Glaucoma-Related Pigment Dispersion Syndrome

Clinical Features

The pigment dispersion syndrome with open-angle glaucoma usually affects individuals under the age of 30 years. In addition to the typical optic nerve degeneration seen in all forms of glaucoma, the pigment dispersion syndrome is characterized by distinctive clinical features. One feature is the deposition of pigment granules from the iris epithelium on various ocular structures, including the trabecular meshwork. This disorder frequently affects young myopic individuals. In the early stages of the disease, affected individuals may have clinical evidence of dispersed pigment without an associated elevation of intraocular pressure and optic-nerve degeneration. However, as the disease progresses, approximately 50% of patients develop increased intraocular pressure and degeneration of the optic nerve, causing permanent loss of sight (Richter et al., 1986).

Siddiqui et al. (2003) reviewed the results from 113 patients newly diagnosed with pigment dispersion syndrome over a 24-year period. The risk of developing pigmentary glaucoma from pigment dispersion syndrome was 10% at 5 years and 15% at 15 years. Young myopic men were most likely to have pigmentary glaucoma. An intraocular pressure greater than 21 mm Hg at initial examination was associated with an increased risk of conversion.

Pigment dispersion syndrome and pigmentary glaucoma result from iridozonular friction causing disruption of the iris epithelium and deposition of iris pigment on the anterior segment structures. Tesser (2003) reported a 48-year-old patient with congenital bilateral iris colobomas (see 120200). Elevated intraocular pressure was present in the eye with a partial iris coloboma and iris transillumination defects but pigment deposition on the ipsilateral corneal endothelium (Krukenberg spindle). The other eye was diagnosed as having mild ocular hypertension, without pigment dispersion or glaucoma, in association with a complete iris coloboma. Tesser (2003) concluded that pigment dispersion was prevented in the eye with the complete iris coloboma.

Grassi et al. (2004) reported an 8-year-old boy with atypical PDS. In addition to iris transillumination defects, iris backbowing, heavy pigmentation of the trabecular meshwork, and elevated intraocular pressure, he had emmetropia, mild posterior subcapsular cataract, small pupils, and peripheral anterior synechiae.

Dorairaj et al. (2007) reported 3 unrelated children with PDS: an 11-year-old girl with bilateral PDS with elevated intraocular pressure whose mother had PDS, and two 12-year-old boys, 1 with a more severe phenotype and both parents affected, and the other with a less severe phenotype and 1 parent affected.

Inheritance

Autosomal dominant inheritance of the pigment dispersion syndrome was documented by Scheie and Cameron (1981) and Mandelkorn et al. (1983), among others.

Mapping

Andersen et al. (1997) performed a genomewide screen using microsatellite repeat markers in 4 pedigrees containing 28 patients showing clinical evidence of the pigment dispersion syndrome. Of these, 14 also had elevated intraocular pressures requiring medical or surgical treatment or both. Linkage was observed between the disease phenotype and markers located on the telomere region of 7q, 7q35-q36. The maximum 2-point lod score for a single pedigree was 5.72 at theta = 0.0 for markers D7S2546 and D7S550. Analysis of affected recombinant individuals demonstrated that the responsible gene is located in a 10-cM interval between markers D7S2462 and D7S2423.

Exclusion Studies

The pigment dispersion syndrome shares several clinical features with the form of autosomal dominant juvenile open-angle glaucoma that shows linkage mapping to 1q21-q31 (137750). The 2 disorders share a similar age of onset and a high prevalence of myopia in affected individuals. Paglinauan et al. (1995) observed a family in which several sibs had severe juvenile glaucoma without clinical features of the pigment dispersion syndrome. The juvenile glaucoma in these patients segregated with markers located on 1q21-q31. One individual in the family had the pigment dispersion syndrome but lacked elevated intraocular pressure or optic nerve damage. This individual had not inherited the 1q21-q31 haplotype from his glaucoma-affected father, suggesting that the pigment dispersion syndrome and chromosome 1-linked juvenile glaucoma are separate entities. In a linkage study involving 3 pigment dispersion syndrome pedigrees, Paglinauan et al. (1995) excluded linkage to the 1q21-q31 region, confirming that these are distinct entities. Wiggs et al. (1995) studied 3 pedigrees in which the pigment dispersion syndrome was not linked to the 1q21-q31 region.

