Discussion
The subjects in OI case group had a mutation of the COL1A1 gene. OI cases had higher IOP (GAT and IOPcc), lower CH and lower CCT than those in the control group. Two of the cases had a known diagnosis of POAG and were on topical therapy and under regular clinical review. Iris TIDs were noted in two of the six patients with OI and one of the unaffected patients. There were no other features of pigment dispersion glaucoma, that is, no Krukenberg’s spindle, dispersed pigment or Zentmayer rings. Iris TIDs are also associated with megalocornea,18 which is a known manifestation of OI. There was no clinical suspicion of megalocornea in any of the subjects.
Genetic mutations in OI
OI was previously described as an autosomal-dominant disorder resulting from mutations in the COL1A1 and COL1A2 genes which code for α1 and α2 chains of type I collagen, respectively. Type I collagen is the most abundant fibrillar collagen of bone, skin and extracellular matrices. In all, 85%–90% of cases of OI are caused by mutations of these two genes. The remainder are recessive forms. Seven types are caused by defects in genes whose protein products interact with collagen for folding or post-translational modifications. Two other rare defects mainly affect bone mineralisation, but also decrease collagen production. The most recently identified genes show primary defects in osteoblast differentiation.1
Collagen mutations may be qualitative (ie, structural) or quantitative. Collagen with a primary structural defect has more severe consequences for intracellular metabolism and matrix structure than does a reduced amount of normal collagen.1 Heterozygous null COL1A1 alleles result in synthesis of a reduced amount (about half) of structurally normal collagen and cause the mildest form of the disorder, OI type I. OI types II–IV commonly are caused by qualitative collagen mutations.19
Our affected subjects have a pathogenic c.1821+1G>A splice site mutation in intron 26 of the COL1A1 gene. Splice site predictive software indicates that this pathogenic mutation would disrupt the donor splice site, leading to abnormal splicing of exon 26.20 This mutation was first reported in an individual with OI type I in 1993 by Stover et al.21 Interestingly, Zhytnik et al later found two unrelated patients with this same mutation. In these two patients, this mutation resulted in phenotypes of different severity: one patient having OI type I and the other having OI type III.22 Genotype−phenotype correlations remain an unresolved issue in our understanding of OI. Cases of interfamilial OI diversity are not rare. Not only genetics but also additional factors, such as epigenetics and environment, might contribute to the development of specific OI phenotypes. Indeed within our group of subjects, all of whom have the same mutation, there is a differing phenotype. Subject 8 is the worst affected, suffering more frequent, disabling and deforming fractures.
Role of collagen in glaucoma
Type I collagen is found in abundance in many ocular tissues, including cornea, sclera, trabecular meshwork (TM) and lamina cribrosa (LC).23 Collagen abnormalities may contribute to the development of glaucoma in a number of ways. Changes in collagen composition of the extracellular matrix of the TM may be responsible for increased outflow resistance and subsequent increased IOP.24 Hernandez et al discussed changes in the connective tissue of the lamina cribrosa in the optic nerve in glaucoma, with an increase in collagen VI and disruption and loss of elastic fibres in the LC playing an important role in the progression of disease.25
Albon et al concluded that mechanical compliance and resilience of the LC decrease with age26 and are associated with differing proportions of collagen subtypes as well as an increase in total collagen.27 These studies suggest an increased susceptibility to permanent deformation with age in the normal population, which may be more significant in those with collagen abnormality.
Glaucoma in animal model COL1A1 mutations
Aihara et al demonstrated elevated IOP in mice with a transgenic mutation in the gene for the α1 subunit of type I collagen. This suggested an association between IOP regulation and fibrillar collagen turnover.28 The same group later reported that aqueous outflow was reduced in mice with this COL1A1 mutation due to increased resistance in the outflow pathway.29 Mabuchi et al used a similar mouse model to demonstrate optic nerve axonal loss (associated with elevated IOP) at 54 weeks of age in those with the targeted COL1A1 mutation.30 These studies suggest that faulty collagen in the TM is one of the mechanisms by which those with COL1A1 mutation are at risk of elevated IOP and subsequent POAG development.
Corneal properties in glaucoma
Reduced CCT is becoming increasingly recognised as an independent risk factor for the development and progression of POAG. In recent studies, reduced CH was a significant predictor of progression in POAG.8–11 In the UK Biobank study, which analysed CH data from 93 345 participants, CH was negatively associated with male sex, age, black ethnicity, self-reported glaucoma, diastolic blood pressure and height. In addition, self-reported glaucoma and CH were significantly associated when CH was less than 10.1 mmHg.17
Corneal properties in human COL1A1 mutations
Dimasi et al analysed the role of mutations in type I collagen genes in CCT and found that CCT was markedly less in patients with OI with mutations in COL1A1 and COL1A2 than matched controls.31 Lagrou et al reported altered corneal properties in children with OI. These children had reduced CCT and CH when compared with age-matched controls.32
CH applications
We can infer information about posterior ocular structures from non-invasive CH measurements. Corneal hysteresis refers to the ability of the cornea to dampen pressure changes, rather than having characteristics of floppiness or rigidity. Wells et al found an association between higher corneal hysteresis values and more optic nerve deformation during acute IOP elevation. They hypothesised that a low CH could correlate with stiffening of the peripapillary sclera and reduced ability to dampen the effects of raised IOP on the optic nerve head.33 Lanzagorta et al, while following up newly diagnosed patients with glaucoma commencing topical treatment, found that the greater the corneal CH at baseline, the greater the LC displacement anteriorly during follow-up, representing recovery to its original position.34 Essentially, eyes with higher hysteresis are better able to recover the original position of the LC when the IOP is lowered.
Study limitations and biases
The major limitation of this study is the small number of subjects. This precluded the possibility of accurate statistical analysis of the data. A potential source of bias came from the fact that subjects 1 and 2 were both on IOP-lowering treatment, which included a PA, at the time of data collection. Pretreatment IOP GAT was used for subject 1, but not for subject 2 as it was unavailable. This likely reduced the true difference in IOP GAT between cases and controls. Several studies have suggested an increase in CH in the first 6–12 months of PA use in treatment-naïve subjects.35–37 Tsikripis et al also suggested a small but significant increase in CCT with PA use.37 Conversely, Meda et al showed a reversible decrease in CH and CCT with PA treatment, but in subjects on long-term treatment.38 Pretreatment IOPcc, CH and CCT measurements were unavailable for both of our PA-treated subjects. As both were on long-term PA treatment, the findings of Meda et al may be more applicable. This may have resulted in a lower-than-expected CCT and CH, thus overestimating the difference between cases and controls.
Subject 8 was unable to comply with contact tonometry and pachymetry. Their IOPg measurement from the ORA was substituted when constructing the graphs. IOPg has been shown to correlate well with IOP GAT,12 15 so this substitution was not felt to have biased the mean IOP GAT difference between the groups.
