Sivley, Melanie D.*
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.
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.
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.
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
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
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.
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.
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.
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
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
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
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
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
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
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
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
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
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.
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.
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
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
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.
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
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
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
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
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
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.
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
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
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.
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.
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.
School of Optometry
University of Alabama at Birmingham
1716 University Blvd HPB 523
Birmingham, AL 35294
Received June 13, 2012; accepted October 29, 2012.
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