Choroideremia

👪

Inheritance

1

X-linked recessive HP:0001419

Affected males are hemizygous for a CHM loss-of-function variant. Carrier females typically show a patchy, mottled fundus pigmentation from X inactivation mosaicism and are usually visually asymptomatic, though a minority with skewed inactivation develop symptomatic disease.

X-linked recessive inheritance

Show evidence (2 references)

PMID:30627697 SUPPORT Other

"Choroideremia is an X-linked inherited chorioretinal dystrophy leading to blindness by late adulthood."

Establishes the X-linked inheritance and the natural endpoint of the disease. Evidence source is OTHER because this is a review.

PMID:20301511 SUPPORT Other

"Although carrier females are generally asymptomatic, signs of chorioretinal degeneration can be reliably observed with fundus autofluorescence imaging, and – after age 25 years – with careful fundus examination."

GeneReviews substantiates the carrier-female description in this block, and adds the detectability threshold (fundus autofluorescence at any age, fundus examination after 25) that this entry previously stated only as "patchy, mottled fundus pigmentation". Evidence source is OTHER because GeneReviews is an expert-curated clinical synthesis.

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Discussions and Knowledge Gaps

1

Which cell type is the primary site of pathogenesis in choroideremia - the retinal pigment epithelium, the photoreceptor, or the choriocapillaris - and which must a gene therapy vector therefore reach?

KNOWLEDGE GAP choroideremia_primary_cell_type

Attached to

pathophysiology#Progressive Chorioretinal Degeneration

Reviews state plainly that the exact site of pathogenesis remains unclear while all three tissues degenerate. This is not an academic point. The choice of vector, promoter, and route of delivery in gene therapy follows directly from which cell must be transduced, and the phase 3 trial of subretinal AAV2-REP1 failed its primary endpoint with the authors attributing part of the shortfall to trial design rather than to the mechanism. Without knowing the primary target, an unsuccessful trial cannot distinguish an inadequate approach from an inadequately targeted one.

Proposed experiments

Cell-type-restricted Chm deletion and rescue in a conditional model

chm_cell_type_specific_rescue

Delete and separately restore Chm under retinal pigment epithelium-, photoreceptor- and choroidal endothelium-specific drivers in a conditional mouse or larger-eye model, and determine which single-cell-type deletion reproduces, and which single-cell-type rescue prevents, the chorioretinal atrophy phenotype.

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Pathophysiology

4

CHM Loss of Function and REP1 Deficiency

A hemizygous loss-of-function variant in CHM - most often nonsense, frameshift, splice or deletion, with essentially no missense hotspot - abolishes Rab escort protein 1. REP1 is not itself an enzyme: it binds newly synthesized Rab GTPases and presents them to Rab geranylgeranyltransferase, then escorts the prenylated Rab to its target membrane. The gene is expressed ubiquitously, so the lesion is systemic even though the disease is not.

Protein prenylation GO:0018342 ↓ DECREASED

Downstream

Defective Rab Prenylation and Intracellular Vesicle Trafficking

Show evidence (1 reference)

PMID:30627697 SUPPORT Other

"Choroideremia is caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), an ubiquitously expressed protein involved in intracellular trafficking and prenylation activity."

Identifies the gene, the protein and its two coupled functions - prenylation and intracellular trafficking - and states the ubiquitous expression that makes the eye-restricted phenotype notable. Evidence source is OTHER because this is a review.

Defective Rab Prenylation and Intracellular Vesicle Trafficking

Without REP1 a subset of Rab GTPases goes unprenylated and cannot associate with the membranes whose traffic they direct. The consequence is a vesicle trafficking deficiency, which in the retina plausibly disrupts the processes that depend most heavily on high-throughput membrane traffic: daily phagocytosis and digestion of shed photoreceptor outer segment discs by the retinal pigment epithelium, melanosome and lysosome transport, and outer-segment renewal itself. The paralogue REP2 substitutes for REP1 in most tissues, which is why the systemic prenylation defect is clinically silent outside the eye.

retinal pigment epithelial cell CL:0002586 photoreceptor cell CL:0000210

Vesicle-mediated transport GO:0016192 ↓ DECREASED Rab protein signal transduction GO:0032482 ↓ DECREASED

Downstream

Progressive Chorioretinal Degeneration

Show evidence (1 reference)

PMID:29555028 SUPPORT Other

"Mutations in the Rab escort protein-1 (REP-1), an ubiquitously encoded protein of the CHM gene, lead to prenylation and vesicle trafficking deficiency in the protein, resulting in the progressive degeneration of choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors."

