Exfoliation Syndrome: Disease Characteristics Research Report

Scope. This report distinguishes exfoliation syndrome (XFS)—the matrix-deposition disorder—from exfoliation glaucoma (XFG), its major sight-threatening complication. Evidence labels used below are human clinical, human observational, human molecular, in vitro, animal model, or computational. Associations are not described as causal unless experimentally established.

The following table provides a knowledge-base-oriented synopsis.

Table: Compact evidence-based summary of exfoliation syndrome identity, risk architecture, phenotypes, mechanism, diagnosis, prognosis, management, and research gaps. Quantitative findings and suggested knowledge-base ontology annotations are included.

1. Disease information

Definition

Exfoliation syndrome is a chronic, strongly age-dependent, complex disorder of extracellular-matrix (ECM) production and clearance. Abnormal fibrillar exfoliation material (XFM) accumulates most visibly in the ocular anterior segment—especially on the anterior lens capsule, pupillary margin, iris, ciliary body, zonules, and trabecular meshwork. Similar material has been reported histologically in visceral tissues, supporting the concept of a systemic matrix disorder, although its clinically established morbidity is predominantly ocular. A useful abstract-level definition is: “Pseudoexfoliation syndrome (PXS) is a systemic condition with eye manifestations.” (Human pathology/review.) (elhawy2012pseudoexfoliationsyndromea pages 1-2)

XFS is not synonymous with XFG. XFG is secondary, usually open-angle glaucoma caused when XFM and liberated iris pigment increase aqueous-outflow resistance and intraocular pressure (IOP), followed by glaucomatous retinal-ganglion-cell and optic-nerve injury. Estimates suggest that approximately 44% of affected people may develop XFG, but conversion varies by population, ascertainment, and follow-up. XFG accounts for approximately 25% of open-angle glaucoma worldwide in some estimates. (li2021loxl1genepolymorphisms pages 1-2, bernstein2018exfoliationsyndromea pages 1-4)

Identifiers and synonyms

• Preferred name: exfoliation syndrome.
• MONDO: MONDO:0008327.
• OMIM: commonly represented as Exfoliation syndrome 1 / XFS1, #177650; database release should be checked before production ingestion.
• MeSH: Exfoliation Syndrome / Pseudoexfoliation Syndrome.
• Common synonyms: pseudoexfoliation syndrome, pseudo-exfoliation syndrome, PXS, PEX, PEXS, XFS, exfoliative syndrome, capsular glaucoma with pseudoexfoliation when glaucoma is present.
• Related but distinct: exfoliation glaucoma/pseudoexfoliation glaucoma (XFG/PXG/PEG); true capsular exfoliation, an occupational/infrared-associated delamination of the lens capsule, is not XFS.
• ICD: coding is jurisdiction/version dependent. XFS without glaucoma is generally placed under “other specified cataract/anterior-segment” categories, whereas capsular/exfoliation glaucoma is coded within secondary glaucoma categories. Exact ICD-10-CM/ICD-11 codes should be validated against the target terminology release rather than inferred from literature.

The evidence summarized here is aggregated disease-level evidence from cohorts, case-control studies, tissue studies, registries, GWAS, and reviews—not individual EHR-derived patient data.

2. Etiology and risk architecture

Causal and susceptibility factors

XFS is multifactorial and polygenic. No single variant is necessary or sufficient. Aging is the dominant background determinant; genetic susceptibility, environmental exposure, ECM dysregulation, oxidative stress, inflammation, and impaired proteostasis converge over decades.

LOXL1 is the strongest replicated susceptibility gene. It encodes lysyl oxidase-like 1, an enzyme involved in collagen/elastin cross-linking and elastic-fiber homeostasis. Common variants rs1048661, rs3825942, and rs2165241 are repeatedly associated with XFS/XFG, but their effects differ by ancestry and risk alleles can reverse direction between populations. A 2021 meta-analysis included 5,022 cases and 8,962 controls and found ancestry-dependent associations; this establishes susceptibility, not monogenic causality. Li et al., published 28 April 2021, DOI. (li2021loxl1genepolymorphisms pages 1-2)

A major 2017 GWAS meta-analysis included 9,035 cases and 17,008 controls across 25 strata, identifying a rare protective LOXL1 coding variant and susceptibility loci near/in POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A, in addition to LOXL1 and CACNA1A. The protective variant is conventionally reported as LOXL1 p.Tyr407Phe (p.Y407F). Aung et al., May 2017, Nature Genetics, DOI. (aung2017geneticassociationstudy pages 24-38) Open Targets independently maps LOXL1 (ENSG00000129038) to MONDO:0008327 and links supporting literature including PMIDs 17690259, 18037624, 18385788, 19343041, 24938310, and 36653562. (OpenTargets Search: pseudoexfoliation syndrome,exfoliation glaucoma-LOXL1)

These are common/rare germline susceptibility alleles, not somatic cancer-like mutations. They should not ordinarily be labeled “pathogenic” under ACMG/AMP Mendelian criteria. Population frequencies are too high, penetrance is incomplete and age dependent, and no validated carrier-frequency concept applies. There is no established role for aneuploidy, translocation, repeat expansion, mitochondrial mutation, germline mosaicism, anticipation, or consanguinity.

