Alternative titles; symbols
SNOMEDCT: 111514006, 44219007; ICD9CM: 365.52; DO: 13641;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q24.1 | {Exfoliation syndrome, susceptibility to} | 177650 | Autosomal dominant | 3 | LOXL1 | 153456 |
A number sign (#) is used with this entry because of evidence that susceptibility to the exfoliation syndrome (XFS) is conferred by variation in the LOXL1 gene (153456) on chromosome 15q24.
Exfoliation syndrome (XFS) is a common age-related disorder of the extracellular matrix that is frequently associated with severe chronic secondary open-angle glaucoma and cataract. XFS syndrome may affect up to 30% of people over 60 years of age worldwide and is biomicroscopically diagnosed by abnormal microfibrillar deposits on ocular structures that line the aqueous-bathed surfaces of the anterior segment (summary by Schlotzer-Schrehardt and Naumann, 2006).
Forsius (1981) considered the exfoliation syndrome to be a disorder of the suspensory ligament. Secondary glaucoma results from effects of exfoliated lens material ('capsular glaucoma'). The disorder was first described by Lindberg (1917), Forsius's teacher. Forsius himself had the disorder.
Yuksel et al. (2001) described the ocular hemodynamics in pseudoexfoliation syndrome and pseudoexfoliation glaucoma. They found that the hemodynamic parameters in the retrobulbar vessels were altered in patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma and that these alterations were more prominent in the glaucoma patients. Specifically, they found decreases in the mean peak systolic velocity of the central retinal artery as well as in the end diastolic velocities of the central retinal artery and the short posterior temporal ciliary arteries. However, the resistive indices were increased in the ophthalmic artery.
Gasch et al. (2003) concluded that XFS caused abnormalities in the zonules, ciliary body, iris, trabecular meshwork, and corneal endothelium, which could lead to significant clinical problems, including cataract surgery complications and glaucoma.
Konstas et al. (2004) performed a retrospective analysis of 167 patients with exfoliation glaucoma in Greece, Spain, Russia, and Hungary. They found that intraocular pressure reduction helped to prevent glaucoma progression in patients with exfoliation glaucoma, although it did not guarantee the prevention or worsening of the disease.
Grodum et al. (2005) found that pseudoexfoliation was a strong independent risk factor for glaucoma in patients with ocular hypertension.
Schlotzer-Schrehardt and Naumann (2006) reviewed the ocular and systemic manifestations and pathophysiology of pseudoexfoliation syndrome.
In light of its peculiar population distribution, this disorder seems to have an important genetic basis (Forsius, 1981). In Finland and elsewhere in Scandinavia, it may have a frequency as high as 20% in persons over age 80 years. It is frequent in Lapps and northern-living Russians, but Forsius (1981) found it totally lacking in Eskimos. It has been found in Canada, but in persons of Scandinavian extraction. It is rare in Germany and in the United Kingdom, but frequent in Amerindians, in Greece, and in the African Bantu.
Gasch et al. (2003) reported the high prevalence of exfoliation syndrome in Azerbaijan; patients were designated as having XFS if exfoliation material was apparent on the anterior lens capsule and/or at the pupillary border during routine postdilation biomicroscopy. The youngest patient with XFS was 46 years old. XFS was present in 32% of those over 60 years of age. The prevalence increased with age. XFS was bilateral in 48% of those affected. The reported prevalence among individuals older than 60 years ranged from 0% among Eskimos to 38% among the Navajo of New Mexico.
Krishnadas et al. (2003) determined the prevalence and risk factors for pseudoexfoliation in a rural population of southern India. The prevalence was 6.0%, increased with age, and was greater in males. Prevalence of glaucoma among patients with pseudoexfoliation was 7.5%; exfoliation was present in 26.7% of patients with primary open-angle glaucoma. Pseudoexfoliation also increased the risks of operative complications during cataract surgery.
Rotchford et al. (2003) determined the prevalence and clinical features of XFS among black South Africans. They examined 1,840 individuals, 40 years of age or older, from Hlabisa and Temba. Prevalence of XFS was 7.7% in Hlabisa and 6.0% in Temba. Prevalence increased with age, with 18.9% (Hlabisa) and 16.5% (Temba) of those aged 70 years or older affected. Clinical appearance was similar to that reported in other ethnic groups. Exfoliative glaucoma accounted for approximately one-fourth of open-angle glaucoma (OAG) cases. Among patients with XFS and OAG, 16 of 18 were blind in one or both eyes. Rotchford et al. (2003) concluded that open-angle glaucoma associated with XFS appeared to be associated with a poor prognosis.
Pasquale et al. (2014) detailed lifetime solar exposure in individuals with XFS in the United States (118 cases and 106 controls) and in Israel (67 cases and 72 controls). In multivariable analyses, each degree of weighted lifetime average residential latitude away from the equator was associated with 11% increased odds of XFS.
