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PRIMARY CARE OPTOMETRY NEWS November 2007
The Optometrist's Role in Diagnosing and Managing Fabry Disease

CE Information

Introduction An introduction to Fabry disease: Genetics, signs and treatments Robert J. Desnick, MD, PhD Overview of the long-term progression of Fabry disease Irene Maumenee, MD Diagnosing Fabry disease in the OD’s chair Leonid Skorin Jr., OD, DO, FAAO Incorporating the understanding of genetic disorders into the optometric practice J. James Thimons, OD Educating patients and their families on Fabry disease Scott E. Brodie, MD, PhD

This course is jointly sponsored by The State University of New York State College of Optometry, Vindico Medical Education and Primary Care Optometry News. It is COPE-approved for 2 continuing education credits.

Supported by an educational grant from Genzyme Corporation

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Introduction

Fabry disease, a recessive X-linked disorder that results from a deficiency of the lysosomal hydrolase α-galactosidease A, occurs in all ethnic groups. It is estimated that approximately one in 40,000 males has the disease.

Eye care professionals are in an excellent position to diagnose Fabry disease in its early stages. Corneal deposits are seen in affected males and heterozygous females when other manifestations of the disease are in early stages. Along with corneal opacities, posterior spokelike cataracts are said to be pathognomonic for Fabry disease. Conjunctival and retinal vascular changes are nonspecific but suggestive of the disease.

Fabry disease is a painful and debilitating disease that results in systemic manifestations that lead to heart failure, stroke, liver failure and a shortened life expectancy. If ophthalmic health care professionals are educated to effectively identify the ocular findings of Fabry disease, then patients can be referred to appropriate treatment earlier and more often.

This monograph highlights presentations and discussions from an expert panel review in which experts addressed Fabry disease, its mode of inheritance and its clinical manifestations. I would like to thank the faculty for sharing their expertise and insights at that expert panel review and in this monograph.

Michael D. DePaolis, OD, FAAO
Editor, Primary Care OpPtoOmetry News

Michael D. DePaolis, OD, FAAO, Course Director, is a clinical associate in the Department of Ophthalmology at the University of Rochester in New York. He has a private practice in Rochester, N.Y. Leonid Skorin Jr., OD, DO, FAAO, is a senior staff member of the Albert Lea Eye Clinic of the Mayo Health System in Albert Lea, Minn. Robert J. Desnick, MD, PhD, is a professor and chairman of the Department of Genetics and Genomic Sciences at Mount Sinai School of Medicine in New York. J. James Thimons, OD, is medical director of the Ophthalmic Consultants of Connecticut in Fairfield, Connecticut. Irene Maumenee, MD, is a professor of ophthalmology at Johns Hopkins University in Baltimore. She has an appointment in medicine and pediatrics. Scott E. Brodie, MD, PhD, is associate professor of ophthalmology at Mount Sinai School of Medicine in New York and serves as chief of ophthalmology at the James J. Peters VA Medical Center in Bronx, N.Y.

An introduction to Fabry disease: Genetics, signs and treatments
Robert J. Desnick, MD, PhD

Fabry disease is an often undiagnosed, X-linked genetic disorder that has prominent ocular features. The disease results from the deficient activity of the lysosomal hydrolase α-galactosidase A.¹ The enzymatic defect leads to the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids in the plasma and in the lysosomes of tissues throughout the body.

Clinical onset in childhood or adolescence is characterized by severe pain in the extremities (acroparesthesias), excruciating pain crises, gastrointestinal manifestations, skin lesions due to the vascular involvement (angiokeratoma), decreased sweat (hypohidrosis) and characteristic corneal/ lenticular opacities.

With advancing age, the progressive lysosomal GL-3 accumulation, particularly in the microvasculature, leads to renal failure, vascular disease of the heart and brain, cardiomegaly and premature demise.

Diagnosis of affected patients is important since specific treatment by enzyme replacement therapy with recombinant human α-galactosidase A has been shown safe and effective in clinical trials, and early intervention prior to irreversible damage is key to successful treatment.^2-8

The classical phenotype

Clinical onset in classically affected males, who have absent or severely deficient α-galactosidase A activity, usually occurs during childhood or adolescence. Early manifestations include acroparesthesias, periodic excruciating pain crises, hypohidrosis, angiokeratoma, post-prandial cramping and diarrhea, and characteristic corneal and lenticular opacities. With advancing age, progressive vascular glycosphingolipid deposition causes ischemia and infarction leading to cardiac, cerebral and renal vascular disease.

With increasing age, the major morbid symptoms result from the progressive involvement of the vascular system. Proteinuria, isosthenuria, gradual deterioration of renal function and development of azotemia occur.⁹ Death most often results from uremia. Cardiovascular findings may include hypertension, left ventricular hypertrophy (LVH), hypertrophic cardiomyopathy, anginal chest pain, myocardial ischemia or infarction and congestive heart failure.^1,10 Cerebrovascular manifestations result primarily from multifocal small vessel involvement, ¹¹ and early onset cryptogenic strokes have been shown to be caused by previously unrecognized Fabry disease.¹²

The later-onset phenotype

Affected males with the later-onset phenotype have residual α-galactosidase A activity due to missense and splicing mutations. They lack the early manifestations of classically affected patients, including angiokeratoma, acroparesthesias, hypohidrosis, gastrointestinal complications and the corneal/lenticular opacities. ^13-16 The later-onset patients typically present with cardiac, renal or cerebrovascular manifestations.

Heterozygous females

The clinical manifestations in DNA-diagnosed heterozygous females from classically affected families range from asymptomatic throughout a normal lifespan to as severe as affected males, presumably due to skewed X-chromosomal inactivation.

Treatment

Medical management

The single most debilitating and morbid aspect of Fabry disease is the excruciating pain. Prophylactic administration of low maintenance dosages of diphenylhydantoin, carbamazepine or gabapentin may decrease the frequency and severity of the periodic crises of excruciating pain and constant discomfort.¹⁷ Diphenylhydantoin and carbamazepine may be used in combination if either alone has not significantly reduced the pain. Narcotic analgesics and nonsteroidal anti-inflammatory drugs should be avoided.

“The single most debilitating and morbid aspect of Fabry disease in childhood is the excruciating pain. With advancing age, renal failure, cardiac disease and strokes lead to early demise.” — Robert J. Desnick, MD, PhD

Control of hypertension is essential to minimize renal, cardiovascular and cerebrovascular disease. Successful heart transplantation of a heterozygote with end-stage cardiomyopathy has been reported. Obstructive lung disease has been documented in older hemizygotes and heterozygotes, with more severe impairment in smokers. Patients with reversible obstructive airway disease may benefit from bronchodilation therapy. Prophylactic oral anticoagulants are recommended, as these patients are prone to stroke. Pancrelipase or metoclopramide can help with gastrointestinal symptoms.

Dialysis and renal transplantation

Since renal insufficiency is the most frequent complication in patients with this disease, chronic hemodialysis or renal transplantation have become life-saving procedures in patients who develop end-stage renal disease. Patients enter dialysis at an average age of approximately 40 years and have a 3-year survival of approximately 60%.¹⁸ Successful transplantation will correct renal function. The normal α-galactosidase A activity in the allograft will catabolize the turnover of endogenous renal glycosphingolipid substrates. However, renal transplantation should be undertaken only in patients with clinically significant renal failure. Transplanted patients with Fabry disease do at least as well as patients with other causes of renal failure.^19,20 Transplantation of kidneys from Fabry heterozygotes should be avoided.