Environmental and lifestyle factors

Human observational evidence implicates lifetime latitude, cold climate, greater summer outdoor exposure, and reflected light. In a US/Israeli case-control study of adults aged ≥60 years, each degree farther from the equator was associated with 11% higher odds of XFS (OR 1.11, 95% CI 1.05–1.17); each additional average summer outdoor hour/week had OR 1.04 (1.00–1.07). US work over snow or water had OR 3.86 (1.36–10.9). Greater sunglasses use was inversely associated in the US (OR 0.98 per 1% increment) but not Israel. Pasquale et al., December 2014, DOI. These findings are vulnerable to recall, selection, and residual confounding and do not prove that UV causes XFS or sunglasses prevent it. (pasquale2014solarexposureand pages 1-2)

Other reported associations include heavy coffee/caffeine intake, low folate, higher homocysteine, outdoor occupations, more sunny days, and lower ambient temperature. Evidence for smoking, alcohol, diabetes, and cardiovascular factors is inconsistent and does not support causal classification. UV can upregulate lysyl-oxidase/ECM responses in experimental eye and skin systems, offering a plausible gene–environment mechanism, but replicated genotype-by-exposure interaction estimates remain lacking. (pasquale2014considerationforgeneenvironment pages 4-6, pasquale2014considerationforgeneenvironment pages 2-4, kang2020cohortstudyof pages 6-7)

Protective factors: LOXL1 p.Y407F is the clearest genetic protective association. Sunglasses/ocular UV protection and folate sufficiency are biologically plausible environmental protective factors, but neither has preventive-trial confirmation. No drug, dietary supplement, or behavior is proven to prevent XFS.

3. Phenotypes

XFS is generally late-onset, insidious, chronic, progressive, and variably asymmetric. It is uncommon before 50–60 years and becomes increasingly prevalent with age. A clinically unilateral presentation frequently represents asymmetric bilateral disease.

The characteristic lens pattern and associated iris, zonular, and trabecular findings are well documented. Zonular loss can cause vitreous loss, lens or intraocular-lens complex dislocation, and difficult cataract surgery. (elhawy2012pseudoexfoliationsyndromea pages 1-2, borjan2023pseudoexfoliativesyndromein pages 2-3)

Quality of life declines primarily through visual-field loss, impaired acuity, medication burden, treatment adverse effects, surgery, and loss of independence. Disease-specific EQ-5D or PROMIS norms were not identified. In an Indian tertiary-care cohort of 6,284 XFS eyes, XFG was present in 29%; the study reported substantial visual impairment and 28.2% absolute blindness at presentation, illustrating referral-setting burden rather than population risk.

4. Genetic, molecular, and epigenetic information

LOXL1 is a susceptibility gene, not a fully penetrant causal gene. Common coding variants include p.Arg141Leu (rs1048661) and p.Gly153Asp (rs3825942); rs2165241 is intronic. Functional studies support effects on LOXL1 expression, processing, stability, or aggregation, but population-dependent allele reversal means simple loss-of-function/gain-of-function labels are inadequate. A cited functional study is Sharma et al., 2016, PMID 26997634. (li2021loxl1genepolymorphisms pages 21-21)

Additional loci implicate calcium signaling (CACNA1A), proteasome maturation (POMP), membrane biology (TMEM136), phospholipid metabolism (AGPAT1), RNA binding/ECM regulation (RBMS3), and semaphorin signaling (SEMA6A). Earlier candidate-gene signals involving CNTNAP2, CLU, MMP1/MMP3, GST genes, adenosine receptors, and LYST are less definitive than GWAS evidence. (elhawy2012pseudoexfoliationsyndromea pages 1-2, aboobakar2022thegeneticsof pages 6-8)

Epigenetic regulation of LOXL1 and ECM/stress-response genes is an active hypothesis. DNA methylation, histone regulation, microRNAs, and environmentally responsive transcription may explain part of age and exposure dependence, but no epigenetic biomarker is clinically validated. No reproducible large chromosomal abnormality is established.

