Pathophysiology of Rett syndrome-Can CSF phenyethylamine be a possible biological marker?-

Rett 综合征的病理生理学-脑脊液苯乙胺可以成为可能的生物标志物吗？-

• 批准号: 10670772
• 负责人: OHTAKI Etsuo
• 金额: $ 1.79万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670772/
• 关键词: Rett syndrome; phenylethylamine; neuromodulator; cerebrospinal fluid

To clarify the mechanism of brain impairment in Rett syndrome (RS), we measured the cerebrospinal quid (CSF) levels of β-phenylethylamine (PEA). We measured CSF PEA levels in 17 children with RS, in 13 control children with no neurologic disease. CSF levels of PEA were also determined in patients with other age-matched neurological diseases including 4 patients with epilepsy and mental retardation and 5 patients with autistic disorder. The l7 RS children included 9 in stage II, 7 in stage III, and.1 in stage IV ( mean age, 52.7 j ± 27.4 months). We also measured the CSF levels of homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethylene glyco1 (MHPG) using previously described methods.ィイD11 ,2ィエD1The extraction of PEA from CSF was performed by a method described previously.ィイD13ィエD1The mean CSF level of PEA in patients with RS (287.2 ± j285.9 pg/m1) was significantly lower than that of controls (936.2i ± 519.2 pg/ml), being 31% of control values (p < 0.05). The CSF PEA levels of … More the patients with stage II RS (n = 9) (age, 34.6 ± 9.2), patients with stage III (n = 7) (age, 64.1 ± 7.7) and 1 patient with stage IV (age, 137.0) were , 187.5 ± 158.7, 417.0 ± 387. 1, 276.3 pg/ml, respectively. The CSF PEA levels in stage II were significantly lower than those of stage III (p < 0.05). The mean CSF levels of PEA in children with epilepsy and mental retardation, or autistic disorder were not significantly different from controls lacking neurological disease. The mean CSF levels of HVA and MHPG in subjects with RS were not significantly different from those in controls.Recently, we established the methodology for measurement of PEA levels in CSF and found the CSF PEA level in Parkinson disease was lower than age-matched control, with a significant negative correlation between CSF level of PEA and PD severity (Hoehn and Yahr stage).ィイD13ィエD1 Those results have strongly suggested that the CSF levels of PEA reflect the dopaminergic neuron degeneration in PD. The most striking findings of our present studies are the marked reduction of PEA levels in CSF in girls with RS. This is the first demonstration of decreased CSF level of PEA in RS. Our study also revealed that CSF levels or HVA and MHPG, the metabolites of dopamine and norepinephrin are not decreased in patients with RS.Neuropathologic study has shown that melanin content is markedly decreased in substantia nigra zona compacta, but no difference in the number of neurons in the substantia nigra in-nine girls with RS. These findings may support the dysmaturation of dopaminergic neuron in RSィイD14ィエD1. The significance of decreased CSF PEA levels found in our study may reflect the additional evidence of the impairment of nigrostriatal dopaminergic neurons, because PEA was synthesized in these neurons. It is of interest that the most striking reduction in PEA levels in CSF occurred in the youngest girls with RS. It is during this period that disease onset is noted. This may also be the period of developmental arrest at the neurobiological level.Recently, mutations in MECP2, that has a role in a epigenetic regulation of gene expression, was discovered in patients with RS.ィイD15ィエD1 The link between this discovery and the alteration of CSF PEA should be clarified, especially during the early phase of disease onset. Less

为了阐明Rett综合征（RS）脑损伤的机制，我们测量了脑脊液（CSF）中β-苯乙胺（PEA）的水平。我们测量了17例RS患儿的脑脊液PEA水平，13例无神经系统疾病的对照患儿。同时测定了其他年龄匹配的神经系统疾病患者脑脊液中PEA的水平，包括4例癫痫和智力迟钝患者和5例自闭症患者。17例RS患儿包括II期9例，III期7例。IV期1例（平均年龄52.7±27.4个月）。我们还使用先前描述的方法测量了脑脊液中高香草酸（HVA）和3-甲氧基-4-羟基-苯乙二醇1 （MHPG）的水平。用前面描述的方法从脑脊液中提取PEA。RS患者脑脊液PEA平均水平（287.2±j285.9 pg/ml）显著低于对照组（936.2i±519.2 pg/ml），为对照组的31% （p < 0.05）。ⅱ期RS患者（n = 9）（年龄34.6±9.2），ⅲ期患者（n = 7）（年龄64.1±7.7），ⅳ期1例（年龄137.0），脑脊液PEA水平分别为187.5±158.7,417.0±387。分别为1,276.3 pg/ml。ⅱ期脑脊液PEA水平明显低于ⅲ期（p < 0.05）。癫痫、智力迟钝或自闭症患儿脑脊液中PEA的平均水平与无神经系统疾病的对照组无显著差异。RS患者脑脊液中HVA和MHPG的平均水平与对照组无显著差异。最近，我们建立了测量脑脊液PEA水平的方法，发现帕金森病患者脑脊液PEA水平低于年龄匹配的对照组，脑脊液PEA水平与PD严重程度（Hoehn和Yahr分期）呈显著负相关。这些结果强烈提示脑脊液中PEA的水平反映了PD患者多巴胺能神经元的退化。本研究最显著的发现是女生RS患者脑脊液中PEA水平显著降低，这是RS患者脑脊液中PEA水平下降的首次证明，我们的研究还揭示了RS患者脑脊液中HVA和MHPG，多巴胺和去甲肾上腺素的代谢物并未降低，神经病理学研究显示黑质致密带黑色素含量明显降低。这些发现可能支持RS中多巴胺能神经元发育异常。本研究发现脑脊液PEA水平降低的意义可能反映了黑质纹状体多巴胺能神经元受损的额外证据，因为PEA是在这些神经元中合成的。有趣的是，脑脊液中PEA水平最显著的降低发生在患有RS的最年轻女孩身上。正是在这一时期，疾病的发病被注意到了。在神经生物学水平上，这也可能是发育停滞的时期。最近，在RS患者中发现了MECP2的突变，它在基因表达的表观遗传调控中起作用。这一发现与脑脊液PEA的改变之间的联系应该得到澄清，特别是在疾病发病的早期阶段。少

项目成果

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Yamashita Y, Matsuishi T, Ishibashi M, et al.: "Decrease in benzodiazepine receptor binding in the brains of adult patients with Rett sundrome"J Neurol Sci. 154. 146-150 (1998)

Yamashita Y、Matsuishi T、Ishibashi M 等人：“雷特综合征成年患者大脑中苯二氮卓受体结合的减少”J Neurol Sci。