Enzyme replacement therapy

Enzyme replacement therapy with recombinant human α-galactosidase A has been shown in randomized, double-blind, placebo-controlled trials to be safe and effective at 1 mg/kg every 2 weeks. ^2-8 Enzyme replacement cleared the vascular endothelial glycolipid deposits and reversed, stabilized or markedly improved the disease symptoms. Of note, early intervention is essential to avoid the irreversible renal, cardiac and cerebrovascular manifestations of the disease.

References

1. Desnick RJ, Ioannou YA, and Eng CM, a-Galactosidase A deficiency: Fabry disease. In Scriver CR, Beaudet AL, Sly WS, et al. (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York, McGraw-Hill, 2001, 3733-3774.
2. Schiffmann R, Murray GJ, Treco D, et al. Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci USA. 2000;97:365-370.
3. Eng CM, Banikazemi M, Gordon R, et al. A phase 1/2 clinical trial of enzyme replacement in Fabry disease: Pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet. 2001;68:711-722.
4. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A — Replacement therapy in Fabry’s disease. N Eng J Med. 2001;345:9-16.
5. Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: A randomized controlled trial. JAMA. 2001;285:2743-2749.
6. Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet. 2004;75:65-74.
7. Banikazemi M, Bultas J, Waldek S, et al. Agalsidase beta therapy for advanced Fabry disease: A randomized trial. Ann Intern Med. 2007;146:77-86.
8. Germain DP, Waldek S, Banikazemi M, et al. Substained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol. 2007;18(5):1547-1557.
9. Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry renal disease: Influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore). 2002;81:122-138.
10. Linhart A, Lubanda JC, Palecek T, et al. Cardiac manifestations in Fabry disease. J Inherit Metab Dis. 2001;24 Suppl 2:75-83.
11. Fellgiebel A, Muller MJ, Ginsberg L. CNS manifestations of Fabry’s disease. Lancet Neurol. 2006;5:791-795.
12. Rolfs A, Bottcher T, Zschiesche M, et al. Prevelance of Fabry disease in patients with cryptogenic stroke: A prospective study. Lancet. 2005;366:1794-1796.
13. Elleder M, Bradova V, Smid F, et al. Cardiocyte storage and hypertrophy as a sole manifestation of Fabry’s disease. Report on a case simulating hypertrophic non-obstructive cardiomyopathy. Virchows Arch A Pathol Anat Histopathol. 1990;417:449-455.
14. von Scheidt W, Eng CM, Fitzmaurice TF, et al. An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med. 1991;324:395-399.
15. Nakao S, Takenaka T, Maeda M, et al. An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333:288-293.
16. Nakao S, Kodama C, Takenaka T, et al. Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int. 2003;64:801-807.
17. Ries M, Mengel E, Kutschke G, et al. Use of gabapentin to reduce chronic neuropathic pain in Fabry disease. J Inherit Metab Dis. 2003;26:413-414.
18. Thadhani R, Wolf M, West ML, et al. Patients with Fabry disease on dialysis in the United States. Kidney Int. 2002;61:249-255.
19. Mignani R, Gerra D, Maldini L, et al. Long-term survival of patients with renal transplantation in Fabry’s disease. Contrib Nephrol. 2001;229-233.
20. Tsakiris D, Simpson HK, Jones EH, et al. Report on management of renal failure in Europe, XXVI, 1995. Rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant. 1996;11 Suppl 7:4-20.

Overview of the long-term progression of Fabry disease
Irene Maumenee, MD

Fabry disease is a rare lysosomal storage disease. It is X-linked and affects men and, more mildly, women, although occurrence is more frequent in women due to the female genetic makeup of two X chromosomes vs. one X chromosome in males. Fabry disease affects one in approximately 40,000 men and two in approximately 40,000 women, or three in 80,000. ^1-3

The disease is slowly progressive, which results in a reduced life expectancy if left untreated. The life expectancy of patients with Fabry disease varies, but the disease was at one time considered universally fatal in males in the third or fourth decade.³ Features of the disease include generic symptoms of chronic illness, so the diagnosis is often overlooked. Physicians should be aware of the disease so that patients can receive early treatment, which is available.

Lysosomal disease

Fabry disease is a lysosomal storage disease due to abnormal degradation and accumulation in the lysosomes. Among these disorders, Fabry disease is a sphingolipidoses, reflecting that the accumulating undegraded compounds are glycosphingolipids. Forty subtypes of lysosomal storage diseases are recognized, and, as a group, they affect more than one in 5,000 people.

Lysosomal storage diseases are characterized as diseases of abnormal degradation; macromolecular breakdown substances from the extracellular space are taken into the cell through the cell membrane by a process called endocytosis. Lysosomes are cell structures that contain a large number of degradative enzymes. Digestive vacuoles form as lysosomes fuse with the single membrane-bound macromolecules, expanding into joined structures. Diagnosis can be made with a simple biopsy and light microscopy but, most effectively, through electron microscopy.

Overview of Fabry disease

The German dermatologist Johannes Fabry and the English surgeon and dermatologist William Anderson first described the disease at approximately the same time. Therefore, it is also known as Anderson-Fabry disease.³ Another term for the disease is angiokeratoma corporis diffusum, named for small, slightly raised, dark red vascular abnormalities on the surface of the skin, which, particularly when occurring densely in the bathing trunk area of the body, suggest the diagnosis of Fabry disease.

The disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, which leads to an accumulation of globotriaosylceramide. Two major clinical groups exist within patients diagnosed with Fabry disease: those with a total absence of enzyme activity, resulting in the classical disease, and those with residual enzymatic activity, resulting in a milder disease with a later onset.

Fabry disease is a microvascular disease of the heart, the kidney and the brain; complications in any of these organs can be fatal.^2-8 A patient can undergo a stroke, heart attack or progressive renal failure. None of these symptoms is diagnostic, nor necessarily associated with a genetic disease. Even though these events may occur more frequently in the family history, the diagnosis of Fabry disease is often overlooked for extended periods and, occurrence in the family may remain undiagnosed.

“Fabry disease is a microvascular disease of the heart, the kidney and the brain; complications in any of these organs can be fatal.” — Irene Maumenee, MD

Because the diagnosis is often missed for many generations, the pedigrees may be extensive, making the evaluation of even remote family members essential, as they may be clinically asymptomatic. Many patients will make changes in lifestyle to prevent painful episodes. Abdominal pain and cramping after eating is often simply accepted; pain in the hands and feet after exercise may result in less exercise. Poor sweating with heat intolerance may result in avoidance of the outdoors. Consequently, the diagnosis is typically delayed in affected men and may occur late in life in heterozygous females. It is not uncommon for the diagnosis to be made when the patient suffers from the severe renal, cardiac or cerebrovascular manifestations of the disease, but it is often unrecognized even at end-stage disease because renal failure, cardiac disease and strokes are common.

