Abstract
Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from deficiency of alpha galactosidase A and accumulation of globotriaosyl ceramide (Gb3) in cells throughout the body. Despite X-linked inheritance, females with Fabry disease may manifest significant multi-system pathology with effects on organ function, physical symptoms, quality of life and survival. Lyonisation within the peripheral blood results in some females exhibiting normal plasma or leucocyte enzyme activities which can lead to difficulties in diagnosis. Evidence of Gb3 storage has been found in urine and plasma and by histological analysis of renal and cardiac biopsies. However the disease causing mechanisms, given the presence of some enzyme activity from the normal alpha galactosidase A gene are not clear. Therapeutic effects of alpha galactosidase A have been demonstrated in the clinical trials, registries and case studies of females with documented improvements in pain, quality of life, left ventricular cardiac mass, and stabilised renal function. The optimum timing for initiation of enzyme replacement therapy nor its role in pregnancy and lactation is unknown. There is a necessity to develop strategies to identify which females are most like to benefit from Fabry specific therapy.
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References
Kint JA (1970) Fabry’s disease: alpha-galactosidase deficiency. Science 167:1268–1269
MacDermot KD, Holmes A, Miners AH (2001) Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 38:769–775
Deegan PB, Baehner AF, Barba Romero MA, Hughes DA, Kampmann C, Beck M (2006) Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet 43:347–352
Whybra C, Kampmann C, Willers I et al (2001) Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 24:715–724
Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff CM, Beck M (2003) Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study. J Inherit Metab Dis 26:617–627
Whybra C, Miebach E, Mengel E et al (2009) A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease. Genet Med 11:441–449
Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373
Happle R (2006) X-chromosome inactivation: role in skin disease expression. Acta Paediatr Suppl 95:16–23
Mills K, Morris P, Lee P et al (2005) Measurement of urinary CDH and CTH by tandem mass spectrometry in patients hemizygous and heterozygous for Fabry disease. J Inherit Metab Dis 28:35–48
Cable WJ, McCluer RH, Kolodny EH, Ullman MD (1982) Fabry disease: detection of heterozygotes by examination of glycolipids in urinary sediment. Neurology 32:1139–1145
Gupta S, Ries M, Kotsopoulos S, Schiffmann R (2005) The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine (Baltimore) 84:261–268
Osunkoya AO, Agte SD, Laszik ZA (2006) 67-year-old woman with chronic proteinuria. Focal segmental and global glomerulosclerosis with light microscopic and ultrastructural features consistent with Fabry disease. Arch Pathol Lab Med 130:e93–e95
Chimenti C, Pieroni M, Morgante E et al (2004) Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 110:1047–1053
Aerts JM, Groener JE, Kuiper S et al (2008) Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci USA 105:2812–2817
Mehta A, Clarke JT, Giugliani R et al (2009) Natural course of Fabry disease: changing pattern of causes of death in. J Med Genet 8:548–552
Ashton-Prolla P, Ashley GA, Giugliani R, Pires RF, Desnick RJ, Eng CM (1999) Fabry disease: comparison of enzymatic, linkage, and mutation analysis for carrier detection in a family with a novel mutation (30delG). Am J Med Genet 84:420–424
Desnick RJ, Bernstein HS, Astrin KH, Bishop DF (1987) Fabry disease: molecular diagnosis of hemizygotes and heterozygotes. Enzyme 38:54–64
Kleijer WJ, Hussaarts-Odijk LM, Sachs ES, Jahoda MG, Niermeijer MF (1987) Prenatal diagnosis of Fabry’s disease by direct analysis of chorionic villi. Prenat Diagn 7:283–287
Desnick RJ (2007) Prenatal diagnosis of Fabry disease. Prenat Diagn 8:693–694
Bennett RL, Hart KA, O’rourke E et al (2002) Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors. J Genet Couns 11:121–146
Raas-Rothschild A, Lacombe D (2008) Fabry disease prenatal diagnosis. Prenat Diagn 28:268
Nakao S, Takenaka T, Maeda M et al (1995) An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 3(333):288–293
Redonnet-Vernhet I, Ploos van Amstel JK, Jansen RP, Wevers RA, Salvayre R, Levade T (1996) Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene. J Med Genet 33:682–688
Wilcox WR, Oliveira JP, Hopkin RJ et al (2008) Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 93:112–128
Giacomini PS, Shannon PT, Clarke JT, Jaigobin C (2004) Fabry’s disease presenting as stroke in a young female. Can J Neurol Sci 31:112–114
Whybra C, Wendrich K, Ries M, Gal A, Beck M (2001) Clinical manifestation in female Fabry disease patients. Contrib Nephrol 136:245–250
Galanos J, Nicholls K, Grigg L, Kiers L, Crawford A, Becker G (2002) Clinical features of Fabry’s disease in Australian patients. Intern Med J 32:575–584