5. Environmental information

Relevant exposure categories are solar/ocular UV and reflected light, cold/latitude-associated climate, outdoor occupation, caffeine/coffee, and nutritional factors affecting folate–homocysteine metabolism. Non-melanoma skin cancer, used as a proxy for cumulative UV exposure, was associated with 40% higher XFG risk in 120,307 US participants followed for >25 years (445 incident cases; adjusted RR 1.40, 95% CI 1.08–1.82), with stronger associations below age 65 and at northern latitudes. Kang et al., March 2020, DOI. This remains proxy-based observational evidence. (kang2020cohortstudyof pages 2-3, kang2020cohortstudyof pages 6-7)

No infectious bacterium, virus, fungus, or parasite has been established as a cause. Upregulation of “viral gene-expression pathways” in lens RNA-seq refers to host pathway annotation and must not be interpreted as evidence of infection. (mullany2022rnasequencingof pages 1-2)

6. Mechanism and pathophysiology

Ordered causal chain

1. Advanced age plus polygenic susceptibility—especially LOXL1 regulatory/coding architecture—leads to vulnerable elastic-fiber and ECM homeostasis in anterior-segment tissues.
2. Environmental stressors, plausibly ocular UV/cold-reflection exposure, lead to oxidative stress and stress-responsive LOXL1/TGF-β expression; this interaction is biologically supported but partly inferred.
3. TGF-β dysregulation, inflammation, and redox imbalance lead to increased production and altered assembly of fibrillin-, elastin-, basement-membrane-, and LOXL1-containing matrix components.
4. LOXL1 misfolding plus proteasome, autophagosome, lysosome, microtubule, and mitochondrial dysfunction leads to defective intracellular quality control and extracellular accumulation of aggregated XFM; causality is strongest in patient-derived cellular work but remains incompletely demonstrated in vivo.
5. XFM deposition on iris, lens, ciliary epithelium, zonules, and trabecular meshwork leads to two branches:
6. zonular/iris injury leads to poor dilation, pigment liberation, phacodonesis, lens instability, and cataract-surgical complications;
7. trabecular XFM and pigment loading leads to increased aqueous-outflow resistance and elevated/fluctuating IOP.
8. Sustained IOP and associated vascular/oxidative stress lead to retinal-ganglion-cell axonal injury, optic-nerve cupping, progressive visual-field loss, and potentially irreversible blindness.

TGF-β1/2, LOXL1, fibrillin-1, LTBP1, clusterin, ApoE, and matrix metalloproteinase/tissue-inhibitor balance are central molecular candidates. Early XFS aqueous humor reportedly contains approximately threefold higher IL-6 and IL-8; IL-6 induces several XFM-associated ECM transcripts in cultured ciliary epithelial cells and Tenon fibroblasts. (shyam2023geneticandepigenetic pages 43-47, borras2018growthfactorsoxidative pages 8-10)

Patient-derived XFG Tenon fibroblasts exhibit defective lysosomal positioning, microtubule organization, autophagic processing, and mitochondrial health. The authors’ central model is LOXL1 proteopathy superimposed on impaired autophagic clearance. Bernstein et al., July 2018, DOI. (bernstein2018exfoliationsyndromea pages 1-4)

Molecular profiling

• Bulk RNA-seq: Lens capsular epithelium from 25 XFS and 39 controls identified 2,882 differentially expressed genes. The abstract reports: “Genes associated with viral gene expression pathways were among the most upregulated, alongside genes encoding ribosomal and mitochondrial respiratory transport chain proteins.” Cell-adhesion/type-IV-collagen transcripts were downregulated. Mullany et al., 29 March 2022, DOI. (mullany2022rnasequencingof pages 1-2)
• Prediagnostic metabolomics: In 205 incident XFG cases and 205 matched controls, plasma collected a mean 11.8 years before diagnosis showed FDR-significant associations for lysophosphatidylcholines, phosphatidylethanolamine plasmalogens, triglycerides, and steroids. Cortisone had OR 0.49 per SD (95% CI 0.32–0.74). This is biomarker discovery, not clinical validation or proof of protection. Kang et al., 11 August 2022, DOI. (kang2022prediagnosticplasmametabolomics pages 1-2)
• Single-cell/spatial/CRISPR: No mature XFS single-cell atlas, spatial transcriptomic reference, or replicated genome-wide functional screen was identified. These are priority gaps.

Suggested GO terms include extracellular matrix organization, elastic-fiber assembly, collagen fibril organization, TGF-β receptor signaling, response to oxidative stress, autophagy, lysosomal transport, proteasomal protein catabolism, mitochondrial electron transport, and inflammatory response. Suggested CL concepts include lens epithelial cell, non-pigmented ciliary epithelial cell, iris pigment epithelial cell, trabecular-meshwork cell, corneal endothelial cell, fibroblast, and retinal ganglion cell.

