Ferdinandusse S, Denis S, Clayton P T, Graham A, Rees J E, Allen J T, McLean B N, Brown A Y, Vreken P, Waterham H R, Wanders R J
Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands.
Nat Genet. 2000 Feb;24(2):188-91. doi: 10.1038/72861.
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.
感觉运动神经病与多种遗传性疾病相关，包括夏科-马里-图斯病、X连锁肾上腺脑白质营养不良/肾上腺脊髓神经病和雷夫叙姆病。在后两种疾病中，神经病被认为是由特定脂肪酸的积累所致。我们在此描述了三名血浆中降植烷酸（一种支链脂肪酸）和C27胆汁酸中间体浓度升高的患者。其中两名患者患有成人起病的感觉运动神经病。一名患者还患有色素性视网膜炎，提示雷夫叙姆病，而另一名患者腿部有上运动神经元体征，提示肾上腺脊髓神经病。第三名患者是一名无神经病的儿童。在所有三名患者中，我们发现了α-甲基酰基辅酶A消旋酶（AMACR）缺乏。该酶负责将降植烷酰辅酶A和C27胆汁酰辅酶A转化为它们的（S）-立体异构体，而（S）-立体异构体是唯一可通过过氧化物酶体β-氧化降解的立体异构体。基于在大肠杆菌中的分析，对患者的AMACR cDNA进行序列分析鉴定出两个可能导致疾病的不同突变。我们的发现对不明病因的成人起病神经病的诊断具有重要意义。
