Fabry disease, also known as Anderson-Fabry disease, is a multisystem disorder resulting from an X-linked inborn error of metabolism. The disease results from genetic mutations which cause decreased or absent expression of hydrolase alpha-galactosidase A, ultimately resulting in abnormal accumulation of globotriaosylceramide (Gb3) in various organ systems 8.
The clinical manifestations are variable and may depend on the specific gene defect and degree of residual enzyme activity. Both male and heterozygous females can exhibit a severe phenotype.
Fabry disease was initially described in males with a form of severe disease, a phenotype known as a "classic" Fabry. However, it is now recognized that there are both early and late-onset forms of the disease in males, depending on the genetic aberration and degree of enzymatic compromise 8.
Similarly, females that have heterozygous genetic involvement have a spectrum of presentation ranging from asymptomatic to severe. This may be explained by variable expression of the mutated X-linked gene 8.
Small vessel ischaemia is the main mechanism of central nervous system manifestations, with ischaemic strokes, especially of the posterior circulation being common. Multi-infarct dementia can ensue, although MRI T2 hyperintensities in the white matter of the frontal and parietal lobes can be seen in asymptomatic patients. MRI is used to monitor treatment response.
T1 weighted images also demonstrate high signal in the deep grey matter especially that of the pulvinar, relating to mineralisation (see basal ganglia T1 hyperintensity). Exclusive involvement of pulvinar is thought to be characteristic of the condition 4.
Both T2 and T1 changes have been seen to regress with treatment if instituted early enough.
Acroparesthesia is a common manifestation, more so than ischaemic changes described above, and can be debilitating 6.
Autonomic (sympathetic) nervous system involvement can lead to gastrointestinal autonomic dysfunction.
Renal involvement begins with proteinuria progressing to end stage renal failure usually in the 4th decade. On imaging, the kidneys have non-specific findings of medical renal disease including increased echogenicity, thinned renal cortex, and multiple renal cysts. The cysts are perhaps the most specific sign, typically small and of uniform size, located just beneath the capsule, aiding in differentiating these from autosomal dominant polycystic kidney disease (ADPKD).
Fabry disease is affiliated with corneal verticillata and lenticular abnormalities. Recent studies have proposed eye signs in Fabry disease in association with α-galactosidase A mutations could be an indicator of disease severity 7.
Focal myocardial fibrosis leads to left ventricular hypertrophy. Thickening of the aortoventricular valve is seen in 25% of patients. Mitral valve disease with thickening and regurgitation is also demonstrated.
Avascular necrosis of the femoral head has been described.
There can be chronic obstructive airways disease like symptoms with bronchial wall thickening.
Treatment and prognosis
Enzyme substitution (hydroxylase alpha-galactosidase) is efficacious in rectifying the metabolic deficit. It consists of an intravenous infusion which is typically given every two weeks 8. Enzyme replacement has been shown to improve some deposition-related components of the disease, including some reversal in cardiac enlargement and clearance of excessive glycolipids from renal podocytes 9.
A modestly-sized (n=110) retrospective Dutch study showed median life expectancy of 57 years for males and 72 for females 10.
History and etymology
First described in 1898 by Johanne Fabry, German dermatologist (1860-1930).
- 1. Lidove O, Klein I, Lelièvre JD et-al. Imaging features of Fabry disease. AJR Am J Roentgenol. 2006;186 (4): 1184-91. doi:10.2214/AJR.05.0019 - Pubmed citation
- 2. De Cobelli F, Esposito A, Belloni E et-al. Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy. AJR Am J Roentgenol. 2009;192 (3): W97-102. doi:10.2214/AJR.08.1201 - Pubmed citation
- 3. Moore DF, Ye F, Schiffmann R et-al. Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease. AJNR Am J Neuroradiol. 2003;24 (6): 1096-101. Pubmed citation
- 4. Linhart A, Kampmann C, Zamorano JL et-al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur. Heart J. 2007;28 (10): 1228-35. doi:10.1093/eurheartj/ehm153 - Pubmed citation
- 5. Kolodny EH, Pastores GM. Anderson-Fabry disease: extrarenal, neurologic manifestations. J. Am. Soc. Nephrol. 2002;13 Suppl 2 (suppl 2): S150-3. J. Am. Soc. Nephrol. (full text) - Pubmed citation
- 6. Mehta A, Hughes DA. Fabry Disease. 2002 Aug 5 [Updated 2013 Oct 17]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1292/
- 7. Pitz S, Kalkum G, Arash L, Karabul N, Sodi A, Larroque S, Beck M, Gal A. Ocular signs correlate well with disease severity and genotype in Fabry disease. PloS one. 10 (3): e0120814. doi:10.1371/journal.pone.0120814 - Pubmed
- 8. Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. (2018) Molecular genetics and metabolism. 123 (4): 416-427. doi:10.1016/j.ymgme.2018.02.014 - Pubmed
- 9. Arends M, Biegstraaten M, Hughes DA, Mehta A, Elliott PM, Oder D, Watkinson OT, Vaz FM, van Kuilenburg ABP, Wanner C, Hollak CEM. Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors. (2017) PloS one. 12 (8): e0182379. doi:10.1371/journal.pone.0182379 - Pubmed
- 10. Vedder AC, Linthorst GE, van Breemen MJ, Groener JE, Bemelman FJ, Strijland A, Mannens MM, Aerts JM, Hollak CE. The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels. (2007) Journal of inherited metabolic disease. 30 (1): 68-78. doi:10.1007/s10545-006-0484-8 - Pubmed
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