Retinal arterial tortuosity, often described as familial retinal arteriolar tortuosity, is a rare autosomal dominant retinal vasculopathy with characteristic tortuosity of second and higher order retinal arterioles, episodic retinal hemorrhage, and transient visual symptoms. Familial cases have been linked to heterozygous COL4A1 variants, placing the disorder within the COL4A1-related small-vessel basement-membrane disease spectrum.
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name: Retinal Arterial Tortuosity
creation_date: "2026-05-06T19:00:30Z"
updated_date: "2026-05-06T19:44:31Z"
description: >-
Retinal arterial tortuosity, often described as familial retinal arteriolar
tortuosity, is a rare autosomal dominant retinal vasculopathy with
characteristic tortuosity of second and higher order retinal arterioles,
episodic retinal hemorrhage, and transient visual symptoms. Familial cases
have been linked to heterozygous COL4A1 variants, placing the disorder within
the COL4A1-related small-vessel basement-membrane disease spectrum.
references:
- reference: DOI:10.1007/s00417-014-2800-6
title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: COL4A1 p.Gly510Arg segregates with familial retinal arteriolar tortuosity.
supporting_text: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
- reference: DOI:10.1002/ajmg.c.32099
title: Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: COL4A1/2 disease has variable multiorgan manifestations and includes retinal arterial tortuosity.
supporting_text: Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.
- reference: DOI:10.1186/s12886-020-01413-0
title: Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: Valsalva-like exertion can trigger sub-ILM hemorrhage in FRAT.
supporting_text: Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism.
- reference: DOI:10.1016/j.ajoc.2019.03.001
title: Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: Swept-source OCT angiography can quantify retinal arteriolar tortuosity in FRAT.
supporting_text: Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography.
- reference: DOI:10.1016/j.ajoc.2021.101230
title: A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: Familial retinal arteriolar tortuosity can present with sudden visual loss and resolving retinal hemorrhage.
supporting_text: A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss.
- reference: DOI:10.1038/srep18602
title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: Col4a1 mutant mice support a primary vascular defect model for retinal pathology.
supporting_text: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.
- reference: DOI:10.1038/s41433-022-02278-x
title: Retinal arterial tortuosity in Ehlers-Danlos syndromes
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: Ehlers-Danlos syndromes are part of the retinal arterial tortuosity differential context.
supporting_text: Retinal arterial tortuosity in Ehlers-Danlos syndromes.
- reference: DOI:10.1159/000456069
title: Familial Retinal Arteriolar Tortuosity with Acute Hippocampal Infarction
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: Familial retinal arteriolar tortuosity has been reported with brain ischemic lesions in a case report.
supporting_text: Familial Retinal Arteriolar Tortuosity with Acute Hippocampal Infarction.
- reference: DOI:10.1212/wnl.0000000000209796
title: "Clinical Reasoning: A 50-Year-Old Man With Intracerebral Hemorrhage and Tortuous Retinal Arterioles"
found_in:
- Retinal_Arterial_Tortuosity-deep-research-falcon.md
findings:
- statement: Tortuous retinal arterioles can be a clue in COL4A1/2-related cerebral small-vessel disease workup.
supporting_text: "Clinical Reasoning: A 50-Year-Old Man With Intracerebral Hemorrhage and Tortuous Retinal Arterioles."
category: Mendelian
disease_term:
preferred_term: retinal arterial tortuosity
term:
id: MONDO:0008373
label: retinal arterial tortuosity
synonyms:
- Familial retinal arteriolar tortuosity
- Familial retinal arterial tortuosity
- Retinal arteriolar tortuosity
- Retinal hemorrhage with vascular tortuosity
- FRAT
- RATOR
parents:
- Retinal Vascular Disorder
- Arterial Disorder
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Familial retinal arteriolar tortuosity has been described as an autosomal
dominant disorder, including pedigrees with affected parents and children.
evidence:
- reference: PMID:25228067
reference_title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
OBJECTIVES: Our aim was to determine the molecular cause of autosomal
dominant familial retinal arteriolar tortuosity (FRAT) in a family with
three affected subjects.
explanation: >-
The study objective explicitly characterizes the familial disorder as
autosomal dominant.
- reference: PMID:30931409
reference_title: Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PURPOSE: Familial retinal arteriolar tortuosity (FRAT) is a rare autosomal
dominant disorder that is characterized by tortuosity of the second and
higher order retinal arterioles.
explanation: >-
This FRAT imaging report also states the autosomal dominant inheritance
pattern.
pathophysiology:
- name: COL4A1 collagen IV basement membrane defect
description: >-
Heterozygous COL4A1 pathogenic variants disrupt type IV collagen-dependent
basement membrane structure, providing an upstream molecular mechanism for
retinal small-vessel fragility.
cell_types:
- preferred_term: retinal blood vessel endothelial cell
term:
id: CL:0002585
label: retinal blood vessel endothelial cell
biological_processes:
- preferred_term: extracellular matrix organization
modifier: ABNORMAL
term:
id: GO:0030198
label: extracellular matrix organization
evidence:
- reference: PMID:25228067
reference_title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sanger sequencing confirmed that all three patients harbored the same
pathogenetic mutation in COL4A1.
explanation: >-
The familial FRAT pedigree segregated a pathogenic COL4A1 variant in all
affected individuals.
- reference: PMID:26813606
reference_title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of
basement membranes, cause multisystem disorders in humans and mice.
explanation: >-
This mouse mechanistic study supports COL4A1 as a basement-membrane
collagen relevant to small-vessel disease.
downstream:
- target: Primary retinal vascular structural defect
description: >-
Altered type IV collagen in vascular basement membrane compromises retinal
vessel structure and stability.
- name: Primary retinal vascular structural defect
description: >-
COL4A1-associated retinal disease is driven by primary vascular defects,
producing abnormal retinal vessel morphology, vascular tortuosity,
hemorrhage susceptibility, and neovascular/fibrotic lesions in experimental
models.
cell_types:
- preferred_term: retinal blood vessel endothelial cell
term:
id: CL:0002585
label: retinal blood vessel endothelial cell
biological_processes:
- preferred_term: blood vessel morphogenesis
modifier: ABNORMAL
term:
id: GO:0048514
label: blood vessel morphogenesis
- preferred_term: angiogenesis
modifier: INCREASED
term:
id: GO:0001525
label: angiogenesis
evidence:
- reference: PMID:26813606
reference_title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
To identify the cell-type responsible for pathogenesis we generated a
conditional Col4a1 mutation and determined that primary vascular defects
underlie Col4a1-associated retinopathy.
explanation: >-
Conditional mouse data identify the retinal vascular compartment as the
primary disease-driving tissue.