Animal Model

John et al. (1998) characterized the DBA/2J mouse that develops glaucoma subsequent to anterior segment changes including pigment dispersion and iris atrophy. Using crosses between DBA/2J and C57BL/6J mice, Chang et al. (1999) demonstrated that there are 2 chromosomal regions that contribute to the anterior segment changes and glaucoma. Progeny homozygous for the DBA/2J allele (ipd) of one locus on mouse chromosome 6 developed an iris pigment dispersion similar to human pigment dispersion syndrome (GPDS1), which maps to human chromosome 7q, a region with homology of synteny to mouse chromosome 6. Progeny homozygous for the DBA/2J allele (isa) of a different locus on chromosome 4 develop an iris stromal atrophy phenotype. Chang et al. (1999) suggested that the Tyrp1 gene (115501) is a candidate for isa and likely causes iris stromal atrophy via a mechanism involving pigment production. Progeny homozygous for both the isa and ipd alleles develop an earlier onset and more severe disease involving pigment dispersion and iris stromal atrophy.

Pigmentary glaucoma is a significant cause of human blindness. Abnormally liberated iris pigment and cell debris enter the ocular drainage structures, leading to increased intraocular pressure and glaucoma (Sugar, 1966). Using high-resolution mapping techniques, sequencing, and functional genetic tests, Anderson et al. (2002) further pursued the DBA/2J model of pigmentary glaucoma. They showed that iris pigment dispersion (ipd) and iris stromal atrophy (isa) result from mutations in related genes encoding melanosomal proteins. Ipd is caused by a premature stop codon mutation (arg150 to ter; R150X) in the Gpnmb gene (604368), as proved by the occurrence of Ipd only in mice homozygous with respect to this mutation; otherwise, similar mice that are not homozygous for the R150X mutation of Gpnmb do not develop Ipd. Anderson et al. (2002) found that Isa is caused by a recessive mutant allele of the Tyrp1 gene and rescued by the transgenic introduction of wildtype Tyrp1. They hypothesized that Ipd and Isa alter melanosomes, allowing toxic intermediates of pigment production to leak from melanosomes, causing iris disease and subsequent pigmentary glaucoma. This is supported by the rescue of Ipd and Isa in the DBA/2J strain with substantially decreased pigment production. The data suggested that pigment production and mutant melanosomal protein genes may contribute to human pigmentary glaucoma. The fact that hypopigmentation profoundly alleviates the disease in DBA/2J mice indicates that therapeutic strategies designed to decrease pigment production may be beneficial in human pigmentary glaucoma.

Lu et al. (2011) used quantitative trait locus mapping methods and gene set analysis to evaluate Gpnmb coexpression networks in wildtype and mutant cohorts. Covariates of wildtype Gpnmb were involved in melanin synthesis and cell migration, whereas the covariates of mutant Gpnmb were involved in posttranslational modification, stress activation, and sensory processing. Lu et al. (2011) showed that the R150X mutation in Gpnmb dramatically modified its list of genetic covariates, which might explain the associated ocular pathology in pigment dispersion syndrome.

Reichstein et al. (2007) used annexin-V (131230) labeling to determine the in vivo time course and spatial distribution of retinal ganglion cells (RGCs) undergoing apoptotic death in DBA/2 mice. Apoptotic RGC death was maximal between 12 and 15 months of age and occurred in clusters. The clusters were initially located in the midperipheral retina and progressively occurred closer to the optic nerve head with increasing age. Retrograde axonal transport in the glaucomatous mouse retina was functional until at least 2 to 3 days prior to initiation of apoptotic RGC cell death.

Marneros and Olsen (2003) found that abnormalities in the iris and ciliary body of Col18a1 (120328) -/- mice demonstrated the important role of collagen XVIII in the function of ocular basement membranes. The absence of collagen XVIII altered the properties of basement membranes and led to severe defects in the iris, showing striking similarities to human pigment dispersion syndrome. In addition, loss of collagen XVIII created changes that allowed clump cells to migrate out of the iris. These cells had not been well characterized previously. The authors showed that clump cells are macrophage-like cells and are able to penetrate the internal limiting membrane in mutant mice. The disease mechanism of human pigment dispersion syndrome was not well understood, but Col18a1 -/- mice might serve as a model and demonstrate the potential importance of alterations in extracellular matrix components in this disease.