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.
The rat liver carnitine palmitoyltransferase 1 (L-CPTl) is the key regulatory enzyme of fatty acid oxidation in the liver, with malonyl-CoA acting as a physiological inhibitor. L-CPT1 is anchored into the outer mitochondria1 membrane (OMM) with a Ncyto-Ccyto topology by two transmembrane domains located within the N-terminal domain (residues 1 to 148). We have previously shown that this domain contains all of the informations for targeting the protein to the mitochondria. Moreover, replacement of the N-terminal domain by a specific O M M signal anchor sequence led to the unfolding of the cytosolic C-terminal domain of L-CPTI which is less active and malonyl-CoA insensitive. This has indicated that the N-terminal domain of L-CPTI is essential for maintenance of an optimal conformation of the catalytic C-terminal domain. Other molecular biological studies have now confirmed that the N-terminus of the enzyme is essential for expression of malonyl-CoA sensitivity and full activity of the protein. However, its role in maintenance of the folding state of the catalytic C-terminal domain of L-CPT1 has not been further explored. This and other aspects will be discussed.
82Mitochondria1 carnitine acylcarnitine translocase (CACT) deficiency: identification of new cases using a novel assay followed by molecular analysis of the C A C T gene. L. Ijlst', J.P.N Ruiter', W. Oostheim', H.R. Waterham', V.83 Peroxisomal beta-oxidation in yeast: new insights into the mechanisms involved with emphasis on the role of P E X l l P and YPR128CP, two peroxisomal membrane proteins, in betaoxidation and peroxisomal proliferation.
Collectively, these observations provide evidence that there is an overall reduction in peroxisomal gene expression and peroxisomal proteins in GM neurons in MS. Changes in peroxisomal function may contribute to neuronal dysfunction and degeneration in MS.
The alterations in serum amino acid levels seen in mice models are not seen in patients with mutations in the HNF-1alpha gene. This suggests differences in mouse and man in the regulation of amino acid transport and has not provided us with a phenotypic marker to use before confirmatory genetic testing.
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