Q J Med 2002; 95: 647-653
© 2002 Association of Physicians
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New developments in the management of Anderson-Fabry disease
From the Department of Haematology, Royal Free Hospital, London
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Summary |
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 Top Summary IntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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Anderson-Fabry disease (AFD) is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriasylceramide throughout diverse cells, tissues and organs of the body. The disease usually presents in childhood, is progressive, and results in increasing disability and premature death. Female carriers tend to be less severely affected. AFD is difficult to diagnose because of its heterogeneous signs and symptoms. Awareness is low among health professionals, and diagnosis is typically delayed for several years after first presentation. Treatment was formerly entirely symptomatic, but enzyme replacement therapy has recently been licensed and management is evolving from genetic counselling and palliative care to early diagnosis and active intervention.
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Introduction |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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Anderson-Fabry disease (AFD) (also known as Fabry disease, see box) is a rare, X-linked lysosomal storage disorder (LSD), caused by an inborn deficiency of
-galactosidase A (-GalA). The resulting inability to catabolize glycosphingolipids causes progressive accumulation of globotriasylceramide (Gb3) in endothelial cells, vascular smooth muscle, erector pilori muscles in the skin, myocardium, corneal epithelial cells, and in organs such as the kidney, pancreas, bowel and lung.1 The resulting symptoms usually appear during childhood and adolescence, followed by disease progression and premature death. AFD is the second most common of the 40 LSDs (after Gaucher disease), with an incidence of one in 117,000 in Australia2 and one in 476,000 in the Netherlands.3 Milder, atypical AFD with symptoms confined to one organ may be more common (see below). The majority of patients identified in studies are Caucasian, but AFD has been reported in other racial groups.4
The -GalA gene is located on the X chromosome (Xq22), and the inheritance of AFD consequently follows an X-linked pattern. Hemizygous males carry a defective X chromosome and develop classical AFD. Heterozygous females have one normal and one abnormal X chromosome; they usually have milder disease than hemizygous males.
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Pathogenesis |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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The pathogenesis of Fabry disease is not well understood. It is attractive to assume that the clinical manifestations are the direct result of accumulation of Gb3 within a range of cell types and tissues, leading to disturbed cell/organ function. This explanation is likely to be simplistic, however. It is well recognized that tissue damage in Gaucher disease, the commonest lysosomal disorder, results from inflammation, cytokine release from macrophages engorged with storage material and abnormal intra- and inter-cellular signalling.5 These processes, triggered by the presence of excessive tissue Gb3 storage, are likely to be equally important in Fabry disease.
It is intriguing that heterozygous females have detectable—indeed, sometimes even normal—circulating levels of enzyme, and yet are usually affected by organ damage. Uptake and intracellular localization of the enzyme within lysosomes of diverse cells of different tissues is likely to be very important. A mouse model of Fabry disease has been developed, and may yield clues regarding the pathogenesis.6
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Signs and symptoms of AFD |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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Although clinically heterogenous, classical AFD is usually a slowly progressive disease in which signs and symptoms change as the patient ages (see Table 1
). The main causes of death are renal failure, heart disease or stroke around the age of 50 years for hemizygous men7 and 70 years for obligate carrier women.8
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Appearance
Hemizygous males often have a characteristic appearance—prominent supraorbital ridges, frontal bossing and thickening of the lips—recognizable around ages 12–14.7 They may also have sparse facial and body hair, and may report retarded growth and delayed puberty. Musculoskeletal defects are common, and include limited extension and clubbing of the fingers.
Pain
Neuropathic pain is the ‘clinical hallmark of AFD’,7 and typically appears during childhood, declining as patients age. Pain may be chronic or experienced as episodic AFD ‘crises' or acroparaesthesia. Patients describe it as an excruciating burning sensation in the palms and soles, often radiating to the proximal extremities and occasionally to the abdomen. AFD pain may occur spontaneously, but is exacerbated by temperature changes, fever, stress, physical exercise and alcohol.
Angiokeratomas
Angiokeratomas are small, raised, dark-red spots and are the ‘characteristic rash of AFD’,7 though they may be absent in patients with atypical AFD.9 Lesions develop slowly in the ‘bathing trunk’ area (Figure 1), especially on the penis, scrotum, buttocks, inner thighs and back. They generally appear around the age of 14–16 and with advancing age they spread to become visible on the lips, hands and toes.
