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Optometry & Vision Science:
doi: 10.1097/OPX.0b013e31827ec7eb
CLINICAL COMMUNICATIONS: Clinical Review

Fabry Disease: A Review of Ophthalmic and Systemic Manifestations

Sivley, Melanie D.*

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Author Information

*OD, FAAO

School of Optometry, University of Alabama at Birmingham, Birmingham, Alabama.

Melanie Sivley School of Optometry University of Alabama at Birmingham 1716 University Blvd HPB 523 Birmingham Alabama 35294 e-mail: msivley@uab.edu

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Abstract

ABSTRACT: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by accumulation of Gb-3 (globotriaosylceramide) in cellular lysosomes of tissues throughout the body. With advancing age, lysosomal Gb-3 accumulates in blood vessel walls, nerve cells, smooth muscle, and vital organs. Premature death commonly results from renal failure, heart attack, and stroke when the diagnosis is delayed or overlooked. One of the earliest and most distinctive physical features of FD is a whorl-like keratopathy. This finding is easily identifiable during a routine eye examination with a slit lamp, making eye care practitioners uniquely postured to identify patients and families with this incurable genetic disorder. Much of the pain, suffering, and adverse impact of FD can be avoided if an alert eye care expert sees the patient at an early age, identifies the condition, and makes the appropriate referral. The importance of obtaining a thorough medical history, ancestral health history, and review of systems to correlate ocular and systemic manifestations is emphasized. This report reviews the multisystem involvement of FD and describes the clinical characteristics and expected chronological appearance of ophthalmic and systemic manifestations. The discoveries of late-onset variants, increased prevalence, and modified inheritance pattern of FD are discussed. The profound therapeutic effects of recombinant enzyme replacement therapy (ERT) on multiple organ systems are detailed and demonstrated in a Fabry proband. Improved quality and quantity of life after initiation of ERT underscore the importance of early recognition and correlation of FD symptoms and clinical signs. Treatment strategies and the effectiveness of new adjunctive chaperone therapy are addressed.

Fabry disease (FD) is a rare X-linked lipid storage disorder characterized by a deficiency or absence of the lysosomal enzyme α-galactosidase-A (α-gal-A), causing progressive accumulation of globotriaosylceramide (Gb-3) in cells throughout the body, widespread ischemia, and irreversible vital organ damage. Before the availability of hemodialysis and enzyme replacement therapy (ERT), FD was often fatal because of stroke, heart attack, and progressive renal failure at an early age.1–4

Fabry disease affects multiple systems throughout the body and mimics other disorders, so diagnostic delays are common.3 A hallmark clinical feature of this disorder is bilateral keratopathy, which is present in most FD patients at a young age and visible with a slit lamp.5–7 Other ocular manifestations are prognostic for systemic involvement and progression of the disease.4,6

Ophthalmic practitioners are uniquely postured to identify this incurable, but treatable, inherited disorder. The optometrist must be vigilant in obtaining complete personal and family medical histories and comprehensive reviews of systems in all patients to connect ocular manifestations to systemic diseases. Early recognition of ophthalmic clinical features of FD facilitates early diagnosis and referral for ERT to improve quality and quantity of life.8–11 Much of the pain, suffering, and adverse impact of FD can be avoided if an alert eye care expert recognizes the condition and makes the appropriate referral.

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EPIDEMIOLOGY AND GENETICS

The gene mutations that cause FD result in reduced or absent levels of α-gal-A in cellular lysosomes.1–4 The severity of the disease is proportional to the amount of α-gal-A activity.2,3 Three distinct phenotypes of FD are recognized:

* Males with classic manifestations. Classic FD is a term reserved for males having absolutely no α-gal-A activity. Individuals with this phenotype will develop the full complement of clinical signs and symptomatology, with symptom onset in childhood. This mutation occurs in approximately 1 in approximately 37,000 to 60,000 males.2,4

* Males with atypical manifestations. Some gene mutations result in partial α-gal-A activity. These patients may experience symptoms in childhood, but they do not manifest the spectrum of classic FD.12 Adult-onset cardiac and renal variants seem to be much more prevalent than the classic phenotype and may explain many cases of midlife cardiac and renal disease.12,13

* Females with variable manifestations. Once considered carriers only, females are now recognized as being affected with variable penetrance.14,15

Fabry disease is the only known X-linked sphingolipid storage disorder.2 More than 300 mutations of α-gal-A deficiency have been identified, nearly 40 of which have been correlated with the classic phenotype (no α-gal-A activity).2,16,17 For decades, FD was believed to be an X-linked recessive disorder. However, it is now recognized as affecting males and females equally, which is more consistent with X-linked dominant inheritance with variable penetrance.18,19

Males are termed hemizygotes because they can only inherit the mutation from their mothers.18,20,21 The son of a hemizygote will not inherit the mutation because he inherits his father’s Y chromosome, which precludes male-male transmission; all daughters of a hemizygote will inherit the Fabry mutation from their father, who contributes an X chromosome to female offspring.2,22

Females are known as heterozygotes because they can inherit the mutation from either parent.18,20,21 The phenotypic variation seen in heterozygotes is caused by random X-inactivation, or lyonization,23 a chromosomal phenomenon that occurs when the defective gene is countered by a normal maternal X chromosome, allowing traits of the mutated X chromosome to be expressed to varying degrees.14,15 Daughters of heterozygotes have a 50% chance of inheriting the mutation from their mothers, and sons of heterozygotes have a 50% chance of being affected.2,22

Awareness of the inheritance pattern of FD is particularly important for asymptomatic females with a family history of FD.18,24 The presumed X-linked dominant inheritance pattern of FD is illustrated in Fig. 1. The pedigree of a Fabry hemizygote encountered by the author is shown in Fig. 2.

Figure 1
Figure 1
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Figure 2
Figure 2
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PATHOGENESIS

Fabry disease causes Gb-3 accumulation to progress unchecked in tissues throughout the body, causing vessel attenuation and restricted blood flow to vital organs, visceral tissues, and nerve fibers.1,5,25 The specific gene mutation involved determines the degree of lipid metabolic blockade and disease severity.6,26,27

Lysosomal storage of Gb-3 begins in utero and increases over time.28 In the classic form affecting males, symptoms emerge in childhood.1–4 Partial enzyme activity results in variable symptoms in heterozygotes14 and in males and females affected with a late-onset renal or cardiac variant.12–13,29 A diagram of lipid dysmetabolism in FD is shown in Fig. 3.

Figure 3
Figure 3
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MORBIDITY AND MORTALITY

Before renal dialysis and ERT, premature death often resulted from stroke, heart attack, or renal failure before age 50 years in hemizygous males.1,4,30,31 Heterozygotes experience variable morbidity,14,15 and individuals with the late-onset cardiac and renal variants usually develop disease after age 50 years.4,12,13,29 Compared with the general population, the median life span of untreated FD patients is reduced by approximately 20 to 25 years for males and 10 to 15 years for females.32,33

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OPHTHALMIC MANIFESTATIONS

Cornea

The most distinctive and prevalent clinical feature of FD is a bilateral whorl-shaped keratopathy known as corneal verticillata (meaning “vortex”).1,4,7,34 The Gb-3 is deposited by limbal blood vessels at the level of the epithelial basement membrane and visualized as yellowish brown inclusions emanating radially from a single vortex; the corneal stroma and endothelium are spared in FD.1,35 More fully developed vortices involve the upper cornea,1 an example of which was observed by the author and is shown in Fig. 4. These findings are detectable with a biomicroscope in symptomatic and asymptomatic males and females at a young age—long before irreversible organ damage occurs.2,13,27,36 Fabry keratopathy is present in virtually all heterozygotes by the age of 10 years and in 97% of classically affected males by the age of 4 years, regardless of which mutation is involved.1,6 These distinctive corneal findings have been reported as early as 6 months of age.37 Corneal verticillata are more prominent (well defined) in heterozygous females than in classically affected males and almost never affect vision.1,4,6,38

Figure 4
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Differential diagnoses for corneal verticillata are listed in Table 1. Certain drugs are known to cause keratopathy similar in appearance to Fabry verticillata, including amiodarone, tamoxifen, quinacrine, cocaine, hydroxychloroquine, gold salts, amodiaquine, indomethacin, meperidine, chlorpromazine, and PUVA (ultraviolet A light) therapy with methoxsalen.1,7,39,40 A diagnostic dilemma exists in adults already taking one or more of these medications,41,42 but in young patients with no such drug history, bilateral subepithelial corneal whorls should be considered diagnostic for FD until proven otherwise. A clear understanding of a patient’s medical history is therefore crucial in determining whether characteristic corneal findings are FD related.