Nakayama Y, Tsumura K, Yamashita N, Yoshimaru K (1999) Dynamic left ventricular arterial pressure gradient and sick sinus syndrome with heterozygous Fabry’s disease improved following implantation of a dual chamber pacemaker. Pacing Clin Electrophysiol 22:1114–1115
Cantor WJ, Daly P, Iwanochko M, Clarke JT, Cusimano RJ, Butany J (1998) Cardiac transplantation for Fabry’s disease. Can J Cardiol 14:81–84
Kleinert J, Dehout F, Schwarting A et al (2006) Prevalence of uncontrolled hypertension in patients with Fabry disease. Am J Hypertens 19:782–787
Yuen NW, Lam CW, Chow TC, Chiu MC (1997) A characteristic dissection microscopy appearance of a renal biopsy of a Fabry heterozygote. Nephron 77:354–356
Mehta A, Ricci R, Widmer U et al (2004) Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 34:236–242
Mitsias P, Levine SR (1996) Cerebrovascular complications of Fabry’s disease. Ann Neurol 40:8–17
Grewal RP, McLatchey SK (1992) Cerebrovascular manifestations in a female carrier of Fabry’s disease. Acta Neurol Belg 92:36–40
Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH (2007) Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis 30:943–951
Wang RY, Lelis A, Mirocha J, Wilcox WR (2007) Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 9:34–45
MacDermot KD, Holmes A, Miners AH (2001) Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 38:750–760
Linhart A, Kampmann C, Zamorano JL et al (2007) Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J 28: 1228–1235
Eng CM, Banikazemi M, Gordon RE et al (2001) A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 68:711–722
Schiffmann R, Kopp JB, Austin HA III et al (2001) Enzyme replacement therapy in Fabry disease: a randomized controlled trial. J Am Med Assoc 285:2743–2749
West M, Nicholls K, Mehta A et al (2009) Agalsidase alfa and kidney dysfunction in Fabry disease. J Am Soc Nephrol 20:1132–1139
Hughes DA, Elliott PM, Shah J et al (2007) Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomized, double-blind, placebo-controlled clinical trial of agalsidase-alfa. Heart 94:153–158
Moore DF, Altarescu G, Herscovitch P, Schiffmann R (2002) Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease. BMC Neurol 2:4
Schiffmann R, Floeter MK, Dambrosia JM et al (2003) Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 28:703–710
Hoffmann B, Garcia dL, Mehta A, Beck M, Widmer U, Ricci R (2005) 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 42:247–252
Hoffmann B, Reinhardt D, Koletzko B (2004) Effect of enzyme-replacement therapy on gastrointestinal symptoms in Fabry disease. Eur J Gastroenterol Hepatol 16:1067–1069
Hajioff D, Goodwin S, Quiney R, Zuckerman J, MacDermot KD, Mehta A (2003) Hearing improvement in patients with Fabry disease treated with agalsidase alfa. Acta Paediatr Suppl 92:28–30
Beck M, Ricci R, Widmer U et al (2004) Fabry disease: overall effects of agalsidase alfa treatment. Eur J Clin Invest 34:838–844
Banikazemi M, Ullman T, Desnick RJ (2005) Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy. Mol Genet Metab 85:255–259
Germain DP, Waldek S, Banikazemi M et al (2007) Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol 18:1547–1557
Banikazemi M, Bultas J, Waldek S et al (2007) Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 146:77–86
Hajioff D, Hegemannn S, Conti G et al (2006) Agalsidase alpha and hearing in Fabry disease: data from the Fabry Outcome Survey. Eur J Clin Invest 36:663–667
Hoffmann B, Schwarz M, Mehta A, Keshav S (2007) Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin Gastroenterol Hepatol 5:1447–1453
Hoffmann B, Beck M, Sunder-Plassmann G, Borsini W, Ricci R, Mehta A (2007) Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy–a retrospective analysis from the Fabry Outcome Survey. Clin J Pain 23:535–542
Wendt S, Whybra C, Kampmann C, Teichmann E, Beck M (2005) Successful pregnancy outcome in a patient with Fabry disease receiving enzyme replacement therapy with agalsidase alfa. J Inherit Metab Dis 28:787–788
Benichou B, Goyal S, Sung C, Norfleet AM, O’Brien F (2009) A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease. Mol Genet Metab 96:4–12
Vedder AC, Breunig F, Donker-Koopman WE et al (2008) Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3. Mol Genet Metab 94:319–325
Whybra C, Kampmann C, Krummenauer F et al (2004) The Mainz severity score index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet 65:299–307
Eng CM, Germain DP, Banikazemi M et al (2006) Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med 8:539–548
Hughes DA, Ramaswami U, Elliott P et al. Guidelines for the diagnosis and management of Anderson-Fabry Disease. Publications and statistics 2005. Available from http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4118404
Connock M, Juarez-Garcia A, Frew E et al (2006) A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1. Health Technol Assess 10:iii–113
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Hughes, D. (2010). Fabry Disease in Females. In: Elstein, D., Altarescu, G., Beck, M. (eds) Fabry Disease. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9033-1_21
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DOI: https://doi.org/10.1007/978-90-481-9033-1_21
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