corneal opacities

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: 

Tangier Disease

Clinical Characteristics
Ocular Features: 

This disorder of lipoprotein metabolism is associated in many cases with corneal infiltrates, cicatricial ectropion, poor lid closure, and exposure keratopathy.  The corneal clouding alone generally cause little reduction of acuity but those with poor lid function and exposure keratopathy may have severe vision loss.  There may be weakness in the periorbital and lid muscles.  The corneal infiltration occurs late in life but is progressive with older individuals having the greatest visual impairment.  The corneal infiltrates are described as a “dot-like haze”, more prominent centrally and located in the stroma.  On electron microscopy, deposits in the conjunctiva are described as birefringent lipid particles located in pericytes and fibrocytes.  Lipid deposition occurs throughout the body including the conjunctiva.  Corneal hypesthesia has been reported.

In a series of 13 patients, ectropion and corneal scarring were reported in 3 and corneal infiltrates in 9.  Four had orbicular muscle weakness.  The latter together with corneal hypesthesia may be the earliest ocular signs of Tangier disease and should suggest the diagnosis even before the corneal clouding occurs.

Systemic Features: 

Patients with Tangier disease have significant enlargement of the liver, spleen and lymph nodes.  The tonsils are also frequently enlarged and have a characteristic yellow-orange  coloration.  The enlargement of these organs is due to lipid infiltration.  Plasma levels of cholesterol and HDL are characteristically slightly low while triglycerides are mildly elevated.  Peripheral neuropathy and muscle atrophy can be debilitating.  Severe coronary artery disease is common with onset sometime in the 5th decade.

Genetics

Tangier disease is an autosomal recessive disorder resulting from mutations in the ATP-binding cassette-1 gene ABCA1 (9p31.1) located in exon 22.  Parental consanguinity is common.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder beyond local organ treatment as indicated.
 

References
Article Title: 

Ocular complications of Tangier disease

Pressly, T. A.; Scott, W. J.; Ide, C. H.; Winkler, A.; Reams, G. P. : Ocular complications of Tangier disease. Am. J. Med. 83: 991-994, 1987.

PubMed ID: 
3314502

LCAT Deficiency

Clinical Characteristics
Ocular Features: 

Norum disease and fish-eye disease are discussed as a single entry in this database because they are both caused by mutations in the same gene (LCAT).  Most patients are diagnosed as young adults.  Corneal opacities are may be the only clinically significant abnormality in fish-eye disease whereas anemia and renal complications are more significant in Norum disease.   Lipid deposition in the cornea is responsible for the corneal opacities and may cause significant reduction in vision.  However, opacities are concentrated near the limbus.  The cornea in fish-eye disease has twice the normal amount of cholesterol and vacuoles in the stroma and Bowman's.  Vision ranges from 20/40 to hand motions, with onset in the first two decades and progression throughout life.  The opacities form a mosaic pattern of small dot-like grey-white-yellow opacities.  The fish-eye designation comes from the corneal clouding resembling boiled fish eyes.

Systemic Features: 

Lecithin:cholesterol acyltransferase (LCAT) is a disorder of lipoprotein metabolism resulting in reduced plasma cholesterol esterifying activity.  The mutation leading to Norum disease causes normocytic hemolytic anemia with significant proteinuria secondary to renal failure.  However, patients with fish-eye disease do not have anemia or renal disease.  Red blood cells may have increased cholesterol content and foam cells are found in bone marrow and in the glomerular tufts of the kidney.  Peripheral neuropathy is sometimes present.   Circulating cholesterol, triglycerides and phospholipids are elevated whereas high-density lipoprotein (HDL), apoA-I and apoA-II are reduced.  However, premature atherosclerosis is not a feature contrary to expectations.  

LCAT deficiency does not have hepatomegaly, splenomegaly or enlarged lymph glands as found in another disorder of lipoprotein metabolism with low HDL levels known as Tangier disease (205400).

Genetics

Complete LCAT deficiency (Norum) disease and partial deficiency (fish-eye disease) are autosomal recessive disorders secondary to mutations in the LCAT gene located on chromosome 16 (16q22.1).  The mutation is located in codon 123 in fish-eye disease and in codon 4 of Norum disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severe visual impairment secondary to corneal clouding is an indication for corneal transplantation.  Renal failure may require renal transplantation.
 

References
Article Title: 

Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin:cholesterol acyltransferase deficiency and fish-eye disease.

Rader, D. J.; Ikewaki, K.; Duverger, N.; Schmidt, H.; Pritchard, H.; Frohlich, J.; Clerc, M.; Dumon, M.-F.; Fairwell, T.; Zech, L.; Santamarina-Fojo, S.; Brewer, H. B., Jr. : Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin:cholesterol acyltransferase deficiency and fish-eye disease. J. Clin. Invest. 93: 321-330, 1994.

PubMed ID: 
8282802

A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.

Funke, H.; von Eckardstein, A.; Pritchard, P. H.; Albers, J. J.; Kastelein, J. J. P.; Droste, C.; Assmann, G. : A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.  Proc. Nat. Acad. Sci. 88: 4855-4859, 1991.

PubMed ID: 
2052566

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