20 Apr 2015

Could the treatment for the untreatable—that is, motor neuron disease—be as simple as, “Hold the bread”? Vivian Drory and colleagues at the Tel Aviv Sourasky Medical Center in Israel suggest that gluten sensitivity might masquerade as amyotrophic lateral sclerosis in a rare subset of cases. In the April 13 JAMA Neurology, they report that some people diagnosed with ALS generate antibodies to an enzyme that processes gluten, a protein found in wheat, barley, and rye. These autoantibodies may be a sign of neurological gluten sensitivity, which is not the same as the classical celiac disease in which an inappropriate immune response to gluten inflames the gut. While the observational data reported here are preliminary, they imply that a small proportion of people diagnosed with ALS might instead have a problem with gluten. Importantly, this would be treatable, said first author Beatrice Nefussy.

Other scientists contacted by Alzforum were skeptical about a link between gluten and this motor neuron disease. One recent study reported no evidence of higher ALS rates among nearly 30,000 people with celiac disease (Ludvigsson et al., 2014). Michael Swash of Royal London Hospital was unconvinced that avoiding gluten could treat motor neuron symptoms. “I think it is the wrong way to go,” he said. “There is no evidence whatsoever to think that would have any benefit.”

Drory’s interest in gluten was piqued by a patient with ALS who was recently diagnosed with celiac disease. Delving into the scientific literature for any link between the two illnesses, co-first author Avi Gadoth noticed two case reports of something that looked like clinical ALS but turned out to be celiac disease (Turner et al., 2007; Brown et al., 2010). In each case, switching to a gluten-free diet halted progression and improved the symptoms. The diet switch could not completely reverse the movement problems, since axon damage had already occurred. “The recovery was very substantial,” wrote one of those case study authors, Kevin Talbot of the University of Oxford in the U.K., in an email to Alzforum. “Our case is merely evidence that gluten sensitivity can damage the central nervous system,” he wrote. “It does not support any relationship between gluten intolerance and ALS.”

Drory wondered if any other ALS patients at her medical center might have gluten sensitivity. “We knew chances were slim, but we thought if even one in 100 [cases] turns out to be celiac disease, maybe we can save them,” Nefussy said. The authors tested serum samples from 150 people with ALS and 115 healthy volunteers for celiac disease, using enzyme-linked immunosorbent assays (ELISAs) for antibodies to gluten peptides and to the enzyme transglutaminase 2 (TG2).  When transglutaminases process gluten they make it more immunogenic. Celiac patients generate autoantibodies to gluten and to TG2 (Di Sabatino et al., 2012). Only one person, a control, had TG2 antibodies. Nefussy suspects this person had undiagnosed celiac disease. One person in the ALS group had antibodies to gluten, but not TG2.

Because not all gluten sensitivity manifests as celiac disease, the researchers broadened their study to cover a new entity called non-celiac gluten sensitivity. NCGS has emerged as a sort of catchall to describe people who have trouble with gluten, but do not have the celiac-associated antibodies or a wheat allergy. Researchers have linked NCGS to a variety of neurological manifestations, including ataxia, autism, and schizophrenia (Genuis and Lobo, 2014). Swash noted that the concept of NCGS remains speculative, and no one has worked out how gluten might lead to neurological pathology. Drory agreed that it has not been confirmed that all of these neurological syndromes are a direct result of gluten sensitivity, rather than a chance occurrence of both neurological disease and gluten sensitivity in one person.

To look for evidence of NCGS, Nefussy focused on a different version of transglutaminase, TG6. She suspected it might be related to NCGS because it is mainly expressed in the brain, rather than the intestine (Liu et al., 2013). Previously, researchers found anti-TG6 antibodies in what has been described as gluten ataxia. The TG6 antibody titer paralleled the amount of gluten the patient ate, indicating the gluten induced the autoimmune reaction (Hadjivassiliou et al., 2008). Mutations in TG6 have also been linked to spinocerebellar ataxia in China (Wang et al., 2010; Li et al., 2013). However, the relationship between neurological symptoms and gluten sensitivity has been contested.  TG6 antibodies did not help identify people with neurological symptoms, and antibody levels did not correlate with gluten intake in one study (Lindfors et al., 2011).

In Drory’s study, ELISAs indicated that 23 people with ALS had TG6 antibodies, including the person who had anti-gluten antibodies. Clinically, there was no difference between these people and the others in the study, the authors reported. “We might diagnose ALS, but some of these patients could have an ALS disease mimic that is autoimmune-mediated,” speculated Drory in an email to Alzforum. That is, the autoimmune response to TG6 might damage motor neurons the same way the anti-TG2 response attacks the intestine lining.

Swash suggested that, more likely, neurons damaged by ALS release transglutaminase, stimulating an immune response. Others have also suggested transglutaminase leaking from the spinal cord to the bloodstream as a potential marker for tissue damage in ALS (Fujita et al., 1998).

Drory's group found that five control participants had TG6 antibodies, as well. The authors were not sure how to interpret this finding, but conjectured they might develop neurological symptoms in the future.

Scientists have not assessed transglutaminase antibodies in other neurodegenerative diseases, though they have studied the enzymes themselves. Transglutaminase was upregulated in the hippocampuses of people who died of Alzheimer’s (Appelt et al., 1996). Some researchers have suggested the enzyme might crosslink proteins such as Aβ, tau, huntingtin, and α-synuclein, contributing to their aggregation (reviewed in Jeitner et al., 2009).