States the full causal chain this node sits in - prenylation failure to trafficking deficiency to degeneration of the three affected tissues. Evidence source is OTHER because this is a review with a computational modelling component.

Progressive Chorioretinal Degeneration

Photoreceptors, retinal pigment epithelium and choriocapillaris all degenerate, producing the scalloped, sharply demarcated atrophy that exposes bare sclera and gives the disease its name. Which tissue fails first is not settled: the RPE, the photoreceptor and the choroid are all plausible primary sites, they are metabolically interdependent, and the loss of any one would take the others with it. This entry records that uncertainty rather than resolving it, because the answer determines which cell type gene therapy must reach.

retinal pigment epithelial cell CL:0002586 photoreceptor cell CL:0000210 choroidal cell of the eye CL:0000348

Photoreceptor cell maintenance GO:0045494 ↓ DECREASED

optic choroid UBERON:0001776 pigmented layer of retina UBERON:0001782

Downstream

Centripetal Field Loss and Blindness in Late Adulthood

Show evidence (1 reference)

PMID:30627697 SUPPORT Other

"The exact site of pathogenesis remains unclear but results in degeneration of the photoreceptors, retinal pigment epithelium and choroid."

Supports both halves of this node - the three-tissue degeneration, and the explicit statement that the primary site is unresolved. Evidence source is OTHER because this is a review.

Centripetal Field Loss and Blindness in Late Adulthood

Atrophy begins in the midperiphery and advances inward, sparing a shrinking central island of retinal pigment epithelium that preserves good central acuity long after the peripheral field has gone - patients are often legally blind by field criteria while still reading. That island's area, measured by fundus autofluorescence, declines exponentially with age at a rate independent of how much was present at baseline, so the disease follows a strikingly regular course over about six decades and log-transformed residual RPE area serves as an anatomic trial endpoint. Central vision fails when the island is finally consumed, typically in the fifth to seventh decade.

Visual perception GO:0007601 ↓ DECREASED

Show evidence (3 references)

PMID:20301511 SUPPORT Other

"Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life."

GeneReviews states the symptom sequence this node models - night blindness first, then peripheral field, with central vision spared until late - which this entry previously asserted without a citation. Evidence source is OTHER because GeneReviews is an expert-curated clinical synthesis.

PMID:32362554 SUPPORT Human Clinical

"The loss of residual RPE area in untreated eyes with CHM follows the AEM over approximately 60 years."

Establishes the exponential decay of residual retinal pigment epithelium over roughly six decades that this node describes. Evidence source is HUMAN_CLINICAL rather than OTHER because this is a meta-analysis of individual-eye patient data that reports its own quantitative result, not a narrative synthesis.

PMID:32362554 SUPPORT Human Clinical

"The decline rate of log-transformed RPE area was 0.050 (95% confidence interval, 0.046-0.055) log(mm2)/year and was independent of the baseline RPE area"

Quantifies the decline rate and supports the specific claim that it does not depend on baseline area, which is what makes the log-transformed measure usable as a uniform endpoint across disease stages.

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Pathograph

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Phenotypes

4

Eye 3

Night Blindness Nyctalopia HP:0000662

Show evidence (2 references)

PMID:30627697 SUPPORT Other

"The exact site of pathogenesis remains unclear but results in degeneration of the photoreceptors, retinal pigment epithelium and choroid."

Supports this phenotype only indirectly: the quoted sentence establishes that photoreceptors are among the degenerating tissues, which is the substrate for nyctalopia, but it does not mention night blindness. It is retained as mechanistic backing only; the direct evidence is the GeneReviews item below.

PMID:20301511 SUPPORT Other

"Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life."