- reference: PMID:26813606
reference_title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Retinal examinations revealed serous chorioretinopathy, retinal
hemorrhages, fibrosis or signs of pathogenic angiogenesis with
chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant
eyes depending on age and the specific mutation.
explanation: >-
Mutant Col4a1 mice develop retinal hemorrhage and pathogenic angiogenic
lesions, supporting the downstream vascular injury model.
downstream:
- target: Retinal arteriolar tortuosity
description: >-
Primary vascular structural defects manifest clinically as tortuous
retinal arterioles.
- target: Retinal hemorrhage episodes
description: >-
Fragile retinal vessels are susceptible to hemorrhage, especially during
pressure-raising events.
- target: Reactive Muller glial response
description: >-
Retinal vascular injury in Col4a1 mutant mice is accompanied by glial
activation and pro-angiogenic signaling.
- name: Retinal hemorrhage episodes
description: >-
Fragility of tortuous retinal arterioles predisposes affected individuals to
recurrent intraretinal, preretinal, or sub-internal limiting membrane
hemorrhage, often with acute visual symptoms.
cell_types:
- preferred_term: retinal blood vessel endothelial cell
term:
id: CL:0002585
label: retinal blood vessel endothelial cell
evidence:
- reference: PMID:32293357
reference_title: "Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism: an observational case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This is the first reported case of a FRAT patient suffering from bilateral
and multiple Valsalva-related sub-ILM hemorrhages which were treated by
both observation and Nd: YAG laser treatment.
explanation: >-
The case report directly links FRAT with bilateral Valsalva-related
sub-ILM retinal hemorrhage episodes.
- reference: PMID:34825110
reference_title: A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Bilateral retinal arteriolar tortuosity as well as retinal hemorrhage was
seen.
explanation: >-
The family case series documents concurrent retinal arteriolar tortuosity
and retinal hemorrhage.
- name: Reactive Muller glial response
description: >-
In Col4a1 mutant mouse retina, vascular pathology is accompanied by focal
activation of retinal Muller glia and increased pro-angiogenic factor
expression, suggesting a secondary retinal injury response downstream of the
primary vascular defect.
cell_types:
- preferred_term: Muller glial cell
term:
id: CL:0000125
label: glial cell
biological_processes:
- preferred_term: glial cell activation
modifier: INCREASED
term:
id: GO:0061900
label: glial cell activation
- preferred_term: angiogenesis
modifier: INCREASED
term:
id: GO:0001525
label: angiogenesis
evidence:
- reference: PMID:26813606
reference_title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We also found focal activation of Müller cells and increased expression of
pro-angiogenic factors in retinas from Col4a1(+/Δex41)mice.
explanation: >-
This mouse study supports a secondary Muller glial activation and
pro-angiogenic response after Col4a1-associated retinal vascular injury.
phenotypes:
- category: Ophthalmologic
name: Retinal arteriolar tortuosity
diagnostic: true
frequency: VERY_FREQUENT
description: >-
Tortuosity of the second and higher order retinal arterioles is the defining
funduscopic feature of familial retinal arterial tortuosity.
phenotype_term:
preferred_term: Retinal arteriolar tortuosity
term:
id: HP:0001136
label: Retinal arteriolar tortuosity
evidence:
- reference: PMID:30931409
reference_title: Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PURPOSE: Familial retinal arteriolar tortuosity (FRAT) is a rare autosomal
dominant disorder that is characterized by tortuosity of the second and
higher order retinal arterioles.
explanation: >-
This directly defines the core retinal arteriolar tortuosity phenotype.
- category: Ophthalmologic
name: Retinal hemorrhage
description: >-
Affected individuals can develop retinal hemorrhage, including sub-internal
limiting membrane or bilateral hemorrhage.
phenotype_term:
preferred_term: Retinal hemorrhage
term:
id: HP:0000573
label: Retinal hemorrhage
evidence:
- reference: PMID:34825110
reference_title: A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The ophthalmologic examination showed retinal hemorrhage bilaterally.
explanation: >-
This family case series directly supports retinal hemorrhage as a clinical
manifestation.
- reference: PMID:32293357
reference_title: "Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism: an observational case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BACKGROUND: Bilateral and multiple Valsalva-related sub-internal limiting
membrane (ILM) hemorrhages in a familial retinal arteriolar tortuosity
(FRAT) patient is rare, and we treated this patient by both observation
and Neodymium yttrium aluminum garnet (Nd: YAG) laser membranotomy
methods.
explanation: >-
This report supports sub-ILM hemorrhage as a documented hemorrhagic
presentation in FRAT.
- category: Ophthalmologic
name: Sudden transient visual loss
description: >-
Hemorrhagic episodes can produce sudden visual loss that improves as blood
clears.
phenotype_term:
preferred_term: Sudden transient visual loss
term:
id: HP:0000572
label: Visual loss
temporality: TRANSIENT
evidence:
- reference: PMID:34825110
reference_title: A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PURPOSE: To report family members with familial retinal arteriolar
tortuosity (FRAT) identified after sudden visual loss.
explanation: >-
The case series was ascertained through sudden visual loss in affected
family members.
- reference: PMID:32293357
reference_title: "Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism: an observational case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CASE PRESENTATION: A 13-year-old female student presented with sudden
visual loss and central scotoma in both eyes after running 800 m at the
school gym.
explanation: >-
This FRAT case directly connects exertion-triggered hemorrhage with sudden
visual loss.