Nefussy and colleagues reasoned that if anyone with TG6 antibodies did have NCGS, avoiding gluten should help. They offered those patients assistance in going gluten-free. Unfortunately, by the time they had the ELISA results, most of those people had died and the others had progressed to a late stage of disease. Nefussy does not believe the diet would have helped because much neuronal damage had already been done. In a new prospective trial, she aims to enroll people in earlier stages of ALS who test positive for TG6 antibodies, and start them on a gluten-free diet. The treatment will include strict supervision by a nutritionist, Nefussy said. People with ALS often have poor appetites and difficulty chewing and swallowing, so getting sufficient calories is already a challenge.

In past years, the topic of gluten sensitivity and celiac disease has generated some discussion in the ALS chatroom of PatientsLikeMe. ALS patients who were gluten sensitive or had celiac disease shared there that going on a gluten-free diet did not affect their ALS symptoms. Some noted that their overall health improved, others reported unwanted weight loss. Curiously, however, Stephen Hawking, who at 73 exemplifies long-term survival with an unusual form of ALS, is reported to follow a gluten-free diet.—Amber Dance

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Ludvigsson JF, Mariosa D, Lebwohl B, Fang F. No association between biopsy-verified celiac disease and subsequent amyotrophic lateral sclerosis--a population-based cohort study. Eur J Neurol. 2014 Jul;21(7):976-82. Epub 2014 Apr 7 PubMed.
2. Turner MR, Chohan G, Quaghebeur G, Greenhall RC, Hadjivassiliou M, Talbot K. A case of celiac disease mimicking amyotrophic lateral sclerosis. Nat Clin Pract Neurol. 2007 Oct;3(10):581-4. PubMed.
3. Brown KJ, Jewells V, Herfarth H, Castillo M. White matter lesions suggestive of amyotrophic lateral sclerosis attributed to celiac disease. AJNR Am J Neuroradiol. 2010 May;31(5):880-1. Epub 2009 Nov 12 PubMed.
4. Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR. The function of tissue transglutaminase in celiac disease. Autoimmun Rev. 2012 Aug;11(10):746-53. Epub 2012 Feb 3 PubMed.
5. Genuis SJ, Lobo RA. Gluten sensitivity presenting as a neuropsychiatric disorder. Gastroenterol Res Pract. 2014;2014:293206. Epub 2014 Feb 12 PubMed.
6. Liu YT, Tang BS, Lan W, Song NN, Huang Y, Zhang L, Guan WJ, Shi YT, Shen L, Jiang H, Guo JF, Xia K, Ding YQ, Wang JL. Distribution of transglutaminase 6 in the central nervous system of adult mice. Anat Rec (Hoboken). 2013 Oct;296(10):1576-87. Epub 2013 Jul 8 PubMed.
7. Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008 Sep;64(3):332-43. PubMed.
8. Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, Jiang H, Zhang P, Shen L, Guo JF, Li N, Li YR, Lei LF, Zhou J, Du J, Zhou YF, Pan Q, Wang J, Wang J, Li RQ, Tang BS. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain. 2010 Dec;133(Pt 12):3510-8. Epub 2010 Nov 23 PubMed.
9. Li M, Pang SY, Song Y, Kung MH, Ho SL, Sham PC. Whole exome sequencing identifies a novel mutation in the transglutaminase 6 gene for spinocerebellar ataxia in a Chinese family. Clin Genet. 2013 Mar;83(3):269-73. Epub 2012 May 29 PubMed.
10. Lindfors K, Koskinen O, Laurila K, Collin P, Saavalainen P, Haimila K, Partanen J, Mäki M, Kaukinen K. IgA-class autoantibodies against neuronal transglutaminase, TG6 in celiac disease: no evidence for gluten dependency. Clin Chim Acta. 2011 Jun 11;412(13-14):1187-90. Epub 2011 Mar 29 PubMed.
11. Fujita K, Honda M, Hayashi R, Ogawa K, Ando M, Yamauchi M, Nagata Y. Transglutaminase activity in serum and cerebrospinal fluid in sporadic amyotrophic lateral sclerosis: a possible use as an indicator of extent of the motor neuron loss. J Neurol Sci. 1998 Jun 11;158(1):53-7. PubMed.
12. Appelt DM, Kopen GC, Boyne LJ, Balin BJ. Localization of transglutaminase in hippocampal neurons: implications for Alzheimer's disease. J Histochem Cytochem. 1996 Dec;44(12):1421-7. PubMed.
13. Jeitner TM, Pinto JT, Krasnikov BF, Horswill M, Cooper AJ. Transglutaminases and neurodegeneration. J Neurochem. 2009 May;109 Suppl 1:160-6. PubMed.

External Citations

1. PatientsLikeMe
2. gluten-free diet

Further Reading

Papers

1. Oono M, Okado-Matsumoto A, Shodai A, Ido A, Ohta Y, Abe K, Ayaki T, Ito H, Takahashi R, Taniguchi N, Urushitani M. Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 1. J Neurochem. 2013 Aug 30; PubMed.
2. Turner MR, Goldacre R, Ramagopalan S, Talbot K, Goldacre MJ. Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study. Neurology. 2013 Oct 1;81(14):1222-5. Epub 2013 Aug 14 PubMed.

News

1. ALS: T Cells Step Up 19 Sep 2009
2. Microglia in ALS: Helpful, Harmful, or Neutral? 10 Oct 2008