Ocular manifestations of Fabry disease within in a single kindred

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1 Optometry (2010) 81, Ocular manifestations of Fabry disease within in a single kindred Albert M. Morier, O.D., M.A., a John Minteer, O.D., b Robert Tyszko, O.D., b Rachel McCann, O.D., c M. Virginia Clarke, R.N., d and Marsha F. Browning, M.D., M.P.H. d,e a Albany Medical College, Albany, New York; b Private practice, Peterborough, New Hampshire; c Private practice, Saratoga Springs, New York; d Lysosomal Disease Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts; and e Harvard Medical School, Boston, Massachusetts. KEYWORDS Fabry disease; Ocular manifestations; Optical coherence tomography; Corneal verticillata Abstract BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder that causes progressive complications within the kidneys, brain, and heart. Ocular manifestations of this disease are often present at a very young age, thereby facilitating early diagnosis, before the signs and symptoms of renal disease, stroke, or hypertrophic cardiomyopathy. Early diagnosis by the eye care provider may eventually reduce the morbidity and mortality of this disease through the institution of therapy before the development of sclerotic end organ damage. This study evaluated 23 Fabry-affected members of a single cohort for the presence of ocular signs of Fabry disease. METHODS: Twenty-three patients of a single family were seen on a single day. Patients were given comprehensive ophthalmic examinations and completed a health and lifestyle questionnaire. RESULTS: Eight hemizygous men (mean age, 32.3 years) and 15 heterozygous women (mean age, 26.9 years) from a single family of 43 known Fabry patients were evaluated. Corneal verticillata was present in all patients. Additional findings in the male patients included anterior capsule opacity (25% total) and Fabry cataract (12.5%). Thinning of the retinal nerve fiber layer was observed in one man whose medical history was significant for stroke. Conjunctival and/or retinal vessel tortuosity was present in the majority of patients (62.5% and 75% of hemizygotes, respectively; 40% and 13.3% heterozygotes, respectively). Additional findings in the women included anterior capsule opacity. The majority of patients (87.5% hemizygotes, 60% heterozygotes) felt Fabry disease had an impact on their quality of life. CONCLUSIONS: All evaluated patients who had Fabry disease had corneal verticillata, which generally does not affect vision and is readily recognizable by slit lamp examination. Greater than 60% showed conjunctival and/or retinal vessel tortuosity. The eye care provider can play a crucial role in the early recognition of ocular manifestations of Fabry disease and decrease both the time to accurate diagnosis and the delay in the institution of disease-modifying therapy. Optometry 2010;81: Corresponding author: Albert M. Morier, O.D., 1426 Altamont Ave., Schenectady, New York amorier1@nycap.rr.com Fabry disease is a progressive, debilitating, and eventually fatal disease first described by Johannes Fabry in Germany and William Anderson in England at the end of the 19th century. 1,2 Fabry disease is 1 of more than 50 lysosomal storage disorders 3 with an estimated prevalence /$ -see front matter Ó 2010 American Optometric Association. All rights reserved. doi: /j.optm

2 438 Optometry, Vol 81, No 9, September 2010 of 1 in 40,000 men. 4 However, recent population screening reports suggest its occurrence may actually be as high as 1 in 3,100 men. 5 The occurrence in women has been estimated to be twice as high as in men (1 in 20,000), 6 but the true prevalence in women is unknown. Fabry disease is a single-gene Mendelian disorder of X- linked inheritance. It is an inborn error of metabolism that results in deficient enzyme levels of alpha-galactosidase A (AGAL), 7 an enzyme important for the breakdown of various glycoproteins in the body. Measured enzyme activity levels of less than 2% can be found in many hemizygous men who then become prone to life-threatening complications in vital organs and other morbidities. Late-onset renal and cardiac variants have been reported with some residual enzyme activity greater than 2%. 5 The activity of the enzyme in heterozygous women can overlap with the activity in normal women Evidence has accumulated confirming that most of the mutation-positive women will experience signs and/or symptoms of the disease, although with a variable later onset of presentation. 