, Benjamin M. Nash, Shyamanga Borooah, Lauren N. Ayton, Alexis Ceecee Britten-Jones, Thomas L. Edwards, Jonathan B. Ruddle, Abhishek Sharma, Rowan G. Porter, Tina M. Lamey, Terri L. McLaren, Samuel McLenachan, Danial Roshandel, and Fred K. Chen. Retinal dystrophies associated with peripherin-2: genetic spectrum and novel clinical observations in 241 patients. Investigative Ophthalmology & Visual Science, 65:22, May 2024. URL: https://doi.org/10.1167/iovs.65.5.22, doi:10.1167/iovs.65.5.22. This article has 24 citations and is from a domain leading peer-reviewed journal.
(seddon2024clinicalandimaging pages 1-2): Johanna M. Seddon, Dikha De, Laura Grunenkovaite, and Daniela Ferrara. Clinical and imaging characteristics of prph2 retinopathies in a longitudinal cohort and diagnostic implications. Investigative Ophthalmology & Visual Science, 65:31, Dec 2024. URL: https://doi.org/10.1167/iovs.65.14.31, doi:10.1167/iovs.65.14.31. This article has 2 citations and is from a domain leading peer-reviewed journal.
(abeshi2017genetictestingfor pages 3-3): Andi Abeshi, Francesca Fanelli, Tommaso Beccari, Munis Dundar, Benedetto Falsini, and Matteo Bertelli. Genetic testing for central areolar choroidal dystrophy. The EuroBiotech Journal, 1:23-25, Oct 2017. URL: https://doi.org/10.24190/issn2564-615x/2017/s1.07, doi:10.24190/issn2564-615x/2017/s1.07. This article has 3 citations.
(chiang2023electrophysiologicalevaluationof pages 18-18): Tsun-Kang Chiang and Minzhong Yu. Electrophysiological evaluation of macular dystrophies. Journal of Clinical Medicine, 12:1430, Feb 2023. URL: https://doi.org/10.3390/jcm12041430, doi:10.3390/jcm12041430. This article has 9 citations.
(jeffery2024retinaldystrophiesassociated pages 2-3): Rachael C. Heath Jeffery, Jennifer A. Thompson, Johnny Lo, Enid S. Chelva, Sean Armstrong, Jose S. Pulido, Rebecca Procopio, Andrea L. Vincent, Lorenzo Bianco, Maurizio Battaglia Parodi, Lucia Ziccardi, Giulio Antonelli, Lucilla Barbano, João P. Marques, Sara Geada, Ana L. Carvalho, Wei C. Tang, Choi M. Chan, Camiel J. F. Boon, Jonathan Hensman, Ta-Ching Chen, Chien-Yu Lin, Pei-Lung Chen, Ajoy Vincent, Anupreet Tumber, Elise Heon, John R. Grigg, Robyn V. Jamieson, Elisa E. Cornish, Benjamin M. Nash, Shyamanga Borooah, Lauren N. Ayton, Alexis Ceecee Britten-Jones, Thomas L. Edwards, Jonathan B. Ruddle, Abhishek Sharma, Rowan G. Porter, Tina M. Lamey, Terri L. McLaren, Samuel McLenachan, Danial Roshandel, and Fred K. Chen. Retinal dystrophies associated with peripherin-2: genetic spectrum and novel clinical observations in 241 patients. Investigative Ophthalmology & Visual Science, 65:22, May 2024. URL: https://doi.org/10.1167/iovs.65.5.22, doi:10.1167/iovs.65.5.22. This article has 24 citations and is from a domain leading peer-reviewed journal.
(camargo2022newinsightson pages 6-8): João Paulo Kazmierczak de Camargo, Giovanna Nazaré de Barros Prezia, Naoye Shiokawa, Mario Teruo Sato, Roberto Rosati, and Angelica Beate Winter Boldt. New insights on the regulatory gene network disturbed in central areolar choroidal dystrophy—beyond classical gene candidates. Frontiers in Genetics, May 2022. URL: https://doi.org/10.3389/fgene.2022.886461, doi:10.3389/fgene.2022.886461. This article has 5 citations and is from a peer-reviewed journal.
(camargo2022newinsightson pages 8-9): João Paulo Kazmierczak de Camargo, Giovanna Nazaré de Barros Prezia, Naoye Shiokawa, Mario Teruo Sato, Roberto Rosati, and Angelica Beate Winter Boldt. New insights on the regulatory gene network disturbed in central areolar choroidal dystrophy—beyond classical gene candidates. Frontiers in Genetics, May 2022. URL: https://doi.org/10.3389/fgene.2022.886461, doi:10.3389/fgene.2022.886461. This article has 5 citations and is from a peer-reviewed journal.
(chen2017guca1amutationcauses pages 9-10): Xue Chen, X. Sheng, Wenjuan Zhuang, Xiantao Sun, Guohua Liu, Xun Shi, Guofu Huang, Yan-fang Mei, Yingjie Li, Xinyuan Pan, Ya-ni Liu, Zi-li Li, Qingshun Zhao, B. Yan, and Chen Zhao. Guca1a mutation causes maculopathy in a five-generation family with a wide spectrum of severity. Genetics in Medicine, 19:945-954, Aug 2017. URL: https://doi.org/10.1038/gim.2016.217, doi:10.1038/gim.2016.217. This article has 26 citations and is from a highest quality peer-reviewed journal.
(camargo2022newinsightson pages 15-16): João Paulo Kazmierczak de Camargo, Giovanna Nazaré de Barros Prezia, Naoye Shiokawa, Mario Teruo Sato, Roberto Rosati, and Angelica Beate Winter Boldt. New insights on the regulatory gene network disturbed in central areolar choroidal dystrophy—beyond classical gene candidates. Frontiers in Genetics, May 2022. URL: https://doi.org/10.3389/fgene.2022.886461, doi:10.3389/fgene.2022.886461. This article has 5 citations and is from a peer-reviewed journal.
