Neuromuscular Service, Department of Neurology, Tel Aviv Medical Center, Tel Aviv, Israel.
Clinical Immunology Laboratory, Tel Aviv Medical Center, Tel Aviv, Israel.
JAMA Neurol. 2015 Jun;72(6):676-81. doi: 10.1001/jamaneurol.2015.48.
Celiac disease is an autoimmune disorder triggered by gluten in genetically predisposed individuals. Gluten sensitivity can cause neurologic manifestations, such as ataxia or neuropathy, with or without gastrointestinal symptoms. Many patients with gluten ataxia produce antibodies toward the newly identified neuronal transglutaminase 6 (TG6). Two case reports described patients initially diagnosed with amyotrophic lateral sclerosis (ALS) and ultimately with celiac disease who improved with a strict gluten-free diet.
To evaluate the prevalence of celiac disease-related antibodies and HLA antigen alleles, as well as TG6 antibodies, in patients with ALS and healthy individuals serving as controls to determine whether a neurologic presentation of a gluten-related disorder mimicking ALS might occur in some patients.
DESIGN, SETTING, AND PARTICIPANTS: In a case-control study conducted in an ALS tertiary center, we measured serum levels of total IgA antibodies, IgA antibodies to transglutaminase 2 (TG2) and endomysium, as well as IgA and IgG antibodies to deamidated gliadine peptide and TG6 and performed HLA antigen genotyping in 150 consecutive patients with ALS and 115 healthy volunteers of similar age and sex. Participants did not have any known autoimmune or gastroenterologic disorder and were not receiving any immunomodulatory medications. The study was conducted from July 1, 2010, to December 31, 2012.
Antibody levels and frequency of individuals with abnormal antibody values as well as frequency of HLA antigen alleles were compared between patient and control groups.
All patients and control group participants were seronegative to IgA antibodies to TG2, endomysium, and deamidated gliadine peptide. Twenty-three patients (15.3%) were seropositive to TG6 IgA antibodies as opposed to only 5 controls (4.3%) (P = .004). The patients seropositive for TG6 showed a classic picture of ALS, similar to that of seronegative patients. Fifty patients and 20 controls were tested for celiac disease-specific HLA antigen alleles; 13 of 22 TG6 IgA seropositive individuals (59.1%) were seropositive for celiac disease-related alleles compared with 8 (28.6%) of the 28 seronegative individuals (P = .04). Mean (SD) levels of IgA antibodies to TG2 were 1.78 (0.73) in patients and 1.58 (0.68) in controls (normal, <10). In a subset of study participants, mean levels of deamidated gliadin peptide autoantibodies were 7.46 (6.92) in patients and 6.08 (3.90) in controls (normal, <16). Mean levels of IgA antibodies to TG6 were 29.3 (30.1) in patients and 21.0 (27.4) in controls (P = .02; normal, <26).
The data from this study indicate that, in certain cases, an ALS syndrome might be associated with autoimmunity and gluten sensitivity. Although the data are preliminary and need replication, gluten sensitivity is potentially treatable; therefore, this diagnostic challenge should not be overlooked.
乳糜泻是一种自身免疫性疾病，由遗传易感性个体中的麸质触发。麸质敏感性可引起神经病学表现，如共济失调或神经病，伴有或不伴有胃肠道症状。许多乳糜泻患者会产生针对新鉴定的神经元转谷氨酰胺酶 6（TG6）的抗体。两项病例报告描述了最初被诊断为肌萎缩侧索硬化症（ALS）最终被诊断为乳糜泻的患者，这些患者通过严格的无麸质饮食得到了改善。
评估乳糜泻相关抗体和 HLA 抗原等位基因以及 TG6 抗体在 ALS 患者和作为对照的健康个体中的患病率，以确定某些患者是否可能出现类似 ALS 的与麸质相关疾病的神经表现。
设计、地点和参与者：在 ALS 三级中心进行的病例对照研究中，我们测量了 150 例连续 ALS 患者和 115 名年龄和性别相似的健康志愿者的总 IgA 抗体、IgA 抗体转谷氨酰胺酶 2（TG2）和内肌膜以及 IgA 和 IgG 抗体脱酰胺谷氨酰胺肽和 TG6 的血清水平，并进行了 HLA 抗原基因分型。参与者没有任何已知的自身免疫或胃肠疾病，也没有服用任何免疫调节药物。该研究于 2010 年 7 月 1 日至 2012 年 12 月 31 日进行。
比较了患者组和对照组之间抗体水平和个体异常抗体值的频率以及 HLA 抗原等位基因的频率。
所有患者和对照组参与者的 IgA 抗体 TG2、内肌膜和脱酰胺谷氨酰胺肽均为阴性。23 名患者（15.3%）对 TG6 IgA 抗体呈阳性，而仅 5 名对照者（4.3%）呈阳性（P = 0.004）。对 TG6 呈阳性的患者表现出典型的 ALS 表现，与阴性患者相似。50 名患者和 20 名对照者接受了乳糜泻特异性 HLA 抗原等位基因检测；22 名 TG6 IgA 阳性者中有 13 名（59.1%）为乳糜泻相关等位基因阳性，而 28 名阴性者中仅有 8 名（28.6%）（P = 0.04）。患者组的 TG2 IgA 抗体平均（SD）水平为 1.78（0.73），对照组为 1.58（0.68）（正常，<10）。在研究参与者的亚组中，脱酰胺谷氨酰胺肽自身抗体的平均水平为 7.46（6.92）在患者和 6.08（3.90）在对照组（正常，<16）。患者组的 TG6 IgA 抗体平均水平为 29.3（30.1），对照组为 21.0（27.4）（P = 0.02；正常，<26）。
本研究的数据表明，在某些情况下，ALS 综合征可能与自身免疫和麸质敏感性有关。尽管数据是初步的，需要复制，但麸质敏感性是潜在可治疗的；因此，不应忽视这种诊断挑战。
