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. 2001 Nov;38(11):750–760. doi: 10.1136/jmg.38.11.750

Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males

K MacDermot 1, A Holmes 1, A Miners 1
PMCID: PMC1734761  PMID: 11694547

Abstract

OBJECTIVES—To determine the natural history of Anderson-Fabry disease (AFD) as a baseline for efficacy assessment of potentially therapeutic drugs.
DESIGN—The first large cross sectional study of a patient cohort from the AFD clinical and genetic register (UK), maintained for the last 15 years.
MEASURES—Prevalence, mortality, frequency of AFD manifestations, and impact of disease on patient lives, assessed from the AFD register and the disease specific questionnaire.
RESULTS—The median cumulative survival was 50 years (n=51), which represents an approximately 20 year reduction of life span. Neuropathic pain was present in 77% (n=93) with mean pain score of 5 (scale 0-10) despite treatment with anticonvulsants and opiates. Pain stopped in only 11%. Cerebrovascular complications developed in 24.2% and renal failure in 30%. The onset and progression of serious AFD manifestations was highly variable. The relationship of gastrointestinal manifestations on weight, using body mass index (BMI), was significant (p=0.01). High frequency sensorineural deafness was confirmed in 78% of audiograms. Neuropathic pain and angiokeratoma were absent in five adult males (~5%). Median age at diagnosis of AFD was 21.9 years (n=64).
IMPACT OF DISEASE—Attendance at school, sports, and social activity were significantly affected by AFD. Only 56.6% (n=46) of patients were employed. Psychosexual effects of genital angiokeratoma, genital pain, and impotence were not previously recognised.
CONCLUSION—The majority of males experience multiple disease manifestations and the duration of neuropathic pain was lifelong. The AFD register proved useful for the determination of baseline disease parameters in this cohort.