8,10,11 AGAL deficiency prevents the effective metabolism of the glycoprotein globotriaosylceramide (Gb3, formerly referred to as GL3). Consequently, Gb3 deposits within lysosomes in virtually every tissue in the body. 4 Gb3 is progressively stored in the lysosomes of vascular endothelial cells and is likely causative of the initial symptoms of Fabry disease. Increasing storage of Gb3 and the resultant intrinsic inflammatory reactions lead to increased disease burden in the patient with disease progression. The initial symptoms can include angiokeratomas (telangiectatic cutaneous lesions), acroparesthesia (severe pain in hands and feet), hypohidrosis (inability to sweat), gastrointestinal dysmotility, and various ocular manifestations. 12 It should be noted that the episodes of pain associated with the acroparesthesia are extreme and have been described by a female Fabry patient to be worse than childbirth (A.M.M., personal communication). Although not life-threatening, gastrointestinal dysmotility is also a common and significant factor affecting Fabry patients quality of life. As the disease progresses, vascular complications occur within the brain, heart, kidney, and cochlea, resulting in strokes, left ventricular hypertrophic cardiomyopathy, kidney failure, and hearing impairment. 12 Ocular manifestations of Fabry disease have been published by several investigators The most commonly reported ocular finding is corneal verticillata, a bilateral, whorl-like pattern of cream-colored lines usually found in the inferior cornea. These lines are caused by the accumulation of Gb3 at the level of Bowman s membrane, which radiate out in a vortex pattern. In a slit lamp examination, the degree of corneal verticillata can range from very faint to quite obvious but rarely affects visual acuity (see Figure 1). The phenotype in men uniformly includes corneal verticillata and may manifest as early as 6 months of age and is completely penetrant by 10 years of age. 14,21 Peters et al. 24 reported that even heterozygotes demonstrate corneal findings in 70% of cases. Glare is reported in 10% of cases of amiodarone keratopathy 25 ; Figure 1 Corneal verticillata in Fabry disease. Courtesy of R.L. Abbott, M.D. keratopathy originating from both Fabry disease and amiodarone have the same pattern of hyper-reflective deposits in the same layer of the cornea. 26 Conjunctival and retinal blood vessels may exhibit tortuosity and aneurysmal dilatations. One study found this to be the most common ocular manifestation at 97.1%. 18 The pathophysiology is primarily caused by Gb3 accumulation within the vessel walls, resulting in endothelial cell dysfunction, abnormal blood flow, and hypercoagulability. 22 There are 2 types of lenticular changes found to be associated with Fabry disease. One is a granular anterior capsular or subcapsular deposit radiating out from the periphery in a pattern that has been described as a propeller cataract. 21 The second is a whitish, faint, linear cataract at or near the posterior lens capsule. This second type of cataract was first described by Spaeth and Frost 23 in 1965 and is termed a Fabry cataract as it seems to be unique to this condition. This is particularly difficult to see, as it is translucent and is best seen by retro-illumination. Fabry patients often are misdiagnosed initially with other disease states. This is in part because of the nonspecific initial symptoms, such as extremity or abdominal pain and heat intolerance. Serious indicators of this disease, such as microproteinuria, are often silent in the first years, and will likely not be brought to clinical attention until advanced disease burden is present. The most common misdiagnoses of Fabry disease include arthritis, chronic fatigue syndrome, fibromyalgia, hypochondria, lupus, multiple sclerosis, or nonspecific peripheral neuropathy. 27 Additionally, the time from first-reported symptom to the accurate diagnosis of Fabry disease has been reported to be greater than 10 years in men and 13 years in women. 28 This delay in diagnosis is of particular concern because treatment in the presymptomatic, or early clinical stages, has been reported to provide the most effective benefit. 8,10,27,28 Past therapies have been limited to palliative in nature, including kidney transplant, and life expectancy was limited to the fifth decade in males. Recently, multiple pharmacotherapies have become available or are currently in clinical trials, including recombinant enzyme

