Abstract
Fabry disease (FD) is a debilitating progressive multisystem X-linked lysosomal storage disorder. It was generally believed that the disease affects only adult males. Through systematic pedigree analysis, we identified 35 paediatric FD patients (age 1 to 21 years, mean 12.6 years) in 25 families. Predominant signs in this cohort were: acroparesthesia, hypohidrosis, and cornea verticillata. Neurological and psychological changes, such as tinnitus, recurrent vertigo, headache, diminished level of activity, fatigue, and depression were often observed. Angiokeratoma and gastrointestinal symptoms were frequent. Some patients also showed cardiac abnormalities. Six children and adolescents (three males and three females) over 14 years of age had renal involvement (all with proteinuria, one male had a decreased creatinine clearance of 62 ml/min). No males, but three females (1.5, 4 and 9 years of age), were free of signs and symptoms. Males (n=15, age 1 to 21 years, mean 12.4 years) and females (n=20, age 1.5 to 20 years, mean 12.7 years) showed comparable disease severity. However, the clinical courses demonstrated a wide intra- and interfamilial variability and tended to be more heterogeneous in the girls. Female patients are frequently affected at an early age, not much differently than males. They should be carefully examined because most carriers are symptomatic. Conclusion: Fabry disease usually becomes clinically manifest in childhood. Renal involvement can begin in adolescence. The diagnosis is made following a high level of suspicion or systematic pedigree analysis. It is crucial for paediatric Fabry disease patients to have early access to optimal supportive symptomatic management. Enzyme replacement therapy has shown promising effectiveness in adults. Considering its widespread therapeutic and potential preventive benefits, enzyme replacement therapy should be initiated at an early stage, prior to the onset of irreversible complications.
Similar content being viewed by others
Abbreviations
- FD :
-
Fabry disease
- GALA :
-
α-galactosidase A
- Gb 3 :
-
globotriaosylceramide
References
Argoff CE, Barton NW, Brady RO, Ziessman HA (1998) Gastrointestinal symptoms and delayed gastric emptying in Fabry's disease: response to metoclopramide. Nucl Med Commun 19: 887–891
Birklein F (2002) Mechanism-based treatment principles of neuropathic pain. Fortschr Neurol Psychiatr 70: 88–94
Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L (1967) Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 276: 1163–1167
Cable WJ, Dvorak AM, Osage JE, Kolodny EH (1982) Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves. Neurology 32: 347–353
El-Shahawy MA, Mesa C, Koss M, Campese VM (1996) A 19-year-old female with fever, acroparesthesia, and progressive deterioration of renal function. Am J Nephrol 16: 417–424
Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ (2001) Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease. N Engl J Med 345: 9–16
Epinette WW, Norins AL, Drew AL, Zeman W, Patel V (1973) Angiokeratoma corporis diffusum with α-L-fucosidase deficiency. Arch Dermatol 107: 754–757
Gehler J, Sewell AC, Becker C, Hartmann J, Spranger J (1981) Clinical and biochemical delineation of aspartyl-glycosaminuria as observed in two members of an Italian family. Helv Paediatr Acta 36: 179–189
Hilz MJ, Stemper B, Kolodny EH (2000) Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients. Pain 84: 361–365
Inagaki M, Ohno K, Ohta S, Sakuraba H, Takeshita K (1990) Relief of chronic burning pain in Fabry disease with neurotropin. Pediatr Neurol 6: 211–213
Kampmann C, Baehner F, Whybra C, Martin C, Wiethoff CM, Ries M, Gal A, Beck M (2002) Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol 40: 1668–1674
Kanzaki T, Yokota M, Mizuno N, Matsumoto Y, Hirabayashi Y (1989) Novel lysosomal glycoaminoacid storage disease with angiokeratoma corporis diffusum. Lancet 1: 875–877
Lao LM, Kumakiri M, Mima H, Kuwahara H, Ishida H, Ishiguro K, Fujita T, Ueda K (1998) The ultrastructural characteristics of eccrine sweat glands in a Fabry disease patient with hypohidrosis. J Dermatol Sci 18: 109–117
Lenoir G, Rivron M, Gubler MC, Dufier JL, Tome FS, Guivarch M (1977) Fabry's disease. Carbamazepine therapy in acrodyniform syndrome. Arch Fr Pediatr 34: 704–716
Lockman LA, Hunninghake DB, Krivit W, Desnick RJ (1973) Relief of pain of Fabry's disease by diphenylhydantoin. Neurology 23: 871–875
Luciano CA, Russell JW, Banerjee TK, Quirk JM, Scott LJ, Dambrosia JM, Barton NW, Schiffmann R (2002) Physiological characterization of neuropathy in Fabry's disease. Muscle Nerve 26: 622–629
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
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
Mayes JS, Scheerer JB, Sifers RN, Donaldson ML (1981) Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry's disease. Clin Chim Acta 112: 247–251
Miyatake T, Atsumi T, Obayashi T, Mizuno Y, Ando S, Ariga T, Matsui-Nakamura K, Yamada T (1979) Adult type neuronal storage disease with neuraminidase deficiency. Ann Neurol 6: 232–244
O'Brien BD, Shnitka TK, McDougall R, Walker K, Costopoulos L, Lentle B, Anholt L, Freeman H, Thomson AB (1982) Pathophysiologic and ultrastructural basis for intestinal symptoms in Fabry's disease. Gastroenterology 82: 957–962
Qin G, Takenaka T, Telsch K, Kelley L, Howard T, Levade T, Deans R, Howard BH, Malech HL, Brady RO, Medin JA (2001) Preselective gene therapy for Fabry disease. Proc Natl Acad Sci USA 98: 3428–3433
Ries M, Wendrich K, Whybra C, Kampmann C, Gal A, Beck M (2001) Angiokeratoma and pain, but not Fabry's disease: considerations for differential diagnosis. Contrib Nephrol 136: 256–259
Ries M, Mengel M, Kutschke G, Kim KS, Birklein F, Krummenauer F, Beck M (2003) Use of gabapentin to reduce chronic neuropathic pain in Fabry disease. J Inherit Metab Dis 26: 413–414
Schiffmann R, Kopp JB, Austin HA 3rd, Sabnis S, Moore DF, Weibel T, Balow JE, Brady RO (2001) Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 285: 2743–2749
Wenger DA, Sattler M, Mueller OT, Myers GG, Schneiman RS, Nixon GW (1980) Adult GM1 gangliosidosis: clinical and biochemical studies on two patients and comparison to other patients called variant or adult GM1 gangliosidosis. Clin Genet 17: 323–334
Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, Bruhl K, Gal A, Bunge S, Beck M (2001) Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 24: 715–724
Whybra C, Wendrich K, Miebach E, Baehner F, Ries M, Schmiedeskamp C, Kampmann C, Beck M (2001) Fabry disease: Mainz Severity Score Index (MSSI). J Inherit Metab Dis 24[Suppl.2]: 133–134
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
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ries, M., Ramaswami, U., Parini, R. et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr 162, 767–772 (2003). https://doi.org/10.1007/s00431-003-1299-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-003-1299-3