7. Anatomical structures affected

The primary organ is the eye, especially its anterior segment. Principal sites are anterior lens capsule, lens epithelium, iris pigment epithelium and stroma, pupillary sphincter, ciliary epithelium/body, zonular fibers, trabecular meshwork, Schlemm canal region, corneal endothelium, and iris vasculature. Secondary glaucomatous injury affects retinal ganglion cells, optic-nerve head/lamina cribrosa, and visual pathways.

Suggested UBERON concepts: eye, anterior segment of eye, lens capsule, iris, ciliary body, cornea/corneal endothelium, trabecular meshwork, retina, optic nerve. Suggested GO cellular components: extracellular matrix, elastic fiber, basement membrane, endoplasmic reticulum, autophagosome, lysosome, mitochondrion, and proteasome.

XFS may be clinically unilateral, but asymmetric bilateral involvement is common. Histologic deposits have been reported in lung, liver, kidney, gallbladder, skin, heart/pericardiac vessels, and cerebral meninges. Associations with cardiovascular, cerebrovascular, hearing, and systemic vascular disease remain heterogeneous; systemic screening beyond ordinary age-appropriate care is not established solely because XFS is present. (bora2024cardiovascularmanifestationsof pages 7-8, elhawy2012pseudoexfoliationsyndromea pages 1-2)

8. Temporal development

Onset is usually late adult/geriatric and insidious. A practical clinical continuum is: (1) early/asymmetric deposits with normal IOP; (2) established XFS with poor dilation, pigment release, and zonular dysfunction; (3) XFS with ocular hypertension; (4) XFG with structural/functional damage; and (5) advanced glaucoma or lens/IOL-bag instability.

The disorder is chronic and does not spontaneously remit. Apparent unilateral disease can convert to bilateral clinical disease over years. XFG can progress faster than POAG: over three years, one study observed mean-deviation change of −3.17 dB versus −1.25 dB, VFI change of −7.65% versus −1.90%, and guided-progression-analysis progression in 58% versus 13%. Therefore, early recognition and tighter IOP targets are important.

9. Inheritance and population

Inheritance is multifactorial/polygenic, with familial aggregation, incomplete and strongly age-dependent penetrance, and variable expressivity. No conventional carrier state, anticipation, or Mendelian recurrence estimate is appropriate.

Published prevalence ranges from <0.4% to >20%, depending heavily on age, ancestry, geography, examination technique, and study design; approximately 80 million people have been estimated to be affected globally. Latitude examples cited in the gene–environment literature range from 1.1% in Sri Lanka to 22% in Finland, but cross-study methodological differences preclude a simple latitude-prevalence equation. (li2021loxl1genepolymorphisms pages 1-2, pasquale2014considerationforgeneenvironment pages 2-4)

High prevalence has been reported in Nordic, Mediterranean, Russian, Middle Eastern, South Asian, and some Indigenous populations, while XFS is not restricted to any ancestry. LOXL1 haplotypes and risk directions vary geographically. Female predominance appears in some older cohorts but is inconsistent after accounting for longevity and ascertainment; no universal sex ratio should be assigned. Incidence per 100,000/year is not globally standardized.

10. Diagnostics

Diagnosis is clinical:

1. Slit-lamp examination before and after dilation for pupillary-border and anterior-lens XFM, including the classic central disc/clear intermediate zone/peripheral granular ring.
2. Assessment of pupil dilation, iris transillumination, pigment dispersion, phacodonesis, lens position, and cataract.
3. Goldmann applanation tonometry, ideally at different times because IOP fluctuates.
4. Gonioscopy for angle configuration, trabecular pigmentation, and Sampaolesi line.
5. Optic-disc examination, OCT RNFL/ganglion-cell analysis, and standard automated perimetry to diagnose/stage XFG.
6. Pachymetry and corneal endothelial assessment when clinically or surgically indicated.

Differential diagnoses include pigment dispersion syndrome (younger, often male; Krukenberg spindle, mid-peripheral transillumination, posterior iris bowing), uveitic pigment/debris, true capsular exfoliation, amyloid or inflammatory deposits, and primary open-angle/angle-closure glaucoma. XFM on lens/pupil and zonular weakness favor XFS. (rong2024lackofassociation pages 8-9)

There is no recommended routine LOXL1 test: common risk alleles have poor specificity and ancestry-dependent effects. WGS, WES, panels, CMA, karyotyping, FISH, mtDNA, and repeat-expansion testing have no routine diagnostic role. RNA-seq, proteomics, metabolomics, aqueous biomarkers, systemic immune indexes, and liquid biopsy remain research tools.

