corneal dystrophy

Corneal Dystrophy, Fuchs Endothelial, Early Onset

Clinical Characteristics
Ocular Features: 

This is one of several adult onset corneal endothelial dystrophy (see Fuchs endothelial corneal dystrophy, late onset, (610158) for more forms of adult Fuchs endothelial dystrophy).  The onset of this type is considerably earlier than in the more common adult onset type (610158) .  Endothelial disease has been noted as early as three years of age but onset is likely later than in the congenital forms (CHED1; 121700), (CHED2; 217700).  In early onset Fuchs dystrophy, most individuals have evident disease by the third and fourth decades and many have advanced disease by the fourth and fifth decades.  The sex ratio among affected individuals is closer to 1:1 in this disorder compared with the more common adult onset type in which the disease is more common in females.

In this early onset disorder the guttae are small and more rounded than those in the later onset endothelial dystrophies, and are closer to the center of the endothelial cells.  The progression of corneal decompensation is temporally similar to that of the late onset dystrophies, resulting in clinically advanced disease within 3 to 4 decades.  The progression of disease has been documented through quantifying the number of guttae over time.   Among 26 patients, the number increased as much as 29.1% over a 30 month period, and an exponential increase was noted after age 50 years.  The inferotemporal quadrant of the cornea had the greatest proportion of guttae.  As in other forms of endothelial corneal dystrophy, Descement's  membrane is thickened and exhibits nodularity with secondary apoptosis of endothelial cells.

Systemic Features: 

None have been reported.

Genetics

A mutation in the COL8A2 gene, L450W, located on chromosome 1 (1p34.3-p32.3) seems to be responsible for this disease.  The gene codes for the alpha-2 chain of collagen VIII which is an important component of Descemet's membrane.  Like many other collagen diseases, this disorder is transmitted as an autosomal dominant.

This gene is also mutant in posterior polymorphous corneal dystrophy 2 (609140) and both types of dystrophy have been reported in the same family suggesting they may be the same disorder with variable expressivity.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation is the treatment of choice for advanced disease.

References
Article Title: 

Missense mutations in COL8A2,the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy

Biswas S, Munier FL, Yardley J, Hart-Holden N, Perveen R, Cousin P, Sutphin JE, Noble B, Batterbury M, Kielty C, Hackett A, Bonshek R, Ridgway A, McLeod D,Sheffield VC, Stone EM, Schorderet DF, Black GC. Missense mutations in COL8A2,the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. 2001 Oct 1;10(21):2415-23.

PubMed ID: 
11689488

Inheritance of Fuchs' combined dystrophy

Magovern M, Beauchamp GR, McTigue JW, Fine BS, Baumiller RC. Inheritance of Fuchs' combined dystrophy. Ophthalmology. 1979 Oct;86(10):1897-923.

PubMed ID: 
399801

Harboyan Syndrome

Clinical Characteristics
Ocular Features: 

The combination of congenital endothelial dystrophy and progressive neural deafness is known as Harboyan syndrome.  This disorder must be distinguished from another autosomal recessive disorder, congenital endothelial dystrophy 2 or CHED2 (217700), in which deafness does not occur.  While the corneal disease in Harboyan is present at birth, the deafness often does not become obvious until the second and third decades of life although audiometry can detect some hearing loss in the first decade.  The cornea is thickened and edematous resulting in various degrees of visual impairment, even to the level of counting fingers.  Electrophysiologic studies have been normal.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder caused by a mutation in the SLC4A11 gene located on chromosome 20 (20p13-12).  It is allelic to simple, congenital endothelial corneal dystrophy (CHED2) (217700).  About half of reported cases occur sporadically and the rest have been reported in offspring of consanguineous matings.  Less than 30 cases have been reported worldwide.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Corneal transplantation is the treatment of choice and can result in substantial visual improvement.

References
Article Title: 

Congenital hereditary endothelial dystrophy with

Desir J, Abramowicz M. Congenital hereditary endothelial dystrophy with
progressive sensorineural deafness (Harboyan syndrome).
Orphanet J Rare Dis. 2008 Oct 15;3:28. Review.

PubMed ID: 
18922146

Congenital corneal dystrophy

Harboyan G, Mamo J, Kaloustian V der, Karam F. Congenital corneal dystrophy.
Progressive sensorineural deafness in a family.
Arch Ophthalmol. 1971 Jan; 85(1):27-32.

PubMed ID: 
5312820

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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