Fabry's disease (or Anderson-Fabry disease) is an X-linked lysosomal storage disorder due to mutation within the gene for a-galactosidase A (aGal A) (Figure 19.2). The resulting inability to catabolize glycosphingolipids leads to progressive accumulation of the substrate globotriasylceramide (Gb3) in a range of tissues. In contrast to GD, the lipid accumulation in Fabry's disease affects a range of cells (e.g. endothelial cells, epithelial cells, myocytes) within a broad range of tissues and organs, particularly the kidneys (leading to renal failure), heart (causing ventricular hypertrophy and conduction disturbances) and vasculature of the CNS. It is one of the commonest lysosomal storage disorders, with an incidence of approximately 1 in 100 000. It is panethnic.
Diagnosis is by assay of aGalA activity in leucocytes and detection of molecular abnormalities within the aGalA gene. More than 200 different mutations have been described, and most lead to complete loss of enzyme activity. Tissue diagnosis is by renal, skin or cardiac biopsy.
Clinical features are legion. Although females are heterozygous, they are usually symptomatic and may be as severely affected as males. A skin rash (angiokeratoma) and pain in limbs (acro-paraesthesia) are early symptoms (under 10 years old). In late childhood, reduced sweating, abdominal symptoms and lymphoedema are characteristic. Renal failure, cardiac failure, stroke, epilepsy and CNS/sensory organ involvement are later features. Life expectancy is 40-50 years for men and 50-65 years for most women.
ERT for Fabry's disease has been available since 2001. Two formulations are available: a recombinant galactosidase that is translated in CHO cells and mannose terminated (agalsidase, Genzyme Corporation, MA, USA) and an enzyme of identical amino acid sequence that is translated in a human fibroblast cell line wherein post-translational modification is performed within the human cell itself (Transkarcytic Therapies, MA, USA). The infused enzyme in Fabry's disease must be taken up by lysosomes within cells in diverse organs and tissues; hence, targeting is of crucial importance. No direct comparative data on the two formulations are available, but in randomized placebo-controlled trials both preparations appear to be well tolerated and to have clinical efficacy. Intravenous infusions are administered every 2 weeks and have been shown to reduce substrate levels in plasma, urine and tissue biopsy. Beneficial clinical effects of ERT have been observed in renal and cardiac function, pain, hearing loss and gastrointestinal symptoms.
At present, protocols advise commencement of ERT in any Fabry sufferer - male or female - with pain, renal or cardiac disease, neurological abnormalities or significant vascular disease. It is clear that ERT will not reverse significant organ damage (e.g. renal failure) but may slow progression. In Fabry's disease, as in many other LSDs, the key to successful ERT may be prevention of substrate accumulation by early intervention in childhood.
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