- category: Ophthalmologic
name: Central scotoma
description: >-
Premacular or sub-ILM hemorrhage can cause central scotoma during acute
episodes.
phenotype_term:
preferred_term: Central scotoma
term:
id: HP:0000603
label: Central scotoma
evidence:
- reference: PMID:32293357
reference_title: "Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism: an observational case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CASE PRESENTATION: A 13-year-old female student presented with sudden
visual loss and central scotoma in both eyes after running 800 m at the
school gym.
explanation: >-
The reported FRAT patient had central scotoma during the acute
hemorrhagic episode.
genetic:
- name: COL4A1
association: Causative
presence: Positive
gene_term:
preferred_term: COL4A1
term:
id: hgnc:2202
label: COL4A1
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
variants:
- name: COL4A1 p.Gly510Arg
type: missense
description: >-
The heterozygous COL4A1 p.Gly510Arg missense variant segregated with
familial retinal arteriolar tortuosity in the reported pedigree and has
also been described in broader COL4A1-related disease.
evidence:
- reference: PMID:25228067
reference_title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The p. Gly510Arg variant in COL4A1 was absent in DNA from an available
unaffected daughter, from a set of control alleles, and from publicly
available databases.
explanation: >-
The familial sequencing study reports absence of the variant in
unaffected and control datasets, supporting pathogenicity.
notes: >-
COL4A1 is the best-supported causal gene for familial retinal arteriolar
tortuosity. COL4A2 is relevant to the broader COL4A1/2 small-vessel disease
spectrum, but disease-specific COL4A2 evidence for isolated FRAT remains
limited.
evidence:
- reference: PMID:25228067
reference_title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The molecular basis of familial retinal arteriolar tortuosity was
identified for the first time, thus expanding the human phenotypes linked
to COL4A1 mutations.
explanation: >-
The paper identifies COL4A1 as the molecular cause in a familial FRAT
pedigree.
- reference: PMID:25228067
reference_title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These data indicate that identical mutations in COL4A1 can originate both
eye-restricted and systemic phenotypes.
explanation: >-
The same COL4A1 variant can produce isolated ocular FRAT or broader
systemic COL4A1-related disease.
environmental:
- name: Valsalva-like exertional trigger
presence: Positive
description: >-
Exertion or Valsalva-like pressure increases can trigger hemorrhage
episodes in genetically susceptible retinal vessels.
evidence:
- reference: PMID:32293357
reference_title: "Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism: an observational case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient was diagnosed as having Valsalva retinopathy associated with
FRAT.
explanation: >-
This case directly identifies a Valsalva-related hemorrhagic episode in
FRAT.
diagnosis:
- name: Fundus examination and retinal vascular imaging
description: >-
Diagnosis is based on the characteristic retinal arteriolar tortuosity
pattern, supported by fundus photography, fluorescein angiography, OCT, and
OCT angiography to localize hemorrhage and quantify vessel tortuosity.
diagnosis_term:
preferred_term: retinal vascular imaging
term:
id: MAXO:0001155
label: eye examination
results: >-
Second and higher order retinal arteriolar tortuosity, retinal hemorrhage,
and increased objective tortuosity measurements support diagnosis.
evidence:
- reference: PMID:30931409
reference_title: Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CONCLUSIONS AND IMPORTANCE: Our results are consistent with the hypothesis
that patients with FRAT have higher objective measurements of tortuosity
compared to controls.
explanation: >-
Swept-source OCTA can objectively quantify the retinal vascular
tortuosity phenotype.
- reference: PMID:32293357
reference_title: "Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism: an observational case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient was diagnosed as having Valsalva retinopathy associated with
FRAT.
explanation: >-
The case report supports clinical ophthalmic diagnosis during an acute
hemorrhagic presentation.
- name: COL4A1 molecular testing
description: >-
COL4A1 sequencing can confirm the molecular diagnosis in familial cases and
should be interpreted in the context of possible broader COL4A1/2
vasculopathy.
diagnosis_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
results: Heterozygous pathogenic COL4A1 variants support familial FRAT.
evidence:
- reference: PMID:25228067
reference_title: Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Molecular methods included whole exome sequencing analysis and Sanger
sequencing validation of putative causal mutation in DNA from affected
individuals.
explanation: >-
This supports exome sequencing with Sanger validation as a molecular
diagnostic approach for familial FRAT.
- name: COL4A1/2 multiorgan risk assessment
description: >-
Patients with COL4A1 or COL4A2 variants may need individualized neurologic,
ophthalmologic, renal, and cardiovascular assessment because retinal
arterial tortuosity can occur within a variable multiorgan vasculopathy.
evidence:
- reference: PMID:39016117
reference_title: Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
COL4A1/2 variants are associated with highly variable multiorgan
manifestations.
explanation: >-
This systematic review and cohort-based protocol supports evaluating RAT
in the broader COL4A1/2 disease context.
- reference: PMID:39016117
reference_title: Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We propose a protocol for prevention and management based on individualized
risk estimation and periodic multiorgan evaluations.
explanation: >-
This supports periodic multiorgan surveillance when a COL4A1/2 variant is
identified.
treatments:
- name: Observation for resolving retinal hemorrhage
description: >-
Observation is appropriate for many retinal hemorrhage episodes, with
follow-up until hemorrhage resolves and visual acuity recovers.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:34825110
reference_title: A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He was followed without intervention. Retinal hemorrhage gradually
decreased and resolved after 3 months.
explanation: >-
The family case series supports observation without intervention for a
retinal hemorrhage episode.
- name: Nd:YAG laser membranotomy for selected premacular hemorrhage
description: >-
Nd:YAG laser membranotomy can be considered in selected large premacular or
sub-ILM hemorrhages when rapid visual recovery is needed, but safety and
follow-up should be individualized.
treatment_term:
preferred_term: Nd:YAG laser membranotomy
term:
id: NCIT:C15466
label: Laser Therapy
target_phenotypes:
- preferred_term: Retinal hemorrhage
term:
id: HP:0000573
label: Retinal hemorrhage
evidence:
- reference: PMID:32293357
reference_title: "Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by Valsalva-like mechanism: an observational case report."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Nd: YAG laser could be considered for treating premacular hemorrhage in
FRAT patient especially when a quick vision recovery was needed.
explanation: >-
A single case report supports laser membranotomy as an option for selected
premacular hemorrhage, so support is partial rather than definitive.
notes: >-
Retinal arterial tortuosity is curated here as the ocular FRAT/RATOR disorder
rather than the broader multisystem COL4A1/2 syndrome. The broader syndrome is
represented in diagnosis and management context because COL4A1 variants can
produce either eye-restricted or systemic phenotypes.
