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Case Report: Asymmetric Retinal and Fundal Fluorescein Angiogram Findings in Col4A1 Mutation

Yan Tong Koh*,  Conrad Schmoll
Published in World Journal of Medical Case Reports (Volume 7, Issue 1)
Received: 7 September 2025     Accepted: 18 September 2025     Published: 23 January 2026
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Abstract

Purpose: We aim to describe the fundal fluorescein angiography (FFA) findings in a patient with COL4A1 mutation which to date has not been described in this condition. We hope to highlight the variability in ocular phenotypes seen in COL4A1 mutation, even between eyes in the same patient. Methods: Case Report. Results: A 14 year-old girl with a history of cerebral palsy, cerebral visual impairment and COL4A1 mutation with porencephaly has been attending the eye service for bilateral aphakic glaucoma with previous bilateral glaucoma tube surgery on Latanoprost, Brinzolamide and Timolol to both eyes. She developed a spontaneous right vitreous haemorrhage and anterior chamber hyphaema, subsequently requiring a vitrectomy and anterior chamber washout due to elevated intraocular pressure. Intraoperatively, she was noted to have extensive ischemic changes in the right eye. In her left fundus, there were sclerosed arterioles emanating from the disc, with the rest of the retina being normal. Despite the vitrectomy, the right eye vitreous haemorrhage and hyphaema recollected over time with persistently high intraocular pressure. She underwent a repeat vitrectomy and washout, subsequent cyclodiode laser and evisceration after she developed a painful blind right eye. During the course of her treatment, a FFA for her left eye was performed. Delay in arm-retinal time and a “fern-leaf” pattern of capillary leakage was noted. Discussion: The disease resulting from COL4A1 mutation is extremely variable. We report a patient with COL4A1 mutation with asymmetric retinal pathology with one eye eventually needing evisceration. This case highlights the need to have a high index of suspicion for early detection and asymmetric disease. There should be a low threshold for further evaluation such as FFA or optical coherence tomography (OCT) angiography to evaluate for ocular perfusion. Although COL4A1 is a systemic disease, it can have asymmetric presentation between two eyes.

Published in World Journal of Medical Case Reports (Volume 7, Issue 1)
DOI 10.11648/j.wjmcr.20260701.11
Page(s) 1-4
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

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Copyright © The Author(s), 2026. Published by Science Publishing Group
Previous article
Keywords