Table 1
Table 1
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Lens

Two types of lens opacification have been identified. These represent Gb-3 deposits within crystalline lens epithelium and are best seen in retroillumination.7,34,43 “Classic” Fabry cataracts appear as off-axis or dendritic subcapsular opacities along the posterior lens suture lines and have the distinction of being the only ophthalmic finding diagnostic for FD.43 “Propeller” cataracts are radially oriented spokes in the equatorial region or within the subcapsular space.1,6 Fabry-related cataracts appear in the second decade of life and are seen in up to 70% of males, less often in females.1,5,6 Drugs known to mimic Fabry lens opacities include amiodarone, corticosteroids, gold salts, and PUVA therapy using methoxsalen.40 Fig. 5 shows the off-axis posterior subcapsular lens opacity in a hemizygote and his heterozygous daughter encountered by the author.

Figure 5
Figure 5
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Conjunctiva and Retina

Conjunctival vessel tortuosity is caused by disruption in blood vessel architecture by Gb-3 accumulation in vascular endothelium; telangiectasias are focal areas of vascular thinning caused by loss of sympathetic tone (a dysautonomic manifestation of FD).25,44,45 Conjunctival varicosities appear between the second and third decades of life and are observed in nearly 100% of hemizygous males and about one-half of heterozygous females.1,5,6 Similar blood vessel anomalies are seen in the retina in nearly 80% of hemizygous males.1,6,46 Retinal vessel tortuosity and telangiectasias are commonly present without systemic hypertension in FD.7,47,48 Retinal vaso-occlusive disorders may develop because of blood vessel attenuation and venular compression by stiff lipid-laden arterioles. Impaired vasoreactivity and intravascular inflammation further contribute to the formation of FD-related retinal vasculopathies7,49,50; these include branch retinal vein occlusion,1 central retinal artery occlusion,51 cilioretinal artery occlusion,34 and subfoveal choroidal neovascularization.52

Conjunctival and retinal vessel anomalies suggest abnormal blood flow in vessels throughout the body and, therefore, predictors of more severe systemic involvement.4,6,7,53 Examples of FD-related ocular vasculopathies observed by the author are shown in Figs. 6 and 7.

Figure 6
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Figure 7
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NEURO-OPHTHALMOPATHY

Blood vessel attenuation and incompetence and intravascular thrombosis caused by increased platelet reactivity cause vascular insufficiency and ischemia in optic nerve tissues and cerebral vasculature.50,54–56

Amaurosis fugax, nystagmus, diplopia (caused by extraocular muscle palsies), internuclear ophthalmoplegia, disc edema, and optic atrophy cause vision disturbances and visual field defects that often prompt discovery of the disease.44,50 Enlargement of the blind spot caused by suspected subclinical optic neuropathy was reported in nearly 40% of males in one study.5

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DRY EYE SYNDROME

Approximately 50% of FD patients experience decreased tear production, making dry eye syndrome (DES) a common finding.7,44 Fabry disease–related DES is caused by Gb-3 deposits in autonomic ganglia and directly into the lacrimal gland,44,49,50 resulting in diminished lacrimal function and ocular surface dryness.7,57

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OCULAR ADNEXAL AND CRANIOFACIAL CHARACTERISTICS

Periorbital fullness, prominent supraorbital ridges, bushy eyebrows, and bilateral ptosis may be observed in both males and females, but facial dysmorphology is not considered a prominent sign of FD.58 Course craniofacial features are more commonly seen in hemizygotes and include a broad nasal base, full lips, a prominent chin, prominent earlobes, and posteriorly rotated ears.59

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OTHER OCULAR FINDINGS

Less reported ophthalmic manifestations of FD include lid edema,1,7,34 conjunctival chemosis,60 and chronic uveitis.61 No empirical association between refractive error and α-gal-A deficiency has been shown, but about 40% are reportedly myopic.1,5

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SYSTEMIC MANIFESTATIONS

Neurologic Disorders

The most commonly reported systemic manifestations of FD are disorders of the central, peripheral, and autonomic nervous systems.4,44,50 Neuropathic pain is usually the earliest symptom reported by FD patients.1,2,62 Acroparasthesias are painful parasthesias of the extremities triggered by exercise, temperature changes, and stress.4,50 These painful shocklike sensations in the hands and feet affect 75% of males by age 9 years and 50% of females by age 10 to 17 years.46,63 Extreme pain attacks known as “Fabry crisis” may be accompanied by fever (caused by hypothalamic dysregulation44) and last several hours or days, often requiring hospitalization.4,7,50

Dysautonomia is caused by Gb-3 accumulation in autonomic ganglia, neurons, and unmyelinated nerve fibers of the extremities,62,64 where lipid infiltration of small nerve fibers leads to peripheral nerve decomposition and diminished end-organ function.49,50,65 Manifestations of autonomic dysfunction in FD include hypohidrosis (reduced sweating caused by lipid deposition into the eccrine cells of the sweat glands44), hyperhidrosis (excessive sweating66), diminished temperature, pain and vibration perception (caused by impaired skin blood flow, vasomotor reactivity, and small nerve fiber decomposition44,49,50), diminished autonomic skin responses (to histamine injection, scratching the skin, and insect bites44), and exaggerated pain with cold exposure (caused by diminished thermal recovery by impaired nerves49,65). Reduced tear and saliva production, heart conduction defects, and reduced pupillary response to pilocarpine are also caused by lipid infiltration of small nerve fibers.44 Similar small nerve fiber compromise is found in other autonomic neuropathies, such as amyloid neuropathy, familial dysautonomia, hereditary sensory neuropathy,44 and restless legs syndrome,67 which is also linked to neuropathic pain in FD.

Reduced sympathetic tone of blood vessels further exacerbates dysautonomia and promotes structural alterations of vasculature throughout the body.35,45,50,68

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Cerebrovascular Disease

Cerebrovascular abnormalities are a leading cause of neuropathology in FD25,69 and primarily involve the posterior cerebral circulation, where lipid storage in cerebral microvasculature causes mechanical stenosis, reduced cerebral blood flow, and ischemia.45,50,70,71 Accumulation of Gb-3 in serum further contributes to cerebral ischemia and infarction by promoting intravascular thrombosis and vaso-occlusion.50,56,69,72 Reduced sympathetic tone in basilar and middle cerebral arteries may lead to dolichoectasia (vessel elongation and distention) and compression of cranial nerves (especially III, V, VI, VII, or VIII).68,73 White matter lesions and cortical atrophy may be seen on brain magnetic resonance imaging in FD patients with CNS involvement.74

The incidence of stroke in hemizygotes aged 25 to 44 years is 12 times greater than that of the general population in that age group.75 Most strokes are ischemic (87%), and most patients do not experience renal or cardiac events before their first stroke.70,71