datasets:
Retinal arterial tortuosity (often discussed clinically as familial retinal arteriolar tortuosity, FRAT; also termed retinal arterial tortuosity, RATOR) is a rare, typically autosomal-dominant retinal vasculopathy characterized by marked tortuosity/contortion of second- and third-order retinal arterioles, with relative sparing of first-order arterioles and the venous system; this funduscopic pattern is repeatedly described as pathognomonic in familial forms. (zenteno2014nextgenerationsequencing pages 1-2, vilimelis2015newgenesinvolved pages 65-72, gasparini2024multiorganmanifestationsof pages 2-2)
A typical clinical issue is episodic retinal hemorrhage (intraretinal, preretinal/subhyaloid, sub-internal limiting membrane [sub-ILM], and occasionally subretinal/vitreous), causing transient visual impairment often triggered by minor stress, exertion, or Valsalva-like maneuvers; many episodes resolve spontaneously with good visual recovery. (gasparini2024multiorganmanifestationsof pages 2-2, chen2020bilateralandmultiple pages 1-3, saraf2019familialretinalarteriolar pages 3-5)
Synonyms / alternative names (as used in the literature retrieved here): - Familial retinal arteriolar tortuosity (FRAT) - Familial retinal arterial tortuosity - Retinal arterial tortuosity (RATOR) - fRAT (abbreviation used in some sources) (zenteno2014nextgenerationsequencing pages 1-2, vilimelis2015newgenesinvolveda pages 84-91, gasparini2024multiorganmanifestationsof pages 2-2)
ICD-10/ICD-11 / MeSH / Orphanet IDs: Not explicitly provided in the retrieved full-text excerpts; Open Targets indicates Orphanet as a source but did not return an Orphanet disease identifier in the retrieved evidence. (OpenTargets Search: retinal arterial tortuosity,familial retinal arterial tortuosity-COL4A1)
The disease knowledge in this report derives primarily from: - Human case reports/series (FRAT clinical phenotype and hemorrhage triggers/outcomes). (chen2020bilateralandmultiple pages 1-3, obayashi2021acaseseries pages 2-4) - Human genetics studies (segregating COL4A1 variant for FRAT). (zenteno2014nextgenerationsequencing pages 4-5) - Model organism mechanistic work (Col4a1 mutant mice with retinal vascular pathology). (alavi2016col4a1mutationscause pages 2-3) - Aggregated disease-level evidence / protocols from a 2024 systematic review + cohort-based management protocol for COL4A1/2-related disease (in which retinal arterial tortuosity is a component feature). (gasparini2024multiorganmanifestationsof pages 19-19)
Genetic (major): Familial retinal arteriolar/arterial tortuosity is strongly linked to monoallelic pathogenic variants in COL4A1 (and more broadly retinal arterial tortuosity is associated with COL4A1/COL4A2). (zenteno2014nextgenerationsequencing pages 4-5, gasparini2024multiorganmanifestationsof pages 2-2, OpenTargets Search: retinal arterial tortuosity,familial retinal arterial tortuosity-COL4A1)
Mechanistic concept: COL4A1 encodes the type IV collagen α1 chain, a core component of vascular basement membranes. Glycine substitutions in the collagenous domain can disrupt collagen IV assembly and secretion (see Mechanism section). (zenteno2014nextgenerationsequencing pages 4-5)
While disease susceptibility is genetic, episodic hemorrhages are frequently reported to be precipitated by: - Physical exertion / minor trauma (gasparini2024multiorganmanifestationsof pages 2-2, zenteno2014nextgenerationsequencing pages 1-2) - Valsalva-like maneuvers/straining (e.g., running) (chen2020bilateralandmultiple pages 1-3)
In a 13-year-old FRAT patient, hemorrhages occurred after running 800 m, consistent with a Valsalva-like trigger. (chen2020bilateralandmultiple pages 1-3)
No specific protective factors (genetic or environmental) were identified in the retrieved sources.
Gene–environment interactions are implied by variable expressivity and hemorrhage triggers (exertion/trauma), and by explicit suggestions that environmental factors and/or genetic modifiers influence phenotype (ocular-only FRAT vs multisystem COL4A1 disease). (zenteno2014nextgenerationsequencing pages 4-5, vilimelis2015newgenesinvolveda pages 95-96)
A structured phenotype summary is provided in the table artifact below.
| Phenotype feature | Suggested HPO term(s) | Typical onset / course | Triggers / modifiers | Complications / QoL impact | Quantitative data | Key notes / citations |
|---|---|---|---|---|---|---|
| Retinal arteriolar tortuosity distribution in familial disease (FRAT/RATOR) | Retinal vascular tortuosity [suggest HP term: retinal arteriolar tortuosity if curated]; Abnormality of retinal vasculature (suggested) | Often recognized in childhood or early adulthood; usually chronic/stable between hemorrhagic episodes | May become clinically relevant during exertion or minor trauma because hemorrhage can occur despite otherwise stable vessel morphology | Can predispose to recurrent retinal hemorrhage and transient visual disturbance; funduscopic pattern is considered highly characteristic/pathognomonic | Classic pattern: marked tortuosity of second- and third-order retinal arterioles with normal first-order arteries and venous sparing | Core diagnostic description repeated across FRAT/COL4A1 literature (zenteno2014nextgenerationsequencing pages 1-2, vilimelis2015newgenesinvolved pages 65-72, vilimelis2015newgenesinvolveda pages 84-91, gasparini2024multiorganmanifestationsof pages 2-2, saraf2019familialretinalarteriolar pages 1-2) |
| EDS-associated retinal arterial tortuosity phenotype | Abnormal retinal vasculature; Retinal vascular tortuosity (suggested) | Adult cohort described; variable severity from mild to severe | Not clearly linked to hypertension or diabetes in the cohort studied | Usually an imaging finding; establishes that tortuosity also occurs outside FRAT and may broaden differential diagnosis | In 142 EDS patients, 37.3% definite RAT, 10.6% possible RAT, 52.1% no RAT; among definite RAT eyes: 39.2% mild, 40.2% moderate, 20.6% severe; vessel involvement: 84.9% first-order arterioles, 35.8% macular arterioles, 1.9% arteriovenous | Important differential: unlike FRAT, EDS-associated RAT commonly involved first-order arterioles (ghoraba2023retinalarterialtortuosity pages 2-5, ghoraba2023retinalarterialtortuosity pages 1-2, ghoraba2023retinalarterialtortuosity pages 5-5) |