There is evidence (Streeten et al., 1986) that pseudoexfoliation syndrome is a type of elastosis associated with the excess synthesis of elastic microfibrillar components such as fibrillin-1 (FBN1; 134797). Because TGF-beta is a major modulator of extracellular matrix formation (see TGFB1, 190180), Schlotzer-Schrehardt et al. (2001) analyzed the expression of various forms of TGF-beta and the TGFB1 latent form binding proteins LTBP1 (150390) and LTBP2 (602091) in anterior segment tissues, aqueous humor, serum, and Tenon's capsule biopsy tissue from patients with PEXS and controls. Significantly increased concentrations of both total and active TGFB1 were found in the aqueous humor of PEXS eyes with and without glaucoma compared to controls, and the expression of TGFB1, LTBP1, and LTBP2 was markedly increased in anterior segment tissues of PEXS eyes, particularly in the nonpigmented epithelium of the ciliary body. Latent TGFB1 staining was consistently associated with PEXS material deposits, and double immunolabeling revealed clear colocalization of LTBP1 and LTBP2 with latent TGFB1 and FBN1 on PEXS fibrils. FBN1 mRNA expression was upregulated in vitro by TGFB1. Schlotzer-Schrehardt et al. (2001) concluded that TGFB1, LTBP1, and LTBP2 play a significant role in PEX syndrome.
Adenosine is increasingly released in metabolic stress conditions, such as hypoxia or ischemia, and regulates many physiologic processes, such as aqueous humor secretion and intraocular pressure, via activation of the adenosine receptors. Schlotzer-Schrehardt et al. (2005) reported that, while all 4 adenosine receptor subtypes (ADORA1, 102775; ADORA2A, 102776; ADORA2B, 600446; and ADORA3, 600445) were coexpressed in the ciliary body of control eyes, a selective, approximately 10-fold upregulation of ADORA3 mRNA and protein was consistently found in the nonpigmented ciliary epithelium of all eyes from patients with pseudoexfoliation of the lens, with or without glaucoma. All all 4 adenosine receptor subtypes were differently distributed in the ciliary epithelium of control eyes, with the A3 receptor being localized to the basolateral membrane infoldings of the nonpigmented epithelial cells.
Zenkel et al. (2006) investigated the role of the extracellular chaperone clusterin in the pathophysiology of pseudoexfoliation syndrome/glaucoma, which is characterized by the stable deposition of abnormal extracellular fibrillar material in anterior segment tissues. Clusterin mRNA was ubiquitously expressed in most ocular cells and tissues, particularly in the epithelium of ciliary processes, whereas the protein usually localized in extracellular structures, such as ocular basement membranes and stromal fibers. However, in XFS eyes, significant downregulation of clusterin mRNA was seen in all anterior segment tissues, irrespective of the presence of or type of glaucoma, compared with normal and glaucomatous control eyes. Posterior segment tissues did not show any differential expression. Clusterin levels in aqueous humor were significantly reduced in eyes with XFS. The expression of clusterin mRNA and protein in nonpigmented ciliary epithelial cells was significantly downregulated by TGF-beta-1 (TGFB1; 190180) in vitro. Considering the known role of clusterin as a highly efficient extracellular chaperone, Zenkel et al. (2006) concluded that its deficiency in the anterior segment of XFS eyes might promote the stress-induced aggregation and stable deposition of the pathologic extracellular matrix product characteristic of XFS syndrome.
Using a proteomic approach, Ovodenko et al. (2007) identified novel components of the lenticular exfoliation material, including cell adhesion molecules, extracellular matrix proteins, prostaglandins, complement proteins, matrix metalloproteases, and specific inhibitors.
Ye et al. (2015) noted that there is a high prevalence of PEXS in the Uighur population. They studied lens capsule specimens from 10 PEXS Kashi Uighur patients and 10 age-related cataract patients from the same population. Hypermethylation in 6 CpG islands of the LOXL1 gene promoter was higher in the PEXS patients compared with the cataract only patients. In addition, LOXL1 mRNA and protein expression levels were lower in the PEXS patients. Ye et al. (2015) suggested that epigenetic regulation might play a role in the pathogenesis of PEXS.
Berner et al. (2019) sequenced the LOXL1 locus in 5,570 individuals with PEXS and 6,279 controls from 9 countries, and found that a noncoding sequence variant, rs7173049A-G, located 432 bp downstream of the stop codon showed a decrease of PEXS risk. Berner et al. (2019) showed that this variant did not have an apparent effect on LOXL1 transcription, but exhibited allele-specific binding of the transcription factor thyroid hormone receptor-beta (THRB; 190160), which influenced expression of ISLR2 (614179) and STRA6 (610745). Berner et al. (2019) next evaluated expression of ISLR2 and STRA6 in iris and retina from individuals with PEXS and showed that they were both downregulated compared to controls. Furthermore, expression of components of the retinoic acid signaling pathway, including CRBP1 (180260), CRABP2 (180231), RARA (180240), and RXRA (180245), was also decreased in iris and ciliary body from patients with PEXS compared to controls. Berner et al. (2019) concluded that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEXS, and that rs7173049A-G has a protective effect against the disorder through upregulation of SRA6 in ocular tissues.
