corneal haze

Neuraminidase Deficiency

Clinical Characteristics
Ocular Features: 

A cherry red spot is may be seen in late childhood or early adolescence.  It occurs in nearly 100% of patients with type I while only 75% of type II patients have this feature possibly because their early death from the more severe systemic disease prevents full ascertainment.  Visual acuity is reduced, sometimes severely.  Some but not all individuals have corneal and lens opacities.  A subtle corneal haze has also been seen.  Nystagmus has been reported. 

Systemic Features: 

This is a neurodegenerative disorder with progressive deterioration of muscle and central nervous system functions.  Myoclonus, mental deterioration, hepatosplenomegaly, muscle weakness and atrophy are common.  The defect in neuraminidase activity leads to abnormal amounts of sialyl-oligosaccharides in the urine.  Spinal deformities such as kyphosis are common.  Deep tendon reflexes are exaggerated.  Ataxia and hearing loss may be present.  Coarse facies, a barrel chest, and short stature are characteristic.  Hepatic cells contain numerous vacuoles and numerous inclusions.

Sialidosis types I and II are both caused by mutations in the neuroaminidase gene.  Type I is associated with milder disease than type II which has an earlier age of onset and may present in infancy or even begin in utero.  Early death within two years of age is common in the congenital or infantile forms.  There is, however, significant variability in age of onset and the course of disease among types. 

Genetics

The sialidoses are autosomal recessive lysosomal storage disorders resulting from mutations in the NEU1 gene (6p21.3) which lead to an intracellular accumulation of glycoproteins containing sialic acid residues.  Both types I and II are caused by mutations in the same gene. 

Treatment
Treatment Options: 

Treatment is focused on symptom management. 

References
Article Title: 

Corneal Dystrophy, Reis-Bücklers

Clinical Characteristics
Ocular Features: 

This is an anterior corneal dystrophy involving the epithelium and Bowman membrane.  Opacities consisting of spots and lines form in the central portion of the anterior cornea creating haziness with relative sparring of the periphery.  These can be seen as early as 4-5 years of age but few symptoms occur until the epithelium breaks down causing painful corneal erosions.  Visual acuity eventually drops as the corneal haze increases along with increasing irregularity of the epithelial surface.

Ultrastructural studies reveal degenerative changes in all epithelial cells and almost complete Bowman membrane replacement with disoriented collagen fibrils.

A comparative histological study of Reis-Bucklers and Thiel-Behnke dystrophies concluded that these are distinct CDB (corneal dystrophy Bowman) disorders and suggested the former be called CDB type I, and the latter CDB type II.  Type II is considered unique on the basis of the ‘curly’ fibers seen in the Bowman and subepithelial layers, while type I has bandshaped granular Masson-positive subepithelial deposits and ‘rod-shaped bodies’ resembling granular dystrophy.  Type I described here generally leads to greater vision loss than type II.

Systemic Features: 

No systemic disease is associated with Reis-Bucklers corneal dystrophy.

Genetics

This disorder seems to be closely related to the more common Thiel-Behnke dystrophy as the corneal disease is caused in both cases by missense mutations in the TGFBI gene on chromosome 5 (5q31). The mutation in Reis-Bucklers results in a p.Arg124Leu amino acid substitution whereas most cases of Thiel-Behnke dystrophy are the result of a p. Arg555Gln substitution.  Both disorders are inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ablation of the diseased cornea can improve vision and provide temporary relief from the erosions.

References
Article Title: 

Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature

Kuchle M, Green WR, Volcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bucklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995 Jul;14(4):333-54. Review.

PubMed ID: 
7671605

Corneal Dystrophy, Subepithelial Mucinous

Clinical Characteristics
Ocular Features: 

This disorder, reported so far in a single family, is an anterior corneal dystrophy with onset in the first decade of life.  The frequency of epithelial erosions tended to subside during adolescence but visual acuity continued to decline secondary to subepithelial nodular opacities and a generalized haze most dense centrally. No geographic lines are present and cystic changes in the epithelium were absent.  Bowman layer and deeper stuctures of the cornea are unaffected. Patients may have 20/30 vision into the fifth decade but after that it may decrease into the 20/400 range.  EM revealed accumulations of subepithelial fibrillar material.  Light microscopy and immunohistochemistry showed the material to be chondroitin-4-sulfate and dermatan sulfate.

Systemic Features: 

No systemic disease association has been reported.

Genetics

In the single 3 generation family reported, the pattern of inheritance was consistent with autosomal dominant inheritance.  No locus or mutation has been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual treatment for acute corneal erosions might be beneficial but other treatments have not been reported.  Penetrating keratoplasty and superficial keratectomy have been used on several patients but followup is not available.

References
Article Title: 

Corneal Dystrophy, Recurrent Epithelial Erosions

Clinical Characteristics
Ocular Features: 

Individuals have the onset of recurrent corneal erosions as a result of as yet unknown disease processes.  Onset is in the first decade of life (even in the first year of life)  often with some subepithelial haze or blebs while denser centrally located opacities develop with time.  Erosions often are precipitated by relatively minor trauma and are often difficult to treat, lasting for up to a week.  Fortunately, the erosions become less frequent as patients age and may cease altogether by the fifth decade of life.

Systemic Features: 

No systemic disease is associated with ERED.

Genetics

The few reported families have all had an autosomal dominant pattern of inheritance.  So far no locus or molecular defect has been identified.

The clinical features of this condition are found in other corneal dystrophies and it is likely that at least some of the reported cases may have had other unrecognized corneal conditions.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual corneal erosion treatment of hypertonic solutions, bandage patching, and lubricating ointments may be helpful for acute erosions.  No long term preventative treatment has been found effective.  Corneal transplants remain clear centrally although peripheral opacities may reappear within a few years.