| Retinal hemorrhages: intraretinal / subretinal / premacular-sub-ILM | Retinal hemorrhage; Intraretinal hemorrhage; Subretinal hemorrhage; Preretinal hemorrhage / Premacular hemorrhage (suggested) | Episodic; often sudden onset with spontaneous resolution over weeks to months | Exercise, minor trauma, Valsalva-like maneuvers/straining; running has been reported as a trigger | Acute visual loss, central scotoma; occasional ERM after intervention; anxiety/functional limitation during episodes | FRAT family reports describe recurrent perifoveal/foveal hemorrhages; in one 13-year-old case: 6 sub-ILM hemorrhages OD (largest ~1.5 DD) and 2 OS (largest 5.5 DD) | Hemorrhage is the main vision-threatening event in FRAT; sub-ILM/premacular hemorrhage well documented by fundus/OCT/FFA (vilimelis2015newgenesinvolveda pages 93-95, vilimelis2015newgenesinvolved pages 93-95, chen2020bilateralandmultiple pages 1-3, chen2020bilateralandmultiple pages 3-5, chen2020bilateralandmultiple media c2e15b79) |
| Transient vision loss / blurred vision / central scotoma | Transient visual loss; Blurred vision; Central scotoma (suggested) | Usually episodic and linked to hemorrhage rather than progressive neuroretinal degeneration | Often precipitated by hemorrhage after exertion or minor trauma | Temporary loss of reading/central vision; can be bilateral in severe premacular hemorrhage; long-term prognosis often good if hemorrhage clears | Visual acuity in the 2020 case improved from 20/100 OD, 20/160 OS to 20/16 OD, 20/20 OS after combined treatment/observation | Most affected individuals are asymptomatic between episodes, but hemorrhage can cause transient marked impairment (saraf2019familialretinalarteriolar pages 1-2, gasparini2024multiorganmanifestationsof pages 2-2, chen2020bilateralandmultiple pages 1-3, chen2020bilateralandmultiple pages 3-5) |
| Nailbed capillary tortuosity | Capillary tortuosity (suggested) | Chronic accompanying microvascular finding when present | No specific trigger established | May indicate extra-retinal microvascular involvement; little direct QoL impact but useful diagnostically | Historical reports note marked nailbed capillary tortuosity; one thesis notes abnormal capillary tortuosity threshold >~20%, with one family showing >30% loops affected | Supports systemic small-vessel involvement beyond the retina in some families (vilimelis2015newgenesinvolved pages 65-72, vilimelis2015newgenesinvolveda pages 65-72) |
| Systemic associations: HANAC-spectrum COL4A1 disease | Hematuria; Cerebral aneurysm; Muscle cramps; Leukoencephalopathy; Raynaud phenomenon; Arrhythmia (suggested HPO mappings) | Variable; penetrance and expressivity are highly heterogeneous, including asymptomatic/oligosymptomatic carriers | Likely modified by genotype plus environmental/genetic modifiers | Renal disease, aneurysm risk, muscle symptoms, neurologic disease; requires multidisciplinary surveillance | In aggregated COL4A1/2 data: retinal arterial tortuosity 58/685 (8.5%); among asymptomatic/oligosymptomatic carriers undergoing ophthalmic workup, retinal vascular tortuosity detected in 5/13 (38.5%) | Same COL4A1 p.Gly510Arg variant can present as isolated FRAT or multisystem HANAC-like disease, demonstrating variable expressivity (vilimelis2015newgenesinvolved pages 95-96, gasparini2024multiorganmanifestationsof pages 2-2, gasparini2024multiorganmanifestationsof pages 19-19, vilimelis2015newgenesinvolveda pages 95-96, zenteno2014nextgenerationsequencing pages 4-5) |
| Brain small-vessel disease / intracerebral hemorrhage / ischemic lesions in COL4A1/2-related disease | Intracerebral hemorrhage; Cerebral small vessel disease; Lacunar stroke; Leukoencephalopathy (suggested) | Can occur from childhood to adulthood; chronic vasculopathy with risk of hemorrhagic and ischemic events | Blood-pressure burden and trauma likely relevant modifiers; monogenic background is primary | Major morbidity from stroke, seizures, cognitive/neurologic impairment; retinal arteriolar tortuosity can be a valuable diagnostic clue | Literature aggregation in COL4A1/2 disease: stroke 203/685 (29.6%), seizures/epilepsy 199/685 (29.0%), porencephaly/schizencephaly 168/685 (24.5%); case reports include hippocampal infarction and ICH with tortuous retinal arterioles | Retinal arteriolar tortuosity is emphasized as a clue that should prompt evaluation for monogenic COL4A1/2 vasculopathy (kim2017familialretinalarteriolar pages 2-4, bouchart2024clinicalreasoninga pages 3-5, gasparini2024multiorganmanifestationsof pages 2-2, gasparini2024multiorganmanifestationsof pages 19-19) |
| Course and intervention-associated sequelae after premacular hemorrhage | Epiretinal membrane; Wrinkling of retinal internal limiting membrane (suggested) | Usually recovery after spontaneous resorption or drainage; sequelae may follow laser membranotomy | Procedure-related risk with Nd:YAG membranotomy | ERM, ILM wrinkling, rarely other iatrogenic macular complications; affects metamorphopsia risk and follow-up needs | In the 2020 bilateral case, ERM developed in the left eye despite excellent acuity recovery | Supports careful individualized management; observation alone is reasonable for smaller hemorrhages, laser may accelerate recovery in selected large premacular bleeds (chen2020bilateralandmultiple pages 5-5, chen2020bilateralandmultiple pages 1-3, chen2020bilateralandmultiple pages 3-5) |
Table: This table summarizes the main clinical phenotype features reported for familial retinal arterial/arteriolar tortuosity and related COL4A1/2-associated presentations, including suggested HPO mappings, course, triggers, complications, and quantitative findings. It is useful for structured knowledge-base curation and differential diagnosis, including comparison with EDS-associated retinal arterial tortuosity.