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Kidney Disease

Renal failure is a prominent feature of FD and was the most common cause of premature death before ERT.27,32,76 Accumulation of Gb-3 in renal tissues and microvasculature causes kidneys to lose their ability to filter and excrete waste from the body.77,78 Proteinuria often presents in adolescence in FD.4,79 However, this first sign of measurable renal disease often goes undetected until urinary protein levels and serum creatinine levels increase in the third decade, causing estimated glomerular filtration rate to decrease.77,80 Fabry disease should be considered in patients with proteinuria and progressive chronic kidney disease especially if blood pressure is not elevated and there is a family history of renal disease.27,47,48

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Cardiac Disorders

Left ventricular hypertrophy (LVH) is the most common cardiac manifestation of FD and accounts for most of the chest pain (angina) in FD patients.33,81 Deposition of Gb-3 within the atria, cardiac muscle, and valves of the heart leads to coronary artery disease, valve disease, myocardial fibrosis and LVH.81–84 Cardiac arrhythmias are caused by lipid infiltration of small nerve fibers.44 Cardiac signs and symptoms usually begin in the third and fourth decades, although arrhythmias and LVH have been reported in male children.4,28,63,85 Males who express the late-onset cardiac variant typically present in the fifth to eighth decades with arrhythmias, mitral insufficiency, LVH, or coronary heart disease.13,86,87

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Gastroenteropathy

Intense postprandial abdominal indigestion, cramping, nausea, and diarrhea are caused by Gb-3 deposits in vascular endothelium, autonomic ganglia, nerve fibers of intestinal nerve plexuses, and smooth muscle.4,50 These gastrointestinal (GI) disturbances can be debilitating and affect 20% of symptomatic males by age 8 years.88,89 Malabsorption and reports of up to 10 bowel movements per day may contribute to poor weight gain, and stunted growth may result from malabsorption in FD.88,90

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Skin Disorders

Principal dermatologic findings are lesions resulting from weakened capillary walls, creating vascular ectasias within the dermis and epidermis.53,91 These nonblanching purplish red elevations are called angiokeratomas4, 92,93 and emerge between the ages of 5 and 13 years.4,53 Angiokeratomas increase in number and distribution with age53 and are primarily distributed around the umbilicus, buttocks, and genitals4,53; maculomas are flat angiokeratomas that develop on the palms of the hands, plantar surfaces of the feet, nail folds, and lips.94,95 Late-onset variants of FD manifest similar skin lesions.3,8,96 Maculomas on the palms and angiokeratomas in the “bathing trunk” area of a hemizygote encountered by the author are shown in Fig. 8.

Figure 8
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Lower limb pitting edema in the absence of significant renal or cardiac disease is commonly described in advanced FD.4 Pitting edema may progress to nonpitting lymphedema, a manifestation of chronic venous obstruction. The exact mechanism is not known, but severe structural and functional changes of the lymphatic microvessels of the skin have been identified.53,93 Angiokeratomas and lymphedema are significant because they are associated with more severe systemic disease.4,6,53,57 A photograph of lymphedema of the right lower extremity of a classically affected hemizygote encountered by the author is pictured in Fig. 9.

Figure 9
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Respiratory Disorders

Obstructive and restrictive lung disease occurs regardless of smoking history and increases with age.97,98 Dyspnea, chronic coughing, and wheezing are caused by stiffening of the airways by Gb-3 deposits.99 Most FD patients with pulmonary symptoms (96%) have clear lung fields on radiography and respond only moderately to bronchodilators.97 Nocturnally obstructive airway (sleep apnea) symptoms are commonly reported in FD.100

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Hearing and Balance Abnormalities

Vestibulo-auditory deficits reflect lipid storage within inner ear vasculature and within nerve cells of the cochlea.50,101,102 Auditory symptoms include tinnitus and sensorineural hearing loss.101–103 Vestibular abnormalities ranging from dizziness to episodes of debilitating rotational vertigo, with or without associated hearing loss, have also been reported.104–106 Megadolichobasilar compression of cranial nerve VII (vestibulocochlear nerve) has been suggested as a cause of episodes of paroxysmal vertigo in FD.4,68

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Hematologic Disorders

Increased endothelial prothrombotic factors and increased platelet reactivity contribute to thrombogenesis and embolic vascular events.51,72,107 Intravascular thrombosis leads to brain infarctions, heart attack, thrombophlebitis, and ocular vaso-occlusive disease,50 including central retinal artery occlusion51 and branch retinal vein occlusion.1,7,34 Nearly 15% of FD patients experienced at least one thrombotic event before age 45 years in one study.56

Anemia in FD is caused by decreased red blood cell survival, systemic inflammation, impaired renal function, and heart failure.4,108 Elevated C-reactive protein, an indicator of acute inflammation, has been identified in 82% of FD patients with anemia, and 67% of FD patients with anemia have concomitant renal disease.108 This suggests a strong association between FD and anemia, but it is unclear if anemia is a cause or effect of FD because anemia is a risk factor for renal disease, heart failure, and stroke, all of which are significant manifestations of FD.

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Psychiatric Disorders

Fabry disease has a negative impact on school attendance, participation in sports, employment opportunities, and social life.28,37,76 Chronic multisystem disease often results in a sedentary lifestyle, less social interaction, low self-esteem, and diminished quality of life.11,109,110 There is increasing evidence of depression, alcoholism, drug dependency, dementia, and even suicide among FD patients.111–113 Fabry males are more likely than females to have depression and behavioral disorders partly because males tend to experience more severe disease.109,112

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Growth, Development, and Sexual Function

Fabry males exhibit greater height and weight variances than females; often below the US 50th percentile.63 Malabsorption caused by the GI manifestations of FD at an early age may contribute to stunted growth.4,88 Delayed puberty is also commonly seen in adolescents with FD.114 Impotence (caused by ischemia and malperfusion of the genitals4,32) and priapism (caused by autonomic dysregulation of arterial inflow45,115) have been reported in hemizygotes.

Heterozygotes are now recognized as subject to the full complement of Fabry symptomatology rather than asymptomatic carriers as once believed.29,76,98,116 Women with FD are uniquely challenged with hormone and fertility issues,117 and depression is compounded by the guilt of transmitting an FD gene mutation to their children.98

Fabry disease causes significant morbidity in childhood.118 Life-threatening vital organ involvement is rare in young patients, but proteinuria and chronic kidney disease may develop before age 16 years in classically affected males.119 Cardiac arrhythmias and LVH have been reported in male children4,85 and Fabry-related transient ischemic attack and stroke have been reported as early as age 12 years.46,118

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DIAGNOSIS

Diagnostic delays and misdiagnosis allow Gb-3 accumulation to progress unchecked in vascular endothelium, serum, and vital organ tissues, thus promoting irreversible organ damage.2,4,46,50 Involvement of the vertebrobasilar distribution often leads to an initial misdiagnosis of multiple sclerosis in adults.50,120 Elevated erythrocyte sedimentation rate frequently leads to a misdiagnosis of rheumatologic disease, especially junenile rheumatoid arthritis, in nearly one-half of children with FD.4,46 Common misdiagnoses for FD are listed in Table 2.2,46,50,120

Table 2
Table 2
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Fabry signs and symptoms with a positive family history are strongly suggestive of FD and justify a presumptive diagnosis.2,121,122 A definitive diagnosis in hemizygous males requires enzyme assays to measure α-gal-A enzyme activity4,13 or the presence of undegraded intralysosomal Gb-3 known as myelin bodies (or “zebra” bodies) on electron microscopy.10,94,122 Electron micrographs showing myelin bodies in renal vascular endothelium and within podocytes are depicted in Fig. 10. Plasma enzyme activity may be within reference range, with a negative tissue biopsy in heterozygous females; in these cases, gene mutation analysis is required to diagnose FD.123–125

Figure 10
Figure 10
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SCREENING