Direct evidence for this phenotype and for its position first in the symptom sequence, which the previously cited item did not supply. Evidence source is OTHER because GeneReviews is an expert-curated clinical synthesis rather than a primary study.

Constriction of Peripheral Visual Field HP:0001133

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:32362554 SUPPORT Human Clinical

"However, the long-term natural history of the residual retinal pigment epithelium (RPE) is unclear, with reported RPE area decline rates varying widely among patients."

Supports the residual-island framing of field loss in this disease, and documents the inter-patient variability in rate that this phenotype's progression reflects.

Progressive Visual Loss VERY_FREQUENT HP:0000529

Show evidence (1 reference)

PMID:37814062 SUPPORT Human Clinical

"Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss."

States progressive vision loss as the defining outcome. VERY_FREQUENT is a Pattern C mapping of that definitional framing (docs/frequency-evidence-guidelines.md); no proportion is reported.

Other 1

Chorioretinal Atrophy VERY_FREQUENT HP:0000533

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29555028 SUPPORT Other

"resulting in the progressive degeneration of choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors"

Names the progressive degeneration of choriocapillaris and RPE that constitutes this finding. VERY_FREQUENT is a Pattern C mapping of that definitional framing (docs/frequency-evidence-guidelines.md); no proportion is reported.

🧬

Genetic Associations

1

CHM (Hemizygous loss-of-function variants in males)

Gene: CHM hgnc:1940 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:30627697 SUPPORT Other

"Choroideremia is caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), an ubiquitously expressed protein involved in intracellular trafficking and prenylation activity."

Assigns causation to CHM and identifies the encoded protein and its function. Evidence source is OTHER because this is a review.

💊

Medical Actions

1

Subretinal AAV2-REP1 Gene Therapy (Timrepigene Emparvovec)

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

Subretinal delivery of an AAV2 vector carrying CHM, intended to restore REP1 in the surviving central island. The randomized phase 3 trial in 169 adult men did NOT meet its primary endpoint of best-corrected visual acuity improvement at 12 months, so key secondary endpoints were not formally tested; a numerically larger proportion of treated than control participants gained 10 or more ETDRS letters. Adverse events were mostly mild or moderate. This is recorded as an investigational therapy with a negative pivotal trial, not as standard of care. The authors identify entry criteria (more preserved retinal area), surgical technique and endpoint selection as the levers for future studies - which is consistent with the natural history data showing residual RPE area, not acuity, to be the quantity that changes measurably.

Mechanism Target:

RESTORES CHM Loss of Function and REP1 Deficiency — Vector-delivered CHM is intended to restore REP1 expression in retinal cells, acting on the trigger lesion itself rather than on any downstream consequence.

Show evidence (1 reference)

PMID:37814062 SUPPORT Human Clinical

"A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the..."

Establishes that this gene-replacement approach was tested against the causative lesion at pivotal scale. Marked PARTIAL because the trial did not demonstrate benefit on its primary endpoint.

Show evidence (1 reference)

PMID:37814062 SUPPORT Human Clinical

"The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement."

Records the negative pivotal result directly. Marked PARTIAL rather than REFUTE because the trial establishes that the approach was tolerated and showed a numerical secondary signal, while failing to demonstrate benefit on its prespecified primary endpoint.

🔬

Clinical Trials

1

NCT03496012 PHASE_III COMPLETED

STAR: randomized, masked phase 3 trial of high-dose versus low-dose subretinal timrepigene emparvovec versus untreated control in adult men with choroideremia, with 12-month best-corrected visual acuity change as the primary endpoint. The primary endpoint was not met.

Target Phenotypes: Progressive visual loss HP:0000529 Chorioretinal atrophy HP:0000533

Show evidence (1 reference)

PMID:37814062 SUPPORT Human Clinical

"In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months"

Reports the trial's primary endpoint result with the per-arm proportions.