Angiogram, Col4A1, Heterogenous, Retina

1. Introduction
The COL4A1 gene on chromosome 13q34 encodes the alpha 1 chain of type IV collagen, which is a component of basal membranes expressed mainly in the brain, muscles, kidneys and eyes
[1]
. Mutations in COL4A1 can cause multisystem disorders with extremely variable human phenotypes, with disease onset as early as in the fetal period. Neurological manifestations such as cerebral microangiopathy, familial porencephaly
[1, 2]
https://jamanetwork.com/journals/jamaophthalmology/fullarticle/425446 - ref-eog90011-1, neonatal and adult intracerebral haemorrhages, small vessel disease of the brain and aneurysms have been reported. In the eye, associated findings include keratoconus, cataract, posterior lenticonus, anterior segment dysgenesis, retinal arteriolar tortuosity and retinal haemorrhages
[3-5]
. There is in addition a specific phenotype called HANAC (hereditary angiopathy with nephropathy, aneurysm, and muscle cramps)
[5-7]
.
Few studies have provided detailed retinal imaging and findings in association with COL4A1. In our study, we aim to describe the FFA findings in a patient with COL4A1 mutation which to date has not been described previously in this condition. We also hope to highlight the variability in ocular phenotypes seen in COL4A1 mutation, even between eyes in the same patient.
2. Case Report
A 14 year old girl with a history of cerebral palsy, cerebral visual impairment and COL4A1 mutation with porencephaly has been attending the eye service for bilateral aphakic glaucoma with previous bilateral glaucoma tube surgery on Latanoprost, Brinzolamide and Timolol to both eyes. She had no significant family history of note. She developed a spontaneous right vitreous haemorrhage and anterior chamber hyphaema. B-mode ultrasound did not demonstrate any retinal breaks or detachment on serial monitoring. The vitreous haemorrhage and hyphaema were non-resolving but as she was relatively comfortable with normal intraocular pressures (IOP), the family’s preference was to observe. Her right IOP subsequently elevated to 30mmHg and she was listed for an urgent vitrectomy and anterior chamber washout. Intraoperatively, she was noted to have extensive right rubeosis iridis with right retinal ischemia and vitreous membranes, widespread vascular occlusion, new vessels at the optic disc and macular subhyaloid haemorrhage. In the left fundus, there were sclerosed arterioles emanating from the disc (Figure 1). The retinal venules were otherwise grossly normal with no retinopathy or ectatic vessels noted. There were no new vessels or signs of ischaemia. Despite the vitrectomy, the right eye vitreous haemorrhage and hyphaema recollected over time with persistently high intraocular pressures. A repeat right eye anterior chamber washout and vitrectomy was scheduled, along with a FFA for her left eye in view of the vascular anomalies noted in the fellow eye previously. Intraoperatively, she was found to have a funnel shaped detachment in her right eye which was assessed to be inoperable. Cyclodiode laser was thus performed to control IOP for her right eye. FFA performed for her left eye. (Figure 2) revealed delay in arm-retinal time with the arteriovenous phase at 34 seconds, with persistent patchy and mottled choroidal filling. Figures 3, 4 show twig-like abnormalities of retinal vasculature with no significant areas of peripheral ischemia or capillary fallout. A “fern-leaf” pattern of capillary leakage and pinpoint areas of hyperfluoresence were visible in the temporal and inferotemporal quadrant (Figure 3). This persisted into the later phases of the FFA (Figure 5). Her IOP in the right eye remained elevated and developed in a painful blind eye. She subsequently underwent right eye evisceration. The left eye has not to date developed any retinal neovascularisation or rubeosis, after two years’ follow-up but ongoing treatment for the pre-existing aphakic glaucoma has been required.
Figure 1. Left eye fundal photo: Sclerosed ghost-like arterioles emanating from the disc (labelled with arrow). Retinal venules were otherwise grossly normal with no retinopathy or ectatic vessels noted.
Figure 2. Left eye FFA: Delay in arm-retinal time with the arteriovenous phase at 34 seconds, with persistent patchy and mottled choroidal filling.
Figure 3. Left eye FFA: “Fern-leaf” pattern of capillary leakage and pinpoint areas of hyperfluoresence is visible in the temporal and inferotemporal quadrant.
Figure 4. Left eye FFA: Twig-like abnormalities of retinal vasculature with no significant areas of peripheral ischemia or capillary fallout.
Figure 5. Left eye FFA: Late phase.
3. Discussion
The COL4A1 gene is located on the 13q34 chromosome and contains 52 exons, which encodes the α1 chain of collagen IV. Members of the type IV collagen family are essential components of all basement membranes and define structural stability as well as tissue-specific functions
[1]
. The clinical spectrum of COL4A1 mutations has progressively enlarged, with evidence of neonatal and adult intracerebral hemorrhages, aneurysms, ocular manifestations of variable type, and nephropathy
[1-5]
. Most COL4A1 mutations are autosomal dominantly inherited, but the phenotypic spectrum is highly heterogeneous. The disease resulting from COL4A1 mutation is extremely variable
[8]
. Additional modifying factors, either environmental or genetics, are likely involved and remain to be identified. Sporadic individuals with severe presentation may harbor a de novo mutation
[8]
.
Allelic heterogeneity may contribute to the phenotypic heterogeneity observed. Mutations involving glycine residues that belong to exons 24-25 of COL4A1 are involved in the HANAC syndrome. These mutations cluster in a CB3 (IV) region of the triple-helical domain, which encompasses major integrin-binding sites
[9]
. Genotype-phenotype correlation studies conducted in patients mutated in a triple-helix glycine residue suggest a position-dependent effect of the mutation on the phenotype. Substitutions involving a glycine located in the C-terminal part the triple-helix tend to be associated with brain haemorrhage that occur at a younger age and are more severe that those located in the N-terminal part
[10]
. The presence of retinal artery hypertortuosity is highly penetrant in Glycine substitutions involving the first N-terminal third of the helix domain, as compared to substitutions near to the C-terminus that are more prone to the development of eye congenital malformations
[10]
. Mice experiments also suggest that the biological impact of quantitative mutations is milder than dominant negative mutations. However, genotype-phenotype correlation analyses conducted in patients failed to demonstrate that quantitative mutations are associated with a milder phenotype
[10]
. These observations still need to be replicated and refined by additional studies. While it is known that heterogeneity occur between patients, our report highlights the asymmetric presentation that can happen between two eyes, even in the same patient.
Our patient developed strikingly asymmetrical retinal pathology – the right eye developed neovascular glaucoma with widespread retinal ischemia, neovascularisation and eventual tractional retinal detachment. It subsequently required evisceration for a painful blind eye. The fundus on the left eye, on the contrary, had no significant ischemia or retinal tortuosity, as confirmed on intra-operative FFA, despite the significantly attenuated retinal arterioles. This case highlights the need to have a high index of suspicion for asymmetric disease and a low threshold for further evaluation such as FFA or OCT angiography to evaluate for ocular perfusion. Although COL4A1 is a systemic disease, it can have asymmetric presentation between two eyes. This case also highlights the importance of early detection and high index of suspicion for retinal ischemia, with FFA a useful investigation in these patients.
Few studies have provided detailed retinal imaging and findings in association with COL4A1. A study by Zenteno et al published retinal findings associated with familial retinal arteriolar tortuosity (FRAT) in cases with COL4A1 mutations
[11]
. Alavi et al investigated retinal pathology in mice carrying dominant-negative COL4A1 mutations by examining retinas longitudinally in vivo using FFA, fundoscopy and OCT. 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
[12]
. These findings were not seen in our patient.
4. Conclusion
In conclusion, we report a patient with COL4A1 mutation with asymmetric retinal pathology with one eye eventually needing evisceration. Few studies have provided detailed retinal imaging and findings in association with COL4A1. There can be wide variability of ocular phenotypes related to COL4A1, even between eyes in the same patient. There should be a high index of suspicion for early detection with early consideration of FFA or OCT angiography to evaluate for ocular perfusion.
Abbreviations