Screening for FD is particularly useful in high-risk populations and for identifying late-onset phenotypes.126–129 Prenatal screening is also available, and results can be confirmed postpartum.4,121 Genetic counseling is highly recommended for families affected by FD or any genetic disorder.18,24

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TREATMENT

Enzyme Replacement Therapy

Enzyme replacement therapy with recombinant α-gal-A was approved in Europe in August 2001 (the agalsidase-alpha form, produced from Chinese hamster ovarian cells130) and US Food and Drug Administration (FDA) approved in April 2003 (the agalsidase-beta form, produced using human fibroblasts131). Enzyme replacement therapy is now available worldwide.78,132–134

Early intervention with ERT has been shown to prevent irreversible complications,135 reverse pathogenesis in early and advanced stages,8,136 and improve the overall quality of life 11,110,137 in Fabry adults and children.9,28,138,139 However, ERT alone does not reduce proteinuria48; skin findings, ocular manifestations, and anemia are not reversed with ERT.6,53,108

Over time, ERT has been shown to:

* Clear accumulated Gb-3 from vascular endothelium, plasma, renal podocytes, and cardiac and brain tissues10,140

* Stabilize kidney function and slow renal deterioration141,142

* Reduce stroke frequency4

* Reduce cardiac arrhythmias and improve myocardial function143,144

* Improve neuropathy and relieve neuropathic pain27,145,146

* Improve small nerve fiber69,145 and autonomic function, including sweat function147 and sympathetic skin responses148

* Relieve GI symptoms88

* Reverse mild to moderate hearing loss and vertigo106,131,149

* Reduce lymphedema4

* Improve heat and exercise tolerance150

A hemizygous male with advanced FD before ERT initiation was encountered by the author. His renal indices before and after ERT are shown in Table 3.

Table 3
Table 3
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When to Initiate ERT

Because the long-term treatment goal is prevention of irreversible damage to vital organs, ERT should be initiated as early as possible after the diagnosis of FD in all patients.10,136,142,151 Agalsidase has been shown to be safe and effective in women146,152,153 and in children with FD9,28,138 and is even safe in pregnancy.154–156 A summary of palliative therapies for systemic manifestations of FD is shown in Table 4. These should be used as indicated in conjunction with ERT, and possibly chaperone therapy, in the future.12,78,157–159

Table 4
Table 4
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ERT Dosage and Administration

Dosing of ERT is based on body weight and administered by intravenous infusion of 1 mg/kg every 2 weeks. Infusions are preceded by administration of antipyretics and require about 2 hours.160 Enzyme replacement therapy is covered by most medical insurances.7

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Adverse Events

Potential antigenic properties of agalsidase have been blamed for severe allergic reactions in a small percentage (1%) of patients on ERT.161 It is therefore recommended that when ERT is administered to a patient for the first time, infusion should take place in a medical setting.

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Chaperone Therapy

It is believed that resistance to ERT is caused by characteristics of the enzyme’s molecules, which may prohibit distribution to certain cell types in the heart, kidney, and brain.162,163 Chaperone molecules are smaller and more widely distributed to all cell types, so when chaperone molecules bind to the recombinant, it is more easily transmitted across the blood-brain barrier.163,164 Migalastat hydrochloride as chaperone therapy for ERT has been shown to substantially increase cellular α-gal-A activity and reduce lysosomal Gb-3 levels compared with ERT alone.157,158 Chaperone therapy is not currently FDA approved.

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CONCLUSIONS

This review underscores the importance of recognizing clinical eye signs of FD, a genetic disorder characterized by progressive lipid storage in tissues throughout the body, widespread ischemia, and irreversible vital organ damage. Without treatment, FD can cause death caused by stroke, heart attack, and renal failure at an early age. Heightened awareness of key ophthalmic manifestations will facilitate early diagnosis and referral for life-giving ERT, which is now available worldwide, proven safe, and effective in all age groups, and covered by most insurances.

Diagnostic delays exponentially increase the risk for irreversible vital organ damage and premature death. Because ophthalmic signs are present in most FD patients at a young age, optometrists are uniquely postured to identify these families by slit lamp findings and history. Vigilance in taking a thorough personal and family medical history and review of systems on every patient is imperative to correlate ocular and systemic findings. In children and adults who present with distinctive ocular findings and a history of unexplained childhood illnesses and/or suspicious family history of renal, cardiac, or cerebrovascular disease, FD should be considered among differential diagnoses.

Once a diagnosis of FD is confirmed and ERT is initiated, patients should be monitored lifelong by a team of well-coordinated specialists, to include optometric and ophthalmic physicians, internists, cardiologists, neurologists, nephrologists, dermatologists, otolaryngologists, gastroenterologists, counselors, and geneticists.

Melanie Sivley

School of Optometry

University of Alabama at Birmingham

1716 University Blvd HPB 523

Birmingham, AL 35294

e-mail: msivley@uab.edu

Received June 13, 2012; accepted October 29, 2012.

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REFERENCES

1. Sher NA, Letson RD, Desnick RJ. The ocular manifestations in Fabry’s disease. Arch Ophthalmol 1979; 97: 671–6.

2. Masson C, Cisse I, Simon V, Insalaco P, Audran M. Fabry disease: a review. Joint Bone Spine 2004; 71: 381–3.

3. Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, Breunig F, Charrow J, Germain DP, Nicholls K, Banikazemi M. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007; 30: 184–92.

4. Banikazemi M. Medscape Reference: Genetics of Fabry Disease. Available at: http://www.emedicine.com/ped/topic2888.htm. Accessed September 12, 2007.

5. Orssaud C, Dufier J, Germain D. Ocular manifestations in Fabry disease: a survey of 32 hemizygous male patients. Ophthalmic Genet 2003; 24: 129–39.

6. Sodi A, Ioannidis AS, Mehta A, Davey C, Beck M, Pitz S. Ocular manifestations of Fabry’s disease: data from the Fabry Outcome Survey. Br J Ophthalmol 2007; 91: 210–4.

7. Depaolis M, Desnick R, Maumanee I, Sorkin LJ, Thimons J, Brodie S. The optometrist’s role in diagnosing and managing Fabry disease. Primary Care Optom News 2007;(Suppl):2–18. Available at: http://www.vindicomeded.com/cmelc/pcon_monograph1107.asp. Accessed November 16, 2012.

8. Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007; 146: 77–86.

9. Ramaswami U, Parini R, Pintos-Morell G, Kalkum G, Kampmann C, Beck M. Fabry disease in children and response to enzyme replacement therapy: results from the Fabry Outcome Survey. Clin Genet 2011; 81: 485–90.

10. Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB, Desnick RJ, O’Callaghan M. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int 2002; 62: 1933–46.

11. Watt T, Burlina AP, Cazzorla C, Schonfeld D, Banikazemi M, Hopkin RJ, Martins AM, Sims K, Beitner-Johnson D, O’Brien F, Feldt-Rasmussen U. Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: findings from the Fabry Registry. Genet Med 2010; 12: 703–12.

12. Fervenza FC, Torra R, Lager DJ. Fabry disease: an underrecognized cause of proteinuria. Kidney Int 2008; 73: 1193–9.

13. Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 2006; 79: 31–40.

14. Maier EM, Osterrieder S, Whybra C, Ries M, Gal A, Beck M, Roscher AA, Muntau AC. Disease manifestations and X inactivation in heterozygous females with Fabry disease. Acta Paediatr Suppl 2006; 95: 30–8.

15. Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, Bultas J, Lubanda JC, Elleder M, Karetova D, Pavlikova M, Hrebicek M. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. J Mol Med (Berl) 2005; 83: 647–54.

16. Ashley GA, Shabbeer J, Yasuda M, Eng CM, Desnick RJ. Fabry disease: twenty novel alpha-galactosidase A mutations causing the classical phenotype. J Hum Genet 2001; 46: 192–6.