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Hypohidrosis
Hypohidrosis (occasionally anhidrosis) is common, and causes heat intolerance. Patients do not tolerate exercise well, and may suffer nausea, dyspnoea, lightheadedness and headache, or complete collapse with loss of consciousness.10 Reduced production of tears and saliva also occurs.11
Ocular abnormalities
The eyes are affected in most AFD patients,12 and cornea verticillata (a cream, whorl-shaped opacity) is diagnostic. Subcapsular cataract also occurs, as do tortuous vascular lesions on the retina and conjunctiva, which sometimes cause severe visual loss. In a cohort of 12 patients (24 eyes) reviewed at our centre, cornea verticillata was present in 23/24, tortuous vascular lesions in 11/24 and cataract in 2/24.
Hearing loss
High frequency sensorineural hearing loss (SNHL) is common. In a cohort of 15 male patients at our centre, 4 had bilateral and 7 had unilateral SNHL; only 3 had normal hearing.
Gastrointestinal symptoms
Gastrointestinal (GI) symptoms of AFD tend to occur after meals and comprise recurrent bouts of abdominal pain in the mid and lower abdomen. Nausea, vomiting and feelings of abdominal distension are common.
Renal function
Kidney involvement is common in classical AFD (Figure 2). In 1996, the ERA-EDTA Registry reported that each year 4–13 AFD patients begin renal replacement therapy in Europe. This is likely to be an underestimate, because of the low response rate from renal centres to the Registry.13 Age of onset of end-stage renal failure is usually in the 30s, and is rare, although not unknown, in childhood. There is considerable inter- and intra-family variation in the impact of AFD on the kidney.
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Cardiac function
Common cardiac defects include left and right ventricular hypertrophy, enlarged left atrium, heart valve abnormalities and conduction disturbance. Cardiac involvement may be the only symptom in some hemizygous males9 and up to 5% of males with hypertrophic cardiomyopathy may have a ‘cardiac’ variant of AFD.14
Nervous system
Manifestations include transient ischaemic attack (TIA) or stroke, which frequently recurs and has a poor prognosis.15,16 Disturbed concentration, dizziness, dementia, headaches, and learning difficulties also occur.7 The peripheral nervous system may also be affected, with disturbances of touch, pain and sensitivity to temperature.
Respiratory function
Significant airflow obstruction is common in patients with AFD, and smoking is particularly inadvisable as it seriously exacerbates pulmonary impairment.17
AFD in women
In a recent survey that included all known symptomatic adult obligate carriers in the UK AFD register with confirmed pedigree structure and AFD diagnosis, multiple and serious manifestations of AFD were present in 30% of the women. These included TIA and stroke, renal failure, mitral valve disease, disabling neuropathic pain, fibromyalgia and personality disorder or suicidal thoughts.8
Seventy per cent reported neuropathic pain, diarrhoea and constipation occurred in over 40%, while angiokeratoma and hypohidrosis occurred in one third. Whybra et al.18 argue that the inheritance of Fabry disease is more accurately termed X-linked dominant. The underlying mechanism whereby heterozygous females develop symptoms is unknown—many have almost normal levels of circulating enzyme and the random process of X-chromosome inactivation means their tissues should be a mosaic of approximately equal numbers of normal and deficient cells.
Psychosocial impact of AFD
AFD frequently has a serious impact on quality of life, exacerbated by the shame and embarrassment anecdotally reported by AFD families. Patients also comment on poor on-going medical care even after diagnosis,7 suggesting that professionals' lack of understanding and sympathy may affect quality of life.
AFD has a significant impact on school attendance, employment and social life in males and females.
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A difficult diagnosis |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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AFD certainly presents a diagnostic challenge, as it is a protean disease potentially involving many organ systems and has a wide differential diagnosis (Table 2
). Initial presentation may be to a dermatologist, ophthalmologist, paediatrician or nephrologist, but increasingly patients are diagnosed because of a positive family history. It is often missed,19 and there is a need to increase awareness. In UK males, diagnosis of AFD takes a mean of 8.18 years from onset of neuropathic pain and a mean of 10.70 years from the onset of angiokeratoma.7
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A number of investigations are helpful in assessing and confirming the diagnosis (Table 3
). In males the diagnosis will be confirmed by enzyme assay, but heterozygous females may have normal -GalA levels, and confirmation by genetic tests and measurement of Gb3 in blood or urine is required. The gene for -galactosidase A is on Xq22 and more than 200 mutations have been identified.20 Most are small deletions or insertions, and numerous single base substitutions leading to missense or nonsense mutations are reported. The mutations are usually ‘private’ (restricted to a single or few families) and usually lead to complete lack of detectable enzyme.
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New developments in treatment |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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There is currently no cure for AFD and until recently treatment was entirely symptomatic (Table 4
). The successful use of ERT in Gaucher disease, where it is now the current standard of care21 has led to recognition of its potential role in treating other lysosomal disorders such as AFD.22 Drug development was given further impetus by legislation in the USA and the European Union that provided commercial incentives to companies producing ‘orphan’ drugs.
