Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorption and vitamin K deficiency

Background 2‐Methylacyl‐CoA racemase interconverts the 2‐methyl group of pristanoyl‐CoA or the 25‐methyl group of hydroxylated cholestanoyl‐CoAs, allowing further peroxisomal desaturation of these compounds in man by the branched chain acyl‐CoA oxidase, which recognise only the S‐isomers. Hence, oxidation studies in fibroblasts, currently based on the use of racemic substrates such as [1–14C] pristanic acid, do not allow us to distinguish between a deficient racemase or an impaired oxidase. Design To evaluate the racemase activity directly, the 2R‐isomer of[1–14C] pristanic acid, as well as the 2R‐isomer of 2‐methyl‐[1–14C] hexadecanoic, a synthetic pristanic acid substitute, were prepared and their degradation by cultured human skin fibroblasts was compared to that of the racemic substrates. Results In fibroblasts in a young girl, presenting with elevated urinary levels of trihydroxycholestanoic acid metabolites but normal plasma levels of very long chain fatty acids, a partial deficient degradation of racemic [1–14C] pristanic acid was observed. Incorporation of 2R‐[1–14C] pristanic acid in glycerolipids of the patient's fibroblasts proceeded normally, but breakdown was impaired. Similar findings were seen with the 2R‐isomer of 2‐methyl‐[1–14C] hexadecanoic. These data, combined with the fact that the branched chain acyl‐CoA oxidase, catalyzing the first oxidation step of pristanic acid and bile acid intermediates in man, appeared normal, suggested a peroxisomal β‐oxidation defect in the patient at the level of 2‐methylacyl‐CoA racemase. Conclusion Carboxy‐labelled 2R‐methyl branched chain fatty acids might be useful tools to document cases of racemase deficiencies. Because a brother of the patient died with a diagnosis of vitamin K deficiency, an impaired racemase might be responsible for other cases of unexplicable malabsorption.