title: Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy.
abstract: Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. 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 alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. 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.
authors.affiliation: Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Ferdinandusse
authors.forename: S
authors.initials: S
authors.lastname: Denis
authors.forename: P T
authors.initials: PT
authors.lastname: Clayton
authors.forename: A
authors.initials: A
authors.lastname: Graham
authors.forename: J E
authors.initials: JE
authors.lastname: Rees
authors.forename: J T
authors.initials: JT
authors.lastname: Allen
authors.forename: B N
authors.initials: BN
authors.lastname: McLean
authors.forename: A Y
authors.initials: AY
authors.lastname: Brown
authors.forename: P
authors.initials: P
authors.lastname: Vreken
authors.forename: H R
authors.initials: HR
authors.lastname: Waterham
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D003001:Cloning, Molecular; D004926:Escherichia coli; D005260:Female; D015417:Hereditary Sensory and Motor Neuropathy / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D020675:Peroxisomes / Q000201:enzymology*; D017354:Point Mutation; D019998:Racemases and Epimerases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D011994:Recombinant Proteins; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase