DEFINITION
Wagner disease is a rare hereditary vitreoretinopathy characterized by an anomaleous vitreous associated with myopia, cataract, chorioretinal atrophy, and peripheral tractional or rhegmatogenous retinal detachment.
EPIDEMIOLOGY
About 100 patients with Wagner syndrome from only a few pedigrees have been described in the literature. Not more than 50 families or simplex cases of VCAN-related vitreoretinopathy have been reported, including families with ERVR (erosive vitreoretinophathy). Wagner syndrome is a very rare disorder.
SYMPTOMS
Wagner disease is also called VCAN-related vitroretinopathy because is characterized by:
* “Optically empty vitreous" on slit-lamp examination and avascular vitreous strands and veils
* Mild or occasionally moderate to severe myopia
* Presenile cataract
* Night blindness of variable degree associated with progressive chorioretinal atrophy
* Retinal traction and detachment at advanced stages of the disease
* Reduced visual acuity resulting from the above manifestations
* Absence of systemic abnormalities
Not every clinical finding listed above is observed in every affected individual. The hallmark, however, is the empty vitreous.
VCAN-Related Vitreoretinopathy, 2012
THE GENE
CHEMICAL STRUCTURE AND IMAGES
Wagner disease is a connective tissue disorder affecting the collagen and is associated with mutations in the CSPG2 or VCAN gene (5q13-q14). The human VCAN gene contains 15 exons spanning more than 90 kb. One of these, exon 7, is used in an alternative splice variant.
VCAN, encoding the large extracellular matrix proteoglycan versican, is the only gene in which mutations are known to cause Wagner syndrome and erosive vitreoretinopathy (ERVR). VCAN encodes chondroitin sulfate proteoglycan-2, also known as versican. Versican constitutes 5-15% of the total protein content of the vitreous gel. It is a large proteoglycan that forms large complexes by binding to hyaluronic acid and other vitreous structural molecules.
Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. Versican is a large chondroitin sulfate proteoglycan with an apparent molecular mass of more than 1000kDa. Versican belongs to the lectican protein family, with aggrecan (abundant in cartilage), brevican and neurocan (nervous system proteoglycans) as other members. Versican is also known as chondroitin sulfate proteoglycan core protein 2 or chondroitin sulfate proteoglycan 2 (CSPG2), and PG-M. These proteoglycans share a homologous globular N-terminal, C-terminal, and glycosaminoglycan (GAG) binding regions. The N-terminal (G1) globular domain consists of Ig-like loop and two link modules, and has Hyaluronan (HA) binding properties. Versican occurs in 4 isoforms : V0, V1, V2, V3. The central domain of versican V0 contains both the GAG-α and GAG-β domains. V1 isoforms has the GAG-β domain, V2 has the GAG-α domain, and V3 is void of any GAG attachment domains. The GAGs, being composed of repeating disaccharide units, contribute to the negative charge and many other properties of proteoglycans. The C-terminal (G3) globular domain consists of one or two Epidermal growth factor (EGF) repeats, a C-type lectin domain and complement regulatory protein (CRP)-like domain. The C-terminal domain binds a variety of ligands in ECM which contribute significantly to the functions of lecticans. The role of versican in cell adhesion, migration, and proliferation is extensively studied. Versican is often considered an anti-adhesive molecule. Considering the large size (>1000 kDa) and hydration capability of versican, it is possible that the interaction of integrins (large family of cell adhesion molecules) with their cell surface receptors is sterically hindered.
De novo splice mutation in the versican gene in a family with Wagner syndrome, 2013
DIAGNOSIS
The diagnosis is based on clinical features. Molecular analysis of mutations confirms the diagnosis. The differential diagnosis is with Stickler's disease, the disease Goldmann Favre, the familial exudative vitreoretinopathy, the vitreous coroidoretinopatia autosomal dominant (ADVIRC), the autosomal recessive vitreoretinopathy and Jansen's disease.
Mutation in collagen II alpha 1 isoforms delineates Stickler and Wagner syndrome phenotypes, 2013
PATHOGENESIS
VCAN-related vitreoretinopathy comprises the phenotypic continuum of Wagner vitreoretinal degeneration (Wagner syndrome) and erosive vitreoretinopathy (ERVR), two disorders that were previously thought to be distinct entities based on clinical findings. Wagner syndrome, the first reported inherited vitreoretinal degeneration, was described by Wagner [1938]. ERVR was described in 1994 as a new clinical entity with some features that overlapped with Wagner syndrome. Once the molecular basis of Wagner syndrome, originally described by Wagner in 1938, and ERVR, originally described by Brown and colleagues in 1994, was identified, the high similarity of the clinical phenotypes and the fact that both were caused by mutations in the same gene led to the conclusion that both were descriptions of the same disorder, which has been called VCAN-related vitreoretinopathy.
VCAN-Related Vitreoretinopathy, 2012
Vitreus body
The vitreous body is a connective tissue transparent gelatinous structure, colorless, non-vascularized nor innervated. It occupies about 4/5 of the ocular volume. It contributes to the shape and size of the bulb.
This disease (vitreoretinal degeneration), attacking and degrading versican and collagen fibrils cause:
1) Vitreous liquefaction or fluidization
Sinchisi starts at the rear of the vitreous body and then spread to the entire vitreous
Formation of gaps vitreous (optically empty cavities)
In lacunar cavity (empty vitreous) are aggregates of collagen fibers and hyaluronic acid depolymerized
The fluid is given by the depolymerization of hyaluronic acid which increases with age (after 80 years, more than half of the gel is fluidized)
2) Vitreous syneresis
The collagen fibrils that make up the gaps are broken and formed floating filaments of different shapes and sizes within areas of vitreous liquefaction (floaters)
These filaments are described by the patient as "flying flies".
3) Rear vitreous detachment:
The vitreous liquefied, through the holes of the rear cortex, it leads in space retroialiodeo. There is a close correlation between retinal tear and DPV (the incidence of retinal tears in patients with vitreous degeneration is 10-15%, and 80% of patients with retinal tear has DPV)
Genetics of hereditary vitreoretinal degenerations, 2007
PATIENT RISK FACTORS
Wagner disease is inherited as an autosomal dominant trait with near complete penetrance but variable expressivity. Wagner syndrome has been reported in families of various ethnic backgrounds including white, northern European, Japanese, and Chinese.
THERAPY
- Refractive error is corrected by spectacles or contact lenses.
- Visually disabling cataract is treated by cataract surgery. Phacoemulsification and implantation of an intraocular lens in the capsular bag has become the widely adopted standard procedure; however, cataract surgery in patients with vitreoretinopathy and possibly preceding vitrectomy can be difficult and should be performed by an experienced surgeon.
- Posterior capsule opacification after cataract surgery is treated with YAG laser capsulotomy.
- Retinal breaks are treated with laser retinopexy or cryocoagulation if no retinal detachment is present.
- Vitreoretinal surgery is indicated for retinal detachment, vitreoretinal traction involving the macula, or epiretinal membranes involving the macula.
- Annual ophthalmologic examination by a vitreoretinal specialist is indicated.
VCAN-Related Vitreoretinopathy, 2009
Tricarico Lucia, Palagi Silvia