Natural history of Fabry disease

In childhood, patients with Fabry disease experience excruciating pain in the hands and feet,^2-11 often exercise-induced, as well as poor temperature control resulting in unexplained fevers. They have little or no sweating capability, which often leads to exercise intolerance. Postprandial gastrointestinal pain is typical of Fabry disease.¹² Corneal verticillata (or corneal whorling) is often the first finding in girls and is thus of diagnostic significance, though not of clinical significance.^13-15 An ophthalmologist or optometrist may be the first to diagnose Fabry disease in a family by observing corneal verticillata in an asymptomatic female child.

The symptoms that appeared in childhood will persist in adolescence, and proteinuria may occur, but this is rarely discovered.⁸ Gastrointestinal distress may be significant and angiokeratomas — or red spots on the skin that typically develop in the bathing trunk area — may become apparent.^2-12 Acroparesthesia, or a feeling of abnormal painful sensations in the hands and feet, will worsen. Corneal opacities may become more significant, and spokelike lenticular changes may appear.^13-15 Patients are unable to fully participate in athletic activities due to heat intolerance and acroparesthesias and may choose not to participate. As a result, patients may be accused of laziness, often resulting in poor interpersonal relationships and social integration.

In adulthood, gastrointestinal distress may be dramatic, and other symptoms, namely fatigue, cardiac and renal insufficiency and strokes, will become more significant. In addition to corneal changes, a patient may have spokelike cataracts and conjunctival and retinal vascular tortuosity aneurysms.^13-15 Such ocular findings are often diagnostic of the underlying systemic disease, indicating that optometrists and ophthalmologists may be the first line in diagnosis.

Renal insufficiency becomes prominent, characterized by proteinuria and renal failure as the result of renal vascular disease and, ultimately, glomerulosclerosis, or scarring of the kidneys. Chronic dialysis and renal transplantation are typical treatments, but Fabry disease is rarely diagnosed as the underlying cause until histology is obtained.^16-20

Cerebrovascular disease may occur, as well as cardiac dysfunction, hearing loss and tinnitus. In the heart, typical manifestations include cardiomegaly, valvular disease, arrhythmias and heart attacks. Such nonspecific causes of death can be the result of the vascular endothelial disease associated with Fabry disease, as electron-dense lysosomes containing undegraded glycosphingolipids evidence. Complications of the vascular abnormalities in the central nervous system may manifest in strokes, headaches, dizziness or vertigo.

Ocular findings

Vascular tortuosity can be seen in the conjunctival vessels (Figure 1), which can be biopsied. The corneal verticillata typically shows its apex below the midline of the cornea (Figure 2) in a similar distribution to pigment slide, in which pigment is included in the subepithelial tissues and migrates to the center of the cornea. If the tissue sloughs off and the corneal epithelium is replaced by healthy tissue, it becomes difficult for a clinician to detect the changes associated with Fabry disease. In addition, changes can occur on the posterior capsule of the lens, although they can be seen anteriorly as well. They remain undetected by the patient because they do not interfere with vision.

Figure 1. Conjunctival vasculature affected by Fabry disease can include increased tortuosity and kinking of the blood vessels. Image courtesy of Irene Maumenee, MD

Diagnosis

The diagnosis is often overlooked because the clinical and family history are nonspecific. The diagnosis is confirmed on physical examination of the eye or skin or on urinalysis. On birefringent microscopy, the accumulated sphingolipids appear as Maltese crosses, which, prior to electron microscopy of biopsied tissue, was the method employed to diagnose Fabry disease. Enzyme assays of plasma and/or leukocytes provide accurate diagnosis of affected males. For heterozygous females, mutation analysis is required. Prenatal diagnosis is available, and, because Fabry disease is chronic and debilitating, is a reproductive option.

Treatment

Fabrazyme (agalsidase beta, Genzyme) was developed by Robert Desnick, MD, PhD, and is indicated for the treatment of patients with Fabry disease. It is given as an infusion administered every 2 weeks, which is typically initiated in a hospital and then transferred into the home setting. Allergic reaction to the treatment is a possibility.

Patients undergoing treatment have demonstrated reduced pain, a stabilization of renal function and dramatic improvements in their sense of well-being.^16,18,21-27 Recently, studies in advanced patients with Fabry disease with renal insufficiency have shown that enzyme replacement slows disease progression, delaying the complications of Fabry disease.²⁷

The treatment serves as a prototype for all lysosomal storage diseases.^21,23

Figure 2. Corneal verticillata seen in patients with Fabry disease typically shows an apex below the midline of the cornea. Image courtesy of Irene Maumenee, MD

Conclusion

Fabry disease is a chronic disease characterized by fatigue, pain, cardiac and renal failure and strokes. Since many of the symptoms are nonspecific, it is difficult to diagnose. Early diagnosis is key to maintaining a patient’s quality of life and to extending a patient’s life expectancy. The eye care physician can serve as the front line in diagnosis of this disease, since the ocular findings associated with Fabry disease are specific.

An exact DNA analysis aids in mutation analysis, presymptomatic diagnosis, prenatal diagnosis, in vitro preimplantation diagnosis, population screening and heterozygote detection. Approximately 2,300 genetic diseases have ocular involvement, which should prompt ophthalmologists and optometrists to learn more about genetic eye diseases. More information can be found through OMIM, or Online Mendelian Inheritance in Man (ncbi.nlm.nih.gov/sites/entrez?db=OMIM); RetNet, which provides information on inherited retinal diseases (http://www.sph.uth.tmc.edu/Retnet/); POSSUM Web, an Australian databank of genetic disease (www.possum.net.au/); and the National Eye Institute Bank (NEIbank.nei.nih.gov). OMIM, in particular, is a useful tool for the optometric community. OMIM is free and easily accessible, and provides disease characteristics, diagnostic criteria, differential diagnosis, molecular genetics, nomenclature and references.

References

1. Garman SC, Garboczi DN. The molecular defect leading to Fabry disease: Structure of human alpha-galactosidase. J Mol Biol. 2004;337(2):319-335.
2. Masson C, Cissé I, Simon V, et al. Fabry disease: A review. Joint Bone Spine. 2004;71(5):381-383.
3. Kes P, Basic-Jukic N, Brunetta B, Juric I. Anderson-Fabry disease [Article in Croatian]. Acta Med Croatica. 2006;60(1):55-58.
4. Brown LK, Miller A, Bhuptani A, et al. Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med. 1997;155(3):1004-1010.
5. Nicholls K. Cardiac involvement in Fabry’s disease. Heart Lung Circ. 2005;14 Suppl 2:s18-20. Epub 2005 Nov 9.
6. Chabrol B, Mansour H, Cano A. Fabry disease in childhood [Article in French]. Presse Med. 2007;36 Spec No. 1:1S32-35.
7. Kaaroud H, Béji S, Boubaker K, et al. Renal involvement in Fabry disease [Article in French]. Tunis Med. 2007;85(3):240-243.
8. Desnick RJ, Wasserstein MP, Banikazemi M. Fabry disease (alpha-galactosidase A deficiency): Renal involvement and enzyme replacement therapy. Contrib Nephrol. 2001;136:174-192.
9. Gibas AL, Klatt R, Johnson J, et al. A survey of the pain experienced by males and females with Fabry disease. Pain Res Manag. 2006;11(3):185-192.
10. Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: Baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007;30(2):184-192. Epub 2007 Mar 8.
11. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr. 2004;144(5 Suppl):S20-26.
12. Hoffmann B, Keshav S. Gastrointestinal symptoms in Fabry disease: Everything is possible, including treatment. Acta Paediatr Suppl. 2007;96(455):84-86.
13. Sodi A, Ioannidis AS, Mehta A, et al. Ocular manifestations of Fabry’s disease: Data from the Fabry Outcome Survey. Br J Ophthalmol. 2007;91(2):210-214. Epub 2006 Sep 14.
14. Sher NA, Letson RD, Desnick RJ. The ocular manifestations in Fabry’s disease. Arch Ophthalmol. 1979;97(4):671-676.
15. Kuzman T, Juri J, Mrsic M, et al. Ocular findings in Fabry’s disease [Article in Croatian]. Acta Med Croatica. 2006;60(2):163-166.
16. Germain DP, Waldek S, Banikazemi M, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol. 2007;18(5):1547-1557. Epub 2007 April 4.
17. Desnick RJ, Allen KY, Simmons RL, et al. Fabry disease: Correction of the enzymatic deficiency by renal transplantation. Birth Defects Orig Artic Ser. 1973;9(2):88-96.
18. Najarian JS, Desnick RJ, Simmons RL, Krivit W. Correction of enzymatic deficiencies by renal transplantation: Fabry’s disease. Bull Soc Int Chir. 1975;34(1):1-10.
19. Riegel EM, Pokorny KS, Friedman AH, et al. Ocular pathology of Fabry’s disease in a hemizygous male following renal transplantation. Surv Ophthalmol. 1982;26(5):247-252.
20. Meehan SM, Junsanto T, Rydel JJ, Desnick RJ. Fabry disease: Renal involvement limited to podocyte pathology and proteinuria in a septuagenerain cardiac variant. Pathologic and therapeutic implications. Am J Kidney Dis. 2004;43(1):164-171.
21. Desnick RJ. Enzyme replacement and beyond. J Inherit Metab Dis. 2001;24(2):251-265.
22. Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003; 138(4):338-346.
23. Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis. 2004;27(3):385-410.
24. Banikazemi M, Desnick RJ. Does enzyme replacement therapy improve symptoms of Fabry disease in patients undergoing dialysis? Nat Clin Pract Nephrol. 2006;2(2):72-73.
25. Desnick RJ, Banikazemi M. Fabry disease: Clinical spectrum and evidence-based enzyme replacement therapy. Nephrol Ther. 2006;2 Suppl 2:S172-185.
26. Hoffman B, Beck M, Sunder-Plassmann G, et al. Nature and prevalence of pain in Fabry disease and is response to enzyme replacement therapy – a retrospective analysis from the Fabry Outcome Survey. Clin J Pain. 2007;23(6):535-542.
27. Vedder AC, Linthorst GE, Houge G, et al. Treatment of Fabry disease: Outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg. PloS ONE. 2007;2:e598.

Diagnosing Fabry disease As part of the expert panel review on The Optometrist's Role in Diagnosing and Managing Fabry Disease, faculty members discussed the information presented. Following are highlights of the discussion. Michael D. DePaolis, OD, FAAO: A patient with Fabry disease often has a constellation of systemic symptoms, none of which are pathognomonic of the disease; however, two that can be diagnostic from a physical exam standpoint are the ocular findings and the dermatological findings. Are the angiokeratomatous changes characteristically found on certain locations of the body? Irene Maumenee, MD: Angiokeratomas are typically found in the bathing trunk area, umbilicus, buttocks, penis and scrotum. J. James Thimons, OD: Looking at the diverse systemic manifestations of Fabry disease, when in the progression of the disease do the typical external corneal findings occur? Maumenee: The external corneal findings typically occur prior to age 10, and these are often the first findings leading to diagnosis. The angiokeratomas occur early and increase in density with age. They are usually apparent in a patient’s teens and are often unnoticed or a source of embarrassment, so patients rarely volunteer the symptom. Leonid Skorin Jr., OD, DO, FAAO: The angiokeratomas can occasionally occur on the eyelids and the conjunctiva, although they may be sparse. Maumenee: The angiokeratomas are telangiectasias and isolated lesions found even in healthy individuals. Skorin: As a clinical distinction, angiokeratomas are non-blanching; the tortuousities on the conjunctiva would blanch. Scott E. Brodie, MD, PhD: The pattern of the whorls and the location of the center of the vortex seen in the cornea are the normal pattern of corneal cell migration. Anything that happens to mark a few clones of cells that are proliferating at the limbus will show the same findings; Fabry disease simply demonstrates this pattern well. DePaolis: Is this condition truly as rare as current prevalence indicates, or is Fabry disease underdiagnosed? Maumenee: The symptoms are nonspecific and easily overlooked. Families with a history of disease may be extensive, and it may take years before the extent of the disease within a family is fully known. In addition, the first patient with Fabry disease in a family is rarely diagnosed before age 20, and older patients may die from the disease without ever being diagnosed. Fabry disease is much more prevalent than the current number of cases diagnosed.

Diagnosing Fabry disease in the OD's chair
Leonid Skorin Jr., OD, DO, FAAO

A general ophthalmologist or optometrist armed with only the tools of the trade but with a working knowledge of Fabry disease and its symptoms is often able to make an accurate diagnosis in an otherwise asymptomatic patient.

Clinical ocular manifestations

Corneal whorling

The most common clinical manifestation in the eye is the corneal verticillata, or corneal whorl. The first ocular sign in a patient with Fabry disease, corneal verticillata occurs in more than 90% of patients, although it is not always visible because of the sloughing of the epithelium.¹ Corneal whorling is noted in as many as 88% of pediatric patients with Fabry disease,² and one study of pediatric girls indicates that 100% of those studied presented with corneal whorling.³ Corneal whorling is most prominent in female heterozygotes, and it is more commonly noted and exhibited in a more prominent fashion in women than in men.

Corneal whorling occurs in the subepithelium or, possibly, Bowman’s layer, and occurs bilaterally. It can present as a diffuse, nonspecific yellow haze and not necessarily the whorled pattern. When the whorled pattern forms, dense rays are visible, radiating from the center or just below the midline. Some clinicians may refer to this whorled pattern as a vortex, star-shaped or spoke-like pattern. Coloration varies anywhere from cream-colored to bronze streaks.

Corneal whorling associated with Fabry disease has no effect on visual acuity; however, patients presenting with a corneal whorl associated with amiodarone hydrochloride deposits may experience pain and epithelial sloughing so severe that it affects vision. Some patients with Fabry disease may experience difficulty with glare, but similar complaints are noted in cataract patients as well. Symptomatic ocular findings may present later in the disease.

Conjunctival vasculature

Conjunctival vasculature is affected in as many as 60% of patients with Fabry disease.⁴ Most commonly, a saccular type of aneurysmal dilation occurs (Figure), but conjunctival vasculature affected by Fabry disease can include increased tortuosity and kinking of the blood vessels. Presentation can occur anywhere in the conjunctiva, but occurs most often in the inferior bulbar conjunctiva. Similar to patients with corneal verticillata, patients do not experience discomfort or bleeding, although blanching occurs when the vasculature is compressed.

Figure. Sausage-like and markedly dilated conjunctival vessels are typical in patients with Fabry disease. Image courtesy of Leonid Skorin Jr., OD, DO, FAAO

Cataracts

The anterior capsular, or “propeller” cataract, is usually cream-colored and develops more rarely than the “Fabry,” or posterior subcapsular cataract, which has a dendritic-like presentation. Typically whitish, granular and dendritic or spokelike, this posterior subcapsular cataract develops more often in men than in women and rarely affects vision. As in nuclear sclerosis, however, it could affect vision, and cataract extraction is similar in patients with Fabry disease as in any other cataract patient.

Eyelids/tear production

In some patients with Fabry disease, the eyelids may have a persistent, protracted type of swelling or edema, typically affecting the upper eyelids more than the lower eyelids. This is not specific to Fabry disease but is worth noting. Additionally, as many as 50% of patients experience decreased tear production due to a direct deposition of the globotriaosylceramide deposits in the lacrimal gland or through secondary autonomic dysfunction from the accompanying vascular complications,⁵ making dry eye common.

Retinal vasculature

Retinal vasculature can also be affected, with myriad presentations, in patients with Fabry disease. Typically, presentation is in sausage- or corkscrew-like venous dilations, but arterial constriction leading to central retinal artery occlusions also can occur. Retinal and preretinal-type hemorrhages are also seen. Hypertensive retinopathy with disc edema can present, accompanied by perimacular edema, although this is more common in men than in women and is a late complication.

Neuro-ophthalmic presentations

Neuro-ophthalmic presentations, ranging from nystagmus to diplopia, usually due to extraocular muscle palsies that accompany Fabry disease, have rarely been reported in the literature.^6,7 Internuclear ophthalmoplegia has been reported, as well as hypertensive disc edema.^8,9 Additionally, non-arteritic anterior ischemic optic neuropathy-type presentation sometimes occurs, which is vasculopathic-related and results in field defects, most commonly homonymous hemianopsias and impaired pupillary constriction due to autonomic dysfunction.

Ophthalmic evaluation guidelines

Patients with Fabry disease should undergo a full general ocular examination, including an assessment of visual acuity, slit lamp exam and a dilated fundus exam with direct or indirect ophthalmoscopy.¹⁰ Additionally, because these patients occasionally experience homonymous hemianopic defects or other types of visual field defects, an analysis for visual field defects is recommended during this baseline exam and, afterward, on an annual basis, unless the patient becomes symptomatic or experiences changes. The analysis of visual field defects can be performed on an as-needed basis should a patient develop retinal dysfunctions such as ischemic optic neuropathy, macular changes or central retinal artery occlusions; a physician might consider performing an electroretinogram, visual evoked potential, color vision testing and fluorescein angiography.¹⁰ Optical coherence tomography might be considered as well.

If a patient experiences dry eye-type symptomatology, then a standard workup, such as Schirmer’s test, phenol red thread test, fluorescein staining, lissamine green or rose bengal test, can be utilized and tear breakup time determined to find out the severity of the dysfunction. A typical implementation of standard dry eye therapy would be indicated in individuals with Fabry disease who experience dry eye.¹⁰

Patients who develop symptoms such as visual disturbances or light sensitivity should undergo a baseline exam with follow-up every 6 months.¹⁰ Few patients, however, actually become symptomatic.

Confounding diagnoses

Multiple conditions result in ocular changes similar to those that occur in a patient with Fabry disease. Several available drugs can cause deposits on the cornea similar to those represented in corneal whorling, namely amiodarone hydrochloride, as well as chloroquine, chlorpromazine and indomethacin. Eyelid edema is a general presentation, common in patients with cardiac or renal disease, thyroid disease, allergic reactions and blepharochalasis.

Hereditary hemorrhagic telangiectasia and ataxia telangiectasia are rare, but symptoms include conjunctival vessel changes similar to those seen in patients with Fabry disease. The diagnosis of Fabry disease in males can be readily made by determining the α-galactosidase A activity in plasma or leukocytes. In females, the enzyme assay may not be diagnostic, and mutation analysis of the α-galactosidase A gene is required.

Ocular complications

“Corneal verticillata, or corneal whorling, is the most common and first ocular symptom to present in patients with Fabry disease.” — Leonid Skorin Jr., OD, DO, FAAO

Ocular complications can occur in patients with Fabry disease. According to the literature, individuals with Fabry disease needing penetrating keratoplasty (not necessarily related to Fabry disease) experience a poorer prognosis than patients undergoing penetrating keratoplasty who do not have Fabry disease.⁴ Subsequently, corneal surgeons should be aware that a patient has Fabry disease and should warn patients of the complications of the procedure. Disc edema from uncontrolled hypertension may also occur.

Anterior ischemic optic neuropathy may occur from the ischemia alone, but appropriate erythrocyte sedimentation rates should be determined and C-reactive protein tests should be conducted to ensure the neuropathy is not arteritic. Optic atrophy will develop eventually from the anterior ischemic optic neuropathy or from chronic disc edema occurring from uncontrolled hypertension.⁴

Extraocular muscle involvement, or palsies, usually occur secondary to vascular findings and are often accompanied by ischemia. Palsies may cause diplopia, so patients may complain of double vision. Autonomic dysfunction can result in impaired pupillary constriction, causing patients to have difficulties with glare as they become more photophobic and have decreased tear formation, a result of the involvement of the lacrimal gland.

Conclusion

Corneal verticillata, or corneal whorling, is the most common and first ocular symptom to present in patients with Fabry disease. However, it does not affect visual acuity, and ocular presentations that are symptomatic occur later in the disease.

Because patients with Fabry disease present with many ocular complications, an optometrist or ophthalmologist is often the first to diagnose the disease and should be aware of its symptoms to ensure proper follow up and diagnosis.

References

1. Franceshetti A. Fabry’s disease: Ocular manifestations. In: Bergsma D, Bron AJ, Cotlier E (eds). The Eye and Inborn Errors in Metabolism. Vol. 12, No. 3. New York: AR Liss Co.; 1976:195-208.
2. Ries M, Gupta S, Moore DF, et al. Pediatric Fabry disease. Pediatrics. 2005; 115:E344-E355.
3. Sher NA, Letson RD, Desnick RJ. The ocular manifestations in Fabry’s disease. Arch Ophthalmol. 1979;97:671-676.
4. Melton R, Thomas R. Fabry’s keratopathy. Clin Refract Optom. 2006;17:452-453.
5. Cable WJL, Kolodny EH, Adams RD. Fabry disease: Impaired autonomic function. Neurology. 1982;32:498-502.
6. Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s disease. Ann Neurol. 1996;40:8-17.
7. Desnick RJ, Ioannou YA, Eng CM. Alpha-Galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw Hill; 2001:3733-3774.
8. Ho PC, Feman SS. Internuclear ophthalmoplegia in Fabry’s disease. Ann Ophthalmol. 1981;13:949-951.
9. Repka MX. Degenerative and metabolic disease in infants and children. In: Miller NR, Newman NJ (eds). Walsh & Hoyt’s Clinical Neuro-Ophthalmology. 6^th ed., Vol. 3. Philadelphia: Lippincott Williams & Wilkins; 2005:2469-2511.
10. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: Guidelines for the evaluation and management of multi- organ system involvement. Genet Med. 2006;8:539-548.

Ocular manifestations and Fabry disease DePaolis: In the early stages of Fabry disease, the ocular presentations are hard findings without symptoms. If a patient manifests with a vasculopathy and anterior ischemic optic neuropathy, is that secondary to the cardiovascular disease in patients with Fabry disease, or is that an initial presentation? Skorin: Such a manifestation could be secondary to the cardiovascular complications associated with Fabry disease or an initial presentation. Vascular disease within the body causes anterior ischemic optic neuropathy or central retinal artery occlusions. If either presented initially in the office, then an optometrist would have to research from that point, as if it were the initial presentation. For example, if a patient has anterior ischemic optic neuropathy, then the optometrist would perform tests to distinguish if it is non-arteritic or arteritic. Should it be non-arteritic, then the physician would look at the prospective cause, for example, vasculopathic disease. Fabry disease should be considered when the typical corneal opacities are seen by slit lamp examination, as almost all affected males and approximately 90% of female heterozygotes demonstrate the opacities. Brodie: Although it is widely reported that visual acuity is not affected by the corneal or the lenticular lesions, the question of glare remains; the corneal changes must scatter light and cause some degree of glare disability. In my experience, patients rarely volunteer problems with glare. Additionally, while a physician might elicit the complaint, it is nearly impossible to separate a real exaggeration of the usual veiling effects of stray light from the normal difficulty. Skorin: In the general practitioner’s office, the most accurate way to test for glare difficulties, aside from the inaccurate test of shining a bright light in a patient’s eyes, is a brightness acuity test. In my experience, I elicit this test when a patient complains of glare to see if he or she qualifies for cataract surgery. Has a measurable study been conducted on glare difficulty in patients with Fabry disease? Brodie: As far as I know, no formal study has been conducted. Skorin: Perhaps the small number of patients with Fabry disease makes such a study difficult to conduct. DePaolis: Ultimately, corneal findings are not without implication from a visual standpoint. Patients with Fabry disease may not register glare problems on a high-contrast Snellen acuity test, and no impact on vision is likely. However, some symptoms may be present in low-contrast visual acuity testing. Which visual field tests are recommended? Brodie: A 30-2 Humphrey visual field exam is performed routinely when a specific indication is presented. DePaolis: The visual field test assesses overall retinal sensitivity, and is not necessarily conducted in search of some subtle homonymous hemianoptic defect, for example. Brodie: The physician should be looking for a neurological defect. In patients with Fabry disease, the retinal vasculature looks much worse than it acts. Patients with distorted retinal vasculature caused by Fabry disease see much better than patients with the same degree of apparent vasculopathy caused by, for example, diabetes. With Fabry disease, the vasculopathy rarely occludes. Cotton wool spots never form and intraretinal hemorrhages are rare. The pathology in Fabry disease is different than that in diabetes, despite the fact that the tortuosity and the narrowing that occur in both diseases are superficially similar. Skorin: The literature states that preretinal and retinal hemorrhages occur in patients with Fabry disease, but, unlike in patients with diabetes, microaneurysm changes do not occur, and edema occurs more rarely than in patients with diabetes. Brodie: A distinction cannot be made between treating a manifestation of Fabry disease on the retinal vasculature itself vs. treating a manifestation of Fabry disease on the retinal vasculature caused by kidney dysfunction, for example. Skorin: From the neuro-ophthalmologic standpoint, a visual field test should be performed at baseline. A subtle stroke might be picked up in an otherwise asymptomatic patient. DePaolis: What is the importance of blanching vs. non-blanching when it comes to conjunctival saccular aneurysm-like changes? Skorin: Conjunctival vasculature changes occur in the blood vessels; subsequently, when pressed, they should blanch. Angiokeratomatous changes, usually found in a bathing suit-type distribution, but also occasionally found on the eyelids or the conjunctiva, look like small microaneurysms or aneurysms, but they will not blanch when pressure is applied. “Literature indicates they would be two separate entities, but a propeller cataract could very well be a continuation of a dendritic cataract”. — Leonid Skorin Jr., OD, DO, FAAO Maumenee: When the vessel can be compressed or the blood flow stopped, this indicates if the vasculature will blanch. A keratinized lesion that includes some red blood cells will not blanch. Brodie: Additionally, propeller cataracts are rare, but I think the propeller is actually an area of lucency, not cloudiness, and the pathology is no different than that of the typical dendritic cataract. The dendritic opacities are exaggerations of the suture lines in the lens. In the severe case, these creep forward, occurring as wedge-shaped areas of cloudiness; the clear spaces between the wedges form the propeller-like pattern. Skorin: The propeller cataract would not occur independent of a Fabry cataract. The literature indicates they would be two separate entities, but a propeller cataract could very well be a continuation of a dendritic cataract.

Incorporating the understanding of genetic disorders into the optometric practice
J. James Thimons, OD

The future of genetics and evolving technologies will impact patients in the general optometric or ophthalmic practice, and physicians should understand how to use these advancements to better care for patients.

Genetic testing

The implementation of genetic testing would enable clinicians to understand presymptomatic patients and predict adult-onset disorders. Patients could be placed in a channel of care in an antecedent position as opposed to waiting until the systemic situation has elaborated itself to a point of concern. Carrier testing, or testing individuals in a lineage to find out who is at risk, is possible. Prenatal diagnostic testing is going to expand dramatically in the next decade as technology evolves. Newborn screening offers the opportunity for genetic testing, and the concept of preimplantation genetic testing and subsequent treatment bears a reasonable level of scrutiny as well.

Better understanding of pathogenesis and pathophysiology

As technology and knowledge continue to advance, so will the capabilities of genetic testing and, with them, improved understanding of the pathogenesis and pathophysiology of genetic disorders. Myocilin, optineurin and cytochrome enzyme testing have indicated that cases of glaucoma may be caused by genetic mutation,^1-4 and nine genes and 22 loci have been identified in research to determine the genetic causes of glaucoma. In this same vein, heritability characteristics in certain patients with cataracts may be definitive; for example, the ability to identify a patient with Fabry disease as one who will develop a classic dendritiform-like posterior subcapsular cataract impacts the patient’s life.

“The goal of genetic testing is to reverse the clinical presentation of a disease in a patient with successful intervention as early as possible.” —J. James Thimons, OD

Although most physicians are not comfortable making a definitive diagnosis of juvenile glaucoma or other disease based on genetic testing, such diagnoses will be possible in the future. Diagnostic testing for glaucoma is advancing (OcuGene glaucoma genetic test, InSite Vision Incorporated), and assessments for Stargardt disease (ABCA4 microarray test, Asper Biotech) and Leber’s congenital amaurosis (genotyping microarray test, Asper Biotech) have also been developed. More than 1,000 genetic tests are available from commercial or research labs, including tests for various glaucomas, corneal dystrophies, retinal dystrophies, cataracts, age-related macular degeneration and various pathogens. The goal of genetic testing is to reverse the clinical presentation of a disease in a patient with successful intervention as early as possible, before the patient becomes symptomatic or experiences difficulties normally associated with disease.

For example, a polymorphism in complement factor H gene (CFH) on chromosome 1 accounts for 20% to 50% of the overall risk for developing age-related macular degeneration. Genetic testing indicates that carrying a single copy of the polymorphism correlates with a two- to fourfold risk for developing AMD, and carrying two copies correlates with a five- to sevenfold risk for developing the disease. Assuming AMD damage is a result of chronic inflammation mediated by the complement system, individuals at risk can be identified and therapy can be developed to address genetic and environmental concerns. Reducing the damage from AMD early not only impacts the patient’s quality of life, but also contributes significant savings in the overall cost to the health care system. Nearly 300,000 at-risk patients could avoid progressing to advanced AMD by taking recommended antioxidants.⁵

Individuals with the propensity for progression to significant myopia could be identified using genetic testing; an intervention in childhood may prevent the occurrence of common ocular abnormalities.