{ }

Source YAML

click to show

name: Choroideremia
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
description: >
  Choroideremia is an X-linked chorioretinal dystrophy of males caused by
  loss-of-function variants in CHM, which encodes Rab escort protein 1 (REP1).
  REP1 presents newly synthesized Rab GTPases to the geranylgeranyltransferase
  that lipid-modifies them, and an unprenylated Rab cannot dock on the membrane
  it is meant to traffic. The gene is ubiquitously expressed, and the partially
  redundant paralogue REP2 covers for its loss almost everywhere in the body -
  which is why a systemic prenylation defect produces a disease confined to the
  eye. Within the eye it produces a distinctive triad of degeneration affecting
  the photoreceptors, the retinal pigment epithelium and the choriocapillaris,
  and which of those three is the primary site remains genuinely unsettled.
  Clinically it begins as childhood night blindness, progresses through
  centripetal loss of peripheral field with a fundus of scalloped chorioretinal
  atrophy exposing bare sclera, and ends in blindness in late adulthood as the
  last island of central retinal pigment epithelium is lost. The residual RPE
  area declines exponentially with age over roughly six decades, which makes it
  an unusually tractable trial endpoint - though the phase 3 gene therapy trial
  that used visual acuity instead did not meet its primary endpoint.
disease_term:
  preferred_term: choroideremia
  term:
    id: MONDO:0010557
    label: choroideremia
synonyms:
- CHM
- tapetochoroidal dystrophy
- progressive tapetochoroidal dystrophy
parents:
- Ophthalmological Disease
- Inherited retinal dystrophy
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >
    Affected males are hemizygous for a CHM loss-of-function variant. Carrier
    females typically show a patchy, mottled fundus pigmentation from X
    inactivation mosaicism and are usually visually asymptomatic, though a
    minority with skewed inactivation develop symptomatic disease.
  evidence:
  - reference: PMID:30627697
    reference_title: "Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Choroideremia is an X-linked inherited chorioretinal dystrophy leading to blindness by late adulthood."
    explanation: >
      Establishes the X-linked inheritance and the natural endpoint of the
      disease. Evidence source is OTHER because this is a review.
  - reference: PMID:20301511
    reference_title: "Choroideremia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although carrier females are generally asymptomatic, signs of chorioretinal degeneration can be reliably observed with fundus autofluorescence imaging, and – after age 25 years – with careful fundus examination."
    explanation: >
      GeneReviews substantiates the carrier-female description in this block,
      and adds the detectability threshold (fundus autofluorescence at any age,
      fundus examination after 25) that this entry previously stated only as
      "patchy, mottled fundus pigmentation". Evidence source is OTHER because
      GeneReviews is an expert-curated clinical synthesis.
pathophysiology:
- name: CHM Loss of Function and REP1 Deficiency
  description: >
    A hemizygous loss-of-function variant in CHM - most often nonsense,
    frameshift, splice or deletion, with essentially no missense hotspot -
    abolishes Rab escort protein 1. REP1 is not itself an enzyme: it binds newly
    synthesized Rab GTPases and presents them to Rab geranylgeranyltransferase,
    then escorts the prenylated Rab to its target membrane. The gene is expressed
    ubiquitously, so the lesion is systemic even though the disease is not.
  role: trigger
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Protein prenylation
    term:
      id: GO:0018342
      label: protein prenylation
    modifier: DECREASED
  evidence:
  - reference: PMID:30627697
    reference_title: "Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Choroideremia is caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), an ubiquitously expressed protein involved in intracellular trafficking and prenylation activity."
    explanation: >
      Identifies the gene, the protein and its two coupled functions -
      prenylation and intracellular trafficking - and states the ubiquitous
      expression that makes the eye-restricted phenotype notable. Evidence
      source is OTHER because this is a review.
  downstream:
  - target: Defective Rab Prenylation and Intracellular Vesicle Trafficking
    causal_link_type: DIRECT

