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Table of Contents    
Year : 2013  |  Volume : 61  |  Issue : 3  |  Page : 226-230

Gluten ataxia of sporadic and hereditary cerebellar ataxia in patients from mainland China

1 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
2 Department of Neurology, Xiangya Hospital; State Key Laboratory of Medical Genetics of China; Neurodegenerative Disorders Research Center, Central South University, Changsha, Hunan, China
3 State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan, China

Date of Submission30-Nov-2012
Date of Decision01-Apr-2013
Date of Acceptance06-Jun-2013
Date of Web Publication16-Jul-2013

Correspondence Address:
Jun-Ling Wang
Department of Neurology, Xiangya Hospital, Central South University, Changsha - 410008, Hunan
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Source of Support: None, Conflict of Interest: None

PMID: 23860139

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 » Abstract 

Background: Gluten sensitivity (GS) is a spectrum of disorders with diverse manifestations. Recent evidence suggests that ataxia may be the only manifestation of GS and that it may be one of the causes of sporadic ataxia. Aim: To investigate the prevalence of gluten ataxia among patients with ataxia in China. Materials and Methods: Serum levels of anti-gliadin, anti-transglutaminase 2 (TG2), and anti-transglutaminase 6 (TG6) antibodies measured in 125 patients with ataxia (100 patients with sporadic ataxia and 25 patients with hereditary ataxia) and 51 healthy controls by enzyme-linked immunosorbent assay (ELISA). Results: The serum concentrations of anti-gliadin, anti-TG2 IgG, IgA, and TG6-IgG antibodies were elevated in ataxia patients, but the increase was not statistically significant. However, TG6-IgA serum levels were significantly higher in sporadic ataxia as compared to those in healthy controls (P < 0.05). Conclusions: These results provide evidence that sporadic ataxia in a subgroup of patients may be due to gluten ataxia in mainland China. Measurement of serum anti-TG6 antibodies along with anti-TG2 and anti-gliadin antibodies may be useful for diagnosing gluten ataxia.

Keywords: Cerebellar ataxia, gluten ataxia, gluten sensitivity, transglutaminase 6

How to cite this article:
Guan WJ, Liu XJ, Tang BS, Liu YT, Zhou Y, Jiang H, Shen L, Xia K, Wang JL. Gluten ataxia of sporadic and hereditary cerebellar ataxia in patients from mainland China. Neurol India 2013;61:226-30

How to cite this URL:
Guan WJ, Liu XJ, Tang BS, Liu YT, Zhou Y, Jiang H, Shen L, Xia K, Wang JL. Gluten ataxia of sporadic and hereditary cerebellar ataxia in patients from mainland China. Neurol India [serial online] 2013 [cited 2022 Nov 28];61:226-30. Available from: https://www.neurologyindia.com/text.asp?2013/61/3/226/115056

 » Introduction Top

Gluten sensitivity (GS) is a T cell-mediated autoimmune disease with multiorgan involvement, that is involving gastrointestinal system, central nervous system (CNS), skin, and endocrine, and it is characterized by intolerance to dietary gluten. The disease is strongly associated with certain human leucocyte antigen (HLA) class II alleles. [1] Neurological involvement occurs in 10-22.5% of cases. [2] Gluten ataxia is a form of sporadic cerebellar ataxia and is associated with circulating anti-gliadin antibodies. It is the most common neurological manifestation in GS and, most often, these patients do not have other organ involvement. [3] Recent classification of gluten-related disorders include allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis, and gluten ataxia), and possibly immune-mediated (GS) disorders. [4] Accumulating evidence suggests that gluten-mediated immune response is frequently associated with cerebellar ataxia.

In individuals with GS, often anti-gliadin antibodies are used to assess for coeliac disease. In 1996, Hadjivassiliou et al., had used serum anti-gliadin antibodies as a positive serological marker for gluten ataxia in patients with sporadic ataxia. [5] Recent evidence also indicates that auto-antibodies against either transglutaminase 2 (TG2), transglutaminase 6 (TG6), or both can be positive in 85% of patients with ataxia. [6],[7] GS can affect persons of many ethnic background, but rarely has it been reported in Asian countries. [8] A study in Taiwan found gluten ataxia among patients with sporadic ataxia; [9] however, there were no studies to find whether gluten ataxia is prevalent in mainland China among patients with cerebellar ataxia. Hence, in this study, we measured both TG and gliadin autoantibodies in patients with cerebellar ataxia in mainland China.