Definition/diagnostic pattern: “marked contortion of the second- and third-order retinal arteries with no impact on the first-order arteries and the venous system.” (gasparini2024multiorganmanifestationsof pages 2-2)
Hemorrhages and transient visual symptoms: Most affected individuals experience “episodes of transient vision impairment caused by retinal hemorrhage prompted by minor stress or trauma.” (gasparini2024multiorganmanifestationsof pages 2-2)
COL4A1 c.1528G>A (p.Gly510Arg), heterozygous missense: - Identified by WES and confirmed by Sanger in affected family members with FRAT; absent in unaffected daughter and in multiple control datasets. (zenteno2014nextgenerationsequencing pages 1-2, zenteno2014nextgenerationsequencing pages 4-5) - Population data in one study: absent from 200 ethnically matched control alleles and ~8,600 exomes in the NHLBI Exome Variant Server. (zenteno2014nextgenerationsequencing pages 4-5) - Genotype–phenotype variability: the same p.Gly510Arg variant previously reported in HANAC syndrome, while in the FRAT pedigree no extra-ocular features were found, supporting variable expressivity. (zenteno2014nextgenerationsequencing pages 4-5)
Variant localization and domain concept: - The p.Gly510Arg substitution lies within a “critical region (residues 498–528) that includes integrin binding sites” in the collagenous domain. (zenteno2014nextgenerationsequencing pages 4-5)
Glycine substitutions in the collagenous domain are described as disrupting collagen biology: “perturb triple helix assembly, impair secretion of collagen heterotrimers, and cause intracellular accumulation of misfolded proteins.” (zenteno2014nextgenerationsequencing pages 4-5, vilimelis2015newgenesinvolveda pages 95-96)
Multiple sources emphasize that identical COL4A1 mutations can yield ocular-only FRAT vs multisystem disease (HANAC), consistent with modifier effects (genetic background, environment). (vilimelis2015newgenesinvolveda pages 95-96, zenteno2014nextgenerationsequencing pages 4-5)
No disease-specific epigenetic or chromosomal abnormality evidence was identified in the retrieved texts.
No specific environmental toxins, lifestyle factors, or infectious agents were identified as causal. The major “environmental” role described is episode triggering (exertion/trauma/Valsalva-like stress) for hemorrhage in genetically susceptible individuals. (chen2020bilateralandmultiple pages 1-3, saraf2019familialretinalarteriolar pages 3-5)
A unifying model supported by human genetics and mouse data is: 1) COL4A1 pathogenic variant → abnormal type IV collagen network in vascular basement membranes (zenteno2014nextgenerationsequencing pages 4-5) 2) Primary retinal vascular defects (vessel instability/tortuosity, permeability, hemorrhage) (alavi2016col4a1mutationscause pages 7-8, alavi2016col4a1mutationscause pages 2-3) 3) Secondary retinal responses (reactive Müller glia activation; pro-angiogenic factor upregulation; possible neovascular complications in some COL4A1 contexts) (alavi2016col4a1mutationscause pages 7-8) 4) Clinical manifestation as arteriolar tortuosity + hemorrhagic episodes with transient vision loss. (gasparini2024multiorganmanifestationsof pages 2-2, chen2020bilateralandmultiple pages 1-3)
In Col4a1 mutant mice, retinal pathology included hemorrhage and angiogenic lesions. Key quantitative findings include: - Retinal pathology (serous chorioretinopathy, hemorrhages, fibrosis or pathogenic angiogenesis) occurred in up to ~90% of mutant eyes depending on age and allele. (alavi2016col4a1mutationscause pages 1-2) - In a large cohort, penetrance increased with age (estimated 36–43% by P21 and 68–88% after 1 month in one line), and “all mutant eyes exhibited abnormal vascular branching and vascular tortuosity” on fluorescein angiography. (alavi2016col4a1mutationscause pages 2-3) - Cell-type dissection: “Conditional expression of mutant Col4a1 in vascular endothelium, but not RPE, phenocopies the retinal defects.” (alavi2016col4a1mutationscause pages 7-8) - Lesion-associated glial response: Müller cell activation (GFAP/vimentin) and elevated pro-angiogenic factors (Vegfa, Pdgfb, Pgf). (alavi2016col4a1mutationscause pages 7-8)
GO Biological Process (suggested) - extracellular matrix organization - basement membrane organization - angiogenesis / regulation of VEGF signaling - blood vessel morphogenesis - response to oxidative stress / wound healing (secondary)
Cell types (CL suggestions) - vascular endothelial cell - pericyte (retinal microvasculature) - Müller glial cell (reactive gliosis noted) (alavi2016col4a1mutationscause pages 7-8)
UBERON suggestions - retina (UBERON:0000966) - retinal blood vessel (UBERON term as applicable)
Although FRAT is often described as primarily ocular, retinal arteriolar tortuosity can be a clue to broader COL4A1/2 vasculopathy, including cerebral small vessel disease and hemorrhage risk. (bouchart2024clinicalreasoninga pages 3-5)
Onset is often described in childhood or early adulthood in familial FRAT. (zenteno2014nextgenerationsequencing pages 1-2)
Familial FRAT is generally autosomal dominant; one pedigree includes male-to-male transmission and vertical inheritance consistent with AD. (zenteno2014nextgenerationsequencing pages 1-2)
Open Targets annotations for retinal arterial tortuosity and related entries list monoallelic autosomal allelic requirements. (OpenTargets Search: retinal arterial tortuosity,familial retinal arterial tortuosity-COL4A1)
Robust population prevalence estimates were not found in the retrieved evidence. A historical estimate notes “approximately 100 cases described” (as of the cited older literature compilation), reflecting rarity and likely underdiagnosis. (vilimelis2015newgenesinvolved pages 65-72)
Penetrance and expressivity in COL4A1/2-related disease are explicitly described as highly variable, with asymptomatic/oligosymptomatic carriers detectable by protocolized screening. (gasparini2024multiorganmanifestationsof pages 19-19)
Diagnosis is commonly made via: - Dilated fundus examination / color fundus photography identifying the characteristic arteriolar pattern (vilimelis2015newgenesinvolved pages 65-72) - Fluorescein angiography (FA) to document vessel anatomy and hemorrhage-related blocked fluorescence and to exclude leakage in some cases (chen2020bilateralandmultiple media c2e15b79, obayashi2021acaseseries pages 2-4) - Optical coherence tomography (OCT) to localize premacular hemorrhage (subhyaloid vs sub-ILM) and follow resolution (chen2020bilateralandmultiple pages 1-3) - OCT angiography (OCTA), including swept-source OCTA, increasingly used to delineate tortuosity and quantify it objectively (saraf2019familialretinalarteriolar pages 1-2, obayashi2021acaseseries pages 4-5)