- name: Defective Rab Prenylation and Intracellular Vesicle Trafficking
  description: >
    Without REP1 a subset of Rab GTPases goes unprenylated and cannot associate
    with the membranes whose traffic they direct. The consequence is a vesicle
    trafficking deficiency, which in the retina plausibly disrupts the processes
    that depend most heavily on high-throughput membrane traffic: daily
    phagocytosis and digestion of shed photoreceptor outer segment discs by the
    retinal pigment epithelium, melanosome and lysosome transport, and
    outer-segment renewal itself. The paralogue REP2 substitutes for REP1 in most
    tissues, which is why the systemic prenylation defect is clinically silent
    outside the eye.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: Vesicle-mediated transport
    term:
      id: GO:0016192
      label: vesicle-mediated transport
    modifier: DECREASED
  - preferred_term: Rab protein signal transduction
    term:
      id: GO:0032482
      label: Rab protein signal transduction
    modifier: DECREASED
  evidence:
  - reference: PMID:29555028
    reference_title: "Molecular genetics characterization and homology modeling of the CHM gene mutation: A study on its association with choroideremia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the Rab escort protein-1 (REP-1), an ubiquitously encoded protein of the CHM gene, lead to prenylation and vesicle trafficking deficiency in the protein, resulting in the progressive degeneration of choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors."
    explanation: >
      States the full causal chain this node sits in - prenylation failure to
      trafficking deficiency to degeneration of the three affected tissues.
      Evidence source is OTHER because this is a review with a computational
      modelling component.
  downstream:
  - target: Progressive Chorioretinal Degeneration
    causal_link_type: DIRECT

- name: Progressive Chorioretinal Degeneration
  description: >
    Photoreceptors, retinal pigment epithelium and choriocapillaris all
    degenerate, producing the scalloped, sharply demarcated atrophy that exposes
    bare sclera and gives the disease its name. Which tissue fails first is not
    settled: the RPE, the photoreceptor and the choroid are all plausible
    primary sites, they are metabolically interdependent, and the loss of any one
    would take the others with it. This entry records that uncertainty rather
    than resolving it, because the answer determines which cell type gene
    therapy must reach.
  role: effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: choroidal cell of the eye
    term:
      id: CL:0000348
      label: choroidal cell of the eye
  biological_processes:
  - preferred_term: Photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  locations:
  - preferred_term: optic choroid
    term:
      id: UBERON:0001776
      label: optic choroid
  - preferred_term: pigmented layer of retina
    term:
      id: UBERON:0001782
      label: pigmented layer of retina
  conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
  evidence:
  - reference: PMID:30627697
    reference_title: "Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The exact site of pathogenesis remains unclear but results in degeneration of the photoreceptors, retinal pigment epithelium and choroid."
    explanation: >
      Supports both halves of this node - the three-tissue degeneration, and the
      explicit statement that the primary site is unresolved. Evidence source is
      OTHER because this is a review.
  downstream:
  - target: Centripetal Field Loss and Blindness in Late Adulthood
    causal_link_type: DIRECT

