Vitreoretinal Dystrophies

13.1  Stickler Syndrome

13.1.1  Introduction

Stickler syndrome (STK), also known as hereditary progressive arthro-ophthalmopathy [1, 2], is a connective tissue disorder, with ocular, skeletal, and systemic findings. Patients often present at an early age and have other affected family members.

13.1.2  Historical Context

STK was first described by Stickler et al. in 1965 in a five generation family with eleven affected family members [1]. An autosomal dominant disease was identified where affected family members usually presented with retinal detachments in the first decade of life that were often bilateral. Systemic features included a degenerative arthropathy of the metatarsal and metacarpal cartilage surfaces. Additional observations were published in 1967

M.F. Shuler

Retina Specialty Institute, 2010 Northside Drive, #704, Panama

City, FL 32401, USA

J.M. Sullivan

Departments of Ophthalmology (Ira G. Ross Eye Institute), Pharmacology/Toxicology and Physiology/Biophysics; Veterans Administration Western New York Healthcare System, University at Buffalo – State University of New York, Building 20, 3495 Bailey Avenue, Buffalo, NY 14215, USA

B.R. Hurley and J.A. McNamara (*)

Retina Service, Wills Eye Institute, Suite 1020, 840 Walnut Street, Philadelphia, PA 19107, USA

e-mail: jamcnamara@willseye.org

when hearing loss, degenerative joint disease of the spine, and characteristic facies (flattened nasal bridge and short nose) were added as clinical features [2].

13.1.3  Overview with Clinical Significance

The severity of disease varies greatly even within a family. One family member may present during childhood with bilateral retinal detachments while in other members, the disease may manifest as retinal tears in early adulthood.

The ocular findings in STK include progressive myopia with vitreous degeneration, lattice degeneration, and the development of retinal tears [3] (Parma et al. 2002). The myopia tends to be severe and may lead to myopic degeneration (lacquer cracks, pigment epithelial thinning, and choroidal attenuation). The vitreous degeneration occurs at an early age leading to an “optically empty” (transparent) vitreous evident on clinical examination. Perivascular lattice degeneration can be present in a radial and posterior location. Patients are prone to retinal tears, which can occur along the lattice degeneration, resulting in posterior and/or radial tears. Giant retinal tears that span three or more clock hours are not uncommon (Fig. 13.1) [4].

The systemic findings in STK include progressive hearing loss, facial abnormalities, and joint changes. The hearing loss occurs at a young age and is progressive. The facial abnormalities include cleft palate and mandibular hypoplasia, which may result in a characteristic flat facial appearance. The joint changes include joint hypermobility early in the disease course and later degenerative joint changes, which may become disabling. Patients may appear marfanoid in habitus.

Fig. 13.1  Fundus photograph of a giant retinal tear in patient with Stickler syndrome at time of surgical repair

13.1.4  Classification

Classification has been based on vitreoretinal phenotype [3, 5–7]. Type 1 families have the characteristic congenital vitreous anomaly, “membranous vitreous,” and have shown linkage to markers at the COL2A1 locus [6, 8]. Type 2 families have different congenital vitreoretinal phenotypes, “beaded vitreous,” and are usually associated with mutations in the COL11A1 gene encoding the alpha 1 chain of type XI collagen [7, 8]. Recently, reports of families with different correlations in phenotype and genotype have been described, with patients showing type 1 vitreous with mutations in COL11A1 and patients with type 2 vitreous with mutations in COL2A1 gene [5, 9] (Donoso et al. 2002).

13.1.5  Genetics

STK is inherited either as an autosomal dominant disorder with intrafamilial and interfamilial variability of phenotype and almost complete penetrance, or an autosomal recessive disorder (Snead and Yates 1999; Poulson et al. 2004; Edwards 2008). Online mendelian inheritance of man (OMIM) (http://www.ncbi.nih.gov/ sites/entrez) provides links to the genetics of hereditary disorders such as STK (OMIM: 108300, 184840) or other syndromes discussed here (Table 13.1). Patients with STK have been shown to have mutations in three genes that encode different types of procollagen molecules that are expressed in the vitreous. Patients with Type 1 STK have been found to have mutations in the

Type II procollagen gene (COL2A1) on chromosome 12 [6–8, 10–13]. Type XI collagen is also important in the pathogenesis of STK. Patients with mutations in the gene encoding the a−1 chain of type XI collagen (COL11A1) have been shown to have type 2 STK phenotype [6, 8]. An autosomal recessive form of STK has been causally associated with mutations in the COL9A1 gene (van Camp et al. 2006).