3 Morier et al Issue Highlight 439 Figure 2 Family pedigree. Squares and circles represent male and female members of the family, respectively. Red indicates that the individual is affected by Fabry disease. A question mark indicates that the individual s gender has not been recorded. A diagonal line through indicates a deceased individual. Patient numbers correspond to numbers in tables and other figures. replacement therapy (ERT) and oral chaperone therapy. In the United States, the only FDA-approved treatment is enzyme replacement with recombinant alpha-galactosidase A (agalsidase beta, FabrazymeÔ [Genzyme, Cambridge, MA]). 29 When instituted in early stages of disease, it can stabilize and limit the progression of organ damage. The advent of effective treatment makes the burden of presymptomatic diagnosis even more critical. It was the primary aim of this study to assess the prevalence and accurately phenotype the ocular manifestations of Fabry disease within a single kindred of patients with a single gene mutation. Because of the rarity of this disorder, limited published information is available characterizing the ocular manifestations of the disease. Methods Twenty-three subjects (15 women) from a cohort of 41 available patients within a single family consented to participation in this study (see Figure 2). All patients were confirmed to have Fabry disease by either enzymatic or molecular diagnosis, or both (see Table 1). Complete ophthalmic examinations were performed by 3 examiners (A.M.M., J.M., and R.T.). Examinations included visual acuity, refraction, slit lamp examinations, ocular motilities and muscle balance, pupillary responses, tonometry (Goldmann applanation), pachymetry, dilated fundus examinations, and anterior segment and fundus photography. Analysis of the nerve fiber layer and macula was also performed using the Stratus OCTÔ from Carl Zeiss Meditec (Jena, Germany). The patients were separated randomly into 3 groups and examined by 1 of the 3 examiners. Because all the examiners were present at the clinic, any questionable findings were assessed by at least 1 other examiner. A checklist sheet containing a list of Fabry ocular findings was used in addition to the examination forms for each doctor to summarize the results (see Appendix 1). Anterior segment and posterior segment photographs were taken using a Kowa Non-myd a D 5 megapixel camera mounted on a slit lamp and were used to verify presence or absence of vessel tortuosity. The anterior segment digital camera system was not able to capture the corneal verticillata that was observed; instead, drawings were made on the report sheets. The optical coherence tomography (OCT) results were interpreted and recorded by 2 of the examiners (J.M. and R.T.). Conjunctival tortuosity findings were documented for the 4 quadrants. No attempt was made to grade the degree of conjunctival tortuosity because it was felt that the grading system is too arbitrary to be accurate and repeatable. Retinal vessel tortuosity was graded on a scale of 0 (none) to 4 (very significant). Central corneal thickness was assessed using a DGH Pachette 2 model 550 pachymeter. A Fabry patient health and lifestyle questionnaire was given to the patients to have a better understanding of how Fabry disease affects lifestyle. The 4 general categories evaluated were general symptoms, organ involvement, quality of life, and treatment with enzyme replacement therapy (see Appendix 2). Results The mean age (6SD, range) of the evaluated 8 hemizygotes and 15 heterozygotes was 32.3 (11.3, 18-46) and 26.9 (15.4, 7-55) years, respectively (see Table 2). Visual acuities and refractive errors Table 3 shows the refractive errors of the 23 subjects. Most of the subjects had mild refractive errors not requiring prescription. Best-corrected visual acuities of 20/25 or better were achieved in all subjects with the exception of subject 18 who had suffered a childhood trauma resulting in corneal scarring in her right eye. Central corneal thickness Because little difference was found between the 2 eyes in all patients examined, the right and left eyes were averaged and graphed (see Figure 3). Average (left and right eye) central corneal thicknesses (CCTs) were very similar in all of the subjects. The CCTs generally were clustered around the average central corneal thickness values of approximately 555 mm, as reported in many studies. 30,31 Interestingly, the younger patients had a wider variability in CCT than the older subjects. Lenticular changes Two of the 8 (25%) hemizygous men presented with anterior capsule opacities. None of the heterozygous

