The in vitro catalytic activity of two clinically observed mutants of phytanoyl-CoA 2-hydroxylase, an iron(II)/2-oxoglutarate-dependent oxygenase causing Refsum’s Disease, was partially rescued by the use of alternatives to the natural cosubstrate, 2-oxoglutarate; this is the first demonstration of ‘chemical co-substrate rescue’ of mutations to an enzyme causing human disease.