corneal erosions

Corneal Dystrophy, Epithelial Basement Membrane

Clinical Characteristics
Ocular Features: 

The clinical appearance of the cornea in this disorder is non-specific with features found in as many as 75% of older individuals who do not have a corneal dystrophy. Some of the clinical findings are also found in other dystrophies such as Meesmann (122100), Reis-B?ocklers (608470), Lisch dystrophy (300778), lattice type I (122200), and Thiel-Behnke (602082).  The common feature in all these is the formation of microcysts in the epithelium with alterations in the basement membrane.  The pattern is sometimes described as a map-dot-fingerprint dystrophy.  Corneal erosions occur in all to some degree and vision is minimally impacted.  Many patients are asymptomatic unless corneal erosions occur.

Hereditary Cogan microcystic corneal dystrophy is sometimes diagnosed in the first decade of life but more characteristically found in people over the age of 30.  The corneal changes wax and wane and are highly variable between patients.  The dots consist of pseudocysts filled with intracellular debris while the geographic patterns are generated by multilayered basement membrane extensions into the epithelium.  The rupture of these cysts results in corneal erosions.  The underlying defect likely consists of defects in hemidesmosomal junctions.

Systemic Features: 

No systemic disease is associated with this corneal dystrophy.

Genetics

Many individuals with some findings of microcystic dystrophy have no family history of the disease and, as noted above, these are common in older people.  However, autosomal dominant pedigrees have been reported with typical corneal lesions among family members of all ages.  Several point mutations in the TGFBI gene on chromosome 5 (5q31) have been found but this likely accounts for only a small proportion of cases.  Mutations in the same gene have been found in other corneal dystrophies as well (lattice dystrophy I, granular dystrophy, Thiel-Behnke dystrophy, Reis-Bucklers, and combined lattice-granular dystrophy or Avellino type).

Genomic studies will likely clarify the current confusing nosology.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Most patients require no treatment.  Persistent epithelial erosions can be treated with hypertonic solutions or bandage lenses.

References
Article Title: 

Corneal Dystrophy, Meesmann

Clinical Characteristics
Ocular Features: 

Meesmann corneal dystrophy is a disorder of the epithelium and its basement membrane.  Onset is early, even in the first year of life and begins with irritation and often photophobia.  However, some patients remain asymptomatic for many years.  Vision is usually impacted only to a mild degree as a result of surface irregularities and epithelial cysts, which are concentrated most commonly in the interpalpebral regions.  They may only be visible with slit lamp examination. The cysts are usually in the basal cells and are filled with PAS positive material. They may coalesce to form refractile lines and later in life become more opaque. The basement membrane appears coarse and is often abnormally thick.  Bowman layer and the stroma are unaffected.  Corneal sensitivity is reduced.

Stocker-Holt dystrophy (122100) is often lumped with Meesmann dystrophy and, while it is a clinically similar disease, it is usually caused by a different mutation.  The 20 patients reported by Stocker and Holt in 1954 were descendents from Moravia who settled in North Carolina (Meesmann and Wilke's report in 1939 was based on patients in Holstein, Germany).

Systemic Features: 

No systemic disease is associated with this dystrophy.

Genetics

This is a genetically heterogeneous autosomal dominant disorder resulting from mutations in several genes encoding cornea-specific keratins, K12 by KRT12 (similar to Stocker-Holt dystrophy; 122100) and K3 by KRT3 (Meesmann dystrophy) located on chromosomes 17 (q12) and 12 (q13), respectively.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses are poorly tolerated and keratoplasty is rarely indicated.  Treatment is largely directed at symptoms with hypertonic solutions and sometimes with epithelial debridement.  The cystic changes tend to recur following removal of the offending epithelium and even after corneal replacement.

The Arg135Thr mutation in the KRT12 gene found in the German family reported by Meesman and Wilke in 1939 (and a common founder mutation in Europe) can be selectively silenced in vitro by an allele-specific short interfering RNA (siRNA) suggesting a novel approach to therapy.