4 440 Optometry, Vol 81, No 9, September 2010 Table 1 Confirmation of Fabry-affected status Subject number Age (yrs) Gender (M/F) AGAL enzyme level whole blood (nm/punch*h)* Percentile normal AGAL enzyme level leukocytes (nmoles/hr/mg) (U/mg) Mutation status 1 7 F N/A N/A 23 R227Q 2 10 F N/A N/A N/A R227Q 3 15 F 49.6, 2% N/A R227Q 4 17 F 48.7, 2% N/A R227Q 5 17 F 44.3, 2% 29.3 R227Q 6 18 M N/A N/A N/A R227Q 7 20 F 36.5, 2% N/A R227Q 8 20 F 49.6, 2% N/A R227Q 9 20 M N/A N/A N/A R227Q F % 29.3 R227Q F 49.3, 2% N/A R227Q F 30.7, 2% N/A R227Q M N/A N/A 0.2 R227Q F % 41.8 R227Q M N/A N/A 0.2 R227Q M 44.3, 2% N/A R227Q M N/A N/A N/A R227Q F 52.5, 2% N/A R227Q M 29.2, 2% N/A R227Q M 35, 2% N/A R227Q F % 4.6 R227Q F 52, 2% N/A R227Q F 30, 2% 48 R227Q N/A 5 Not applicable. * Performed by whole blood dried blood spot immunofluorescence methodology 39 ; range, nm/punch*h. Performed by fluorometric enzyme assay on leukocytes p-nitrophenol D-galactopyranoside is used. The enzyme catalyzes the formation of p-nitrophenol, which is measured at 405 nm. Expressed as nmoles/h/mg, range, nmoles/h/mg. Performed by fluorometric enzyme assay on leukocytes with 4-methylumbelliferyl-a-D-galactopyranoside as substrate and sodium acetate buffer, (range U/mg). 40,41 women showed these opacities. Of the 23 patients, only a single male hemizygous patient showed a Fabry cataract (see Table 2). Corneal manifestations In all 23 family members, corneal verticillata was present (see Table 2). In some of the patients, the whorling was very faint, but it was seen and verified by at least 2 of the investigators. Three of the subjects had reported that they did not have the corneal changes that their family members had, but with close examination, corneal verticillata was seen. The corneal verticillata was generally seen inferiorly; however, it was also observed superiorly in many subjects involved in this study. Conjunctival blood vessel abnormalities Conjunctival tortuosity was present in 62.5% of the male hemizygotes and 40% of the female heterozygotes (see Table 2 and Figure 4). None of the subjects showed aneurysmal dilatations of the blood vessels. We were careful not to confuse superficial conjunctival vessels from the deeper episcleral vessels (see Figure 5). Retinal blood vessel tortuosity Some degree of retinal vessel tortuosity was observed in 75% of the evaluated men and 13.3% of the women (see Table 2). Figure 6 shows a photograph of retinal blood vessel tortuosity observed in 1 of the study patients. Optical coherence tomography All 23 patients appeared to have normal macular scans. Patient 20 presented with thinning of the nerve fiber layers in both eyes (see Figures 7A,B); however, at age 31, he had suffered a stroke. His visual fields are shown in Figures 8A and B. Ocular motilities, muscle balance, and pupillary responses were normal in all evaluated patients.

5 Morier et al Issue Highlight 441 Table 2 Ocular manifestations of Fabry subjects Patient Age (yr)* M/F Corneal verticillata Anterior capsule opacities Fabry cataract Retinal tortuosity OCT abnormal Pachymetry Conjunctival tortuosity 1 7 F /625 0/ F /632 1/ F /497 1/ F /503 0/ F /579 0/ M /568 2/ F /502 3/ F /537 0/ M /549 1/ F /533 0/ F /555 2/ F /546 0/ M /630 0/ F /533 2/ M /558 1/ M /583 0/ M /538 0/ F /566 0/ M /538 1/ M /570 2/ F /547 0/ F /548 0/ F /572 3/4 - Heterozygotes 100% 0% 10% 13.3% 0% 40% 20% Hemizygotes 100% 25% 12.5% 75% 0% 62.5% 100% * 8 men (average age 32.3 years [range, 18-46], 15 women (average age 26.9 years [range, 7-55]). 1 indicates present; 2 indicates absent. ERT Health and lifestyle questionnaire Patients were questioned on general symptoms, organ involvement, and their quality of life as a result of Fabry disease (see Table 4). Comparing men and women, acroparesthesia was equally prevalent in about 75% of both groups. All the men had hypohydrosis and problems when exercising, whereas only 26.6% of the women presented with these symptoms. As expected (in typical sex-linked diseases), the men had more problems adjusting to hot/cold (75% to 26.6%), gastrointestinal problems (62.5% to 40%), and angiokeratomas (62.5% to 13.3%) than the women. These findings correlate with the previous reported studies from the large cohort in the Fabry Registry (n52,236). 