11. Outcome and prognosis

XFS is not known to shorten life expectancy directly, and disease-specific survival statistics are not applicable. Prognosis is driven by XFG severity, IOP level/fluctuation, baseline field loss, adherence, treatment response, cataract, corneal endothelial reserve, and zonular integrity.

XFG typically presents with higher IOP and more advanced damage and responds less predictably to medication than POAG. Irreversible glaucomatous loss does not recover; cataract-related acuity loss is often reversible, but surgery is technically more hazardous. Lens/IOL-bag dislocation may occur years after cataract surgery. The strongest modifiable prognostic factor is sustained IOP reduction. (aboobakar2022thegeneticsof pages 6-8, borjan2023pseudoexfoliativesyndromein pages 2-3)

12. Treatment

There is no approved disease-modifying treatment that stops XFM production or removes systemic deposits. Management targets complications.

• XFS without glaucoma: periodic IOP, optic-nerve, OCT, and field surveillance; document dilation and zonular status.
• XFG pharmacotherapy: prostaglandin analogues, beta-blockers, carbonic-anhydrase inhibitors, alpha-2 agonists, and rho-kinase inhibitors according to local glaucoma algorithms. Fixed combinations and preservative-free preparations can reduce treatment burden/ocular-surface toxicity. Pharmacogenomic prescribing is not established.
• Laser: SLT is often effective because the trabecular meshwork is pigmented. A 2024 series reported IOP reduction from 26.7 to 18.9 mmHg at three months, a 29.2% reduction and 69.4% success, but durability requires follow-up.
• Cataract surgery: phacoemulsification may lower IOP and improves vision when cataract is significant. Surgeons should anticipate small pupil and zonular weakness; iris hooks/rings, capsular hooks, capsular-tension rings, careful hydrodissection, low-stress fluidics, and secure IOL planning may be required. In a Croatian registry, XFS surgery cost was 1.4-fold higher; XFS was associated with longer surgery and more complications. Borjan et al., December 2023, DOI. (borjan2023pseudoexfoliativesyndromein pages 2-3, borjan2023pseudoexfoliativesyndromein pages 12-14)
• Incisional glaucoma surgery: trabeculectomy with antifibrotic, glaucoma drainage devices, selected angle surgery/MIGS, and cyclodestruction are options according to stage and target IOP. A 2024 PreserFlo series of 29 Asian XFG eyes reduced mean IOP from 32.6 to 16.9 mmHg and medications from 3.4 to 1.0, but had 31% reoperation and 17% hypotony, warranting caution. Wakuda et al., October 2024, DOI. (wakuda2024postoperativeoutcomesof pages 4-6, wakuda2024postoperativeoutcomesof pages 9-10)

Suggested NCIT intervention concepts: ophthalmic solution, prostaglandin analogue therapy, selective laser trabeculoplasty, phacoemulsification, intraocular-lens implantation, capsular-tension-ring placement, trabeculectomy, glaucoma drainage-device implantation, minimally invasive glaucoma surgery, and cyclophotocoagulation.

Current implementation studies include recruiting CANPEX1 (phacoemulsification versus SLT; NCT04416724; planned n=200) and a Helsinki cataract-plus-iStent versus cataract-plus-SLT study (NCT04635020; planned n=285). A completed observational XEN45 study enrolled 350 participants (NCT06993311), although numerical results were unavailable in the retrieved registry record. These test pressure-lowering strategies, not molecular correction of XFS. (NCT06993311 chunk 1, NCT04416724 chunk 1, NCT04635020 chunk 1)

13. Prevention

• Primary: no proven prevention. UV-blocking eyewear is low risk and generally advisable for ocular health, but XFS-specific benefit is unproven. Maintain nutritional folate adequacy rather than prescribing high-dose supplementation. Evidence is insufficient to recommend caffeine restriction solely to prevent XFS.
• Secondary: careful dilated slit-lamp examination in older adults, especially those with family history, high-prevalence ancestry/geography, unilateral XFS, ocular hypertension, or unexplained poor dilation. Monitor both eyes.
• Tertiary: aggressive individualized IOP control, adherence support, regular fields/OCT, cataract-surgical precautions, and long-term monitoring for late IOL-bag instability.
• Not applicable: vaccination, newborn screening, prenatal diagnosis, carrier screening, prophylactic gene therapy, and population genetic screening.

14. Other species and natural disease

No infectious transmission or zoonotic potential exists. A fully validated naturally occurring veterinary counterpart with the characteristic human XFM phenotype is not established. LOXL1 and elastic-fiber biology are evolutionarily conserved, and canine ocular disorders have informed glaucoma research, but canine pigmentary glaucoma should not be annotated as natural XFS without direct pathology.