17. Ries M, Gal A. Genotype-phenotype correlation in Fabry disease. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives From 5 Years of FOS. Oxford, UK: Oxford PharmaGenesis; 2006.

18. Nowakowski RW. Primary Low Vision Care. East Norwalk, CT: Appleton & Lange; 1994.

19. Boys Town National Research Hospital. X-Linked Dominant Inheritance. Available at: http://www.boystownhospital.org/Hearing/info/genetics/concepts/xlink:dom.asp. Accessed July 30, 2009.

20. Dorland WA. Dorland’s Illustrated Medical Dictionary, 27th ed. Philadelphia, PA: Saunders; 1988.

21. Emory University School of Medicine, Department of Human Genetics. Fabry Disease: Important Facts for Women; 2005. Available at: www.genetics.emory.edu/pdf/Fabry.PDF. Accessed September 1, 2007.

22. Fabrazyme: agalsidase beta. Genetics and Inheritance: Fabry Disease. Available at: http://www.fabrazyme.com/hcp/disease/fz_us_hc_ds_genetics.asp. Accessed July 10, 2012.

23. Lyon MF. X-chromosome inactivation and human genetic disease. Acta Paediatr Suppl 2002; 91: 107–12.

24. Bennett RL, Hart KA, O’Rourke E, Barranger JA, Johnson J, MacDermot KD, Pastores GM, Steiner RD, Thadhani R. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors. J Genet Couns 2002; 11: 121–46.

25. Kolodny EH, Pastores GM. CNS pathology and vascular/circulatory abnormalities in Fabry disease. Acta Paediatr Suppl 2006; 95: 55–6.

26. Giannini EH, Mehta AB, Hilz MJ, Beck M, Bichet DG, Brady RO, West M, Germain DP, Wanner C, Waldek S, Clarke JT, Mengel E, Strotmann JM, Warnock DG, Linhart A. A validated disease severity scoring system for Fabry disease. Mol Genet Metab 2010; 99: 283–90.

27. Fervenza FC, Torra R, Warnock DG. Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease. Biologics 2008; 2: 823–43.

28. Pintos-Morell G, Beck M. Fabry disease in children and the effects of enzyme replacement treatment. Eur J Pediatr 2009; 168: 1355–63.

29. Chimenti C, Pieroni M, Morgante E, Antuzzi D, Russo A, Russo MA, Maseri A, Frustaci A. Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 2004; 110: 1047–53.

30. Basic-Jukic N, Kes P, Mokos I, Coric M. Do we need more intensive enzyme replacement therapy for Anderson-Fabry disease? Med Hypotheses 2009; 72: 476–7.

31. Wozniak MA, Kittner SJ, Tuhrim S, Cole JW, Stern B, Dobbins M, Grace ME, Nazarenko I, Dobrovolny R, McDade E, Desnick RJ. Frequency of unrecognized Fabry disease among young European-American and African-American men with first ischemic stroke. Stroke 2010; 41: 78–81.

32. MacDermot KD, Holmes A, Miners AH. Natural history of Fabry disease in affected males and obligate carrier females. J Inherit Metab Dis 2001; 24 (Suppl. 2): 13–4.

33. Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE, Packman S, Sorensen SA, Wilcox WR, Desnick RJ. Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant 2009; 24: 2102–11.

34. Morier AM, Minteer J, Tyszko R, McCann R, Clarke MV, Browning MF. Ocular manifestations of Fabry disease within in a single kindred. Optometry 2010; 81: 437–49.

35. Mastropasqua L, Nubile M, Lanzini M, Carpineto P, Toto L, Ciancaglini M. Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study. Am J Ophthalmol 2006; 141: 709–18.

36. Hoffmann B. Fabry disease: recent advances in pathology, diagnosis, treatment and monitoring. Orphanet J Rare Dis 2009; 4: 21.

37. Franceschetti AT. Fabry disease: ocular manifestations. Birth Defects Orig Artic Ser 1976; 12: 195–208.

38. Roche O, Orssaud C, Germain D, Dufier JL. [Pediatric aspects of Fabry’s disease]. Arch Pediatr 2007; 14: 909–14.

39. Gray AV. Spotting spirals in a small town clinic. EyeNet Magazine June 2001:47–8. Available at: http://aao.org/aao/news/eyenet/archive/06_01/amrounds.html. Accessed May 26, 2009.

40. Bartlett JD. Systemic drugs affecting the eye. In: Bartlett JD, ed. Ophthalmic Drug Facts, 21st ed. St. Louis, MO: Wolters Kluwer Health; 2010: 335–42.

41. Falke K, Buttner A, Schittkowski M, Stachs O, Kraak R, Zhivov A, Rolfs A, Guthoff R. The microstructure of cornea verticillata in Fabry disease and amiodarone-induced keratopathy: a confocal laser-scanning microscopy study. Graefes Arch Clin Exp Ophthalmol 2009; 247: 523–34.

42. Graff JM. Verticillata: 54-Year-Old White Male With Known History of Atrial Fibrillation and Hypertension on Amiodarone: February 21, 2005. Available at: http://webeye.ophth.uiowa.edu/eyeforum/cases/case29.htm. Accessed September 3, 2007.

43. Samiy N. Ocular features of Fabry disease: diagnosis of a treatable life-threatening disorder. Surv Ophthalmol 2008; 53: 416–23.

44. Cable WJ, Kolodny EH, Adams RD. Fabry disease: impaired autonomic function. Neurology 1982; 32: 498–502.

45. Hilz MJ, Kolodny EH, Brys M, Stemper B, Haendl T, Marthol H. Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease. J Neurol 2004; 251: 564–70.

46. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004; 34: 236–42.

47. Eijkelkamp WB, Zhang Z, Remuzzi G, Parving HH, Cooper ME, Keane WF, Shahinfar S, Gleim GW, Weir MR, Brenner BM, de Zeeuw D. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol 2007; 18: 1540–6.

48. Warnock DG. Enzyme replacement therapy and Fabry kidney disease: quo vadis? J Am Soc Nephrol 2007; 18: 1368–70.

49. Hilz MJ. Evaluation of peripheral and autonomic nerve function in Fabry disease. Acta Paediatr Suppl 2002; 91: 38–42.

50. Kolodny EH, Pastores GM. Anderson-Fabry disease: extrarenal, neurologic manifestations. J Am Soc Nephrol 2002; 13 (Suppl. 2): S150–3.

51. Sher NA, Reiff W, Letson RD, Desnick RJ. Central retinal artery occlusion complicating Fabry’s disease. Arch Ophthalmol 1978; 96: 815–7.

52. Sodi A, Bini A, Mignani R, Minuti B, Menchini U. Subfoveal choroidal neovascularization in a patient with Fabry’s disease. Int Ophthalmol 2009; 29: 435–7.

53. Orteu CH, Jansen T, Lidove O, Jaussaud R, Hughes DA, Pintos-Morell G, Ramaswami U, Parini R, Sunder-Plassman G, Beck M, Mehta AB. Fabry disease and the skin: data from FOS, the Fabry Outcome Survey. Br J Dermatol 2007; 157: 331–7.

54. Abe H, Sakai T, Sawaguchi S, Hasegawa S, Takagi M, Yoshizawa T, Usui T, Horikawa Y. Ischemic optic neuropathy in a female carrier with Fabry’s disease. Ophthalmologica 1992; 205: 83–8.

55. Pitz S, Grube-Einwald K, Renieri G, Reinke J. Subclinical optic neuropathy in Fabry disease. Ophthalmic Genet 2009; 30: 165–71.

56. Utsumi K, Ueda K, Watanabe M, Sakamaki M, Arii K, Yamazaki M, Komaba Y, Katsura K, Iino Y, Katayama Y. Thrombosis in Japanese patients with Fabry disease. J Neurol Sci 2009; 283: 83–5.