10 Only one of the men and none of the women were on dialysis. This patient was the oldest man in the group at 45 years and had already had a kidney transplant as well as a stroke. When asked about the quality of life as a result of Fabry disease, only 40% of the women and 12.5% of the men felt Fabry disease had no impact on their quality of life. The remainder of the subjects felt it presented some burden. A total of 13.3% of the women and 12.5% of the men reported that Fabry disease greatly affected their lives. A total of 33.5% of the women and 37.5% of the men reported that Fabry disease somewhat affected their lives. A total of 13.3% of the women and 37.5% of the men felt the disease mildly affected their lives. The overwhelming majority felt it affected their quality of life with varying degrees of severity. Discussion Corneal verticillata was clearly the most important ocular manifestation in this subset of 23 Fabry patients who are all members of 1 family. All patients in this study presented with at least a minimal amount of corneal whirling. Generally, it was seen inferiorly, which was consistent with reports by several other investigators. 18,19 This particular family appeared to have a higher percentage of corneal verticillata than what has been reported in other investigations. 19,21,22 This may be in part because of the founder effect of the mutation present in the GLA gene in this cohort. R227Q (c680g.a exon 5) is known to disrupt a residue at the GLA active site and is known to be associated with classical presentation. 32 Corneal verticillata has minimal, if any, effect on visual acuity in the majority of patients. 25 This is particularly significant, as a practitioner who is not familiar with corneal verticillata as a marker for Fabry disease would not be alarmed at their presence,

6 442 Optometry, Vol 81, No 9, September 2010 Table 3 Refractive errors and best-corrected visual acuities Refractive error Best-corrected visual acuities Patient OD OS Add x x180 20/25 OU 2 Pl x 180 Plano sphere 20/20 OU sphere Plano sphere 20/20- OU x x 90 O.D.: 20/20 O.S.: 20/ x 90 Pl x 90 20/20- OU 6 Plano x sphere O.D.: 20/15-1 O.S.: 20/ Plano sphere Plano sphere 20/20 OU x 90 Plano sphere 20/20 OU 9 Plano sphere sphere 20/20 OU x sphere 20/25 12 OU sphere sphere O.D.: 20/20 O.S.: 20/ sphere sphere O.D.: 20/20 O.S.: 20/ Pl x sphere 20/20 OU sphere x 10 20/20 OU 15 Pl x 105 Pl x 72 20/20 OU x 95 Pl x 90 20/20 OU x x 107 O.D.: 20/20 O.S.: 20/ x x 115 O.D. 20/70* O.S.: 20/ x x /20 OU x x /20 OU sphere sphere /20 OU x x /20 OU sphere sphere O.D.: 20/20-1 O.S.: 20/20 O.D. 5 right eye; O.S. 5 left eye; OU 5 both eyes. * Decreased acuity caused by childhood trauma resulting in corneal scarring in right eye. especially if the visual acuities are not affected. Manifestations in other organ systems become apparent later in the course of the disease and are typically more difficult to find. A slit lamp evaluation is a quick, inexpensive, and noninvasive procedure to perform, and yet very effective in the early detection of corneal verticillata and diagnosis of this disease. However, corneal verticillata is characteristic but not pathognomic for Fabry disease. There are a 650 number of drugs that may result in corneal verticillata: amiodarone, chloroquine, atovaquone, clofazimine, gentamicin (subconjuctival), indomethacin, mepacrine, monobenzone (topical skin ointment), chloropromazine, naproxen, ibuprofen, perhexiline maleate, phenothiazines (other than chlorpromazine), suramin, tilorone hydrochloride, tamoxifen, and gold. 20 Environmental exposure to silica dust and multiple myeloma apparently can also cause cornea verticillata. 20 It is important to note that a Fabry patient may be taking amiodarone for cardiac arrhythmia and Corneal Thickness (microns) Patient # Figure 3 Distribution of central corneal thickness in 23 Fabry patients. Note that right and left eye were averaged and plotted as a single point. White square 5 female; Grey square 5 male. Figure 4 Conjunctival tortuosity seen in patient 23.