(chen2026genotypephenotypeofpatients pages 1-5): Jieqiong Chen, Yu Hong, Minghao Chen, Hong Wang, Yuanyuan Gong, Suqin Yu, weijun wang, Li Su, Ting Zhang, Xinxin Liu, Junran Sun, Tong Li, Huixun Jia, Mei Jiang, Lihong Jiang, Yin Hu, and Xiaodong Sun. Genotype-phenotype of patients with prph2-associated retinal dystrophy: novel insights on foveal structure and visual outcomes. Unknown journal, Feb 2026. URL: https://doi.org/10.21203/rs.3.rs-8587127/v1, doi:10.21203/rs.3.rs-8587127/v1.
(seddon2024clinicalandimaging pages 9-10): Johanna M. Seddon, Dikha De, Laura Grunenkovaite, and Daniela Ferrara. Clinical and imaging characteristics of prph2 retinopathies in a longitudinal cohort and diagnostic implications. Investigative Ophthalmology & Visual Science, 65:31, Dec 2024. URL: https://doi.org/10.1167/iovs.65.14.31, doi:10.1167/iovs.65.14.31. This article has 2 citations and is from a domain leading peer-reviewed journal.
(ruizpastor2023prph2knockinmice pages 1-2): María José Ruiz-Pastor, Xavier Sánchez-Sáez, Oksana Kutsyr, Henar Albertos-Arranz, Carla Sánchez-Castillo, Isabel Ortuño-Lizarán, Natalia Martínez-Gil, Lorena Vidal-Gil, Lucía Méndez, Manuel Sánchez-Martín, Victoria Maneu, Pedro Lax, and Nicolás Cuenca. Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation. Cell Death & Disease, Nov 2023. URL: https://doi.org/10.1038/s41419-023-06243-8, doi:10.1038/s41419-023-06243-8. This article has 7 citations and is from a peer-reviewed journal.
(corradetti2024retinalimagingfindings pages 13-15): Giulia Corradetti, Aditya Verma, Jasaman Tojjar, Louay Almidani, Deniz Oncel, Mehdi Emamverdi, Alec Bradley, Sophiana Lindenberg, Muneeswar Gupta Nittala, and SriniVas R. Sadda. Retinal imaging findings in inherited retinal diseases. Journal of Clinical Medicine, 13:2079, Apr 2024. URL: https://doi.org/10.3390/jcm13072079, doi:10.3390/jcm13072079. This article has 13 citations.
(ruizpastor2023prph2knockinmice pages 3-5): María José Ruiz-Pastor, Xavier Sánchez-Sáez, Oksana Kutsyr, Henar Albertos-Arranz, Carla Sánchez-Castillo, Isabel Ortuño-Lizarán, Natalia Martínez-Gil, Lorena Vidal-Gil, Lucía Méndez, Manuel Sánchez-Martín, Victoria Maneu, Pedro Lax, and Nicolás Cuenca. Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation. Cell Death & Disease, Nov 2023. URL: https://doi.org/10.1038/s41419-023-06243-8, doi:10.1038/s41419-023-06243-8. This article has 7 citations and is from a peer-reviewed journal.
(ruizpastor2023prph2knockinmice pages 14-16): María José Ruiz-Pastor, Xavier Sánchez-Sáez, Oksana Kutsyr, Henar Albertos-Arranz, Carla Sánchez-Castillo, Isabel Ortuño-Lizarán, Natalia Martínez-Gil, Lorena Vidal-Gil, Lucía Méndez, Manuel Sánchez-Martín, Victoria Maneu, Pedro Lax, and Nicolás Cuenca. Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation. Cell Death & Disease, Nov 2023. URL: https://doi.org/10.1038/s41419-023-06243-8, doi:10.1038/s41419-023-06243-8. This article has 7 citations and is from a peer-reviewed journal.
(ruizpastor2023prph2knockinmice pages 8-11): María José Ruiz-Pastor, Xavier Sánchez-Sáez, Oksana Kutsyr, Henar Albertos-Arranz, Carla Sánchez-Castillo, Isabel Ortuño-Lizarán, Natalia Martínez-Gil, Lorena Vidal-Gil, Lucía Méndez, Manuel Sánchez-Martín, Victoria Maneu, Pedro Lax, and Nicolás Cuenca. Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation. Cell Death & Disease, Nov 2023. URL: https://doi.org/10.1038/s41419-023-06243-8, doi:10.1038/s41419-023-06243-8. This article has 7 citations and is from a peer-reviewed journal.
(ayyagari2024currentandfuture pages 1-2): Radha Ayyagari, Shyamanga Borooah, Todd Durham, Claire Gelfman, and Angela Bowman. Current and future directions in developing effective treatments for prph2-associated retinal diseases: a workshop report. Translational Vision Science & Technology, 13:16, Oct 2024. URL: https://doi.org/10.1167/tvst.13.10.16, doi:10.1167/tvst.13.10.16. This article has 3 citations and is from a peer-reviewed journal.
(ayyagari2024currentandfuture pages 6-8): Radha Ayyagari, Shyamanga Borooah, Todd Durham, Claire Gelfman, and Angela Bowman. Current and future directions in developing effective treatments for prph2-associated retinal diseases: a workshop report. Translational Vision Science & Technology, 13:16, Oct 2024. URL: https://doi.org/10.1167/tvst.13.10.16, doi:10.1167/tvst.13.10.16. This article has 3 citations and is from a peer-reviewed journal.
(varela2023genetictreatmentfor pages 13-19): Malena Daich Varela, Anastasios Georgiadis, and Michel Michaelides. Genetic treatment for autosomal dominant inherited retinal dystrophies: approaches, challenges and targeted genotypes. British Journal of Ophthalmology, 107:1223-1230, Aug 2023. URL: https://doi.org/10.1136/bjo-2022-321903, doi:10.1136/bjo-2022-321903. This article has 32 citations and is from a highest quality peer-reviewed journal.
(NCT03920007 chunk 1): Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D. Atsena Therapeutics Inc.. 2019. ClinicalTrials.gov Identifier: NCT03920007
(NCT07265895 chunk 1): Maurizio Battaglia Parodi. Inherited Retinal Diseases: Natural History and Genotype-Phenotype Correlations. IRCCS San Raffaele. 2026. ClinicalTrials.gov Identifier: NCT07265895

