Treatment of the Disease Process
Definitive cures—that is, reversing or correcting underlying genetic defects—are yet to emerge for most heritable disorders. However, some conditions in which metabolic defects have been identified can often be managed through 5 fundamental approaches:
chelation of excessive metabolites
enzyme or gene-product replacements
vitamin and cofactor therapy
drug therapy to reduce accumulation of harmful products
Some genetic disorders affecting the eye that arise from an inborn error of metabolism can be managed effectively through dietary therapy. These conditions include homocystinuria, Refsum disease, gyrate atrophy, galactokinase deficiency, and galactosemia. Implementing a galactose-free diet can reverse some of the main clinical signs of galactosemia (eg, hepatosplenomegaly, jaundice, and weight loss). Progression of cortical cataracts can be avoided, and less extensive lens opacities may even regress with a galactose-free diet. With time, patients with galactosemia are able to metabolize galactose through alternative pathways, obviating the need for lifelong dietary restriction.
Chelation of excessive metabolites
Disorders that result from enzyme or transport protein deficiencies may lead to the accumulation of a metabolite or metal that harms various tissues. For example, in Wilson disease (hepatolenticular degeneration), decreased levels of serum ceruloplasmin result in poor transport of free copper (Cu2+) ions and in storage of copper in such tissues as the brain, liver, and cornea. Resultant clinical signs can be reversed, at least partially, after the administration of D-penicillamine, a chelator of Cu2+. Other copper chelators, such as British anti-Lewisite (BAL), can be used, along with a copper-deficient diet, to reverse the clinical signs of Wilson disease.
Enzyme replacement therapy
Enzyme replacement therapy via plasma infusions in patients with Fabry disease has succeeded in temporarily decreasing plasma levels of the accumulated substrate ceramide trihexoside. The drugs are expensive (current costs at approximately $250,000 per year), presenting a barrier to successful treatment for many patients around the world. Enzyme replacement therapy for Fabry disease is not a cure, but it improves metabolism, curbs disease progression, and potentially reverses some symptoms.
Organ transplantation can be considered a form of regionalized enzyme replacement. In patients with cystinosis, cystine crystals accumulate in the kidneys. When a normal kidney, with its rich source of enzymes, is transplanted into a patient with cystinosis, cystine does not accumulate in the cells of the renal tubules and renal function tends to remain normal. In a complementary approach, stem cell transplantation is being investigated to treat various diseases, including those of the eye.
Vitamin therapy appears to be of benefit in 2 autosomal recessive disorders. In at least some patients with homocystinuria, vitamin B6 (pyridoxine) administration has decreased homocystine accumulation in plasma and reduced the severity of the disorder. Vitamin A and vitamin E therapy have been noted to benefit some patients with neurologic impairment due to abetalipoproteinemia; such therapy is also likely to slow or lessen the development and progression of retinal degeneration. More long-term therapeutic trials are necessary to better define the efficacy of vitamin therapy for these and perhaps other metabolic disorders.
Various genetically determined disorders can be managed by use of an appropriate drug. For example, excess accumulation of uric acid in primary gout can be prevented or reduced either by blocking the activity of the enzyme xanthine oxidase with the drug allopurinol or by increasing excretion of uric acid by the kidneys with the use of probenecid. In familial hypercholesterolemia, the elevated serum cholesterol levels can often be reduced through the use of various cholesterol-lowering drugs or substances that bind bile acids in the gastrointestinal tract.
Appropriate management of sequelae and complications
Some of the sequelae of genetic diseases, such as glaucoma in Axenfeld-Rieger syndrome or cataracts in RP, can be managed successfully to preserve or partially restore vision. However, patients need to understand how treatment of the sequelae or complications may differ according to their individual situations.
Although only a few clinical trials for a limited number of genes are under way, viralmediated gene replacement for inherited retinal diseases is available (see voretigene neparvovec in Chapter 5). The ophthalmologist is obliged either to carefully search the online clinical trials databases and the published literature for treatment trials that the patient may qualify for; or refer the patient to another professional who will conduct such a search for treatment trials for which the patient may qualify. (For a database of clinical studies, see www.clinicaltrials.gov.)
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.