 » Materials and Methods Top

One hundred patients with sporadic cerebellar ataxia, 25 patients with hereditary cerebellar ataxia, and 51 age- and sex-matched healthy controls were recruited from Xiangya Hospital, Central South University between August 2007 and December 2011. To account for differences in genetic background and dietary lifestyle, all subjects were of Chinese Han ethnicity and mainly came from the Hunan, Hubei, Henan and Jiangxi provinces of China. All patients and controls underwent a standardized neurological examination by two neurologists. The criteria for the diagnosis of sporadic cerebellar ataxia included, [10] (1) progressive cerebellar ataxia with no symptomatic cause; (2) absence of family history of neurodegenerative disorder; and (3) negative genetic diagnosis for Friedreich's ataxia and spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, and SCA7). The exclusion criteria included, [11] (1) clinical or magnetic resonance imaging (MRI) features of multiple system atrophy, progressive myoclonic ataxia, fragile-X-associated syndrome, or mitochondrial encephalomyopathy; (2) exposure to alcohol or other toxins; (3) vitamin B12 or E deficiency; and (4) evidence of HIV, syphilis, prion disease, or Whipple disease. Hereditary ataxia subjects were genetically tested for SCA (including 4 SCA1, 3 SCA2, 16 SCA3, and 2 SCA7 patients). All patients underwent an assessment and rating of ataxia scores (SARA), international cooperative ataxia rating scale (ICARS) and a brain MRI scan. The study was approved by the Ethical Committee of the Xiangya Hospital of Central South University (China) and written informed consent was obtained from all patients and controls.

Fasting serum samples were collected from all the subjects early in the morning and stored at −80°C for further analysis. IgA/IgG antibodies against TG2, TG6, and gliadin were measured with a commercial enzyme-linked immunosorbent assay (ELISA) kit (Cusabio Biotech Co Ltd., Newark, DE, USA), following the manufacturer's instructions. The optical density (OD) of each well was determined at a wavelength of 450 nm. The sample was defined as positive when OD was 2.1-fold greater than the relevant negative sample provided by the ELISA kit. All samples were measured in duplicate.

Statistical analysis

Serum levels of anti-gliadin/TG2/TG6 antibodies were recorded as a mean of the OD values ± standard deviation. To compare the demographic characteristics and frequency of antibodies between groups, Chi-square test was used. A student's t-test and Mann-Whitney U test were applied to each OD value comparison between groups. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 13.0 for Windows (SPSS Inc., Chicago, USA).

 » Results Top

Clinical and demographic features of the patients and controls are shown in [Table 1]. Baseline characteristics between the groups were fairly similar.
Table 1: Demographics and clinical data of study participants

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Serum levels of anti-gliadin, anti-TG2, and anti-TG6 IgG/IgA antibodies are summarized in [Figure 1]. The difference in the serum levels of anti-gliadin IgG and IgA antibodies between sporadic ataxia patients and healthy controls was significant (IgG 0.44 ± 0.27 vs. 0.28 ± 0.083, P < 0.05; IgA 0.22 ± 0.10 vs. 0.16 ± 0.057; P < 0.05). There was also a significant difference in the serum anti-TG2 IgG and IgA antibody concentrations between sporadic ataxia patients and healthy controls (IgG 0.23 ± 0.11 vs. 0.17 ± 0.078, P < 0.05; IgA 0.21 ± 0.097 vs. 0.15 ± 0.055, P < 0.05). However, there was no significant difference in the concentration of anti-gliadin and TG2 IgG/IgA antibodies between sporadic and hereditary ataxia patients. The serum level of anti-TG6 IgA antibodies was significantly high in sporadic (0.23 ± 0.13 vs. 0.14 ± 0.069, respectively; P < 0.05) and hereditary ataxia patients (0.20 ± 0.093 vs. 0.14 ± 0.069, respectively; P < 0.05) as compared to healthy controls, but no apparent difference was observed between sporadic and hereditary ataxia groups. However, the serum level of anti-TG6 IgG antibodies did not significantly differ between ataxia patients and healthy controls (P > 0.05).
Figure 1: Serum levels of anti-TG2/TG6/gliadinIgG/IgA antibodies in healthy controls (n=51), sporadic ataxia (n=100), and hereditary ataxia (n=25). Each value above the bar indicates the value of mean of the OD values ± SD of the gluten related autoantibodies. (*P<0.05; **P<0.01; ***P<0.001 were determined by Mann– Whitney U-test)