Orr et al. (2001) developed a clinical grading scheme for exfoliation syndrome and examined a total of 782 patients and relatives in Maritime Canada, ascertaining 467 'definitely affected' individuals. Approximately 30 multiplex families were discovered, including a family with 23 affected individuals among 137 examined members. Orr et al. (2001) observed well-documented paternal transmission, and noted that the clustering of cases in families provided evidence for the involvement of genetic factors. The possibility of homozygosity was suggested in a few patients by the earlier or more frequent presentation of the disorder in the offspring of 2 affected parents or consanguineous pairings. Although a multifactorial mode of inheritance could not be excluded, Orr et al. (2001) stated that exfoliation syndrome appears to be inherited as an autosomal dominant trait with late onset and incomplete penetrance, which pose significant obstacles to pedigree construction. The authors also noted that only 30 (4.1%) of the 731 gradable participants in this study, mostly younger relatives, were found to have no evidence of the disorder, making it difficult to define an exfoliative 'control' state with certainty on the basis of clinical examination.
Thorleifsson et al. (2007) performed a genomewide search which yielded multiple SNPs in the chromosome 15q24.1 region associated with glaucoma. Further investigation revealed that the association was confined to exfoliation glaucoma (XFG).
Associations Pending Confirmation
Krumbiegel et al. (2011) performed a genomewide association study using a DNA-pooling approach involving 80 German patients with PEX syndrome, 80 with PEX glaucoma (PEXG), and 80 controls, with replication in independent German and Italian cohorts of PEXS/PEXG patients and controls. They identified 2 SNPs, located in intron 11 of the CNTNAP2 gene (604569) on chromosome 7q35-q36, that were associated with PEXS/PEXG in both the discovery and replication German cohorts (rs2107856 and rs2141388, combined corrected p = 0.0108 and 0.0072, respectively); the association was not confirmed in the Italian cohort.
Thorleifsson et al. (2007) performed a genomewide search which yielded multiple SNPs in the chromosome 15q24.1 region associated with glaucoma. Further investigation revealed that the association was confined to exfoliation glaucoma (XFG). Two nonsynonymous SNPs in exon 1 of the LOXL1 gene, rs1048661 (153456.0001) and rs3825942 (153456.0002), explained the association, and the data suggested that they confer risk of XFG mainly through exfoliation syndrome (XFS). About 25% of the general population is homozygous for the highest risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low risk haplotypes. The population-attributable risk of the 2 higher risk haplotypes is more than 99%. The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG.
In a Caucasian Australian population-based cohort of 2,508 individuals, 86 (3.4%) of whom were diagnosed with pseudoexfoliation syndrome, Hewitt et al. (2008) confirmed that 2 previously identified nonsynonymous variants in exon 1 of LOXL1, R141L (rs1048661) and G153D (rs3825942), were strongly associated with pseudoexfoliation: 2 copies of the high-risk haplotype at these SNPs conferred a risk of 7.20 (95% CI, 3.04 to 20.75) compared to no copies of the high-risk haplotype. Hewitt et al. (2008) noted that their Caucasian population had a 9-fold lower lifetime incidence of pseudoexfoliation syndrome compared to the Nordic populations studied by Thorleifsson et al. (2007) despite having similar allelic architecture at the LOXL1 locus, and suggested that genetic or environmental factors independent of LOXL1 strongly influence the phenotypic expression of the syndrome.
In a case-control study of 59 Finnish patients with XFS, 82 with XFG, 71 patients with primary open-angle glaucoma (see POAG, 137760), and 26 unaffected individuals, and in a family study of 28 patients with XFS or XFG and 92 unaffected relatives from an extended Finnish family, Lemmela et al. (2009) analyzed 3 SNPs in the LOXL1 gene, the 2 previously studied exonic SNPs rs1048661 and rs3825942, and a SNP in intron 1, rs2165241 (153456.0003). In both studies, the strongest association was with the intronic SNP rs2165241 (p = 2.62 x 10(-13) and p less than 0.0001, respectively); however, no linkage was observed for LOXL1 risk alleles. The corresponding 3-locus haplotype GGT increased the risk of XFS/XFG nearly 15-fold relative to the low-risk GAC haplotype (p = 1.6 x 10(-16)).
In an analysis of 50 black South African patients with XFS and 50 age- and gender-matched controls, Hauser et al. (2015) identified a peak XFS-associated region at the LOXL1 exon 1/intron 1 boundary, which lies in a potential regulatory region for the long noncoding RNA LOXL1AS1 (616800). They replicated the association in populations of European and Asian ancestry. DNase I hypersensitivity sites were found within the region of interest, and in vitro luciferase assays demonstrated that this associated region contains promoter activity and that XFS-associated genetic variants alter this promoter. However, the region did not enhance LOXL1 promoter activity. In addition, Hauser et al. (2015) identified an LOXL1AS1 isoform that is broadly expressed in tissues known to be affected in XFS and demonstrated that the expression of LOXL1AS1 is significantly altered in response to oxidative stress and cyclic mechanical stress in ocular cells. Hauser et al. (2015) suggested that LOXL1AS1 dysregulation contributes to XFS pathogenesis.
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