- name: Centripetal Field Loss and Blindness in Late Adulthood
  description: >
    Atrophy begins in the midperiphery and advances inward, sparing a shrinking
    central island of retinal pigment epithelium that preserves good central
    acuity long after the peripheral field has gone - patients are often legally
    blind by field criteria while still reading. That island's area, measured by
    fundus autofluorescence, declines exponentially with age at a rate
    independent of how much was present at baseline, so the disease follows a
    strikingly regular course over about six decades and log-transformed residual
    RPE area serves as an anatomic trial endpoint. Central vision fails when the
    island is finally consumed, typically in the fifth to seventh decade.
  role: consequence
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: Visual perception
    term:
      id: GO:0007601
      label: visual perception
    modifier: DECREASED
  evidence:
  - reference: PMID:20301511
    reference_title: "Choroideremia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life."
    explanation: >
      GeneReviews states the symptom sequence this node models - night blindness
      first, then peripheral field, with central vision spared until late -
      which this entry previously asserted without a citation. Evidence source
      is OTHER because GeneReviews is an expert-curated clinical synthesis.
  - reference: PMID:32362554
    reference_title: "Long-term Natural History of Atrophy in Eyes with Choroideremia-A Systematic Review and Meta-analysis of Individual-Level Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The loss of residual RPE area in untreated eyes with CHM follows the AEM over approximately 60 years."
    explanation: >
      Establishes the exponential decay of residual retinal pigment epithelium
      over roughly six decades that this node describes. Evidence source is
      HUMAN_CLINICAL rather than OTHER because this is a meta-analysis of
      individual-eye patient data that reports its own quantitative result, not
      a narrative synthesis.
  - reference: PMID:32362554
    reference_title: "Long-term Natural History of Atrophy in Eyes with Choroideremia-A Systematic Review and Meta-analysis of Individual-Level Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The decline rate of log-transformed RPE area was 0.050 (95% confidence interval, 0.046-0.055) log(mm2)/year and was independent of the baseline RPE area"
    explanation: >
      Quantifies the decline rate and supports the specific claim that it does
      not depend on baseline area, which is what makes the log-transformed
      measure usable as a uniform endpoint across disease stages.
phenotypes:
- category: Ocular
  name: Night Blindness
  description: >
    Nyctalopia is typically the presenting symptom, usually in the first or
    second decade, reflecting early rod photoreceptor involvement.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:30627697
    reference_title: "Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The exact site of pathogenesis remains unclear but results in degeneration of the photoreceptors, retinal pigment epithelium and choroid."
    explanation: >
      Supports this phenotype only indirectly: the quoted sentence establishes
      that photoreceptors are among the degenerating tissues, which is the
      substrate for nyctalopia, but it does not mention night blindness. It is
      retained as mechanistic backing only; the direct evidence is the
      GeneReviews item below.
  - reference: PMID:20301511
    reference_title: "Choroideremia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life."
    explanation: >
      Direct evidence for this phenotype and for its position first in the
      symptom sequence, which the previously cited item did not supply. Evidence
      source is OTHER because GeneReviews is an expert-curated clinical
      synthesis rather than a primary study.
- category: Ocular
  name: Chorioretinal Atrophy
  description: >
    Sharply demarcated, scalloped atrophy of choriocapillaris and retinal
    pigment epithelium exposing underlying sclera and choroidal vessels, the
    pathognomonic fundus appearance.
  phenotype_term:
    preferred_term: Chorioretinal atrophy
    term:
      id: HP:0000533
      label: Chorioretinal atrophy
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29555028
    reference_title: "Molecular genetics characterization and homology modeling of the CHM gene mutation: A study on its association with choroideremia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "resulting in the progressive degeneration of choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors"
    explanation: >
      Names the progressive degeneration of choriocapillaris and RPE that
      constitutes this finding. VERY_FREQUENT is a Pattern C mapping of that
      definitional framing (docs/frequency-evidence-guidelines.md); no
      proportion is reported.
- category: Ocular
  name: Constriction of Peripheral Visual Field
  description: >
    Centripetal, ring-then-concentric field loss tracking the advancing edge of
    atrophy, with central acuity preserved until the residual island is
    consumed.
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32362554
    reference_title: "Long-term Natural History of Atrophy in Eyes with Choroideremia-A Systematic Review and Meta-analysis of Individual-Level Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the long-term natural history of the residual retinal pigment epithelium (RPE) is unclear, with reported RPE area decline rates varying widely among patients."
    explanation: >
      Supports the residual-island framing of field loss in this disease, and
      documents the inter-patient variability in rate that this phenotype's
      progression reflects.
- category: Ocular
  name: Progressive Visual Loss
  description: >
    Progressive loss of vision culminating in blindness in late adulthood, after
    a long period in which central acuity is deceptively well preserved.
  phenotype_term:
    preferred_term: Progressive visual loss
    term:
      id: HP:0000529
      label: Progressive visual loss
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37814062
    reference_title: "Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss."
    explanation: >
      States progressive vision loss as the defining outcome. VERY_FREQUENT is
      a Pattern C mapping of that definitional framing
      (docs/frequency-evidence-guidelines.md); no proportion is reported.
genetic:
- name: CHM
  association: Hemizygous loss-of-function variants in males
  notes: >
    CHM encodes Rab escort protein 1. Pathogenic variants are predominantly
    truncating - nonsense, frameshift, splice-site and whole- or partial-gene
    deletions - consistent with a pure loss-of-function mechanism. The paralogue
    REP2 compensates in non-retinal tissues, which restricts the phenotype to
    the eye despite ubiquitous CHM expression.
  gene_term:
    preferred_term: CHM
    term:
      id: hgnc:1940
      label: CHM
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:30627697
    reference_title: "Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Choroideremia is caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), an ubiquitously expressed protein involved in intracellular trafficking and prenylation activity."
    explanation: >
      Assigns causation to CHM and identifies the encoded protein and its
      function. Evidence source is OTHER because this is a review.
treatments:
- name: Subretinal AAV2-REP1 Gene Therapy (Timrepigene Emparvovec)
  description: >
    Subretinal delivery of an AAV2 vector carrying CHM, intended to restore REP1
    in the surviving central island. The randomized phase 3 trial in 169 adult
    men did NOT meet its primary endpoint of best-corrected visual acuity
    improvement at 12 months, so key secondary endpoints were not formally
    tested; a numerically larger proportion of treated than control participants
    gained 10 or more ETDRS letters. Adverse events were mostly mild or moderate.
    This is recorded as an investigational therapy with a negative pivotal trial,
    not as standard of care. The authors identify entry criteria (more preserved
    retinal area), surgical technique and endpoint selection as the levers for
    future studies - which is consistent with the natural history data showing
    residual RPE area, not acuity, to be the quantity that changes measurably.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: CHM Loss of Function and REP1 Deficiency
    treatment_effect: RESTORES
    description: >
      Vector-delivered CHM is intended to restore REP1 expression in retinal
      cells, acting on the trigger lesion itself rather than on any downstream
      consequence.
    evidence:
    - reference: PMID:37814062
      reference_title: "Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66)."
      explanation: >
        Establishes that this gene-replacement approach was tested against the
        causative lesion at pivotal scale. Marked PARTIAL because the trial
        did not demonstrate benefit on its primary endpoint.
  evidence:
  - reference: PMID:37814062
    reference_title: "Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement."
    explanation: >
      Records the negative pivotal result directly. Marked PARTIAL rather than
      REFUTE because the trial establishes that the approach was tolerated and
      showed a numerical secondary signal, while failing to demonstrate benefit
      on its prespecified primary endpoint.
clinical_trials:
- name: NCT03496012
  phase: PHASE_III
  status: COMPLETED
  description: >
    STAR: randomized, masked phase 3 trial of high-dose versus low-dose
    subretinal timrepigene emparvovec versus untreated control in adult men with
    choroideremia, with 12-month best-corrected visual acuity change as the
    primary endpoint. The primary endpoint was not met.
  target_phenotypes:
  - preferred_term: Progressive visual loss
    term:
      id: HP:0000529
      label: Progressive visual loss
  - preferred_term: Chorioretinal atrophy
    term:
      id: HP:0000533
      label: Chorioretinal atrophy
  evidence:
  - reference: PMID:37814062
    reference_title: "Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months"
    explanation: >
      Reports the trial's primary endpoint result with the per-arm proportions.
discussions:
- discussion_id: choroideremia_primary_cell_type
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which cell type is the primary site of pathogenesis in choroideremia - the
    retinal pigment epithelium, the photoreceptor, or the choriocapillaris - and
    which must a gene therapy vector therefore reach?
  attaches_to:
  - "pathophysiology#Progressive Chorioretinal Degeneration"
  rationale: >-
    Reviews state plainly that the exact site of pathogenesis remains unclear
    while all three tissues degenerate. This is not an academic point. The
    choice of vector, promoter, and route of delivery in gene therapy follows
    directly from which cell must be transduced, and the phase 3 trial of
    subretinal AAV2-REP1 failed its primary endpoint with the authors
    attributing part of the shortfall to trial design rather than to the
    mechanism. Without knowing the primary target, an unsuccessful trial cannot
    distinguish an inadequate approach from an inadequately targeted one.
  proposed_experiments:
  - experiment_id: chm_cell_type_specific_rescue
    name: Cell-type-restricted Chm deletion and rescue in a conditional model
    description: >
      Delete and separately restore Chm under retinal pigment epithelium-,
      photoreceptor- and choroidal endothelium-specific drivers in a conditional
      mouse or larger-eye model, and determine which single-cell-type deletion
      reproduces, and which single-cell-type rescue prevents, the chorioretinal
      atrophy phenotype.
references:
- reference: PMID:20301511
  title: Choroideremia.
  tags:
  - GeneReviews
  findings: []

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PMID:20301511

Choroideremia.

No top-level findings curated for this source.

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