FFA

Fundal Fluorescein Angiography

OCT

Optical Coherence Tomography

HANAC

Hereditary Angiopathy with Nephropathy, Aneurysm, and Muscle Cramps

IOP

Intraocular Pressure

FRAT

Familial Retinal Arteriolar Tortuosity
Funding
Content has not been presented prior to this submission.
No grants or funds were utilized in this study.
Author Contributions
Yan Tong Koh: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Resources, Writing – original draft, Writing – review & editing
Conrad Schmoll: Supervision
Conflicts of Interest
The authors declare no conflicts of interest.
References
[1] Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E, John SW. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. 2006 Apr 6; 354(14): 1489-96.

https://doi.org/10.1056/NEJMoa053727

[2] Breedveld G, de Coo IF, Lequin MH, Arts WF, Heutink P, Gould DB, John SW, Oostra B, Mancini GM. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J Med Genet. 2006 Jun; 43(6): 490-5.

https://doi.org/10.1136/jmg.2005.035584

[3] Vahedi K, Massin P, Guichard JP, Miocque S, Polivka M, Goutières F, Dress D, Chapon F, Ruchoux MM, Riant F, Joutel A, Gaudric A, Bousser MG, Tournier-Lasserve E. Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy. Neurology. 2003 Jan 14; 60(1): 57-63.

https://doi.org/10.1212/wnl.60.1.57

[4] Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Ann Neurol. 2007 Aug; 62(2): 177-84.

https://doi.org/10.1002/ana.21191

[5] Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med. 2007 Dec 27; 357(26): 2687-95.

