CLINICAL FINDINGS Ocular changes include marked photophobia, tearing, conjunctival injection, and tarsal papillary hypertrophy. Affected patients develop recurrent episodes of pseudodendrites, which usually do not stain well with fluorescein or rose bengal. Continued episodes of epithelial breakdown can result in corneal vascularization and scarring. It is important to consider this disorder in a young child who may carry a diagnosis of recurrent herpes simplex virus keratitis.
LABORATORY EVALUATION Hypertyrosinemia and tyrosinuria with normal phenylalanine level and biopsy showing soluble tyrosine aminotransferase deficiency are diagnostic.
MANAGEMENT Restriction of dietary intake of tyrosine and phenylalanine can reduce the severity of both the corneal and systemic changes, including cognitive impairment. The institution of appropriate dietary restrictions even later in life can improve mental status.
Alkaptonuria
Alkaptonuria is a rare autosomal recessive disorder with a defect of tyrosine metabolism that maps to gene locus 3q21-q23. The frequency of alkaptonuria is unusually high in the Dominican Republic and Slovakia.
PATHOGENESIS Homogentisate 1,2-dioxygenase, the enzyme necessary to degrade tyrosine and phenylalanine, is deficient in this disorder. Phenylalanine and tyrosine cannot be metabolized beyond homogentisic acid, which is oxidized and polymerized into alkapton, a brown-black material similar to melanin. Alkapton then deposits in connective tissues as dark pigment in a process known as ochronosis.
CLINICAL FINDINGS Patients develop arthropathy, renal calculi, and pigmentation of cartilaginous structures, including earlobes, trachea, nose, tendons, dura mater, heart valves, and prostate. Eventually, medial and lateral rectus muscle tendons and the sclera adjacent to the tendon insertions develop smudgelike pigmentation. Darkly pigmented, dotlike opacities may appear in the corneal epithelium or in the Bowman layer near the limbus.
LABORATORY EVALUATION The urine of affected patients turns dark on standing. Homogentisic acid oxidase deficiency can be shown.
MANAGEMENT No specific therapy is available, although high-dose ascorbic acid may reduce arthropathy in young patients. Gene therapy may be a future treatment.
Cheskes J, Buettner H. Ocular manifestations of alkaptonuric ochronosis. Arch Ophthalmol. 2000;118(5):724–725.
Disorders of Protein Metabolism
Amyloidosis
The amyloidoses are a heterogeneous group of diseases characterized by the extracellular accumulation of amyloid deposits in various tissues and organs, including the cornea and conjunctiva. Amyloid deposits may be composed of many different types of proteins, including immunoglobulin fragments. The deposits are insoluble and inert, but they interfere with normal structure and function of tissues and organs. Ocular findings, as well as associated systemic conditions, are summarized in Table 11-3.
Table 11-3
PATHOGENESIS Amyloid has the following staining characteristics:
positive staining with Congo red dye dichroism and birefringence metachromasia with crystal violet dye
fluorescence in ultraviolet light with thioflavine T stain typical filamentous appearance by electron microscopy
CLINICAL FINDINGS Ocular amyloidosis is classified as either primary (idiopathic) or secondary (to some chronic disease) and either localized or systemic. A useful classification of amyloidosis considers these 4 types. Each type will be discussed separately and is summarized in Table 11-3:
1.primary localized amyloidosis
2.primary systemic amyloidosis
3.secondary localized amyloidosis
4.secondary systemic amyloidosis
Primary localized amyloidosis is the most common form of ocular amyloidosis. Conjunctival amyloid plaques occur in the absence of systemic involvement (Fig 11-4). Primary familial amyloidosis of the cornea (gelatinous droplike corneal dystrophy) and lattice corneal dystrophy types 1 and 3 are special forms of primary localized amyloidosis and are discussed in Chapter 10. Polymorphic amyloid degeneration is discussed in Chapter 12.
Figure 11-4 Conjunctival amyloidosis. (Courtesy of Vincent P. deLuise, MD.)
Primary systemic amyloidosis is a heterogeneous group of diseases in which waxy ecchymotic eyelid papules occur in association with vitreous veils and opacities as well as pupillary anomalies such as light–near dissociation. Orbital involvement, extraocular muscle involvement with ophthalmoplegia, and scleral infiltration with uveal effusion have been reported. The most common form of primary systemic amyloidosis is an autosomal dominant group of diseases linked to 18q11.2- q12.1, with more than 40 different mutations of the transthyretin (TTR, prealbumin) gene described. Lattice corneal dystrophy type II (Meretoja syndrome) is a primary systemic amyloidosis and is discussed in Chapter 10.
Secondary localized amyloidosis is the most common form of amyloidosis of the cornea. It develops in eyes with long-standing chronic inflammatory disease such as trachoma; interstitial keratitis; tumors; or connective tissue disorders, usually rheumatoid arthritis. Corneal involvement may be seen in keratoconus, phlyctenulosis, bullous keratopathy, leprosy (Hansen disease), contact lens wear, trichiasis, tertiary syphilis, uveitis, and climatic droplet keratopathy, in addition to trachoma and interstitial keratitis. Secondary deposition takes the form of a degenerative pannus, lamellar deposits in the deep stroma, or perivascular deposits. Deposits are typically yellowish pink or yellow-gray, depending on the associated disease.
Secondary systemic amyloidosis is seen in association with a number of conditions, including rheumatoid arthritis, Mediterranean fever (brucellosis), bronchiectasis, and leprosy. The eyelids can be affected but less commonly than with primary systemic amyloidosis. Amyloid does not deposit in the cornea in secondary systemic amyloidosis.