References
Article Title: 

Alport Syndrome (Collagen IV-Related Nephropathies)

Clinical Characteristics
Ocular Features: 

X-linked Alport syndrome is a basement membrane disease with important ocular manifestations.  The lens is usually normal at birth but lens opacities eventually occur in a significant number of individuals with the most characteristic type being anterior polar in location.  Involvement of the anterior lens capsule often results in bilateral anterior lenticonus (25%) and may be progressive.  It is claimed that the severity of the lenticonus is a valuable marker in judging the overall disease severity.  In early stages it may be difficult to detect but its presence is suggested by an 'oil droplet' reflex during retinoscopy or slit lamp examination.  All males with anterior lenticonus should be evaluated for Alport syndrome. 

Posterior polymorphous corneal dystrophy and posterior subcapsular opacities have also been noted.  The defect in basement membranes may lead to recurrent corneal erosions, even in children, which can be incapacitating and difficult to treat.  Involvement of Bruch's membrane has been considered the source of retinal pigment epithelial changes described as a flecked retina, or 'fundus albipunctatus', found in 85% of patients.  More recent evidence using OCT suggests that the dot-and-fleck retinopathy results primarily from abnormalities in the internal limiting membrane and the nerve fiber layer.  The yellowish and/or whitish flecks are most commonly located in the posterior pole and particularly in the macula.  There is no night blindness or visual impairment from the retinal involvement.  Fluorescein angiography shows patchy areas of hyperfluorescence.  The amount of visual impairment depends primarily on the extent of lens involvement.

Termporal macular thinning occurs to some extent in all types of Alport syndrome based on OCT findings.   In one series all patients with X-linked disease had temporal thinning suggesting that this might be a useful diagnostic sign.  However, similar thinning is also seen in Leber hereditary optic neuropathy (535000), and dominant optic atrophy (165500).

Systemic Features: 

Nephritis with hematuria secondary to basement membrane disease of the glomeruli is the most life threatening aspect of this disorder.  It occurs in both sexes but more commonly in males in which it has an earlier onset.  Progressive sensorineural hearing loss beginning with high frequencies occurs in many patients, often with subtle onset in childhood, but many adults retain some hearing capacity.  In males, the onset of hearing loss often occurs before kidney disease is evident.  Hearing loss is less frequent and less severe in females.  However, there is considerable clinical and genetic heterogeneity and not all patients have the complete syndrome of nephritis, deafness and ocular disease.  In fact, it has been suggested that Alport syndrome can be subtyped into at least six categories based on the extent of organ involvement.

Genetics

Alport syndrome is a member of a group of disorders known as collagen IV-related nephropathies.  It is a genetically heterogeneous disease with 85% inherited in an X-linked pattern and most of the remainder occurring in an autosomal recessive pattern and only a few seemingly autosomal dominant.  All result from a defect in type IV collagen found in basement membranes.  About 80% of cases have a mutation in the COL4A5 gene which is located at Xq22.3.  Males seem to be more severely affected than females in the X-linked form of the disease but clearly this disorder affects both sexes reflecting the genetic heterogeneity, much of which remains to be delineated.  The autosomal disease generally results from mutations in the COL4A3 or COL4A4 genes and has been seen in both recessive and dominant patterns of transmission.

Pedigree: 
Autosomal dominant
Autosomal recessive
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Renal transplantation can be lifesaving but a minority of individuals develop a specific antiglomerular basement membrane antibody (anti-GBM) that may lead to graft rejection.  Allograft survival rates are generally excellent though.  Lens extraction is beneficial where the media is compromised.

References
Article Title: 

Alport syndrome: a genetic study of 31 families

M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L,
Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic
study of 31 families. Hum Genet. 1992 Dec;90(4):420-6.

PubMed ID: 
1483700

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