using therapeutic contact lenses

Bartow RM. Endocrine disease and the cornea. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 3rd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2011:741–747.

Disorders of Lipid Metabolism and Storage

Hyperlipoproteinemias

Hyperlipoproteinemias are common conditions associated with premature coronary artery and peripheral vascular disease. Recognition of the ocular hallmarks of these diseases, such as xanthelasma and corneal arcus, can result in early intervention and reduced morbidity.

PATHOGENESIS Extracellular deposits consist of cholesterol, cholesterol esters, phospholipids, and triglycerides.

CLINICAL FINDINGS Corneal arcus is a very common degenerative change of older patients and does not require systemic evaluation. However, corneal arcus in individuals younger than 40 years or asymmetric corneal arcus may be associated with a lipid abnormality. These patients should have a systemic workup. Asymmetry may be secondary to carotid atherosclerotic disease on the less affected side.

LABORATORY EVALUATION A fasting and alcohol-restricted lipid profile that includes cholesterol, triglycerides, and high-density and low-density lipoproteins (HDL and LDL, respectively) is required. Patients can then be classified phenotypically to assess their risk for atherosclerotic disease.

MANAGEMENT Early detection gives the patient time to be referred for dietary or drug treatment.

Hypolipoproteinemias

Abnormal reductions in serum lipoprotein levels occur in 5 disorders:

lecithin-cholesterol acyltransferase (LCAT) deficiency Tangier disease

fish eye disease

familial hypobetalipoproteinemia Bassen-Kornzweig syndrome

The last 2 disorders do not result in corneal disease; discussion here focuses on the other 3 disorders.

PATHOGENESIS LCAT promotes removal of excess cholesterol from peripheral tissues to the liver, and a deficiency of this enzyme leads to accumulation of unesterified cholesterol in the tissues. This, in turn, leads to atherosclerosis, renal insufficiency, early corneal arcus, and nebular corneal clouding composed of minute focal lipid deposits.

LCAT deficiency and fish eye disease are allelic variants of the same genetic locus on band 16q22.1. In fish eye disease, LCAT levels are normal, but the enzyme does not function properly. Tangier disease has a complete absence of serum high-density α-lipoproteins and maps to 9q22-q31.

CLINICAL FINDINGS All 3 cornea-affecting hypolipoproteinemias are rare, autosomal recessive

conditions. Familial LCAT deficiency is characterized by peripheral arcus and nebular stromal haze made up of myriad minute focal deposits of lipid that appear early in childhood but do not interfere with vision. Fish eye disease has obvious corneal clouding from minute gray-white-yellow dots that progress from the periphery to decrease vision. Tangier disease features very large orange tonsils; enlarged liver, spleen, and lymph nodes; hypocholesterolemia; and abnormal chylomicron remnants. Corneas show diffuse clouding and posterior focal stromal opacities but no arcus. Neuropathy leads to lagophthalmos and corneal sequelae.

LABORATORY EVALUATION AND MANAGEMENT The serum lipid profile shows characteristic low levels of HDL (markedly low in Tangier disease). Recognition of hypolipoproteinemia can allow the clinician to make appropriate referrals and encourage the patient to seek genetic counseling.

Sphingolipidoses

Sphingolipidoses are rare inherited disorders of complex lipids (gangliosides and sphingomyelin) that involve the cornea in 4 conditions:

Fabry disease (angiokeratoma corporis diffusum), X-linked recessive multiple sulfatase deficiency, autosomal recessive

generalized gangliosidosis (GM1 gangliosidosis type I), autosomal recessive Tay Sachs disease, autosomal recessive

PATHOGENESIS Fabry disease is caused by a deficiency of α-galactosidase A, which leads to the accumulation of ceramide trihexoside in the renal and cardiovascular systems. Generalized gangliosidosis is characterized by deficiencies of β-galactosidases and the accumulation of gangliosides in the central nervous system and of keratan sulfate in somatic tissues. It has been linked to chromosome 3p12-3p13. Tay-Sachs disease is related to the generalized gangliosidoses but results from β-hexosaminidase A deficiency, which leads to accumulation of GM2 gangliosides.

CLINICAL FINDINGS In these conditions, the cornea exhibits distinctive changes consisting of whorllike lines (cornea verticillata) in the basal layers of the epithelium that appear to converge at the inferior central corneal epithelium (Fig 11-2).