Pharmacogenomics

Additionally, genetic testing will play a role in the future of pharmacogenomics. A specific antibiotic or treatment system could be created utilizing the genetic matrix of a specific patient. DNA variations in genes, or polymorphisms, that are responsible for drug metabolism affect a patient’s response to drugs and vary from patient to patient. Tailored treatment would markedly decrease the risk for adverse reactions and maximize the efficacy of drugs, as well as reduce the rising tide of antibiotic and organism resistance.

Advances in genetic testing

The development of tests and technologies that determine risk for common diseases is evolving. Technologies such as microarrays, “lab-on-a-chip” microfluidics and point-of-care testing allow for current analysis of a patient’s genetic status, which allows for specific disease assessment. Available microarrays analyze DNA, RNA or protein; Affymetrix’s Human Genome U133 Plus 2.0 Array, for example, probes all 30,000 human genes and 17,000 variants.

“As genetic testing and technology continue to advance, the future of treatment and the opportunity for gene therapy as a cure become ever closer.” —J. James Thimons, OD

Microfluidics offers another means of genetic analysis, and lab-on-a-chip technologies allow for point-of-care testing. The Affymetrix GeneChip Scanner 3000 has a work station that genetically evaluates a patient, offering output that can be interpreted by a geneticist to facilitate patient diagnosis; however, this technology is not readily available.

Genetics worldwide

China has approved the first commercially licensed gene therapy, an injectable medication that uses an adenoviral vector to deliver a p53 tumor-suppressing gene for the treatment of a form of squamous cell carcinoma of the neck. With treatment, 64% of patients’ tumors showed complete regression and 32% showed partial regression. ⁶

Conclusion

As genetic testing and technology continue to advance, the future of treatment and the opportunity for gene therapy as a cure become ever closer. Research indicates ocular disorders benefit from genetic testing and gene therapy, and cures for disorders such as glaucoma or AMD could be achieved in the future.

References

1. Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;295:1077-1079.
2. Tamm ER. Myocilin and glaucoma: Facts and ideas. Prog Retin Eye Res. 2002;21(4):395-428.
3. Park BC, Tibudan M, Samaraweera M, et al. Interaction between two glaucoma genes, optineurin and myocilin. Genes Cells. 2007;12(8):969-979.
4. Hollander DA, Sarfarazi M, Stoilov I, et al. Genotype and phenotype correlations in congenital glaucoma. Trans Am Ophthalmol Soc. 2006;104:183-195.
5. Bressler NM, et al. Paper 2903, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; 2002; Fort Lauderdale, Fla.
6. Guinn BA, Norris JS, Farzaneh F, Deisseroth AB. International Society for Cell and Gene Therapy of Cancer: 2005 meeting in Shenzhen, China. Cancer Gene Ther. 2007;14(2):128-138.

Genetic testing and Fabry disease DePaolis: If a physician has a 28-year-old male patient with corneal verticillata and general vague symptoms that may suggest Fabry disease, then what should be the next steps? Thimons: Previously, I would have referred him to a cornea specialist for a more definitive assessment, but I do not think that is necessary. I would refer the patient to a dermatologist or a physician with expertise in Fabry disease to confirm the diagnosis. If the diagnosis remained in question, then a genetic assessment would be indicated. DePaolis: Optometrists should not necessarily make the definitive diagnosis, but they should have an awareness of Fabry disease to ensure that appropriate referrals are made. After Fabry disease is confirmed in a patient, do you examine family members? Thimons: Absolutely. Family members should be examined in the incidence of glaucoma as well, as genetic analysis and a number of large studies indicate that the incidence rate is high among siblings.1 Patients should be aware of the horizontal penetration of Fabry disease. Brodie: Which group of clinicians has taken enzyme replacement therapy as their bailiwick, aside from clinicians who are dedicated to metabolic disease, in an ordinary health care community without a university hospital affiliation? Maumenee: At the hospital with which my practice was affiliated, patients with Fabry disease are treated in the genetics unit. Treatment for patients with Fabry disease starts at a university hospital and then can be transferred to a local hospital or outpatient facility. DePaolis: Ultimately, the treatment can distill down to home. Thimons: A working knowledge of the diagnostic and management process is important as well. Should a clinician not understand the treatment options, then he or she should connect to a larger health care system. Once a clinical assessment is made, dermatology is a logical next step. Treatment options that offer long-term success now exist. DePaolis: From a patient management standpoint, the community-based eye care practitioner needs to be a patient’s advocate and needs to follow through. Maumenee: Patients with Fabry disease, even if they are symptomatic, rarely recognize that they have a disease. If a patient has experienced these symptoms since early childhood, then how would he or she know that it is abnormal? Patients with Fabry disease often have been previously diagnosed with psychoses of some sort. A social decline occurs because they have a limited physical ability and stamina as compared to their peers. DePaolis: Physicians looking at objective corneal findings need to ask questions and delve into the patient’s history to a greater degree; if the history dovetails with the objective findings, it makes a more compelling argument for further evaluation. Maumenee: Twenty years of delay was previously noted between first symptoms and a diagnosis of Fabry disease. Fevers of unknown origin in a child are rarely diagnosed as Fabry disease; diagnosis usually occurs late with renal failure. Reference Quigley HA. Chase the family. Arch Ophthalmol. 2006;124(7):1036-1037.

Educating patients and their families on Fabry disease
Scott E. Brodie, MD, PhD

Many nonclinical issues arise when physicians educate patients and their families about Fabry disease. In some sense, the issues apply to all genetic disease. Given the unique combination of genetic implications and symptoms of Fabry disease, patient education should be individualized for each patient and each family. Issues that need to be addressed – for example, a limited lifespan – could be discussed with parents, as opposed to directly with a child. The issues facing a heterozygous female are different than those affecting a teenage male. A patient’s ability to absorb information varies greatly, as does that patient’s predisposition to accept the information and to act on what he or she has learned. The physician’s job largely consists of serving as an educator and providing referrals, particularly when considering treatment that is administered by others.

Fabry disease and patients’ understanding

Patients should understand the basics of the disease, although these basics can be explained to varying degrees based on the baseline sophistication of the individual patient. Patients should know that Fabry disease is an abnormality of metabolism, an inability to break down normally occurring molecules that lead to an accumulation in tissues, and an inherited condition according to the X-linked pattern. Eye care specialists are concerned mostly with signs that rarely, if ever, cause abnormalities in a patient’s visual acuity, but a patient needs to understand that Fabry disease has important medical implications, despite a lack of noticeable impact on a patient’s vision.

“Patient education should be individualized for each patient and each family.” —Scott E. Brodie, MD, PhD

A physician should elicit a patient’s history, particularly if the diagnosis is the first in the patient’s family, noting the possible systemic manifestations of Fabry disease. A patient might have trouble understanding that occurrences he or she has experienced since childhood are abnormal or that systemic manifestations of Fabry disease relate to the findings in the eyes. In my experience, many patients have difficulty relating the various manifestations of the disease and, in patients who are more advanced, those of the nephropathy particularly, as these are more a matter of laboratory results than symptoms.