Real-world imaging example (figure evidence): In a FRAT patient with bilateral premacular hemorrhages, Figure 1 demonstrates tortuous arterioles on fundus photographs and corresponding SD-OCT evidence of dome-shaped sub-ILM hemorrhage. (chen2020bilateralandmultiple media c2e15b79)
In the neurologic setting, retinal arteriolar tortuosity is highlighted as a clue to COL4A1/2-related disorders and helps distinguish from other hereditary CSVDs (e.g., CADASIL, CARASIL, Fabry). (bouchart2024clinicalreasoninga pages 3-5)
Visual prognosis is generally favorable. A case series documented spontaneous resolution of hemorrhage with recovery to 20/20 by 1 year in a teenager, and good outcomes overall with observation. (obayashi2021acaseseries pages 1-2)
A 2019 OCTA-based FRAT report states prognosis is “excellent” with most patients recovering normal acuity after hemorrhage clearance, though some may have mild irreversible impairment due to macular pigment changes. (saraf2019familialretinalarteriolar pages 3-5)
When retinal arteriolar tortuosity occurs in COL4A1/2 vasculopathy, neurologic risks (ICH, cerebral microbleeds, seizures) can dominate morbidity, warranting multidisciplinary evaluation. (bouchart2024clinicalreasoninga pages 3-5)
MAXO suggestions - Observation / watchful waiting - Laser membranotomy (Nd:YAG) - Patient education / avoidance counseling
Avoidance of triggering activities (straining/Valsalva-like maneuvers) is commonly recommended in case management. (saraf2019familialretinalarteriolar pages 1-2)
A 2024 expert protocol proposes baseline and follow-up screening in COL4A1/2 variant carriers, including brain MRI with angiographic sequences, baseline labs (blood count, CK, coagulation indices), and ophthalmologic evaluation with OCT-based monitoring depending on initial severity; prenatal imaging is suggested for pregnancy risk counseling. (gasparini2024multiorganmanifestationsof pages 19-19)
Primary prevention is not established (genetic). Key prevention concepts are: - Secondary prevention / surveillance for COL4A1/2 carriers via periodic multi-organ evaluation (brain imaging, ophthalmology, lab screening). (gasparini2024multiorganmanifestationsof pages 19-19) - Tertiary prevention: avoid triggers for hemorrhage; control modifiable vascular risks (e.g., blood pressure) in those with COL4A1/2 vasculopathy. (bouchart2024clinicalreasoninga pages 3-5)
No naturally occurring veterinary analogs were identified in the retrieved evidence.
A well-developed mechanistic model exists in Col4a1 mutant mice, which recapitulate retinal vascular tortuosity, hemorrhage, and progressive retinopathy; endothelial expression of mutant Col4a1 is sufficient to induce the phenotype. (alavi2016col4a1mutationscause pages 7-8, alavi2016col4a1mutationscause pages 2-3)
A 2023 Eye study used a large institutional repository (STARR) and multimodal imaging to systematically grade RAT in EDS, providing practical prevalence estimates and a grading framework with intergrader agreement (kappa). It reported 37.3% definite RAT and subclassified severity and vessel distributions. (ghoraba2023retinalarterialtortuosity pages 1-2, ghoraba2023retinalarterialtortuosity pages 2-5)
A 2024 Neurology “Clinical Reasoning” article emphasizes that “retinal arteriolar tortuosity, while not always present, is an important finding that strongly suggests the diagnosis of COL4A1/2-related disorders,” integrating ophthalmic findings into monogenic CSVD workups and highlighting management implications (blood pressure control; avoiding head trauma). (bouchart2024clinicalreasoninga pages 3-5)
A 2024 AJMG Seminars paper proposes an explicit screening/management protocol (brain MRI/MRA, baseline labs, ophthalmology/OCT monitoring, prenatal imaging, genetic counseling). This is a concrete step toward standard-of-care harmonization for COL4A1/2 carriers in which retinal arterial tortuosity is a recognized phenotype component. (gasparini2024multiorganmanifestationsof pages 19-19)
An actively recruiting ClinicalTrials.gov study (NCT07374913; sponsor: Meyer Children’s Hospital IRCCS; posted 2021, currently recruiting) operationalizes multi-organ screening for COL4A1/2 variant carriers in routine care settings with standardized ophthalmological OCT assessments, cardiology testing, and exploratory plasma biomarkers (MMP2/MMP9). (NCT07374913 chunk 1)
| Preferred name | Key synonyms / alternative names | MONDO ID(s) | OMIM identifier | Associated gene(s) | Typical inheritance | Key defining diagnostic description |
|---|---|---|---|---|---|---|
| Retinal arterial tortuosity | Retinal arteriolar tortuosity; familial retinal arteriolar tortuosity (FRAT); familial retinal arterial tortuosity; fRAT; retinal arterial tortuosity (RATOR) (zenteno2014nextgenerationsequencing pages 1-2, vilimelis2015newgenesinvolveda pages 84-91, gasparini2024multiorganmanifestationsof pages 2-2) | MONDO:0008373 = retinal arterial tortuosity; MONDO:0012726 = autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (OpenTargets Search: retinal arterial tortuosity,familial retinal arterial tortuosity-COL4A1) | OMIM %180000 for familial retinal arteriolar/arterial tortuosity (vilimelis2015newgenesinvolveda pages 65-72, zenteno2014nextgenerationsequencing pages 1-2, vilimelis2015newgenesinvolveda pages 84-91) | COL4A1 strongly supported; COL4A2 also associated in Open Targets evidence for retinal arterial tortuosity / related syndrome (OpenTargets Search: retinal arterial tortuosity,familial retinal arterial tortuosity-COL4A1, vilimelis2015newgenesinvolveda pages 84-91, gasparini2024multiorganmanifestationsof pages 2-2) | Usually autosomal dominant / monoallelic; vertical transmission and male-to-male transmission reported in families (OpenTargets Search: retinal arterial tortuosity,familial retinal arterial tortuosity-COL4A1, zenteno2014nextgenerationsequencing pages 1-2, vilimelis2015newgenesinvolveda pages 84-91) | Marked tortuosity/contortion of second- and third-order retinal arteries/arterioles, typically with normal first-order arteries and sparing of the venous system; funduscopic appearance described as pathognomonic (vilimelis2015newgenesinvolveda pages 65-72, zenteno2014nextgenerationsequencing pages 1-2, vilimelis2015newgenesinvolved pages 65-72, gasparini2024multiorganmanifestationsof pages 2-2) |
Table: This table summarizes the principal disease names, identifiers, genes, inheritance, and defining diagnostic features for retinal arterial/arteriolar tortuosity. It is useful as a compact normalization reference for disease knowledge-base curation.
