Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease1,2, X-linked adrenoleukodystrophy/adrenomyeloneuropathy3 and Refsum disease4. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of α-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers5,6, which are the only stereoisomers that can be degraded via peroxisomal β-oxidation7,8. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology.
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We thank L. IJlst for support, suggestions and helpful discussion throughout this study, and H. Overmars and A.H. Bootsma for technical assistance. This work was supported by the Princess Beatrix Fund.
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Ferdinandusse, S., Denis, S., Clayton, P. et al. Mutations in the gene encoding peroxisomal α-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 24, 188–191 (2000) doi:10.1038/72861
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