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ODs on the frontline of Fabry disease diagnosis
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While Fabry disease may prove to be fatal if undetected and untreated, optometrists can play a crucial role in the diagnosis of this inherited condition. Once eye care practitioners note the telltale corneal whorling pattern, patients can be referred for diagnostic testing and management, which may include the ultra-orphan drug Fabrazyme (agalsidase beta, Genzyme).
Identified more than a century ago, Fabry disease is a rare, inherited disease caused by the absence of the lysosomal enzyme 
-galactosidase (-GAL). This enzyme deficiency leads to a build-up of glycosphingolipids, which typically results in vascular involvement of the kidneys, heart and central nervous system, according to John King, senior product director for Genzyme Corp. “Death usually occurs in the fourth or fifth decade of life as a result of renal failure, cardiovascular disease or cerebrovascular disease,” he told Primary Care Optometry News.
Difficult diagnosis
Because Fabry disease is inherited, it could be detected prenatally; however, it often remains unrecognized until adulthood, when organ damage occurs, because the symptoms in children tend to be vague, said Mr. King. Early symptoms of the disease include pain in the hands and feet, fever, hypohidrosis and fatigue. “It usually takes about 16 years from presentation of the symptoms to diagnosis. So, when most people are diagnosed, they are typically already in a dialysis center,” he said.
“These patients, on average, see 10 different specialists before a diagnosis is finally made,” said Nasi Samiy, MD, of the Retina Institute of the Carolinas, in an interview. “If one can forge a direct path to diagnosis, then obviously one can potentially have a positive impact on these patients’ lives. This can be accomplished by detecting the disease through some of its very prominent clinical manifestations.”
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RJ Desnick |
Look for ocular opacities, lesions
In its earliest stages, Fabry disease manifests itself with distinct ocular occurrences. Some of the most common signs are corneal opacity and conjunctival and retinal vascular lesions as a result of the generalized disease process, according to information provided by Genzyme. Several lesions that do not affect vision may be pathognomonic for Fabry disease.
“The ophthalmologic changes characteristic of classic Fabry disease are observed in almost all affected males with classic Fabry disease at a young age,” stated Maryam Banikazemi, MD, associate director of the International Center for Fabry Disease at the Mount Sinai School of Medicine. “Therefore, young male patients may be identified in the pre-symptomatic period by an ophthalmologist or optometrist.”
Similar ophthalmologic changes are observed in more than 80% of female heterozygotes, said Dr. Banikazemi. Given this statistic, slit-lamp eye examinations may be used as a primary diagnostic screening tool in females who have family history of Fabry disease or who may have clinical manifestations that suggest Fabry disease. Genetic testing may then be used as a follow-up for those female heterozygotes who test negative with the slit-lamp examination or to confirm diagnosis in patients with positive eye findings.
The changes in the cornea are typically described as a “whorled” pattern. Two types of lens opacities have been recorded in Fabry patients. Fabry cataracts appear as whitish, granular, spoke-like deposits on the posterior surface of the lens. Cream-colored anterior capsular deposits appearing in the lens are seen with a lesser incidence, according to the information published by Genzyme.
Eye care providers critical
“Eye care providers play a central role in the diagnosis of Fabry disease,” said Dr. Samiy. “By and large, no significant ocular symptoms are associated with Fabry disease, and most patients are visually asymptomatic. But if they have an exam at the slit-lamp, the most prominent ocular finding, namely cornea verticillata, may be detected, and the patient can be referred for further management.
“Ophthalmic manifestations of Fabry disease are prominent,” Dr. Samiy continued. “They’re probably the most frequent and the earliest clinical finding in this condition. An eye care provider would be incredibly valuable in diagnosing this condition.”
Once Fabry disease is suspected, patients should be referred to a geneticist or other expert, such as a nephrologist, if kidney failure is an issue, said Dr. Samiy.