https://doi.org/10.1056/NEJMoa071906

[6] Faure C, Castrale C, Benabed A, Cognard P, Lezé R, Castro-Farias D, Gérard M, Louapre C, Paques M. Structural and functional analysis of retinal vasculature in HANAC syndrome with a novel intronic COL4A1 mutation. Microvasc Res. 2023 Jan; 145: 104450.

https://doi.org/10.1016/j.mvr.2022.104450

[7] Trouillet A, Lorach H, Dubus E, El Mathari B, Ivkovic I, Dégardin J, Simonutti M, Paques M, Guillonneau X, Sennlaub F, Sahel JA, Ronco P, Plaisier E, Picaud S. Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome. Neurobiol Dis. 2017 Apr; 100: 52-61.

https://doi.org/10.1016/j.nbd.2016.12.014

[8] Meuwissen ME, Halley DJ, Smit LS, Lequin MH, Cobben JM, de Coo R, van Harssel J, Sallevelt S, Woldringh G, van der Knaap MS, de Vries LS, Mancini GM. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med. 2015 Nov; 17(11): 843-53.

https://doi.org/10.1038/gim.2014.210

[9] Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3 [IV] domain. Am J Med Genet A. 2010 Oct; 152A(10): 2550-5.

https://doi.org/10.1002/ajmg.a.33659

[10] Jeanne M, Gould DB. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Matrix Biol. 2017 Jan; 57-58: 29-44.

https://doi.org/10.1016/j.matbio.2016.10.003

[11] Zenteno JC, Crespí J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, Diaz-Cascajosa J, Marieges MT. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Graefes Arch Clin Exp Ophthalmol. 2014 Nov; 252(11): 1789-94.

https://doi.org/10.1007/s00417-014-2800-6

[12] Alavi MV, Mao M, Pawlikowski BT, Kvezereli M, Duncan JL, Libby RT, John SW, Gould DB. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep. 2016 Jan 27; 6: 18602.

https://doi.org/10.1038/srep18602

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    Koh, Y. T., Schmoll, C. (2026). Case Report: Asymmetric Retinal and Fundal Fluorescein Angiogram Findings in Col4A1 Mutation. World Journal of Medical Case Reports, 7(1), 1-4. https://doi.org/10.11648/j.wjmcr.20260701.11

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    Koh, Y. T.; Schmoll, C. Case Report: Asymmetric Retinal and Fundal Fluorescein Angiogram Findings in Col4A1 Mutation. World J. Med. Case Rep. 2026, 7(1), 1-4. doi: 10.11648/j.wjmcr.20260701.11

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    AMA Style

    Koh YT, Schmoll C. Case Report: Asymmetric Retinal and Fundal Fluorescein Angiogram Findings in Col4A1 Mutation. World J Med Case Rep. 2026;7(1):1-4. doi: 10.11648/j.wjmcr.20260701.11

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  • @article{10.11648/j.wjmcr.20260701.11,
  author = {Yan Tong Koh and Conrad Schmoll},
  title = {Case Report: Asymmetric Retinal and Fundal Fluorescein Angiogram Findings in Col4A1 Mutation},
  journal = {World Journal of Medical Case Reports},
  volume = {7},
  number = {1},
  pages = {1-4},
  doi = {10.11648/j.wjmcr.20260701.11},
  url = {https://doi.org/10.11648/j.wjmcr.20260701.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.wjmcr.20260701.11},
  abstract = {Purpose: We aim to describe the fundal fluorescein angiography (FFA) findings in a patient with COL4A1 mutation which to date has not been described in this condition. We hope to highlight the variability in ocular phenotypes seen in COL4A1 mutation, even between eyes in the same patient. Methods: Case Report. Results: A 14 year-old girl with a history of cerebral palsy, cerebral visual impairment and COL4A1 mutation with porencephaly has been attending the eye service for bilateral aphakic glaucoma with previous bilateral glaucoma tube surgery on Latanoprost, Brinzolamide and Timolol to both eyes. She developed a spontaneous right vitreous haemorrhage and anterior chamber hyphaema, subsequently requiring a vitrectomy and anterior chamber washout due to elevated intraocular pressure. Intraoperatively, she was noted to have extensive ischemic changes in the right eye. In her left fundus, there were sclerosed arterioles emanating from the disc, with the rest of the retina being normal. Despite the vitrectomy, the right eye vitreous haemorrhage and hyphaema recollected over time with persistently high intraocular pressure. She underwent a repeat vitrectomy and washout, subsequent cyclodiode laser and evisceration after she developed a painful blind right eye. During the course of her treatment, a FFA for her left eye was performed. Delay in arm-retinal time and a “fern-leaf” pattern of capillary leakage was noted. Discussion: The disease resulting from COL4A1 mutation is extremely variable. We report a patient with COL4A1 mutation with asymmetric retinal pathology with one eye eventually needing evisceration. This case highlights the need to have a high index of suspicion for early detection and asymmetric disease. There should be a low threshold for further evaluation such as FFA or optical coherence tomography (OCT) angiography to evaluate for ocular perfusion. Although COL4A1 is a systemic disease, it can have asymmetric presentation between two eyes.},
 year = {2026}
}