Mus musculus (NCBI Taxon 10090) LOXL1-deficient models demonstrate systemic elastic-fiber defects and are useful for testing LOXL1 biology. However, they do not consistently reproduce the age-dependent ocular XFM, asymmetric human course, and conversion to XFG. A LOXL1-knockout elastin-homeostasis study is indexed by PMID 32533648. (li2021loxl1genepolymorphisms pages 21-21, bernstein2018exfoliationsyndromea pages 1-4)

15. Model organisms and experimental systems

• Human primary cells: XFG patient-derived Tenon fibroblasts reproduce autophagy/lysosome positioning, microtubule, mitochondrial, LOXL1-processing, and clusterin phenotypes. This is presently one of the most disease-relevant mechanistic systems. Limitation: surgery-derived fibroblasts may reflect advanced glaucoma and treatment exposure rather than disease initiation. (bernstein2018exfoliationsyndromea pages 1-4)
• Ocular cell culture: lens epithelial, non-pigmented ciliary epithelial, and trabecular-meshwork cells are used for TGF-β, UV, oxidative-stress, cytokine, LOXL1, and ECM experiments. They permit perturbation but do not recreate aging, aqueous dynamics, or multicellular XFM assembly.
• LOXL1-null mouse: useful for elastic-fiber and gene-function studies but incompletely phenocopies human XFS.
• Human surgical tissue/aqueous humor: lens capsules, iris/ciliary tissue, aqueous humor, and XFM deposits support transcriptomics, proteomics, microscopy, and biochemical studies but are cross-sectional and often late-stage.
• Major unmet need: an age-dependent, ancestry-aware animal or organoid model that forms authentic XFM and progresses to ocular hypertension/XFG.

Overall assessment

The authoritative interpretation is that XFS is an age-related systemic ECM aggregopathy with ocularly dominant disease. LOXL1 is central but not determinative; ancestry-dependent allele reversal, high risk-allele prevalence, environmental associations, and impaired stress/proteostasis pathways argue against a simple monogenic enzyme-deficiency model. The most immediate clinical opportunity is not genetic testing but earlier recognition, bilateral surveillance, tighter IOP control, and XFS-aware cataract planning. The principal research priorities are functional resolution of LOXL1 and newer loci, replicated gene–environment interaction studies, single-cell/spatial profiling, conversion biomarkers, faithful models, and therapies that reduce XFM production or restore proteostasis.

References

1. (li2021loxl1genepolymorphisms pages 1-2): Xiaoyan Li, Jie He, and Jian Sun. Loxl1 gene polymorphisms are associated with exfoliation syndrome/exfoliation glaucoma risk: an updated meta-analysis. PLoS ONE, 16:e0250772, Apr 2021. URL: https://doi.org/10.1371/journal.pone.0250772, doi:10.1371/journal.pone.0250772. This article has 27 citations and is from a peer-reviewed journal.

2. (bernstein2018exfoliationsyndromea pages 1-4): Audrey M. Bernstein, Robert Ritch, and Jose M. Wolosin. Exfoliation syndrome: a disease of autophagy and loxl1 proteopathy. Journal of glaucoma, 27 Suppl 1:S44-S53, Jul 2018. URL: https://doi.org/10.1097/ijg.0000000000000919, doi:10.1097/ijg.0000000000000919. This article has 34 citations and is from a peer-reviewed journal.

3. (elhawy2012pseudoexfoliationsyndromea pages 1-2): Eman Elhawy, Gautam Kamthan, Cecilia Q Dong, and John Danias. Pseudoexfoliation syndrome, a systemic disorder with ocular manifestations. Human Genomics, Oct 2012. URL: https://doi.org/10.1186/1479-7364-6-22, doi:10.1186/1479-7364-6-22. This article has 197 citations and is from a peer-reviewed journal.

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Genetic association study of exfoliation syndrome identifies a protective rare variant at loxl1 and five new susceptibility loci. Nature Genetics, 49:993-1004, May 2017. URL: https://doi.org/10.1038/ng.3875, doi:10.1038/ng.3875. This article has 185 citations and is from a highest quality peer-reviewed journal.

6. (aboobakar2022thegeneticsof pages 6-8): Inas F. Aboobakar and Janey L. Wiggs. The genetics of glaucoma: disease associations, personalised risk assessment and therapeutic opportunities‐a review. Clinical & Experimental Ophthalmology, 50:143-162, Jan 2022. URL: https://doi.org/10.1111/ceo.14035, doi:10.1111/ceo.14035. This article has 64 citations and is from a peer-reviewed journal.