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Two enzyme formulations are now licensed in Europe for the treatment of AFD: agalsidase alfa, at a dose of 0.2mg/kg intravenously every two weeks (Replagal, Transkaryotic Therapies) and agalsidase beta, at the much higher dose of 1mg/kg intravenously every two weeks. (Fabrazyme, Genzyme Corporation). Agalsidase alfa is produced in a novel fashion using a genetically-engineered human fibroblast cell line. The theoretical advantages of this approach are that post-translational modification of the therapeutic product will be exactly the same as endogenously produced enzyme, potentially leading to better tissue, cellular and subcellular uptake and distribution, as well as reduced immunogenicity. Agalsidase beta is produced in a manner analagous to that for Cerezyme R, the therapeutic product for Gaucher disease, using a Chinese hamster ovary (as opposed to human) cell line.
The product licences are based on the National Institute of Health (NIH) study using agalsidase alfa23 and the trial using agalsidase beta conducted by the Mount Sinai School of Medicine study group (MSSG).24 Both studies were randomized, double-blind and placebo-controlled, but differed in details of their entry criteria and outcome measures. The NIH study recruited 28 men aged over 18 years with neuropathic pain; the MSSG study included 56 men and two women aged over 16 years with serum creatinine 
2.2 mg/dl (194.5 µmol/l). The actively treated group in the NIH study (14 men, mean age 34.0 years) were older and had more clinically measurable disease than in the MSSG study (27 men and 2 women, mean age 32.0 years). The randomized phases of both studies were approximately equal—24 weeks (NIH study) and 20 weeks (MSSG study)—followed in each case by 24 weeks open-label treatment and an extension.
These trials have shown the two preparations to be broadly equivalent as measured by laboratory assessment of treated vs. placebo groups (e.g. statistically significant reductions in urine and plasma Gb3 content, improvement in renal histology). In addition, agalsidase alfa therapy leads to statistically significant improvements in clinical parameters, e.g. pain (as assessed by the Brief Pain Inventory), renal function (glomerular filtration rate, creatinine clearance) (Figure 3), left ventricular mass and cardiac conduction.22,25 Follow-up data for over 2 years' therapy are now available.
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The NIH group has subsequently reported that algalsidase alfa treatment has resulted in significant reduction in abnormal cerebral perfusion and the resolution of abnormally increased cerebrovascular blood flow, which may indicate a reduced risk of stroke though this remains to be demonstrated clinically.26–28 Treatment with algalsidase alfa has also been shown to improve cardiomyopathy in a small and as-yet unpublished randomized controlled study from the Royal Free Hospital, London.29
ERT seems to be well tolerated by patients with AFD. There were more infusion reactions with algasidase beta and adverse reactions occurred more often than with algasidase alfa despite premedication (not given with algasidase alfa). More patients receiving algasidase beta also developed antibodies—possibly due to species-specific post-translational modifications—and this may have some clinical significance in longer-term treatment. Agalsidase beta is infused over 3–4 h (usually in a hospital setting) whereas agalsidase alfa is infused over 40 min, typically at home.
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Future management of AFD |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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Guidelines have yet to be formulated, but the prognosis of AFD is such that ERT is arguably indicated for all symptomatic males and females. Therapy for asymptomatic patients is more controversial, because of the lack of surrogate markers and our inability to predict the pattern of organ involvement and disease severity. However, early intervention offers the best possibility of preventing disease progression to avoid involvement of major organs such as the kidney.
ERT is currently expensive and cost-effectiveness studies have yet to be performed. However, the costs of this effective treatment should be weighed against those of palliative treatment (for example, renal dialysis and transplantation, pacemaker insertion), institutional care following stroke, support from social services and the loss of productivity.
In future, clinical experience and head-to-head studies are likely to clarify the choice of enzyme formulation and dosage of ERT in AFD. Research currently underway into other potential treatments, such as gene therapy, may reduce the cost of treatment and perhaps lead to a cure for AFD. In the meantime, ERT is a major advance in the management of this distressing and disabling condition, and offers a more optimistic outlook for affected families.
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Fabry or Anderson-Fabry disease? |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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The dermatologists William Anderson in the UK and Johannes Fabry in Germany were the first to describe Anderson-Fabry disease. Anderson reported a 39-year-old house painter with multiple telangiectasia at a meeting of the Royal Dermatological Society in 1897, while in 1898 Fabry described ‘angiokeratoma corporis diffusum’ in a 13-year-old boy who had had cutaneous lesions and proteinuria for over three years.1 The condition has been—and is still known as—Fabry or Fabry's disease. However, some authorities feel that Anderson's contribution should be recognized in the alternative name of Anderson-Fabry(‘s) disease, and this nomenclature has been adopted in this article.