13.1.6  Pathophysiology

The secondary vitreous of the human eye occupies a volume of approximately 4.5 mL and is an extensively hydrated gel containing over 98% water. The vitreous is strongly attached at the anterior vitreous base and less well attached to the internal limiting membrane at the posterior pole. Among the macromolecular components of the gel are dilute levels (300 mg/mL total in the human secondary vitreous) of different types of collagens (Types II, IX, and XI) (Bishop 2000; Le Goff and Bishop 2008). These collagens are also the main collagenous components of hyaline cartilage. Type II collagen is fibrillar in nature and contributes to between 60 and 75% of all collagens in the secondary vitreous. Type XI collagen is also fibrillar and contributes between 10 and 25% of the total collagen whereas Type IX collagen is nonfibrillar and contributes up to 25% to the vitreous gel. Heterogeneity in the genotype-phenotype correlation has been shown with the recent findings of mutations in the COL2A1 gene (Type II collagen) in patients having the more common Stickler type 1 (STK1) “membranous” phenotype [5] and mutations in the COL11A1 gene (Type XI collagen) in patients having the less common “beaded” vitreous phenotype in STK type 2 (STK2) [14] (Korkko et al. 1993; Faber et al. 2000; Go et al. 2003; Richards et al. 2000a, 2000b, 2005, 2006; Majava et al. 2007; McAlinden et al. 2008). Mutations in the two fibrillar procollagen genes result in the membranous (Type II) or beaded (Type XI). The type of observable vitreous format in patients suspected of having STK can be used to guide initial gene choices in clinical molecular genetic evaluation.

The nature of vitreous body failures that lead to the ophthalmic problems that occur in STK and Wagner syndrome (see below) must ultimately be understood at the level of the molecular and structural biology of secondary vitreous collagens encoded by genes that

are currently known to be impacted by human mutations in these diseases. All collagens are formed by the interactions of three separate alpha (a) chains to form the triple helical fold of the resultant fibril (Bishop 2000; Le Goff and Bishop 2008; Bornstein 1974). Type II collagen is formed by three identical molecules of Type II a procollagen. Type XI collagen may be formed by two molecules of a-Type XI procollagen and a single molecule of related a-Type V collagen. The Types II and XI collagens form fibrillar collagens. Type IX procollagen, encoded by COL9A1 gene, does not form fibrils on its own and has a structure in which collagenous triple helix forming domains are interrupted by globular domains. Collagen IX is modified with chondroitin sulfate (CS) residues, which is important­ for the interactions between the fibrillar components of the collagen fibrils. The components of a-procollagens that form the triple helical structures are composed of a repeat motif Gly-X-Y where Gly is glycine and X and Y can be any amino acid but are commonly proline and hydroxyproline, which serve to

stabilize the triple helical structure. There are additional amino-terminal and carboxyl-terminal components of the procollagens that reside at the boundaries of the longer components that will form the triple helix. Procollagens are made in cells and secreted into the extracellular space where they are processed by enzymes that remove the N-terminal and C-terminal components, thus freeing the triple helix forming components to interact with resultant short end pieces. The removal of the terminal ends reduces the solubility of the procollagens and allows the collagenous components to interact effectively to form triple helices that become the primary fibrils of vitreous collagen. The two exposed ends of the fibril permit interaction and cross linking to other collagen triple helical fibrils. The collagenous fibers in the vitreous are heterotypic meaning that they form from the interaction of different types of collagens (Types II, IX, and XI). These three collagens, as well as other proteinaceous and glycosaminoglycan components (e.g., fibrillin, opticin, hyaluronic acid, CS), interact to form the body of the

vitreous. It is critical that the heterotypic collagenous fibrils that make up the critical-formed component of the secondary vitreous gel maintain a nonaggregated state (Bos et al. 2001). Aggregation effectively removes formed collagens from the gelled distribution and creates predominantly fluid filled cavities, which are the basis for coalescing syneresis, which is a phenotypic feature of these syndromes.

