Fabry Disease - Why Stroke Neurologists Should Care
Fabry Disease - Why Stroke Neurologists Should Care
Introduction
Fabry disease is a treatable X-linked disorder caused by a deficiency in alpha-galactosidase. Decrease of the enzyme activity leads to accumulation of globosyltriaosylceramide (Gb3) in tissues resulting in progressive organ dysfunction especially of the heart, the renal system and the vascular system.
Frequency of Fabry Disease
The incidence of Fabry disease varies widely from setting to setting. In a recent neonatal screening study, a frequency of 1:4,600 live births was found.1 Other data suggest an incidence of 1:117000.2
Females generally have a more heterogeneous clinical picture due to the variable enzyme activity within the different tissues (lyonisation effect).3 The disease is panethnic.
Pathogenesis
Decrease of alpha-galactosidase activity inhibits the formation of lactosylceramide, an essential step in the formation of ceramide from globoside within the lysosome.
Accumulation of Gb 3 damages renal epithelium and respiratory epithelium, as well as myocardial cells, dorsal root ganglia, neurons and vascular endothelium and smooth muscle cells. The various involvements within the different organ system and the varying clinical picture lead frequently to a delay in aetiologic diagnosis.4
Mutations
More than 200 mutations have been identified within the alpha-galactosidase gene.5 In 90% of affected families point mutations are identified within the seven exons of the alpha-galactosidase gene. Insertional mutations have also been described. Small deletions within the gene are well known but may cause difficulties with genetic diagnosis. The role of some intronic splice site mutations remains controversial.6
Clinical Features
Systemic Characteristics
Several clinical features point to a high likelihood of Fabry disease.7 Cornea verticillata, a whirl-like clouding of the cornea, best seen with slit-lamp examination, in the absence of the use of amiodarone or chloroquine, is very specific. Angiokeratomas, asymptomatic, punctiform papules, often occurring in clusters, are located in the genital area or periumbilical region and less commonly in the mucosal tissues. Angiokeratomas are infrequently found in other diseases.8
Less specific but relevant features for the disease include proteinuria, progressive renal failure, cardiomyopathy, ventricular hypertrophy, myocardial infarction and arrhythmia. These manifestations, together with cerebrovascular syndromes, are the principal causes of the progressive disability and mortality due to Fabry disease.9
- Spada M, Pagliardini S, Yasuda M, et al., "High incidence of later-onset fabry disease revealed by newborn screening", Am J Hum Genet (2006);79: pp. 31 40.
- Meikle PJ, Hopwood JJ, Clague AE, Carey WF, "Prevalence of lysosomal storage disorders", JAMA (1999);281: pp. 249 254.
- Gavazzi C, Borsini W, Guerrini L, et al., "Subcortical damage and cortical functional changes in men and women with Fabry disease: a multifaceted MR study", Radiology (2006);241: pp. 492 500.
- Mehta A, Ricci R, Widmer U, et al., "Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey", Eur J Clin Invest 2004);34: pp. 236 242.
- Garman SC, Garboczi DN, "The molecular defect leading to Fabry disease: structure of human alpha-galactosidase", J Mol Biol (2004);337: pp. 319 335.
- Ishii S, Nakao S, Minamikawa-Tachino R, et al., "Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype", Am J Hum Genet (2002);70: pp. 994 1002.
- Desnick RJ, Brady R, Barranger J, et al., "Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy", Ann Intern Med (2003);138: pp. 338 346.
- Brady RO, Schiffmann R, "Clinical features of and recent advances in therapy for Fabry disease", JAMA (2000);284: pp. 2771 2775.
- Fellgiebel A, Muller MJ, Ginsberg L, "CNS manifestations of Fabry s disease", Lancet Neurol (2006);5: pp. 791 795.
- Mitsias P, Levine SR, "Cerebrovascular complications of Fabry s disease", Ann Neurol (1996);40: pp. 8 17.
- Kleinert J, Dehout F, Schwarting A, et al., "Prevalence of uncontrolled hypertension in patients with fabry disease", Am J Hypertens (2006);19: pp. 782 787.
- Moore DF, Altarescu G, Barker WC, Patronas NJ, Herscovitch P, Schiffmann R, "White matter lesions in Fabry disease occur in prior selectively hypometabolic and hyperperfused brain regions", Brain Res Bull (2003);62: pp. 231 240.
- Hilz MJ, Kolodny EH, Brys M, et al., "Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease", J Neurol (2004);251: pp. 564 570.
- DeGraba T, Azhar S, Dignat-George F, et al., "Profile of endothelial and leukocyte activation in Fabry patients", Ann Neurol (2000);47: pp. 229 233.
- Altarescu G, Moore DF, Schiffmann R, "Effect of genetic modifiers on cerebral lesions in Fabry disease", Neurology (2005);64: pp. 2148 2150.
- Yasuda M, Shabbeer J, Benson SD, et al., "Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele", Hum Mutat (2003);22: pp. 486 492.
- Schiffmann R, Kopp JB, Austin HA, 3rd, et al., "Enzyme replacement therapy in Fabry disease: a randomized controlled trial", Jama, 2001);285: pp. 2743 2749.
- Eng CM, Guffon N, Wilcox WR, et al., "Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry s disease", N Engl J Med (2001);345: pp. 9 16.