References
Article Title: 

Franceschetti Hereditary Recurrent Corneal Erosion

Lisch W, Bron AJ, Munier FL, Schorderet DF, Tiab L, Lange C, Saikia P, Reinhard T, Weiss JS, Gundlach E, Pleyer U, Lisch C, Auw-Haedrich C. Franceschetti Hereditary Recurrent Corneal Erosion. Am J Ophthalmol. 2012 Mar 7. [Epub ahead of print].

PubMed ID: 
22402249

Fabry Disease

Clinical Characteristics
Ocular Features: 

Fabry disease is a lysosomal enzyme (alpha-galactosidase A) deficiency resulting in the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids throughout the body.  The signature ocular manifestation is the whorl-like corneal pattern of lipid (glycosphingolipid) deposits which are present in both hemizygous males and heterozygous females.  These are sometimes referred to as cornea verticillata or Fleischer vortex dystrophy with a pattern similar to that seen in some patients using atabrine or amiodarone.  A general 'haze' throughout the cornea is even more common.  Lens opacities may also be distinctive and generally are one of two types: spoke-like opacities beneath the posterior capsule among males, and wedge-shaped anterior subcapsular deposits, again primarily in males.  The corneal and lens opacities seldom cause significant vision problems.

Involvement of the ocular vessels is present in almost all patients.  A notable increase in tortuosity of conjunctival vessels is present in 97% of hemizygous males and 78% of heterozygous females.  Increased retinal vessel tortuosity is less common but arteriolar involvement significantly increases the risk of central retinal artery occlusions.  An 11 yo Turkish female heterozygote with a cilioretinal artery occlusion and anterior ischemic optic neuropathy in one eye has been reported.

Systemic Features: 

The relatively common occurrence and the protean nature of Fabry disease has lead to its designation by some as the Great Imposter, replacing syphilis to which this term was previously applied.  Compounding the diagnostic difficulties in some individuals is the absence of the complete classical phenotype due to the presence of DNA variants that may modify the expression of some the clinical features.

Most signs present in the first or second decade of life with generally earlier onset in males.  The presence of proteinuria before the age of 20 years in the absence of other primary kidney disease should always raise the possibility of Fabry disease.  However, the diagnosis is often not made until the third decade in males and the fourth decade in females.  Glycosphingolipid inclusion deposits in endothelial cells are responsible for the systemic signs and symptoms including renal and heart disease which are the most common causes of premature death.  Small vessel involvement resulting in cerebrovascular disease and painful peripheral neuropathy can be debilitating. The risk of ischemic strokes is increased.  Cardiac manifestations include hypertrophic cardiomyopathy (60%), mainly involving the left ventricle, and dysfunction of the mitral and aortic valves (10 to 25%).  Dysfunction of renal glomeruli may progress to renal failure by the third to fifth decade in males.  The angiokeratomas and angiomas (most pronounced in a swimming trunk pattern) are secondary to vascular involvement of cutaneous vessels but are non-specific since they also occur in other lysosomal diseases.  The life expectancy of females is reduced by about 5 years and for males about 16 years compared with the general US population.

Involvment of the autonomic system manifests as intermittent fever, hypohidrosis, and poor temperature control.  Some patients have periodic crises of severe pain in the extremities as well as intermittent epigastric pain. Hearing loss and episodic tinnitus are common complaints.

Genetics

This is an X-linked disorder and generally assumed to be recessive although some have suggested dominance since most heterozygous females have significant manifestations that can be life-threatening.  The mutations in the responsible gene (GLA), located at Xq22, involve a variety of deletions, rearrangements and single base pair changes.  Defects in the GLA gene lead to dysfunction of the enzyme alpha-galactosidase A resulting in lysosomal deposition of glycosphingolipids throughout the body, especially in vascular endothelial cells.   

The milder disease and increase in the range of clinical manifestations among females is likely a reflection of variable patterns of X-inactivation.

Increased tortuosity of retinal arterioles is also seen in fucidosis (230000), Williams syndrome (194050), and in a condition known as retinal arteriolar tortuosity (611773, 180000).

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

Enzyme replacement therapy using agalsidase alfa (commercially available as Febrazyme (tm)) have shown promise as measured by renal function, pain intensity, left ventricular size, and general quality of life.  However, the impact on longevity remains to be determined.  Evidence suggests that early treatment is associated with improved outcomes. The corneal and lenticular opacities generally do not require treatment.

Continuous release of cardiac troponin I (cTNI) with elevated serum levels may be a clue to the severity of heart involvement.

References
Article Title: 

Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease

Arends M, Wijburg FA, Wanner C, Vaz FM, van Kuilenburg ABP, Hughes DA, Biegstraaten M, Mehta A, Hollak CEM, Langeveld M. Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease. Mol Genet Metab. 2017 May 4. pii: S1096-7192(17)30156-7.

PubMed ID: 
28495078

Continuous cardiac troponin I release in fabry disease

Feustel A, Hahn A, Schneider C, Sieweke N, Franzen W, Gunduz D, Rolfs A, Tanislav C. Continuous cardiac troponin I release in fabry disease. PLoS One. 2014 Mar 13;9(3):e91757. doi: 10.1371/journal.pone.0091757. eCollection 2014.

PubMed ID: 
24626231

Fabry disease: overall effects of agalsidase alfa treatment

Beck M, Ricci R, Widmer U, Dehout F, de Lorenzo AG, Kampmann C, Linhart A,
Sunder-Plassmann G, Houge G, Ramaswami U, Gal A, Mehta A. Fabry disease: overall effects of agalsidase alfa treatment. Eur J Clin Invest. 2004 Dec;34(12):838-44.

PubMed ID: 
15606727
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