7 Morier et al Issue Highlight 443 Figure 5 Episcleral tortuosity in a non-fabry individual. present with corneal verticillata. Eye care providers must remember that the corneal whorling may be from Fabry disease as opposed to amiodarone. Conjunctival blood vessel abnormalities are commonly reported findings in patients with Fabry disease. Most often reported are conjunctival vessel tortuosity and aneurysmal dilatations resulting from disruption of the normal architecture of the blood vessels caused by accumulation of GL3. 18,19,21,22 In the 23 evaluated family members, conjunctival tortuosity was seen in 62.5% of the affected men and 40% of the women. Sodi et al. 22 note that vessel tortuosity is rarely seen as the only ocular finding and is not a good marker for the diagnosis of Fabry disease. However, these features may represent a sign that microvascular changes are occurring in other end organs and thus may be a good marker to aid in monitoring disease progression throughout the body. 16,22,33 Aneurysmal dilatations of the blood vessels, which had been expected based on previous Figure 6 Retinal blood vessel tortuosity seen in patient 12. Figure 7 A, Nerve fiber layer scan of patient 20 (right eye). B, Nerve fiber layer scan of patient 20 (left eye). reports, 18,19,21 were not observed. From a diagnostic perspective, it is important to note that conjunctival tortuosity and aneurysmal dilatations can be seen in several other conditions (see Table 5). Retinal vessel tortuosity was detected in 75% of the evaluated men and 13.3% of the women. This series mirrored the findings of Nguyen et al. 18 (76.5% of men and 18.8% of women) and Sher et al. 21 (70% of men and 25% of women). Retinal blood vessel tortuosity, although seen in other conditions (see Table 6), is much less common in the general population than in patients with Fabry disease, and the eye care provider should look at this finding carefully. Hypertensive retinopathy is probably the most common condition associated with retinal tortuosity, but in this disorder, tortuosity is accompanied by arterial thinning, arteriolar/venous nicking, and increased arterial reflection. Two photographs of retinal blood vessel tortuosity observed in a non-fabry individual (see Figure 9) and in a study patient (see Figure 6) are provided. Most other studies 18,19,21,22 reported a higher percentage of cataracts, both anterior capsular and posterior capsular (Fabry cataract), than was found in our study (2 men had anterior capsule opacities, and a Fabry cataract was observed in 1 man). This discrepancy may be specific to this genotype, as all subjects were from a single family. It may be also be because of the relatively young average age of this group of patients (i.e., 32.3 years for men and 26.9 years for women) or to our inexperience in identifying these types of cataracts. The authors will be following up with this family closely with subsequent reevaluations of the lenticular manifestations. Best-corrected visual acuity, refractive error, and corneal thickness did not seem to be different in the Fabry patients when compared with the general population. Enlarged blind spot on visual field testing due to subclinical optic

8 444 Optometry, Vol 81, No 9, September 2010 Figure 8 A, Visual field of patient 20 (right eye). B, Visual field of patient 20 (left eye). neuropathy from suspected ischemic edema is well-documented in Fabry disease. 19,34 Also, retinal artery occlusion caused by thrombogenesis has been reported. 35,36 In our study, with the exception of the patient who had a history of a stroke, no abnormalities of the nerve fiber layer or macular thickness were detected. The health and lifestyle questionnaire provided a few surprises. Some have reported that 60% to 100% of female heterozygotes exhibit some signs and/or symptoms of the disease. 8,10,11,37,38 Therefore, we did not expect that acroparesthesia would be equally distributed in the male hemizygotes and the female heterozygotes (w75%). It has, as a result, been suggested that X-linked Fabry disease should no longer be considered a recessive disorder and that heterozygous women should not be called carriers. 8,10,11 Traditional genetic lyonization patterns and skewed X-inactivation does not account for the high prevalence of signs and symptoms present in the Fabry women. Therefore, recent suggestions include referencing Fabry disease as an X- linked dominant disease. 38 Consequently, it is important to identify the heterozygote women, assess them medically, and provide equal consideration, where appropriate, for initiation of therapy. 8,10,11,37,38 Once a Fabry proband has been identified by ophthalmic examination, the entire family should be offered multisystemic care in a center versed in care of Fabry disease, ideally a lysosomal disorders center when available. 