“Most ophthalmologists say they’ve seen this cornea twirling pattern in the eyes, but there hasn’t been anything to treat it,” Mr. King said. “They feel their role is enhanced because they can identify this disease, and now they can refer the patient to a geneticist or a cornea specialist or someone who can actually treat it.”
Enzyme replacement therapy now available
Fabry disease is diagnosed by testing the activity level of -GAL, the enzyme missing in Fabry patients. In 2003, the FDA approved Genzyme’s ultra-orphan drug, Fabrazyme, for treating the disease. Fabrazyme replaces the missing enzyme, delivered as a biweekly infusion.
According to Dr. Banikazemi, clinical trials have demonstrated that this enzyme replacement therapy is safe and well tolerated. “Recent studies have also proven that enzyme replacement therapy can slow the progression of the serious, life-threatening complications of Fabry disease, even in patients who already have significant kidney disease,” she said. “Patients report experiencing significant clinical improvement in pain, sweating, GI symptoms, heat and exercise tolerance and quality of life.
“Significantly, all of the clinical studies to date have pointed to the importance of early diagnosis and intervention,” she told Primary Care Optometry News. “Therefore, early detection through slit-lamp examination could contribute substantially to the successful treatment of Fabry disease.”
Dr. Samiy added, “Fabry disease has a very significant morbidity and mortality associated with it. These are patients who go through tremendous ordeals in their lives and who have a very poor quality of life. If an eye care provider can detect cornea verticillata, the most common ocular – if not clinical – manifestation of Fabry disease, then he or she could potentially be doing a great service to the patient with Fabry disease. Early intervention could possibly have a positive impact on the quality of life.”
Inheritance
Dr. Samiy explained how Fabry disease is inherited. It is a panethnic, enzyme disorder that affects one in 40,000 males. There are differences, however, in its effect on males and females.
“Fabry is an X-linked disorder,” he said. “Females have two X chromosomes, and males have one. So, if you’re a male and your X chromosome has a defect on it, then that disease is going to manifest itself, because you don’t have a second pair.
“In the female, although there are two X chromosomes, one of them is randomly inactivated in each of the cells,” Dr. Samiy continued. “That’s called lyonization. So, by random luck, there are females who will have a very large proportion of the defective X chromosome inactivated, which means they’ll be left with a very large pool in their body of the normal, so these patients are going to be virtually unaffected. They’re going to be like normal individuals,” Dr. Samiy said.
“Then there are those who by random luck have the majority of their normal X chromosome inactivated, so they’re left with a large pool of defective X chromosomes,” he continued. “As a result, they have very severe disease manifestation almost indistinguishable from the male phenotype.”
“A high frequency of ophthalmologic changes in females may help identify the asymptomatic carriers,” Dr. Banikazemi said. “Or it can be used as a diagnostic screening tool for Fabry disease in females who are at risk or who may have clinical manifestations suggestive of Fabry disease.”
For Your Information:
- John King is senior product director for Genzyme. He can be reached at 500 Kendall St., Cambridge, MA 02142; (617) 768-6983; fax: (617) 768-9814; e-mail: john.king@genzyme.com.
- Nasi Samiy, MD, is the CEO and president of the Retina Institute of the Carolinas. He can be reached at 724 Arden Lane, Ste. 220, Rockhill, SC 29732; (803) 323-2020; fax: (803) 323-2024; e-mail: nsamiy@aol.com. Dr. Samiy is a paid consultant for Genzyme.
- Maryam Banikazemi, MD, is assistant professor of pediatrics and human genetics and associate director, International Center for Fabry Disease at the Department of Human Genetics, Mount Sinai School of Medicine. She can be reached at One Gustave L. Levy Place, New York, NY 10029; (212) 241-4247; fax: (212) 348-5811; e-mail: Maryam.Banikazemi@mssm.edu. Dr. Banikazemi has no direct financial interest in the products mentioned in this article, nor is she a paid consultant for any companies mentioned. For more information on Fabry disease and Genzyme, go to www.fabrycommunity.com.