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The prevalence of anti-gliadin/TG2/TG6 antibodies in the ataxia patients and healthy controls is summarized in [Table 2]. The frequency of positive anti-TG6 IgA antibodies was significantly different in sporadic ataxia patients and healthy controls (P < 0.05; df = 2; χ2 test), but no difference was observed between hereditary ataxia patients and healthy controls (P > 0.05; df = 2; χ2 test). However, we were unable to detect statistically significant differences in the prevalence of positive anti-TG2 and anti-gliadin IgA/IgG antibodies for any combination of the three groups. Similarly, there was no significant differences in the frequency of anti-TG6 IgG antibodies (P > 0.05; df = 2; χ2 test). We divided sporadic ataxia patients into two groups according to the prevalence of anti-TG6 IgA antibodies, and patient characteristics are listed in [Table 3]. We detected early onset of disease in patients positive for anti-TG6 IgA (36 ± 14 vs. 43 ± 18; P < 0.05).
Table 2: Prevalence of antibodies in ataxia patients and healthy controls

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Table 3: Characteristics of sporadic ataxia subjects with and without positive findings of anti‑TG6 IgA

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 » Discussion Top

This study for the first time attempted to find the pevelance of gluten ataxia among patients with hereditary ataxia and sporadic ataxia in mainland China. The first serologic test of anti-gliadin antibodies for GS was developed in the early 1980s, [12] but over the past several years, anti-endomysial antibody (EMA), anti-TG2, and anti-deamidatedgliadin peptide (anti-GDP) assays have also been used for the diagnosis of gluten ataxia. Because of low specificity and sensitivity of anti-gliadin antibody assays, positive serology of these antibodies alone may not be useful for diagnosing gluten ataxia. [7] Also, some studies have suggested that anti-gliadin antibodies may not provide adequate major serologic evidence for gluten ataxia. [13] Based on these observations, we explored whether detection of all these antibodies can identify all gluten ataxia patients in the general population and whether TG6 antibodies can serve as a useful biomarker for identifying gluten ataxia. The observations in this study demonstrated a strong association between OD values of anti-gliadin, anti-TG2, anti-TG6 antibodies, and sporadic ataxia in mainland China, thus suggesting the prevalence of gluten ataxia in China, which is in agreement with that in western as well as Japanese studies. [14],[15],[16],[17],[18] Although the use of anti-gliadin antibody testing has become somewhat controversial in the diagnosis of gluten ataxia in recent years, [19] our results were in-line with the traditional view that anti-gliadin antibody testing is essential at the first presentation of sporadic ataxia. [3] Only the levels of anti-TG6 IgA antibodies were significantly different between sporadic ataxia and healthy controls, which indicated that anti-TG6 IgA was the only marker with high sensitivity and specificity. These results suggest an unknown correlation between gluten ataxia and cerebellar ataxia. It is possible that gluten, as a substrate of TG6, may accelerate the autoimmune response process of cerebellar ataxia or anti-TG6 antibodies may be a secondary effect of neuronal damage, rather than being pathogenic. [11]

