Chen Bee C, Balasubramaniam Shanti, McGown Ivan N, O'Neill J Patrick, Chng Gaik S, Keng Wee T, Ngu Lock H, Duley John A
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia.
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia; Metabolic Unit, Department of Pediatric and Adolescent Medicine, Princess Margaret Hospital, 6008 Perth, Western Australia.
Brain Dev. 2014 Aug;36(7):593-600. doi: 10.1016/j.braindev.2013.08.013. Epub 2013 Sep 18.
Lesch-Nyhan disease (LND) is a rare X-linked recessive neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) which is responsible for recycling purine bases into purine nucleotides. Affected individuals have hyperuricemia leading to gout and urolithiasis, accompanied by a characteristic severe neurobehavioural phenotype with compulsive self-mutilation, extrapyramidal motor disturbances and cognitive impairment.
For its theoretical therapeutic potential to replenish the brain purine nucleotide pool, oral supplementation with S-adenosylmethionine (SAMe) was trialed in 5 Malaysian children with LND, comprising 4 related Malay children from 2 families, including an LND girl, and a Chinese Malaysian boy.
Dramatic reductions of self-injury and aggressive behaviour, as well as a milder reduction of dystonia, were observed in all 5 patients. Other LND neurological symptoms did not improve during SAMe therapy.
Molecular mechanisms proposed for LND neuropathology include GTP depletion in the brain leading to impaired dopamine synthesis, dysfunction of G-protein-mediated signal transduction, and defective developmental programming of dopamine neurons. The improvement of our LND patients on SAMe, particularly the hallmark self-injurious behaviour, echoed clinical progress reported with another purine nucleotide depletion disorder, Arts Syndrome, but contrasted lack of benefit with the purine disorder adenylosuccinate lyase deficiency. This first report of a trial of SAMe therapy in LND children showed remarkably encouraging results that warrant larger studies.
莱施-奈恩病（LND）是一种罕见的X连锁隐性神经遗传疾病，由嘌呤补救酶次黄嘌呤磷酸核糖转移酶（HPRT，EC 2.4.2.8）缺乏引起，该酶负责将嘌呤碱基循环利用为嘌呤核苷酸。受影响的个体患有高尿酸血症，导致痛风和尿路结石，同时伴有特征性的严重神经行为表型，包括强迫性自残、锥体外系运动障碍和认知障碍。
鉴于其在补充脑嘌呤核苷酸池方面的理论治疗潜力，对5名马来西亚LND儿童进行了口服补充S-腺苷甲硫氨酸（SAMe）的试验，其中包括来自2个家庭的4名有亲缘关系的马来儿童（包括1名LND女孩）和1名华裔马来西亚男孩。
所有5名患者的自残和攻击行为均显著减少，肌张力障碍也有较轻微的减轻。在SAMe治疗期间，其他LND神经症状未得到改善。
LND神经病理学提出的分子机制包括大脑中GTP耗竭导致多巴胺合成受损、G蛋白介导的信号转导功能障碍以及多巴胺神经元发育编程缺陷。我们的LND患者在SAMe治疗后有所改善，尤其是标志性的自残行为，这与另一种嘌呤核苷酸耗竭性疾病——阿茨综合征报告的临床进展相呼应，但与嘌呤疾病腺苷琥珀酸裂解酶缺乏症缺乏疗效形成对比。这份关于LND儿童SAMe治疗试验的首次报告显示了非常令人鼓舞的结果，值得进行更大规模的研究。