Keywords: Anderson-Fabry disease; natural history; mortality; prevalence

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Selected References

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  1. Abe A., Arend L. J., Lee L., Lingwood C., Brady R. O., Shayman J. A. Glycosphingolipid depletion in fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase. Kidney Int. 2000 Feb;57(2):446–454. doi: 10.1046/j.1523-1755.2000.00864.x. [DOI] [PubMed] [Google Scholar]
  2. Ashton-Prolla P., Tong B., Shabbeer J., Astrin K. H., Eng C. M., Desnick R. J. Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. J Investig Med. 2000 Jul;48(4):227–235. [PubMed] [Google Scholar]
  3. Becker A. E., Schoorl R., Balk A. G., van der Heide R. M. Cardiac manifestations of Fabry's disease. Report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction. Am J Cardiol. 1975 Nov;36(6):829–835. doi: 10.1016/0002-9149(75)90468-3. [DOI] [PubMed] [Google Scholar]
  4. Chatterjee S., Gupta P., Pyeritz R. E., Kwiterovich P. O., Jr Immunohistochemical localization of glycosphingolipid in urinary renal tubular cells in Fabry's disease. Am J Clin Pathol. 1984 Jul;82(1):24–28. doi: 10.1093/ajcp/82.1.24. [DOI] [PubMed] [Google Scholar]
  5. Colombi A., Kostyal A., Bracher R., Gloor F., Mazzi R., Thölen H. Angiokeratoma corporis diffusum--Fabry's disease. Helv Med Acta. 1967 Dec;34(1):67–83. [PubMed] [Google Scholar]
  6. Cox T., Lachmann R., Hollak C., Aerts J., van Weely S., Hrebícek M., Platt F., Butters T., Dwek R., Moyses C. Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet. 2000 Apr 29;355(9214):1481–1485. doi: 10.1016/S0140-6736(00)02161-9. [DOI] [PubMed] [Google Scholar]
  7. Crutchfield K. E., Patronas N. J., Dambrosia J. M., Frei K. P., Banerjee T. K., Barton N. W., Schiffmann R. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology. 1998 Jun;50(6):1746–1749. doi: 10.1212/wnl.50.6.1746. [DOI] [PubMed] [Google Scholar]
  8. Davies J. P., Eng C. M., Hill J. A., Malcolm S., MacDermot K., Winchester B., Desnick R. J. Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries. Eur J Hum Genet. 1996;4(4):219–224. doi: 10.1159/000472202. [DOI] [PubMed] [Google Scholar]
  9. Elhadad S., Melet V., Domniez T., Cosson S., Chollet D., Vedel J. Bloc auriculo-ventriculaire complet révélateur de maladie de Fabry. Arch Mal Coeur Vaiss. 1997 Mar;90(3):393–397. [PubMed] [Google Scholar]
  10. Elleder M., Bradová V., Smíd F., Budesínský M., Harzer K., Kustermann-Kuhn B., Ledvinová J., Belohlávek, Král V., Dorazilová V. Cardiocyte storage and hypertrophy as a sole manifestation of Fabry's disease. Report on a case simulating hypertrophic non-obstructive cardiomyopathy. Virchows Arch A Pathol Anat Histopathol. 1990;417(5):449–455. doi: 10.1007/BF01606034. [DOI] [PubMed] [Google Scholar]
  11. Eng C. M., Banikazemi M., Gordon R. E., Goldman M., Phelps R., Kim L., Gass A., Winston J., Dikman S., Fallon J. T. A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet. 2001 Feb 1;68(3):711–722. doi: 10.1086/318809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Eng C. M., Resnick-Silverman L. A., Niehaus D. J., Astrin K. H., Desnick R. J. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet. 1993 Dec;53(6):1186–1197. [PMC free article] [PubMed] [Google Scholar]
  13. Filling-Katz M. R., Merrick H. F., Fink J. K., Miles R. B., Sokol J., Barton N. W. Carbamazepine in Fabry's disease: effective analgesia with dose-dependent exacerbation of autonomic dysfunction. Neurology. 1989 Apr;39(4):598–600. doi: 10.1212/wnl.39.4.598. [DOI] [PubMed] [Google Scholar]
  14. Gemignani F., Marbini A., Bragaglia M. M., Govoni E. Pathological study of the sural nerve in Fabry's disease. Eur Neurol. 1984;23(3):173–181. doi: 10.1159/000115700. [DOI] [PubMed] [Google Scholar]
  15. Goldman M. E., Cantor R., Schwartz M. F., Baker M., Desnick R. J. Echocardiographic abnormalities and disease severity in Fabry's disease. J Am Coll Cardiol. 1986 May;7(5):1157–1161. doi: 10.1016/s0735-1097(86)80238-8. [DOI] [PubMed] [Google Scholar]
  16. Gordon K. E., Ludman M. D., Finley G. A. Successful treatment of painful crises of Fabry disease with low dose morphine. Pediatr Neurol. 1995 Apr;12(3):250–251. doi: 10.1016/0887-8994(95)00007-3. [DOI] [PubMed] [Google Scholar]
  17. Grewal R. P., Barton N. W. Fabry's disease presenting with stroke. Clin Neurol Neurosurg. 1992;94(2):177–179. doi: 10.1016/0303-8467(92)90079-i. [DOI] [PubMed] [Google Scholar]
  18. Grewal R. P. Psychiatric disorders in patients with Fabry's disease. Int J Psychiatry Med. 1993;23(3):307–312. doi: 10.2190/JKFW-3WXK-QA7N-BYLN. [DOI] [PubMed] [Google Scholar]
  19. Grewal R. P. Stroke in Fabry's disease. J Neurol. 1994 Jan;241(3):153–156. doi: 10.1007/BF00868342. [DOI] [PubMed] [Google Scholar]
  20. Gubler M. C., Lenoir G., Grünfeld J. P., Ulmann A., Droz D., Habib R. Early renal changes in hemizygous and heterozygous patients with Fabry's disease. Kidney Int. 1978 Mar;13(3):223–235. doi: 10.1038/ki.1978.32. [DOI] [PubMed] [Google Scholar]
  21. Hilz M. J., Stemper B., Kolodny E. H. Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients. Pain. 2000 Feb;84(2-3):361–365. doi: 10.1016/s0304-3959(99)00236-5. [DOI] [PubMed] [Google Scholar]
  22. Iwase M., Yamauchi K., Maeda M., Aoki T., Yokota M., Hayashi H., Sotobata I. [Echocardiographic findings in a case of Fabry's disease with aortic regurgitation and complete AV block, and in his family members]. J Cardiol. 1988 Jun;18(2):589–598. [PubMed] [Google Scholar]
  23. Kahn P. Anderson-Fabry disease: a histopathological study of three cases with observations on the mechanism of production of pain. J Neurol Neurosurg Psychiatry. 1973 Dec;36(6):1053–1062. doi: 10.1136/jnnp.36.6.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lockman L. A., Hunninghake D. B., Krivit W., Desnick R. J. Relief of pain of Fabry's disease by diphenylhydantoin. Neurology. 1973 Aug;23(8):871–875. doi: 10.1212/wnl.23.8.871. [DOI] [PubMed] [Google Scholar]
  25. Mehta J., Tuna N., Moller J. H., Desnick R. J. Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease. Am Heart J. 1977 Jun;93(6):699–705. doi: 10.1016/s0002-8703(77)80064-1. [DOI] [PubMed] [Google Scholar]
  26. Meikle P. J., Hopwood J. J., Clague A. E., Carey W. F. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20;281(3):249–254. doi: 10.1001/jama.281.3.249. [DOI] [PubMed] [Google Scholar]
  27. Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987 Aug;30(2):191–197. doi: 10.1016/0304-3959(87)91074-8. [DOI] [PubMed] [Google Scholar]
  28. Miners A. H., Sabin C. A., Tolley K. H., Jenkinson C., Kind P., Lee C. A. Assessing health-related quality-of-life in individuals with haemophilia. Haemophilia. 1999 Nov;5(6):378–385. doi: 10.1046/j.1365-2516.1999.00347.x. [DOI] [PubMed] [Google Scholar]
  29. Mitsias P., Levine S. R. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996 Jul;40(1):8–17. doi: 10.1002/ana.410400105. [DOI] [PubMed] [Google Scholar]
  30. Morgan S. H., Rudge P., Smith S. J., Bronstein A. M., Kendall B. E., Holly E., Young E. P., Crawfurd M. D., Bannister R. The neurological complications of Anderson-Fabry disease (alpha-galactosidase A deficiency)--investigation of symptomatic and presymptomatic patients. Q J Med. 1990 May;75(277):491–507. [PubMed] [Google Scholar]
  31. Nagao Y., Nakashima H., Fukuhara Y., Shimmoto M., Oshima A., Ikari Y., Mori Y., Sakuraba H., Suzuki Y. Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of alpha-galactosidase A. Clin Genet. 1991 Mar;39(3):233–237. doi: 10.1111/j.1399-0004.1991.tb03018.x. [DOI] [PubMed] [Google Scholar]
  32. Ogawa T., Kawai M., Matsui T., Seo A., Aizawa O., Hongo K., Shibata T., Yoshida S., Okamura T., Nishikawa T. Vasospastic angina in a patient with Fabry's disease who showed normal coronary angiographic findings. Jpn Circ J. 1996 May;60(5):315–318. doi: 10.1253/jcj.60.315. [DOI] [PubMed] [Google Scholar]
  33. Ro L. S., Chen S. T., Tang L. M., Hsu W. C., Chang H. S., Huang C. C. Current perception threshold testing in Fabry's disease. Muscle Nerve. 1999 Nov;22(11):1531–1537. doi: 10.1002/(sici)1097-4598(199911)22:11<1531::aid-mus7>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  34. Schiffmann R., Kopp J. B., Austin H. A., 3rd, Sabnis S., Moore D. F., Weibel T., Balow J. E., Brady R. O. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001 Jun 6;285(21):2743–2749. doi: 10.1001/jama.285.21.2743. [DOI] [PubMed] [Google Scholar]
  35. Scott L. J., Griffin J. W., Luciano C., Barton N. W., Banerjee T., Crawford T., McArthur J. C., Tournay A., Schiffmann R. Quantitative analysis of epidermal innervation in Fabry disease. Neurology. 1999 Apr 12;52(6):1249–1254. doi: 10.1212/wnl.52.6.1249. [DOI] [PubMed] [Google Scholar]
  36. Sheth K. J., Werlin S. L., Freeman M. E., Hodach A. E. Gastrointestinal structure and function in Fabry's disease. Am J Gastroenterol. 1981 Sep;76(3):246–251. [PubMed] [Google Scholar]
  37. Sirvent A. E., Enríquez R., Antolín A., Cabezuelo J. B., Teruel A., Rodríguez Ledesma J. M., Gonzalez C., Reyes A. Fabry's disease presenting with oligoanuric end-stage renal failure. Nephrol Dial Transplant. 1997 Jul;12(7):1503–1505. doi: 10.1093/ndt/12.7.1503. [DOI] [PubMed] [Google Scholar]
  38. Tedeschi G., Bonavita S., Banerjee T. K., Virta A., Schiffmann R. Diffuse central neuronal involvement in Fabry disease: a proton MRS imaging study. Neurology. 1999 May 12;52(8):1663–1667. doi: 10.1212/wnl.52.8.1663. [DOI] [PubMed] [Google Scholar]
  39. Tsakiris D., Simpson H. K., Jones E. H., Briggs J. D., Elinder C. G., Mendel S., Piccoli G., dos Santos J. P., Tognoni G., Vanrenterghem Y. Report on management of renale failure in Europe, XXVI, 1995. Rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant. 1996;11 (Suppl 7):4–20. doi: 10.1093/ndt/11.supp7.4. [DOI] [PubMed] [Google Scholar]
  40. Tsukada N., Hanu N., Oguchi K., Yanagisawa N., Tsukagoshi H., Hattori H. [Fabry's disease with malocclusion and acromegalic-appearance: clinical and electromicroscopic studies (author's transl)]. No To Shinkei. 1980 Mar;32(3):311–319. [PubMed] [Google Scholar]
  41. WISE D., WALLACE H. J., JELLINEK E. H. Angiokeratoma corporis diffusum. A clinical study of eight affected families. Q J Med. 1962 Apr;31:177–206. [PubMed] [Google Scholar]

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