57. Vasta S. ODs play crucial role in identifying Fabry’s disease. Primary Care Optom News, June 2009. Available at: http://www.pconsupersite.com/view.asp?ID=19441. Accessed July 6, 2009.

58. Cox-Brinkman J, Vedder A, Hollak C, Richfield L, Mehta A, Orteu K, Wijburg F, Hammond P. Three-dimensional face shape in Fabry disease. Eur J Hum Genet 2007; 15: 535–42.

59. Ries M, Moore DF, Robinson CJ, Tifft CJ, Rosenbaum KN, Brady RO, Schiffmann R, Krasnewich D. Quantitative dysmorphology assessment in Fabry disease. Genet Med 2006; 8: 96–101.

60. Edwards JD, Bower KS, Brooks DB, Walter A. Fabry disease and chemosis. Cornea 2009; 28: 224–7.

61. Shen YD, Yang CM, Huang JS. Fabry disease manifesting as chronic uveitis–treated with enzyme replacement therapy. Eye (Lond) 2007; 21: 431–2.

62. MacDermot J, MacDermot KD. Neuropathic pain in Anderson-Fabry disease: pathology and therapeutic options. Eur J Pharmacol 2001; 429: 121–5.

63. Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, Lemay R, Tylki-Szymanska A, Wilcox WR. Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res 2008; 64: 550–5.

64. Chowdhury MM, Holt PJ. Pain in Anderson-Fabry’s disease. Lancet 2001; 357: 887.

65. Hilz MJ, Stemper B, Kolodny EH. Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients. Pain 2000; 84: 361–5.

66. Lidove O, Ramaswami U, Jaussaud R, Barbey F, Maisonobe T, Caillaud C, Beck M, Sunder-Plassmann G, Linhart A, Mehta A. Hyperhidrosis: a new and often early symptom in Fabry disease. International experience and data from the Fabry Outcome Survey. Int J Clin Pract 2006; 60: 1053–9.

67. Dominguez RO, Michref A, Tanus E, Amartino H. [Restless legs syndrome in Fabry disease: clinical feature associated to neuropathic pain is overlooked]. Rev Neurol 2007; 45: 474–8.

68. Garzuly F, Marodi L, Erdos M, Grubits J, Varga Z, Gelpi E, Rohonyi B, Mazlo M, Molnar A, Budka H. Megadolichobasilar anomaly with thrombosis in a family with Fabry’s disease and a novel mutation in the alpha-galactosidase A gene. Brain 2005; 128: 2078–83.

69. Dutsch M, Hilz MJ. Neurological complications in Fabry disease. Rev Med Interne 2010; 31 (Suppl. 2): S243–50.

70. Gregoire SM, Brown MM, Collas DM, Jacob P, Lachmann RH, Werring DJ. Posterior circulation strokes without systemic involvement as the presenting feature of Fabry disease. J Neurol Neurosurg Psychiatry 2009; 80: 1414–6.

71. Sims K, Politei J, Banikazemi M, Lee P. Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke 2009; 40: 788–94.

72. Brittig F, Garzuly F, Mazlo M, Hadarits F. [Fabry’s disease associated with basilar artery thrombosis]. Morphol Igazsagugyi Orv Sz 1986; 26: 15–24.

73. Medpix. Vertebrobasilar Dolichoectasia. Available at: http://rad.usuhs.edu/medpix/medpix.html?mode=single&recnum=1402&search=&hi=2#top. Accessed September 3, 2009.

74. Jardim LB, Aesse F, Vedolin LM, Pitta-Pinheiro C, Marconato J, Burin MG, Cecchin C, Netto CB, Matte US, Pereira F, Kalakun L, Giugliani R. White matter lesions in Fabry disease before and after enzyme replacement therapy: a 2-year follow-up. Arq Neuropsiquiatr 2006; 64: 711–7.

75. Mehta A, Ginsberg L. Natural history of the cerebrovascular complications of Fabry disease. Acta Paediatr Suppl 2005; 94: 24–7.

76. Ries M, Ramaswami U, Parini R, Lindblad B, Whybra C, Willers I, Gal A, Beck M. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr 2003; 162: 767–72.

77. Cybulla M, Schaefer E, Wendt S, Ling H, Krober SM, Hovelborn U, Schandelmaier S, Rohrbach R, Neumann HP. Chronic renal failure and proteinuria in adulthood: Fabry disease predominantly affecting the kidneys. Am J Kidney Dis 2005; 45: 82–9.

78. Warnock DG, Daina E, Remuzzi G, West M. Enzyme replacement therapy and Fabry nephropathy. Clin J Am Soc Nephrol 2010; 5: 371–8.

79. Tondel C, Ramaswami U, Aakre KM, Wijburg F, Bouwman M, Svarstad E. Monitoring renal function in children with Fabry disease: comparisons of measured and creatinine-based estimated glomerular filtration rate. Nephrol Dial Transplant 2010; 25: 1507–13.

80. Wanner C, Oliveira JP, Ortiz A, Mauer M, Germain DP, Linthorst GE, Serra AL, Marodi L, Mignani R, Cianciaruso B, Vujkovac B, Lemay R, Beitner-Johnson D, Waldek S, Warnock DG. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry. Clin J Am Soc Nephrol 2010; 5: 2220–8.

81. Linhart A, Kampmann C, Zamorano JL, Sunder-Plassmann G, Beck M, Mehta A, Elliott PM. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J 2007; 28: 1228–35.

82. Kampmann C, Wiethoff CM, Perrot A, Beck M, Dietz R, Osterziel KJ. The heart in Anderson Fabry disease. Z Kardiol 2002; 91: 786–95.

83. Choi S, Seo H, Park M, Kim J, Hwang S, Kwon K, Her K, Won Y. Fabry disease with aortic regurgitation. Ann Thorac Surg 2009; 87: 625–8.

84. Boutouyrie P, Laurent S, Laloux B, Lidove O, Grunfeld JP, Germain DP. Arterial remodelling in Fabry disease. Acta Paediatr Suppl 2002; 91: 62–6.

85. Kampmann C, Wiethoff CM, Whybra C, Baehner FA, Mengel E, Beck M. Cardiac manifestations of Anderson-Fabry disease in children and adolescents. Acta Paediatr 2008; 97: 463–9.

86. Kampmann C, Baehner F, Whybra C, Martin C, Wiethoff CM, Ries M, Gal A, Beck M. Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol 2002; 40: 1668–74.

87. Weidemann F, Niemann M, Warnock DG, Ertl G, Wanner C. The Fabry cardiomyopathy: models for the cardiologist. Annu Rev Med 2011; 62: 59–67.

88. Banikazemi M, Ullman T, Desnick RJ. Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy. Mol Genet Metab 2005; 85: 255–9.

89. Hoffmann B, Keshav S. Gastrointestinal symptoms in Fabry disease: everything is possible, including treatment. Acta Paediatr Suppl 2007; 96: 84–6.

90. Hoffmann B, Schwarz M, Mehta A, Keshav S. Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin Gastroenterol Hepatol 2007; 5: 1447–53.

91. Schiller PI, Itin PH. Angiokeratomas: an update. Dermatology 1996; 193: 275–82.

92. Karen JK, Hale EK, Ma L. Angiokeratoma corporis diffusum (Fabry disease). Dermatol Online J 2005; 11: 8.

93. Amann-Vesti BR, Gitzelmann G, Widmer U, Bosshard NU, Steinmann B, Koppensteiner R. Severe lymphatic microangiopathy in Fabry disease. Lymphat Res Biol 2003; 1: 185–9.

94. Linthorst GE, De Rie MA, Tjiam KH, Aerts JM, Dingemans KP, Hollak CE. Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical or pathological suspicion. Br J Dermatol 2004; 150: 575–7.