7. (pasquale2014considerationforgeneenvironment pages 4-6): Louis R. Pasquale, Jae H. Kang, and Janey L. Wiggs. Consideration for gene-environment interactions as novel determinants of exfoliation syndrome. International Ophthalmology Clinics, 54:29–41, Jan 2014. URL: https://doi.org/10.1097/iio.0000000000000040, doi:10.1097/iio.0000000000000040. This article has 11 citations and is from a peer-reviewed journal.

8. (pasquale2014solarexposureand pages 1-2): Louis R. Pasquale, Aliya Z. Jiwani, Tzukit Zehavi-Dorin, Arow Majd, Douglas J. Rhee, Teresa Chen, Angela Turalba, Lucy Shen, Stacey Brauner, Cynthia Grosskreutz, Matthew Gardiner, Sherleen Chen, Sheila Borboli-Gerogiannis, Scott H. Greenstein, Kenneth Chang, Robert Ritch, Stephanie Loomis, Jae H. Kang, Janey L. Wiggs, and Hani Levkovitch-Verbin. Solar exposure and residential geographic history in relation to exfoliation syndrome in the united states and israel. JAMA ophthalmology, 132 12:1439-45, Dec 2014. URL: https://doi.org/10.1001/jamaophthalmol.2014.3326, doi:10.1001/jamaophthalmol.2014.3326. This article has 93 citations and is from a highest quality peer-reviewed journal.

9. (pasquale2014considerationforgeneenvironment pages 2-4): Louis R. Pasquale, Jae H. Kang, and Janey L. Wiggs. Consideration for gene-environment interactions as novel determinants of exfoliation syndrome. International Ophthalmology Clinics, 54:29–41, Jan 2014. URL: https://doi.org/10.1097/iio.0000000000000040, doi:10.1097/iio.0000000000000040. This article has 11 citations and is from a peer-reviewed journal.

10. (kang2020cohortstudyof pages 6-7): Jae H. Kang, Trang VoPham, Francine Laden, Bernard A. Rosner, Barbara Wirostko, Robert Ritch, Janey L. Wiggs, Abrar Qureshi, Hongmei Nan, and Louis R. Pasquale. Cohort study of non-melanoma skin cancer and the risk of exfoliation glaucoma. Journal of Glaucoma, 29:448-455, Mar 2020. URL: https://doi.org/10.1097/ijg.0000000000001496, doi:10.1097/ijg.0000000000001496. This article has 13 citations and is from a peer-reviewed journal.

11. (rong2024lackofassociation pages 8-9): Shisong Rong and Xinting Yu. Lack of association between loxl1 variants and pigment dispersion syndrome/pigmentary glaucoma: a meta-analysis. Genes, 15:161, Jan 2024. URL: https://doi.org/10.3390/genes15020161, doi:10.3390/genes15020161. This article has 3 citations.

12. (borjan2023pseudoexfoliativesyndromein pages 2-3): Ivan Borjan, Robert Stanić, Ivna Pleština-Borjan, Maja Pavić, Silvia N. W. Hertzberg, Ljubo Znaor, Beáta Éva Petrovski, and Goran Petrovski. Pseudoexfoliative syndrome in cataract surgery—a quality register study and health economic analysis in the split-dalmatia county, croatia. Journal of Clinical Medicine, 13:38, Dec 2023. URL: https://doi.org/10.3390/jcm13010038, doi:10.3390/jcm13010038. This article has 8 citations.

13. (shyam2023geneticandepigenetic pages 43-47): KR Shyam and DP Alone. Genetic and epigenetic regulation of candidate genes associated with pseudoexfoliation. Unknown journal, 2023.

14. (borras2018growthfactorsoxidative pages 8-10): Teresa Borrás. Growth factors, oxidative damage, and inflammation in exfoliation syndrome. Journal of Glaucoma, 27:S54-S60, Jul 2018. URL: https://doi.org/10.1097/ijg.0000000000000904, doi:10.1097/ijg.0000000000000904. This article has 28 citations and is from a peer-reviewed journal.

15. (mullany2022rnasequencingof pages 1-2): Sean Mullany, Henry Marshall, Tiger Zhou, Daniel Thomson, Joshua M. Schmidt, Ayub Qassim, Lachlan S. W. Knight, Georgina Hollitt, Ella C. Berry, Thi Nguyen, Minh-Son To, David Dimasi, Abraham Kuot, Joshua Dubowsky, Rhys Fogarty, Michelle Sun, Luke Chehade, Shilpa Kuruvilla, Devaraj Supramaniam, James Breen, Shiwani Sharma, John Landers, Stewart Lake, Richard A. Mills, Mark M. Hassall, Weng O. Chan, Sonja Klebe, Emmanuelle Souzeau, Owen M. Siggs, and Jamie E. Craig. Rna sequencing of lens capsular epithelium implicates novel pathways in pseudoexfoliation syndrome. Mar 2022. URL: https://doi.org/10.1167/iovs.63.3.26, doi:10.1167/iovs.63.3.26. This article has 11 citations.