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  • TY  - JOUR
T1  - Case Report: Asymmetric Retinal and Fundal Fluorescein Angiogram Findings in Col4A1 Mutation
AU  - Yan Tong Koh
AU  - Conrad Schmoll
Y1  - 2026/01/23
PY  - 2026
N1  - https://doi.org/10.11648/j.wjmcr.20260701.11
DO  - 10.11648/j.wjmcr.20260701.11
T2  - World Journal of Medical Case Reports
JF  - World Journal of Medical Case Reports
JO  - World Journal of Medical Case Reports
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AB  - Purpose: We aim to describe the fundal fluorescein angiography (FFA) findings in a patient with COL4A1 mutation which to date has not been described in this condition. We hope to highlight the variability in ocular phenotypes seen in COL4A1 mutation, even between eyes in the same patient. Methods: Case Report. Results: A 14 year-old girl with a history of cerebral palsy, cerebral visual impairment and COL4A1 mutation with porencephaly has been attending the eye service for bilateral aphakic glaucoma with previous bilateral glaucoma tube surgery on Latanoprost, Brinzolamide and Timolol to both eyes. She developed a spontaneous right vitreous haemorrhage and anterior chamber hyphaema, subsequently requiring a vitrectomy and anterior chamber washout due to elevated intraocular pressure. Intraoperatively, she was noted to have extensive ischemic changes in the right eye. In her left fundus, there were sclerosed arterioles emanating from the disc, with the rest of the retina being normal. Despite the vitrectomy, the right eye vitreous haemorrhage and hyphaema recollected over time with persistently high intraocular pressure. She underwent a repeat vitrectomy and washout, subsequent cyclodiode laser and evisceration after she developed a painful blind right eye. During the course of her treatment, a FFA for her left eye was performed. Delay in arm-retinal time and a “fern-leaf” pattern of capillary leakage was noted. Discussion: The disease resulting from COL4A1 mutation is extremely variable. We report a patient with COL4A1 mutation with asymmetric retinal pathology with one eye eventually needing evisceration. This case highlights the need to have a high index of suspicion for early detection and asymmetric disease. There should be a low threshold for further evaluation such as FFA or optical coherence tomography (OCT) angiography to evaluate for ocular perfusion. Although COL4A1 is a systemic disease, it can have asymmetric presentation between two eyes.
VL  - 7
IS  - 1
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Author Information

  • Yan Tong Koh

    National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore;Royal Hospital for Children & Young People, NHS Lothian, Edinburgh, United Kingdom;Princes Alexandra Eye Pavilion, NHS Lothian, Edinburgh, United Kingdom

    Contact Email

    http://orcid.org/0009-0004-0338-2398

  • Conrad Schmoll

    Royal Hospital for Children & Young People, NHS Lothian, Edinburgh, United Kingdom;Princes Alexandra Eye Pavilion, NHS Lothian, Edinburgh, United Kingdom

    Contact Email

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