95. Wasik JS, Simon RW, Meier T, Steinmann B, Amann-Vesti BR. Nailfold capillaroscopy: specific features in Fabry disease. Clin Hemorheol Microcirc 2009; 42: 99–106.

96. Hogarth V, Dhoat S, Mehta AB, Orteu CH. Late-onset Fabry disease associated with angiokeratoma of Fordyce and multiple cherry angiomas. Clin Exp Dermatol 2011; 36: 506–8.

97. Brown LK, Miller A, Bhuptani A, Sloane MF, Zimmerman MI, Schilero G, Eng CM, Desnick RJ. Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med 1997; 155: 1004–10.

98. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007; 9: 34–45.

99. Magage S, Lubanda JC, Susa Z, Bultas J, Karetova D, Dobrovolny R, Hrebicek M, Germain DP, Linhart A. Natural history of the respiratory involvement in Anderson-Fabry disease. J Inherit Metab Dis 2007; 30: 790–9.

100. Duning T, Deppe M, Keller S, Schiffbauer H, Stypmann J, Bontert M, Schaefer R, Young P. Excessive daytime sleepiness is a common symptom in Fabry Disease. Case Rep Neurol 2009; 1: 33–40.

101. Conti G, Sergi B. Auditory and vestibular findings in Fabry disease: a study of hemizygous males and heterozygous females. Acta Paediatr Suppl 2003; 92: 33–7.

102. Malinvaud D, Avan P, Germain DP, Benistan K, Bonfils P. [The cochlea in Fabry disease: a sensorineural hearing loss model of vascular origin?] Rev Med Interne 2006; 27: 527–31.

103. Sergi B, Conti G. Fabry disease and hearing loss. Comment on: Barras FM, Maire R. Progressive hearing loss in Fabry’s disease: a case report. Eur Arch Otorhinolaryngol 2006;263:688–691. Eur Arch Otorhinolaryngol 2007; 264: 209.

104. Barras FM, Maire R. Progressive hearing loss in Fabry’s disease: a case report. Eur Arch Otorhinolaryngol 2006; 263: 688–91.

105. Pruss H, Bohner G, Zschenderlein R. Paroxysmal vertigo as the presenting symptom of Fabry disease. Neurology 2006; 66: 249.

106. Palla A, Hegemann S, Widmer U, Straumann D. Vestibular and auditory deficits in Fabry disease and their response to enzyme replacement therapy. J Neurol 2007; 254: 1433–42.

107. Rombach SM, Twickler TB, Aerts JM, Linthorst GE, Wijburg FA, Hollak CE. Vasculopathy in patients with Fabry disease: current controversies and research directions. Mol Genet Metab 2010; 99: 99–108.

108. Kleinert J, Dehout F, Schwarting A, de Lorenzo AG, Ricci R, Kampmann C, Beck M, Ramaswami U, Linhart A, Gal A, Houge G, Widmer U, Mehta A, Sunder-Plassmann G. Anemia is a new complication in Fabry disease: data from the Fabry Outcome Survey. Kidney Int 2005; 67: 1955–60.

109. Psychology Information Online. Women and Depression. Available from: http://www.psychologyinfo.com/depression/women.htm. Accessed August 5, 2009.

110. Gold KF, Pastores GM, Botteman MF, Yeh JM, Sweeney S, Aliski W, Pashos CL. Quality of life of patients with Fabry disease. Qual Life Res 2002; 11: 317–27.

111. Sadek J, Shellhaas R, Camfield CS, Camfield PR, Burley J. Psychiatric findings in four female carriers of Fabry disease. Psychiatr Genet 2004; 14: 199–201.

112. Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults with Fabry disease: a common and underdiagnosed problem. J Inherit Metab Dis 2007; 30: 943–51.

113. Grewal RP. Psychiatric disorders in patients with Fabry’s disease. Int J Psychiatry Med 1993; 23: 307–12.

114. Patient.co.uk. Professional Reference: Anderson-Fabry Disease. Available from: www.patient.co.uk/doctor/Anderson-Fabry-Disease.htm. Accessed August 1, 2009.

115. Foda MM, Mahmood K, Rasuli P, Dunlap H, Kiruluta G, Schillinger JF. High-flow priapism associated with Fabry’s disease in a child: a case report and review of the literature. Urology 1996; 48: 949–52.

116. Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM, Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner C, Warnock DG, Lemay RM, Germain DP. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 2008; 93: 112–28.

117. Hauser AC, Gessl A, Harm F, Wiesholzer M, Kleinert J, Wallner M, Voigtlander T, Bieglmayer C, Sunder-Plassmann G. Hormonal profile and fertility in patients with Anderson-Fabry disease. Int J Clin Pract 2005; 59: 1025–8.

118. Ries M, Gupta S, Moore DF, Sachdev V, Quirk JM, Murray GJ, Rosing DR, Robinson C, Schaefer E, Gal A, Dambrosia JM, Garman SC, Brady RO, Schiffmann R. Pediatric Fabry disease. Pediatrics 2005; 115: e344–55.

119. Mehta A, Clarke JT, Giugliani R, Elliott P, Linhart A, Beck M, Sunder-Plassmann G. Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey. J Med Genet 2009; 46: 548–52.

120. Callegaro D, Kaimen-Maciel DR. Fabry’s disease as a differential diagnosis of MS. Int MS J 2006; 13: 27–30.

121. Desnick RJ. Prenatal diagnosis of Fabry disease. Prenat Diagn 2007; 27: 693–4.

122. Warnock DG. Fabry disease: diagnosis and management, with emphasis on the renal manifestations. Curr Opin Nephrol Hypertens 2005; 14: 87–95.

123. Breunig F, Weidemann F, Beer M, Eggert A, Krane V, Spindler M, Sandstede J, Strotmann J, Wanner C. Fabry disease: diagnosis and treatment. Kidney Int Suppl 2003: S181–5.

124. Filoni C, Caciotti A, Carraresi L, Cavicchi C, Parini R, Antuzzi D, Zampetti A, Feriozzi S, Poisetti P, Garman SC, Guerrini R, Zammarchi E, Donati MA, Morrone A. Functional studies of new GLA gene mutations leading to conformational Fabry disease. Biochim Biophys Acta 2010; 1802: 247–52.

125. Mignani R, Morrone A. Is standard GLA gene mutation analysis definitive for the diagnosis of Fabry disease? (author reply). Kidney Int 2009; 75: 1115–6.

126. Hwu WL, Chien YH, Lee NC, Chiang SC, Dobrovolny R, Huang AC, Yeh HY, Chao MC, Lin SJ, Kitagawa T, Desnick RJ, Hsu LW. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat 2009; 30: 1397–405.

127. Linthorst GE, Bouwman MG, Wijburg FA, Aerts JM, Poorthuis BJ, Hollak CE. Screening for Fabry disease in high-risk populations: a systematic review. J Med Genet 2010; 47: 217–22.

128. Takata T, Okumiya T, Hayashibe H, Shimmoto M, Kase R, Itoh K, Utsumi K, Kamei S, Sakuraba H. Screening and detection of gene mutations in Japanese patients with Fabry disease by non-radioactive single-stranded conformation polymorphism analysis. Brain Dev 1997; 19: 111–6.

129. Oqvist B, Brenner BM, Oliveira JP, Ortiz A, Schaefer R, Svarstad E, Wanner C, Zhang K, Warnock DG. Nephropathy in Fabry disease: the importance of early diagnosis and testing in high-risk populations. Nephrol Dial Transplant 2009; 24: 1736–43.

130. Kes P, Basic-Jukic N, Brunetta B, Juric I. [Anderson-Fabry disease]. Acta Med Croatica 2006; 60: 55–8.

131. Beck M. Agalsidase alfa for the treatment of Fabry disease: new data on clinical efficacy and safety. Expert Opin Biol Ther 2009; 9: 255–61.