In our previous study, we identified TG6 as a novel causative gene of SCA by exome sequencing. [20] TG6 is predominantly expressed by a subset of neurons in the central nervous system and deposits of the gene product are present in the cerebellum of patients with gluten ataxia. [8] Although the exact role of TG6 in gluten ataxia remains unclear, growing evidence indicates that antibodies against TG6 could serve as a biomarker to identity a subgroup of patients with GS in addition to conventional anti-gliadin and anti-TG2 antibodies. [6],[11] Our study found that anti-TG6 IgA antibodies, but not anti-TG6 IgG antibodies seem more useful for diagnosing gluten ataxia. Previous studies have found variable prevalence of the these antibodies when evaluated in different assays for gluten ataxia, which may be due to geographical or genetic background differences, variability of the serological assays, or the use of different study samples. [11],[17],[21],[22],[23],[24] Therefore, in future studies, we plan to analyze a larger patient cohort in order to confirm these findings.

In conclusion, our study found that cerebellar ataxia may occur in a subset of patients due to gluten ataxia in mainland China. Moreover, in order to improve the accuracy of gluten ataxia diagnosis, measurement of anti-TG6 antibodies in combination with anti-TG2 and anti-gliadin antibodies may be useful for diagnosing cerebellar ataxia. A gluten-free diet can be considered in these patients in order to improve their neurological symptoms. Because no patients in this study had gastrointestinal symptoms, additional enteroscopy tests or intestinal biopsies were not conducted. Therefore, these patients still require long-term follow-up studies by serial serology and clinical observation.

 » Acknowledgment Top

This work was supported by Grant 2011CB510001 from the Major State Basic Research Development Program of China (973 Program) (to Dr. Bei-sha Tang), Grant 81130021 from the Major Program of National Natural Science Foundation of China (to Dr. Bei-sha Tang), and Grant 2012QNZT107 from the Fundamental Research Funds for the Central Universities of China (to Dr. Jun-ling Wang). The authors would like to thank all of the patients and control subjects for their participation in this study.

 » References Top

1.Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, Davies-Jones GA, Gibson A, Jarratt JA, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998;352:1582-5.  Back to cited text no. 1
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3.Hadjivassiliou M, Grünewald R, Sharrack B, Sanders D, Lobo A, Williamson C, et al. Gluten ataxia in perspective: Epidemiology, genetic susceptibility and clinical characteristics. Brain 2003;126:685-91.  Back to cited text no. 3
4.Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, et al. Spectrum of gluten-related disorders: Consensus on new nomenclature and classification. BMC Med 2012;10:13.  Back to cited text no. 4
5.Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996;347:369-71.  Back to cited text no. 5
6.Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol 2008;64:332-43.  Back to cited text no. 6
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14.Hadjivassiliou M, Boscolo S, Tongiorgi E, Grünewald RA, Sharrack B, Sanders DS, et al. Cerebellar ataxia as a possible organ-specific autoimmune disease. Mov Disord 2008;23:1370-7.  Back to cited text no. 14
15.Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P. Idiopathic cerebellar ataxia associated with celiac disease: Lack of distinctive neurological features. J Neurol Neurosurg Psychiatry 1999;66:32-5.  Back to cited text no. 15
16.Ihara M, Makino F, Sawada H, Mezaki T, Mizutani K, Nakase H, et al. Gluten sensitivity in Japanese patients with adult-onset cerebellar ataxia. Intern Med 2006;45:135-40.  Back to cited text no. 16
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20.Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain 2010;133:3510-8.  Back to cited text no. 20
21.Lindfors K, Koskinen O, Laurila K, Collin P, Saavalainen P, Haimila K, et al. IgA-class autoantibodies against neuronal transglutaminase, TG6 in celiac disease: no evidence for gluten dependency. Clin Chim Acta 2011;412:1187-90.  Back to cited text no. 21
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23.Lewis NR, Scott BB. Meta-analysis: Deamidated gliadin peptide antibody and tissue transglutaminase antibody compared as screening tests for coeliac disease. Aliment Pharmacol Ther 2010;31:73-81.  Back to cited text no. 23
24.Rostom A, Dubé C, Cranney A, Saloojee N, Sy R, Garritty C, et al. The diagnostic accuracy of serologic tests for celiac disease: A systematic review. Gastroenterology 2005;128:S38-46.  Back to cited text no. 24


  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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