Figure 11-2 Whorl-like deposits of sphingolipid in the basal layer of the corneal epithelium in a patient with Fabry disease; identical deposits occur in otherwise asymptomatic female carriers of this disease.

Periorbital edema occurs in 25% of cases, posterior spokelike cataracts in 50%, and conjunctival aneurysms in 60%. Other ocular signs include papilledema, retinal or macular edema, optic atrophy, and retinal vascular dilation. The corneal changes resemble those seen in patients given long-term oral chloroquine or amiodarone therapy.

Hemizygous males with Fabry disease are more seriously affected than heterozygous females and show the typical corneal changes. A heterozygous female with Fabry disease will show the same corneal changes. Fabry disease is also characterized by renal failure, peripheral neuropathy with painful dysesthesias in the lower extremities, and skin lesions (angiokeratomas). The skin lesions are small, round vascular eruptions that later become hyperkeratotic. They consist of an accumulation of sphingolipid within the vascular endothelium.

Multiple sulfatase deficiency combines features of metachromatic leukodystrophy and mucopolysaccharidosis. Affected children have subtle diffuse corneal opacities, macular changes, optic atrophy, and progressive psychomotor retardation. They die in the first decade of life.

Tay Sachs disease primarily involves the retina; however, the corneal endothelial cells can appear distended and filled with single membrane–bound vacuoles.

LABORATORY EVALUATION In Fabry disease, α-galactosidase A level is markedly decreased in urine and plasma. The conjunctival biopsy result may be positive before cornea verticillata are apparent. Prenatal diagnosis can be performed with chorionic villus sampling. Gene sequencing can be helpful

to diagnose Fabry disease in suspected female carriers, since enzyme levels may be close to normal in heterozygotes.

MANAGEMENT If a female patient is diagnosed as an asymptomatic heterozygous Fabry carrier, genetic counseling should be considered. The prognosis for successful PK in these conditions is generally poor. Enzyme replacement with infusion of α-galactosidase A is a therapeutic option, but the long-term benefit has not been proven. The addition of agents that help stabilize native enzymes may improve the efficacy of enzyme replacement therapy.

Guemes A, Kosmorsky GS, Moodie DS, Clark B, Meisler D, Traboulsi EI. Corneal opacities in Gaucher disease. Am J Ophthalmol. 1998;126(6):833–835.

Samiy N. Ocular features of Fabry disease: diagnosis of a treatable life-threatening disorder. Surv Ophthalmol. 2008;53(4):416– 423.

Mucolipidoses

Mucolipidoses (MLs) are autosomal recessive conditions that have features common to both MPSs and lipidoses.

PATHOGENESIS The MLs are inherited disorders of carbohydrate and lipid metabolism combined. Mucopolysaccharides accumulate in the cornea and viscera, and sphingolipids are deposited in the retina and central nervous system. Currently recognized diseases in this class are the following:

ML I (dysmorphic sialidosis) ML II (inclusion-cell disease)

ML III (pseudo-Hurler polydystrophy) ML IV

Goldberg syndrome mannosidosis fucosidosis

All of the above conditions are autosomal recessive. ML IV has been mapped to the short arm of chromosome 19. Histologic examination of corneal scrapings has revealed the accumulation of intracytoplasmic storage material in the epithelium. In fucosidosis, histologic study has revealed that, even when the cornea appears clinically normal, corneal endothelial cells show the presence of cytoplasmic, membrane-bound, confluent areas of fibrillar, granular, and multilaminated deposits. A retinal cherry-red spot and retinal degeneration are also associated with many of these disorders. All are caused by a defect in lysosomal acid hydrolase enzymes.

CLINICAL FINDINGS With the exception of mannosidosis and fucosidosis, all of these conditions are characterized by varying degrees of corneal clouding, which can often be progressive.

LABORATORY EVALUATION Plasma cells are vacuolated, and levels of plasma lysosomal hydrolases are elevated. In ML IV, with corneal clouding from birth, conjunctival biopsy shows fibroblast inclusion bodies that are

single membrane–limited cytoplasmic vacuoles containing both fibrillogranular material and membranous lamellae

lamellar and concentric bodies resembling those of Tay-Sachs disease

There is no evidence of mucopolysacchariduria or cellular metachromasia. Chorionic villus