6 The other unexpected result was that 2 male patients, both of whom are on ERT, still describe their lives as mildly impacted by Fabry disease. Indeed, another male patient who has been on ERT for 5 years says that Fabry disease has had no effect on his life. These surprising responses may be due to subjective differences between patients as far as coping strategies, expectations for treatment, different outcomes from treatment, or degree of impact of the treatment. One thing that was clearly evident, however, was how close knit this entire family was to one another and that they all seemed to strongly support each other. Limitations of this study include that an ascertainment bias may exist. Forty-one available Fabry patients within the family were eligible for participation in this study, and 23 accepted. It is unknown what ascertainment bias may exist (i.e., more or less severely affected patients agreement to participation). Secondly, a locally utilized Fabry health and lifestyle questionnaire (see Appendix 2) was obtained as opposed to traditionally utilized instruments such as the validated SF-36 health-related quality-of-life survey. These results are felt to be accurate, however, because they correlate with the published results from the Fabry Registry, 10 as well as when randomly compared with the patients individual SF-36 (results not shown). Conclusions Fabry disease is an X-linked lysosomal storage disorder with a wide range of symptoms and early features that are very nonspecific, rendering early diagnosis a clinical challenge. Left untreated, this disease leads to an uncomfortable existence and an early death in the fifth decade for men. With the introduction of effective treatment, it is now

9 Morier et al Issue Highlight 445 Table 4 General symptoms Patient health and lifestyle questionnaire Burning in hands and feet Difficulty sweating/exercising Problems adjusting to temperature, hot/cold Stomach problems Heterozygous women 73.3% 26.6% 26.6% 40% 13.3% Hemizygous men 75% 100% 75% 62.5% 62.5% Organ involvement Angiokeratomas Protein in urine Dialysis Kidney transplant TIA/stroke Irregular heartbeat Heterozygous women 20% 0% 0% 0% 13.3% Hemizygous men 87.5% 12.5% 12.5% 12.5% 12.5% Quality of life due to Fabry disease Greatly impacted Somewhat impacted Mildly impacted No impact Heterozygous women 13.3% 33.3% 13.3% 40% Hemizygous men 12.5% 37.5% 37.5% 12.5% TIA 5 Transient ischemic attack. Table 5 Other causes of conjunctival tortuosity and telangiactasis Diabetes mellitus Osler-Weber-Rendu syndrome Sturge-Weber syndrome Carotid-cavernous fistula Radiation therapy Multiple myeloma Sickle cell anemia Polycythemia rubra vera Louis-Bar syndrome Bloome syndrome Data from Samiy. 20 critical to make presymptomatic diagnosis. Because ocular findings are often the earliest presentation of the disease, it is the eye care provider who is ideally positioned to spot the ocular manifestations and make the diagnosis. Cornea Table 6 Other causes of retinal vascular tortuosity Hypertension Anemia Sickle cell retinopathy Polycythemia Leukemia Dysproteinemia Neurofibromatosis type 1 Osler-Weber-Rendu syndrome Aarskog syndrome Wyburn-Mason syndrome Faciocapulohumeral muscular dystrophy Retinal vein occlusion Data from Samiy. 20 Figure 9 Retinal blood vessel tortuosity seen in a non-fabry individual. verticillata is a distinctive and common finding in patients with Fabry disease. It generally does not affect vision and is easy to recognize by slit lamp examination. The challenge is to increase awareness of the unusual signs of Fabry disease and remember their link to this systemic disease. Acknowledgments The authors acknowledge Jim Riley, O.D. His quick diagnosis of the first patient led to the identification of Fabry disease in 44 family members (of whom 23 were evaluated in our study) so far, prolonging their lives and providing hope for the family s future. Albert Morier thanks John Minteer, O.D., Robert Tyszko, O.D., Rachel McCann, O.D., Stephanie Minteer, Sally Howe, and Donna Longo for giving up their time to help coordinate and assess the patients in this study. The authors acknowledge the pedigree research support of Katherine Sims, M.D. (Center for Human Genetic Research and Neurology Department,

10 446 Optometry, Vol 81, No 9, September 2010 Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts), and Danielle Metterville, M.S. (Genetic Counselor, Developmental Neurogenetics Clinic, Neurogenetics DNA and Biochemical Diagnostic Lab, Massachusetts General Hospital, Boston, Massachusetts), and thank Hans Ebels, M.D., Genzyme Corporation, for his editorial support. Finally, the authors thank the family, who could not have been more eager to help us learn more about this disease. Dr. Browning acknowledges NIH U54 and the foundation grant from FSIG and the patients who agreed to participate in this study. References 1. Anderson W. A case of angiokeratoma. Br J Dermatol 1898;10: Fabry J. A contribution to the understanding of modular hemorrhagic purpura. Arch Dermatol Syphilis 1898;43: Staretz-Chacham O, Lang TC, LaMarca ME, et al. Lysosomal storage disorders in the newborn. 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11 Morier et al Issue Highlight 447 Appendix 1 Fabry Patient Sheet

12 448 Optometry, Vol 81, No 9, September 2010 Appendix 2 Patient health and lifestyle questionnaire

13 Morier et al Issue Highlight 449