title: Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Neuromuscular Service, Department of Neurology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Avi
authors: A
authors: Gadoth
authors: Neuromuscular Service, Department of Neurology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Beatrice
authors: B
authors: Nefussy
authors: Clinical Immunology Laboratory, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Margalit
authors: M
authors: Bleiberg
authors: Tissue Typing Laboratory, Rabin Medical Center, Petach Tikva, Israel4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Tirza
authors: T
authors: Klein
authors: Neuromuscular Service, Department of Neurology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Irena
authors: I
authors: Artman
authors: Neuromuscular Service, Department of Neurology, Tel Aviv Medical Center, Tel Aviv, Israel4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Vivian E
authors: VE
authors: Drory
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D019204:GTP-Binding Proteins / Q000276:immunology; D005983:Glutens / Q000276:immunology; D015234:HLA-A Antigens / Q000097:blood / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D015234:HLA-A Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; C532876:TGM6 protein, human; D011503:Transglutaminases; D019204:GTP-Binding Proteins