16. (wakuda2024postoperativeoutcomesof pages 4-6): Hiroyuki Wakuda, Ryota Aoki, and Shunsuke Nakakura. Postoperative outcomes of preserflo microshunt in patients with exfoliation glaucoma. Oct 2024. URL: https://doi.org/10.3390/jcm13206132, doi:10.3390/jcm13206132. This article has 6 citations.

17. (borjan2023pseudoexfoliativesyndromein pages 12-14): Ivan Borjan, Robert Stanić, Ivna Pleština-Borjan, Maja Pavić, Silvia N. W. Hertzberg, Ljubo Znaor, Beáta Éva Petrovski, and Goran Petrovski. Pseudoexfoliative syndrome in cataract surgery—a quality register study and health economic analysis in the split-dalmatia county, croatia. Journal of Clinical Medicine, 13:38, Dec 2023. URL: https://doi.org/10.3390/jcm13010038, doi:10.3390/jcm13010038. This article has 8 citations.

18. (NCT04635020 chunk 1): Prof. Mika Harju. Comparison Of iStent to Laser in Exfoliation Glaucoma Helsinki Study Group. Helsinki University Central Hospital. 2020. ClinicalTrials.gov Identifier: NCT04635020

19. (NCT04416724 chunk 1): Phacoemulsification vs SLT as Initial Treatment for Pseudoexfoliation Glaucoma. Nova Scotia Health Authority. 2022. ClinicalTrials.gov Identifier: NCT04416724

20. (kang2022prediagnosticplasmametabolomics pages 1-2): Jae H. Kang, Oana Zeleznik, Lisa Frueh, Jessica Lasky-Su, A. Heather Eliassen, Clary Clish, Bernard A. Rosner, Louis R. Pasquale, and Janey L. Wiggs. Prediagnostic plasma metabolomics and the risk of exfoliation glaucoma. Aug 2022. URL: https://doi.org/10.1167/iovs.63.9.15, doi:10.1167/iovs.63.9.15. This article has 10 citations.

21. (NCT06993311 chunk 1): SARA POSE BAZARRA. Real World Evidence of Xen45 Gel Implant in Pseudoexfoliation Glaucoma. Xerencia de Xestión Integrada de Ferrol. 2018. ClinicalTrials.gov Identifier: NCT06993311

22. (li2021loxl1genepolymorphisms pages 21-21): Xiaoyan Li, Jie He, and Jian Sun. Loxl1 gene polymorphisms are associated with exfoliation syndrome/exfoliation glaucoma risk: an updated meta-analysis. PLoS ONE, 16:e0250772, Apr 2021. URL: https://doi.org/10.1371/journal.pone.0250772, doi:10.1371/journal.pone.0250772. This article has 27 citations and is from a peer-reviewed journal.

23. (kang2020cohortstudyof pages 2-3): Jae H. Kang, Trang VoPham, Francine Laden, Bernard A. Rosner, Barbara Wirostko, Robert Ritch, Janey L. Wiggs, Abrar Qureshi, Hongmei Nan, and Louis R. Pasquale. Cohort study of non-melanoma skin cancer and the risk of exfoliation glaucoma. Journal of Glaucoma, 29:448-455, Mar 2020. URL: https://doi.org/10.1097/ijg.0000000000001496, doi:10.1097/ijg.0000000000001496. This article has 13 citations and is from a peer-reviewed journal.

24. (bora2024cardiovascularmanifestationsof pages 7-8): Rajal R Bora, Roshan Prasad, Swapneel Mathurkar, Kashish Bhojwani, and Akshansh Prasad. Cardiovascular manifestations of pseudoexfoliation syndrome: a narrative review. Cureus, Jan 2024. URL: https://doi.org/10.7759/cureus.51492, doi:10.7759/cureus.51492. This article has 10 citations.

25. (wakuda2024postoperativeoutcomesof pages 9-10): Hiroyuki Wakuda, Ryota Aoki, and Shunsuke Nakakura. Postoperative outcomes of preserflo microshunt in patients with exfoliation glaucoma. Oct 2024. URL: https://doi.org/10.3390/jcm13206132, doi:10.3390/jcm13206132. This article has 6 citations.

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