132. PRNewswire. New treatment available for Fabry disease in Europe; 2001. Available at: http://www.prnewswire.co.uk/news-releases/new-treatment-available-for-fabry-disease-in-europe-154911285.html. Accessed November 16, 2012.

133. Pastores GM, Thadhani R. Advances in the management of Anderson-Fabry disease: enzyme replacement therapy. Expert Opin Biol Ther 2002; 2: 325–33.

134. Drugs Information Online. FDA approves Fabrazyme as first treatment for Fabry disease; April 23, 2003. Available at: http://www.drugs.com/news/fda-approves-fabrazyme-first-fabry-disease-3273. Accessed October 20, 2009.

135. Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Stork S, Voelker W, Ertl G, Wanner C, Strotmann J. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation 2009; 119: 524–9.

136. Breunig F, Weidemann F, Strotmann J, Knoll A, Wanner C. Clinical benefit of enzyme replacement therapy in Fabry disease. Kidney Int 2006; 69: 1216–21.

137. Hoffmann B, Garcia de Lorenzo A, Mehta A, Beck M, Widmer U, Ricci R. Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey). J Med Genet 2005; 42: 247–52.

138. Ries M, Clarke JT, Whybra C, Timmons M, Robinson C, Schlaggar BL, Pastores G, Lien YH, Kampmann C, Brady RO, Beck M, Schiffmann R. Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease. Pediatrics 2006; 118: 924–32.

139. Ramaswami U, Parini R, Kampmann C, Beck M. Safety of agalsidase alfa in patients with Fabry disease under 7 years. Acta Paediatr 2011; 100: 605–11.

140. Yamadera M, Yokoe M, Beck G, Mihara M, Oe H, Yamamoto Y, Sakoda S. Amelioration of white-matter lesions in a patient with Fabry disease. J Neurol Sci 2009; 279: 118–20.

141. Wilcox WR, Banikazemi M, Guffon N, Waldek S, Lee P, Linthorst GE, Desnick RJ, Germain DP. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet 2004; 75: 65–74.

142. Feriozzi S, Schwarting A, Sunder-Plassmann G, West M, Cybulla M. Agalsidase alfa slows the decline in renal function in patients with Fabry disease. Am J Nephrol 2009; 29: 353–61.

143. Kampmann C, Linhart A, Devereux RB, Schiffmann R. Effect of agalsidase alfa replacement therapy on Fabry disease-related hypertrophic cardiomyopathy: a 12- to 36-month, retrospective, blinded echocardiographic pooled analysis. Clin Ther 2009; 31: 1966–76.

144. Imbriaco M, Pisani A, Spinelli L, Cuocolo A, Messalli G, Capuano E, Marmo M, Liuzzi R, Visciano B, Cianciaruso B, Salvatore M. Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance imaging study. Heart 2009; 95: 1103–7.

145. Hilz MJ, Brys M, Marthol H, Stemper B, Dutsch M. Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy. Neurology 2004; 62: 1066–72.

146. Whybra C, Miebach E, Mengel E, Gal A, Baron K, Beck M, Kampmann C. A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease. Genet Med 2009; 11: 441–9.

147. Schiffmann R, Floeter MK, Dambrosia JM, Gupta S, Moore DF, Sharabi Y, Khurana RK, Brady RO. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 2003; 28: 703–10.

148. Jardim LB, Gomes I, Netto CB, Nora DB, Matte US, Pereira F, Burin MG, Kalakun L, Giugliani R, Becker J. Improvement of sympathetic skin responses under enzyme replacement therapy in Fabry disease. J Inherit Metab Dis 2006; 29: 653–9.

149. Sergi B, Conti G, Paludetti G, Interdisciplinary Study Group On Fabry D. Inner ear involvement in Anderson-Fabry disease: long-term follow-up during enzyme replacement therapy. Acta Otorhinolaryngol Ital 2010; 30: 87–93.

150. Bierer G, Balfe D, Wilcox WR, Mosenifar Z. Improvement in serial cardiopulmonary exercise testing following enzyme replacement therapy in Fabry disease. J Inherit Metab Dis 2006; 29: 572–9.

151. Hoffmann B, Mayatepek E. Fabry disease—often seen, rarely diagnosed. Dtsch Arztebl Int 2009; 106: 440–7.

152. Schiffmann R, Martin RA, Reimschisel T, Johnson K, Castaneda V, Lien YH, Pastores GM, Kampmann C, Ries M, Clarke JT. Four-year prospective clinical trial of agalsidase alfa in children with Fabry disease. J Pediatr 2010; 156: 832–7.

153. Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff CM, Beck M. Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study. J Inherit Metab Dis 2003; 26: 617–27.

154. Thurberg BL, Politei JM. Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature. Hum Pathol 2012; 43: 610–4.

155. Germain DP, Bruneval P, Tran TC, Balouet P, Richalet B, Benistan K. Uneventful pregnancy outcome after enzyme replacement therapy with agalsidase beta in a heterozygous female with Fabry disease: a case report. Eur J Med Genet 2010; 53: 111–2.

156. Wendt S, Whybra C, Kampmann C, Teichmann E, Beck M. Successful pregnancy outcome in a patient with Fabry disease receiving enzyme replacement therapy with agalsidase alfa. J Inherit Metab Dis 2005; 28: 787–8.

157. Benjamin ER, Khanna R, Schilling A, Flanagan JJ, Pellegrino LJ, Brignol N, Lun Y, Guillen D, Ranes BE, Frascella M, Soska R, Feng J, Dungan L, Young B, Lockhart DJ, Valenzano KJ. Co-administration with the pharmacological chaperone AT1001 increases recombinant human alpha-galactosidase A tissue uptake and improves substrate reduction in Fabry mice. Mol Ther 2012; 20: 717–26.

158. Porto C, Pisani A, Rosa M, Acampora E, Avolio V, Tuzzi MR, Visciano B, Gagliardo C, Materazzi S, la Marca G, Andria G, Parenti G. Synergy between the pharmacological chaperone 1-deoxygalactonojirimycin and the human recombinant alpha-galactosidase A in cultured fibroblasts from patients with Fabry disease. J Inherit Metab Dis 2012; 35: 513–20.

159. Rozenfeld P, Neumann PM. Treatment of fabry disease: current and emerging strategies. Curr Pharm Biotechnol 2011; 12: 916–22.

160. Genzyme. Fabrazyme (agalsidase beta): Preparation, Dosage and Administration; 2011. Available at: http://www.fabrazyme.com/hcp/treat/FZ_R_and_A_Fact_Sheet.pdf. Accessed July 10, 2012.

161. Genzyme. Fabrazyme (agalsidase beta): Administration; 2011. Available at: http://www.fabrazyme.com/hcp/product/fz_us_hc_tr_administer.asp. Accessed July 10, 2012.

162. Ishii S. Pharmacological chaperone therapy for Fabry disease. Proc Jpn Acad Ser B Phys Biol Sci 2012; 88: 18–30.

163. Benjamin ER, Flanagan JJ, Schilling A, Chang HH, Agarwal L, Katz E, Wu X, Pine C, Wustman B, Desnick RJ, Lockhart DJ, Valenzano KJ. The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines. J Inherit Metab Dis 2009; 32: 424–40.

164. Khanna R, Soska R, Lun Y, Feng J, Frascella M, Young B, Brignol N, Pellegrino L, Sitaraman SA, Desnick RJ, Benjamin ER, Lockhart DJ, Valenzano KJ. The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. Mol Ther 2010; 18: 23–33.

Keywords:

Fabry disease; globotriaosylceramide (Gb-3); α-galactosidase-A; vascular endothelium; corneal verticillata; enzyme replacement therapy

© 2013 American Academy of Optometry

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