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Inheritance

Subtypes

Pathophysiology

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Phenotypes

Genetic Associations

Medical Actions

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References & Deep Research

Deep Research

1. Disease Information

1.1 Definition and current understanding

1.2 Key identifiers

1.3 Synonyms and alternative names

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors and gene–environment interactions

3. Phenotypes

3.1 Core clinical phenotype and staging

3.2 Frequency and quantitative phenotype statistics (recent cohorts)

3.3 Representative symptoms/signs (suggested HPO terms)

3.4 Quality of life impact

4. Genetic / Molecular Information

4.1 Causal genes (with disease context)

4.2 Pathogenic variants (examples explicitly supported here)

4.3 Genotype–phenotype correlations

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Causal chain (gene to phenotype)

6.2 Molecular pathways/processes implicated (suggested GO terms)

6.3 Cell types involved (suggested CL terms)

6.4 Key 2023 mechanistic advance: PRPH2 knock-in CACD model

6.5 Molecular profiling / multi-omics

7. Anatomical Structures Affected

7.1 Organ/tissue localization (suggested UBERON terms)

7.2 Laterality

8. Temporal Development

8.1 Onset

8.2 Progression

9. Inheritance and Population

9.1 Inheritance pattern

9.2 Epidemiology

10. Diagnostics

10.1 Clinical and imaging diagnostics (2024 state-of-the-art)

10.2 Electrophysiology

10.3 Genetic testing

10.4 Differential diagnosis

11. Outcome / Prognosis

11.1 Visual outcomes

11.2 Prognostic factors

12. Treatment

12.1 Current standard of care

12.2 Advanced therapeutics and experimental directions (2023–2024 priority)

12.3 Clinical trials relevant to CACD genes / IRD endpoints

12.4 Suggested MAXO terms (treatments/actions)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Gaps / Not Available in Retrieved Corpus (explicit)

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