The impact of human mutations on the secondary vitreous gel in STK (and Wagner) syndromes must be considered in the context of how the structure is formed and turned over, to the extent of current knowledge, and an awareness of the mechanisms and constraints that genetic mutations can place upon the biological system that is observed. Given that the mutational impacts are for the most part congenital in STK syndrome, the initial realization of the complete volume of the secondary vitreous appears to be impacted by such mutations. Most of the autosomal dominant STK1 (type 1) STK mutations in COL2A1 create premature stop codons. The mRNAs of these mutant alleles are removed by a surveillance mechanism, called nonsense mediated decay, such that a truncated polypeptide is not synthesized from the mRNA transcribed by the mutant alleles. Given that the Type II collagen molecules occupy the sheer bulk (up to 75%) of the essential formed components of the vitreous gel, the loss of effectively 50% of the synthesis of the wild type a-procollagen 2A molecules can be understood to exert a profound effect on the primary ability to build a secondary vitreous body, or to maintain it at the likely low rate of molecular renewal that is currently expected. The inability to form the correct vitreous system under the constraints of this type of mutation is described as functional haploinsufficiency, or that the single functional wild type allele is unable to produce a sufficient amount of normal protein to guarantee the assembly of the native secondary vitreous gel system. However, missense mutations that alter the coding sequence of Types II and XI collagens can also promote autosomal dominant STK. Clearly, the random appearance of a mutation at a critical region of the collagen molecule, for example, a region involved in the triple helix formation or at the termini used for cross linking or essential posttranslational modification, can lead to an altered behavior or stability of the mutant protein that can impact its interactions with other collagen molecules, other proteins, or glycosaminoglycans in the vitreous body. Similarly,

mutations that alter mRNA intron splicing patterns can lead to the removal of essential exons that subserve critical functions involved in intramolecular or intermolecular interactions. These mutant proteins can also affect the trafficking, stability, or secretion of the normal protein expressed from the nonmutated allele in a process called a dominant negative effect. Thus, missense mutations and splicing mutations can also severely impact the initial formation and stability of the secondary vitreous body as a system (Korkko et al. 1993; Go et al. 2003; Donoso et al. 2003; Richards et al. 2005, 2006; McAlinden et al. 2008).

The discussion raised with respect to COL2A1 mutations pertains as well to mutations in COL11A1 and COL9A1 genes that encode procollagens XI and IX that are involved in the formation of the secondary vitreous gel but are expressed at lower levels. Knowledge about the composition and structure of the heterotypic secondary vitreous fibers is still growing (Bishop 2000; Le Goff and Bishop 2008; Edwards 2008). Fibrillar collagen XI appears to play a structural role in forming the secondary vitreous gel but is expressed to lower levels than type II collagen. Mutations in COL11A1 are known to cause autosomal dominant STK type II syndrome in which the vitreal syneresis is characterized by a beaded pattern (Majava et al. 2007). The mutational impact on secondary vitreous gel formation is likely to be related to either the lack of sufficient wild type material or the impact of mutant proteins on the formation of the secondary gel, likely in unique ways depending upon the nature of the mutational impact at the protein level. Collagen IX is not fibrillar and is interrupted by noncollagenous regions to which glycosaminoglycans can be covalently attached. Because of its nonfibrillar structure, collagen IX may play a more modulatory role in the emergence of the secondary vitreous. It has been suggested that collagen IX coats the surface of the heterotypic fibers and the covalently attached side chain glycosaminoglycans (e.g., CS) allow interfiber bridges to form that allow the fibrillar material to remain in a gel state and not become aggregated. An autosomal recessive nonsense mutation in the COL9A1 gene, in the homozygous state, was recently identified as associated with STK (van Camp et al. 2006). The disease presumably originates from the lack of formation of collagen IX (haploinsufficiency), and indicates a critical role for this protein in the formation of the secondary vitreous body.