Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
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DOI：
10.1093/brain/awu142
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Vincent A
中科院分区：
文献类型：
--
作者：
Carvajal-González A;Leite MI;Waters P;Woodhall M;Coutinho E;Balint B;Lang B;Pettingill P;Carr A;Sheerin UM;Press R;Press R;Lunn MP;Lim M;Maddison P;Meinck HM;Vandenberghe W;Vincent A
参见Martinez-Martinez et al. (doi：）对这篇文章的科学评论。Carvajal-González等人描述了第一个甘氨酸受体抗体患者的前瞻性队列。大多数患有进行性脑脊髓炎，伴有强直和肌阵挛。抗体结合甘氨酸受体α1上的细胞外决定簇以及脊髓和脑干神经元上的甘氨酸受体。患者通过免疫疗法恢复良好。甘氨酸受体抗体的临床相关性尚未得到充分描述。我们前瞻性地确定了52例抗体阳性患者，并整理了他们的临床特征，调查和免疫治疗反应。血清甘氨酸受体抗体终点滴度范围为1：20至1：60 000。在11对样本中，血清水平高于（n = 10）或等于（n = 1）脑脊液水平;在6对中的每一对中都有甘氨酸受体抗体的鞘内合成，可用于详细研究。4名患者还具有高谷氨酸脱羧酶抗体（>1000 U/ml），1名患者具有高电压门控钾通道复合物抗体（2442 pM）。7例滴度极低（<1：50）和未知或替代诊断的患者被排除在进一步研究之外。其余45名患者中有3名患有新发现的胸腺瘤，1名患有淋巴瘤。33例患者被归类为进行性脑脊髓炎伴强直和肌阵挛，2例为僵直人综合征; 5例有边缘系统脑炎或癫痫性脑病，2例以脑干特征为主，2例有脱髓鞘性视神经病变，1例诊断不明确。4名患者（9%）在急性疾病期间死亡，但大多数患者在免疫治疗后表现出显着改善。在最近的随访中（2-7年，中位数3年，自首次抗体检测起），改良兰金量表评分中位数（不包括4例死亡）从最大严重程度时的5分降至1分（P < 0.0001），但5例患者发生复发，部分患者正在减少类固醇或其他维持免疫治疗以及对症治疗。甘氨酸受体抗体在室温下激活甘氨酸受体转染的人胚肾细胞上的补体，并在37°C下引起甘氨酸受体的内化和溶酶体降解。免疫球蛋白G抗体与啮齿动物脊髓和脑干结合，与甘氨酸受体α1单克隆抗体共定位。在56例僵硬人综合征和相关综合征患者的回顾性队列中，还确定了10例甘氨酸受体抗体阳性样本。甘氨酸受体抗体与脊髓和脑干疾病密切相关，大多数患者患有进行性脑脊髓炎伴强直和肌阵挛。抗体证明在体外证据的致病性和患者的免疫治疗反应良好，与此综合征的早期研究，这表明预后不良。甘氨酸受体抗体的存在应有助于确定对免疫疗法有反应的疾病，但这些治疗可能需要持续，可能会发生复发，可能需要维持免疫抑制。
See Martinez-Martinez et al. (doi:) for a scientific commentary on this article. Carvajal-González et al. describe the first prospective cohort of patients with glycine receptor antibodies. The majority have progressive encephalomyelitis with rigidity and myoclonus. The antibodies bind to extracellular determinants on glycine receptor-α1 and to glycine receptors on spinal cord and brainstem neurons. The patients make a good recovery with immunotherapies. The clinical associations of glycine receptor antibodies have not yet been described fully. We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses. Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000. In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study. Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM). Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study. Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma. Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis. Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies. At most recent follow-up, (2–7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments. The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37°C. Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-α1. Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes. Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus. The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis. The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required.
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影响因子：
3.3
作者：
Geis, Christian;Gruenewald, Benedikt;Sommer, Claudia
通讯作者：
Sommer, Claudia
DOI：
10.1093/brain/awq113
发表时间：
2010-06
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Irani SR;Bera K;Waters P;Zuliani L;Maxwell S;Zandi MS;Friese MA;Galea I;Kullmann DM;Beeson D;Lang B;Bien CG;Vincent A
通讯作者：
Vincent A
影响因子：
5.3
作者：
Hansen, Niels;Gruenewald, Benedikt;Geis, Christian
通讯作者：
Geis, Christian
影响因子：
48
作者：
Dalmau, Josep;Gleichman, Amy J.;Hughes, Ethen G.;Rossi, Jeffrey E.;Peng, Xiaoyu;Lai, Meizan;Dessain, Scott K.;Rosenfeld, Mynna R.;Balice-Gordon, Rita;Lynch, David R.
通讯作者：
Lynch, David R.
影响因子：
3.3
作者：
ARAKI, T;YAMANO, M;TOHYAMA, M
通讯作者：
TOHYAMA, M