Fabry disease is an X linked lysosomal storage disorder which is due to deficiency of alpha galactosidase A. The classic form of the disease, in which enzyme activity in males is zero or near zero, is rare and affects approximately 1:100,000 males. However, late onset forms characterised by reduced enzyme activity, often due to missense mutations in the gene, account for the majority of newly diagnosed patients in the UK and the prevalence may be as high as 1:20,000 or so.
Treatment by enzyme replacement therapy (ERT) has changed the natural history of the condition. Whereas twenty years ago death in the 4th or 5th decade of life was to be expected for affected males (females are also affected, with life expectancy reduced by about 2 decades compared to unaffected females), ERT has improved life expectancy by 1-2 decades. However, ERT has to be injected, has short half-life, it does not access the central nervous system, may provoke formation of neutralising antibodies, and often fails to access the target tissue. Small molecules are likely to have better tissue penetration, may cross the blood brain barrier and their use is likely to yield more consistent elevation of enzyme levels. Such treatment is now licensed for individuals who have missense mutations which are translated into misfolded proteins having pathologically reduced but nonetheless present residual endogenous enzyme activity. Two small molecule approaches – substrate reduction and chaperones – will be discussed.