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Notes |
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Address correspondence to Dr A. Mehta, Department of Haematology, Royal Free Hospital, Pond Street, London.
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References |
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TopSummaryIntroductionPathogenesisSigns and symptoms of...A difficult diagnosisNew developments in treatmentFuture management of AFDFabry or Anderson-Fabry disease?References |
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1. Peters FPJ, Vermeulen A, Kho TL. Anderson-Fabry's disease:
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2. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA1999; 281:249–54.
3. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in the Netherlands. Hum Genet1999; 105:151–6.[ISI][Medline]
4. Lee J-K, Kim G-H, Kim J-S, et al. Identification of four novel mutations in five unrelated Korean families with Fabry disease. Clin Genet2000; 58:228–33.[ISI][Medline]
5. Cox TM. Molecular pathogenesis of sphingo lipidoses. J Inherit Metab Dis2001; (Supp 2):106–21.
6. Ohshima T, Murray GJ, Swaim WD, et al. Alpha-galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci USA1997; 94:2540–4.
7. MacDermott KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet2001; 38:750–60.
8. MacDermott KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet2001; 38:769–75.
9. Nakao S, Takenaka T, Maeda M, et al. An atypical varient of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med1995; 333:288–93.
10. Shelley ED, Shelley WB, Kurczynski TW. Painful fingers, heat intolerance, telangiectases of the ear: easily ignored childhood signs of Fabry disease. Pediatr Dermatol1995; 12:215–19.[ISI][Medline]
11. Cable WJ, Kolodny EH, Adams RD. Fabry disease, impaired autonomic function. Neurology1982; 32:498–502.
12. Sher NA, Letson RD, Desnick RJ. The ocular manifestations of Fabry's disease. Arch Ophthalmol1979; 97:671–6.[Abstract]
13. Tsakiris D, Simpson HKL, Jones EHP, et al. Rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant1996; 11:4–20.
14. Sachdev B, Takenaka T, Teraguchi H, et al. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation2002; 105:1407–11.
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16. Grewal RP, Barton NW. Fabry's disease presenting with stroke. Clin Neurol Neurosurg1992; 94:177–9.[ISI][Medline]
17. Rosenberg DM, Ferrans VJ, Fulmer JD, et al. Chronic airflow obstruction in Fabry's disease. Am J Med1980; 68:898–905.[ISI][Medline]
18. Whybra C, Wendrich K, Ries M, Gal A, Beck M. Clinical manifestations in female Fabry disease patients. Contrib Nephrol2001; 136:245–50.[Medline]
19. Morgan SH, d'A Crawford M. Anderson-Fabry disease. A commonly missed diagnosis. Br Med J1988; 297:872–3.[ISI][Medline]
20. Desnick RJ, Ioannou YA, Eng CM. -galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet Al, Sly WS, Valk D, eds. The Metabolic and Molecular Basis of Inherited Disease, 8th edn, Vol. 3. New York, McGraw Hill, 2001:3733–74.
21. Grabowski GA, Leslie N, Wenstrup R. Enzyme therapy for Gaucher's disease: the first 5 years. Blood Reviews1998; 12:115–33.[ISI][Medline]
22. Pastores GM, Thadhani R. Advances in the management of Anderson-Fabry disease: enzyme replacement therapy. Expert Opin Biol Ther2002; 2:1–9.[ISI][Medline]
23. Schiffman R, Kopp JB, Austin AH 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomised controlled trial. JAMA2001; 285:2743–9.
24. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human -galactosidase A replacement in Fabry disease. N Engl J Med2001; 345:9–16.
25. Pastores GM, Thadhani R. Enzyme replacement therapy for Anderson-Fabry disease. Lancet2001; 358:601–3.[ISI][Medline]
26. Moore DF, Herscovitch P, Schiffmann R. Selective arterial distribution of cerebral hyperperfusion in Fabry disese. J Neuroimaging2001; 11:303–7.[ISI][Medline]
27. Moore DF, Scott LT, Gladwin MT, et al. Regional cerebral hyperperfusion and nitric oxide pathway deregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation2001; 104:1506–12.
28. Moore DF, Altarescu A, Ling GSF, et al. Cerebrovascular hyperdynamicity in Fabry disease with reversal following enzyme replacement therapy. Stroke2002; 33:525–31.
29. MacDermott K, Brown A, Jones Y, Zuckerman J. Enzyme replacement therapy reverses the cardiomyopathy of Fabry disease: results of a randomised, double-blind, placebo-controlled trial. Presented at the 10th International Congress of Human Genetics 2001, Vienna. 15–19 May 2001.
An excellent review is: Thandani R. Anderson Fabry disease—a nephrology perspective. J Amer Soc Nephr 2002; (Suppl. 2)13.
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