A patient or the patient’s family or caregivers must consider the impact of Fabry disease. Most patients with Fabry disease live nearly normal lives for many decades. Issues of mental retardation and gross disability are not pertinent to Fabry disease, which is more of a persistent and subtly disabling disease; however, Fabry disease has serious implications for overall health and survival.

Treatment and patients

Patients need to understand the nature of the genetic disorder (an enzyme is missing) and that, with specific treatment, the enzyme can be replaced. Treatment, however, is a lifelong commitment with considerable intrusion in daily life and ability to schedule events or to travel, for example.

The benefits of treatment are evolving as well. Fabrazyme (agalsidase beta, Genzyme) was approved on the basis of its ability to preserve renal function, which is obviously important, given that renal morbidity was previously the major factor limiting life and function in patients with Fabry disease. Patients report substantial mitigation of auxiliary symptoms. However, the treatment’s effect on longevity is unknown, although physicians have every reason to be optimistic.

The economic aspects of treatment also need to be relayed to the patient. Agalsidase beta is expensive. Most insurance companies cover it. Administration of the treatment and monitoring of function thereafter also have associated costs, and, of course, treatment is ongoing throughout a lifetime.

Ocular manifestations and patients

Ocular manifestations often incite curiosity in patients with Fabry disease because the ocular changes are informative and diagnostic, but rarely disabling, and almost never require treatment.

Conjunctival vessel abnormalities are common, although typically asymptomatic. The corneal changes, such as corneal verticillata, are often unnoticed. Many patients, especially affected males, have a uniform involvement of the cornea, creating a diffuse haze, which is easy to miss, even when it is severe. The contrast between the clones of normal and abnormal cells, seen in females, make the most dramatic impact in terms of noticeable corneal changes; consequently, findings are reported as being visible earlier in heterozygous females than in affected males.

Cataracts associated with Fabry disease are distinctive but subtle in the early stages and often are missed by eye care specialists unless they are specifically looking for them. They are most visible against the red reflex. The dendrites start near the equator and track centrally.

Retinal vascular abnormalities are not present in everyone but are distinctive, though not specific, for Fabry disease. Again, the visual complications of Fabry disease seem to rarely affect vision. Patients who are able to understand the genetics should understand what it means to be a female heterozygote, or “carrier female.” The tendency is to think of heterozygote females as less severely affected, but some patients may appreciate the mechanism of lyonization, which can lead to a spectrum of severity in women who are heterozygous for the disease. As previously discussed, the corneal pattern is often more dramatic in heterozygous females, but significant visual complications rarely occur.

Some patients may be prepared to deal with the laws of inheritance; parents might be concerned about the risks to children or other relatives. The risks are the same regardless of whether the carriers are symptomatic, but a patient may have a harder time understanding the genetic implications if he or she is not symptomatic.

Mechanisms of education

The mechanisms of educating patients with Fabry disease are comparable to those for other rare or little known inherited diseases. The greatest impact is achieved through discussions with the patients or their families. This takes time, however, and a physician must allow for it. Additionally, patients are not going to absorb all the information at one sitting or may not remember all the information presented the first time and may require additional discussions. Pamphlets are available to further patient education.

Eventually, the eye care specialist will have to refer patients to a treating physician; this may require some research, to find a physician who can appropriately treat a patient with Fabry disease. The medical geneticists are knowledgeable, and genetic counselors can help educate patients about the genetic implications. The Internet can also provide useful information for patients, and the Fabry Disease Information and Support Group provides information on diagnosis and treatments.

Barriers to patient education

“Because patients are frequently asymptomatic or attribute symptoms to general illness, not a specific disease, denial could impede a patient from accepting the diagnosis and seeking treatment” —Scott E. Brodie, MD, PhD

Most patients newly diagnosed with Fabry disease will be unfamiliar with the disease unless they have affected relatives. Additionally, patients who come for a routine checkup and are suddenly diagnosed with a life-limiting genetic disease are rarely prepared for the news and have difficulty understanding how it will change their lifestyle. A patient may need time to appreciate the impact the diagnosis will have on his or her life. Genetic disease is more complicated and difficult to understand than other kinds of disease, and a patient may also need time to fully understand the information. Because patients are frequently asymptomatic or attribute symptoms to general illness, not a specific disease, denial could impede a patient from accepting the diagnosis and seeking treatment.

Obtaining a family history, particularly when dealing with a genetic disease as subtle as Fabry disease, can be a problem. The outlook and openness of the family greatly impact a physician’s ability to obtain a family history. The Health Insurance Portability and Accountability Act also may impede a physician’s ability to obtain family history information. However, it is especially important to pursue the family history, as this is an X-linked disease, and other affected males and heterozygous female relatives should be identified for early therapeutic intervention and for providing information on future reproductive options. Additionally, local resources are sparse for conditions as rare as Fabry disease. Not all health care communities have specialists who will take responsibility for the care of a patient with such a rare genetic disease.

Conclusion

Although numerous factors, including the scarce occurrence and limited awareness of Fabry disease, can impede a patient diagnosed with Fabry disease from understanding the disease and its implications, the role of the physician is to facilitate a patient’s education. Physicians need to be aware that the process may be slow and may require multiple discussions and methods of education, including pamphlets, Internet searches and patient organizations. The key realization for a physician is that understanding is crucial to a patient’s acceptance and willingness to seek treatment and to make available various reproductive options.

Patient education DePaolis: In terms of barriers to patient education, family and personal history play a significant role in diagnosis and patient education. Some families and individuals are cooperative and forthcoming with such information, but obtaining information from those who are not can be difficult. With treatment, increased longevity cannot be promised, although data indicate that is ultimately true. Are there risks associated with the treatment on which patients should be counseled? Brodie: The intravenous enzyme infusions have been safe and well tolerated. A patient undergoing treatment for Fabry disease should be aware of potential infiltrations that occur with any IV infusion of a biologic agent, as well as infusion-incited reactions that may present as fevers and chills during the infusion. Maumenee: Treatment is initiated in a hospital because of the risk of adverse side effects. A caregiver should have access to steroids and epinephrine in case of a severe allergic reaction. In most patients, these reactions usually only last for several infusions. Premedication with a non-sedating antihistamine and an antipyretic will often preclude or minimize the reaction. DePaolis: Therapy, which is an IV infusion initially lasting up to 4 hours and occurring every 2 weeks, is ongoing throughout a patient’s lifetime. Is there any indication that will ever be tapered down? Brodie: There is no indication that treatment can be tapered down. Maumenee: Treatment is usually not administered until the patient becomes symptomatic, often starting in young boys who experience the periodic pain. Brodie: Patients with a known family history of Fabry disease, who have seen relatives progress, are often easier to motivate to seek treatment than someone who is unfamiliar with the disease. DePaolis: Patients should also be aware that having only a little information can be dangerous. The Internet is a great resource, but not all information posted on it is fact. The Internet might empower patients to form appropriate questions, but, ultimately, an expert in the field is the best source of information. As an eye care specialist diagnosing Fabry disease, part of the job is to refer patients to appropriate channels of treatment and information. A heterozygous female diagnosed with Fabry disease may ask about the ramifications on family planning, but she should be referred to a specialist. Brodie: The acceptance of and interest in genetic counseling varies greatly from person to person. The information disseminated by a physician should be guided by the patient’s approach and attitude.