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
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
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
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
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
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
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
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 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
* Clear accumulated Gb-3 from vascular endothelium, plasma, renal podocytes, and cardiac and brain tissues10,140
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.
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
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.
Received June 13, 2012; accepted October 29, 2012.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
133. Pastores GM, Thadhani R. Advances in the management of Anderson-Fabry disease: enzyme replacement therapy. Expert Opin Biol Ther 2002; 2: 325–33.
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.
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.