References
(zenteno2014nextgenerationsequencing pages 1-2): Juan C. Zenteno, Jaume Crespí, Beatriz Buentello-Volante, Jose A. Buil, Francisca Bassaganyas, Jose I. Vela-Segarra, Jesus Diaz-Cascajosa, and Maria T. Marieges. Next generation sequencing uncovers a missense mutation in col4a1 as the cause of familial retinal arteriolar tortuosity. Graefe's Archive for Clinical and Experimental Ophthalmology, 252:1789-1794, Sep 2014. URL: https://doi.org/10.1007/s00417-014-2800-6, doi:10.1007/s00417-014-2800-6. This article has 55 citations.
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(gasparini2024multiorganmanifestationsof pages 2-2): Simone Gasparini, Simona Balestrini, Luigi Francesco Saccaro, Giacomo Bacci, Giorgia Panichella, Martino Montomoli, Gaetano Cantalupo, Stefania Bigoni, Giorgia Mancano, Simona Pellacani, Vincenzo Leuzzi, Nila Volpi, Francesco Mari, Federico Melani, Mara Cavallin, Tiziana Pisano, Giulio Porcedda, Augusto Vaglio, Davide Mei, Carmen Barba, Elena Parrini, and Renzo Guerrini. Multiorgan manifestations of col4a1 and col4a2 variants and proposal for a clinical management protocol. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, Jul 2024. URL: https://doi.org/10.1002/ajmg.c.32099, doi:10.1002/ajmg.c.32099. This article has 21 citations.
(chen2020bilateralandmultiple pages 1-3): Ting Chen, Hongmei Zheng, Yunyun Wang, Junyi Hu, and Changzheng Chen. Bilateral and multiple sub-internal limiting membrane hemorrhages in a familial retinal arteriolar tortuosity patient by valsalva-like mechanism: an observational case report. BMC Ophthalmology, Apr 2020. URL: https://doi.org/10.1186/s12886-020-01413-0, doi:10.1186/s12886-020-01413-0. This article has 8 citations and is from a peer-reviewed journal.
(saraf2019familialretinalarteriolar pages 3-5): Steven S. Saraf, Ariel J. Tyring, Chieh-Li Chen, Thao Phuong Le, Robert E. Kalina, Ruikang K. Wang, and Jennifer R. Chao. Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography. American Journal of Ophthalmology Case Reports, 14:74-78, Jun 2019. URL: https://doi.org/10.1016/j.ajoc.2019.03.001, doi:10.1016/j.ajoc.2019.03.001. This article has 24 citations.
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(obayashi2021acaseseries pages 2-4): Tomohiro Obayashi, Aki Kato, Harumitsu Suzuki, Kei Ohashi, Munenori Yoshida, Yu Shibata, Yuichiro Ogura, and Tsutomu Yasukawa. A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss. American Journal of Ophthalmology Case Reports, 24:101230, Dec 2021. URL: https://doi.org/10.1016/j.ajoc.2021.101230, doi:10.1016/j.ajoc.2021.101230. This article has 2 citations.
(zenteno2014nextgenerationsequencing pages 4-5): Juan C. Zenteno, Jaume Crespí, Beatriz Buentello-Volante, Jose A. Buil, Francisca Bassaganyas, Jose I. Vela-Segarra, Jesus Diaz-Cascajosa, and Maria T. Marieges. Next generation sequencing uncovers a missense mutation in col4a1 as the cause of familial retinal arteriolar tortuosity. Graefe's Archive for Clinical and Experimental Ophthalmology, 252:1789-1794, Sep 2014. URL: https://doi.org/10.1007/s00417-014-2800-6, doi:10.1007/s00417-014-2800-6. This article has 55 citations.
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(gasparini2024multiorganmanifestationsof pages 19-19): Simone Gasparini, Simona Balestrini, Luigi Francesco Saccaro, Giacomo Bacci, Giorgia Panichella, Martino Montomoli, Gaetano Cantalupo, Stefania Bigoni, Giorgia Mancano, Simona Pellacani, Vincenzo Leuzzi, Nila Volpi, Francesco Mari, Federico Melani, Mara Cavallin, Tiziana Pisano, Giulio Porcedda, Augusto Vaglio, Davide Mei, Carmen Barba, Elena Parrini, and Renzo Guerrini. Multiorgan manifestations of col4a1 and col4a2 variants and proposal for a clinical management protocol. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, Jul 2024. URL: https://doi.org/10.1002/ajmg.c.32099, doi:10.1002/ajmg.c.32099. This article has 21 citations.
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(saraf2019familialretinalarteriolar pages 1-2): Steven S. Saraf, Ariel J. Tyring, Chieh-Li Chen, Thao Phuong Le, Robert E. Kalina, Ruikang K. Wang, and Jennifer R. Chao. Familial retinal arteriolar tortuosity and quantification of vascular tortuosity using swept-source optical coherence tomography angiography. American Journal of Ophthalmology Case Reports, 14:74-78, Jun 2019. URL: https://doi.org/10.1016/j.ajoc.2019.03.001, doi:10.1016/j.ajoc.2019.03.001. This article has 24 citations.
(ghoraba2023retinalarterialtortuosity pages 2-5): Hashem H. Ghoraba and Darius M. Moshfeghi. Retinal arterial tortuosity in ehlers–danlos syndromes. Eye, 37:1936-1941, Oct 2023. URL: https://doi.org/10.1038/s41433-022-02278-x, doi:10.1038/s41433-022-02278-x. This article has 4 citations and is from a peer-reviewed journal.
(ghoraba2023retinalarterialtortuosity pages 1-2): Hashem H. Ghoraba and Darius M. Moshfeghi. Retinal arterial tortuosity in ehlers–danlos syndromes. Eye, 37:1936-1941, Oct 2023. URL: https://doi.org/10.1038/s41433-022-02278-x, doi:10.1038/s41433-022-02278-x. This article has 4 citations and is from a peer-reviewed journal.
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