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1. What does “ataxia” mean?
The term “ataxia” refers to disorders of movement coordination: Movements are carried out to a wrong extent or in a less coordinated manner. Muscle strength is not primarily affected in most cases.
2. Causes of Ataxia?
Since many parts of the nervous system are involved in movement coordination, ataxia may have many causes. However, as the cerebellum is especially involved in movement coordination, diseases of the cerebellum are the cause of ataxia in many cases.
In recent years, evidence is increasing that the immune system might be involved in the development of ataxia.
3. „Gluten-Ataxia“
A special case of immunologically induced ataxia is the so-called “Gluten Ataxia”. As the name implies, in this form of ataxia the cereal protein “gluten” is involved in the pathogenesis as an external trigger (“external factor”); more specifically it is the gluten component “gliadin”.
“Celiac Disease”(CD) is widely known as a gluten-dependent disease. It is characterized by chronic inflammation of the small intestine upon gluten ingestion.
In about 10% of CD patients neurological symptoms are also observed, in many cases as ataxia (“Gluten Ataxia”).
On the other hand, there are also cases where Gluten Ataxia is observed as the only symptom, i.e. without the CD-defining alterations of the small intestinal mucosa.
4. Which antibodies are responsible for Gluten Ataxia?
In recent years, evidence was found that antibodies to a body-specific enzyme, namely transglutaminase 6 (TG6), may be responsible for Gluten Ataxia. Since these antibodies are directed against a body-specific structure (“auto-antigen”), they are referred to as “auto-antibodies”.
In a recent publication De Leo and colleagues (2017) provide evidence that the development of anti-transglutaminase 6 antibody development in children with celiac disease correlates with duration of gluten exposure.
5. What is the scientific evidence for a relationship between auto-antibodies against transglutaminase 6 and gluten ataxia?
There are numerous indications suggesting a link. In a publication in 2008, Hadjivassiliou and colleagues analyzed brain biopsies of CD patients with ataxia and found antibody (type IgA) deposits in the cerebellum. These deposits contained transglutaminase 6.
They concluded: “Antibodies to transglutaminase 6 can serve as a marker … to identify a subgroup of patients with gluten sensitivity.”
In a study published in 2013 by the same group (Hadjivassiliou et al., 2013), these findings were extended and it was found that “Antibodies against TG6 are gluten-dependent and appear to be a sensitive and specific marker of GA (Gluten Ataxia)”.
Furthermore, it was shown that the anti-TG6 antibody level decreased significantly under a gluten-free diet: „We have also demonstrated for the first time that TG6 antibodies are gluten-dependent based on the observation that the TG6 antibody titer significantly reduces within a year of adherence to a gluten-free diet.”
In 2016, Hadjivassiliou and colleagues reported that neurological symptoms in the sense of ataxia together with anti-transglutaminase 6 antibodies are also detectable in “Non-Coeliac Gluten Sensitivity”. They compared patients with neurological symptoms who were diagnosed either with classic Celiac Disease or with “Non-Celiac Gluten Sensitivity”. They found: “Serological positivity for TG6 antibodies was similar in the two groups (67 and 60 %)”.
And they concluded: “The neurological manifestations of CD [Coeliac Disease] and NCGS [Non-Coeliac Gluten-Sensitivity] are similar and equally responsive to a GFD [gluten-free diet].”
As far as auto-antibody diagnostics are concerned, the authors write: “Currently, the best approach is to include all serological testing (anti-TG2, anti-TG6, anti-endomysium antibodies, AGA [Anti-Gliadin Antibodies]) for patients suspected of having GRD [Gluten-Related Diseases].”
As far as the biological activity of anti-transglutaminase 6 antibodies is concerned, the study of Boscolo and colleagues (2010) is of interest: in a mouse model it was shown that antibodies against transglutaminase can trigger ataxia symptoms.
Anti-transglutaminase 6 antibodies were also found in a number of other neurological disorders:
(i) In children with poliomyelitis (Stenberg et al., 2014): “Early brain injury and associated inflammation may predispose to future development of TG6 autoimmunity.”
(ii) In schizophrenic patients (Cascella et al., 2012): “Our results suggest a higher prevalence of TG6 antibodies in SZ [schizophrenia] SZ patients who would benefit from a gluten-free diet. ”
(iii) In Amyotrophic Lateral Sclerosis (Gadoth et al., 2015): “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. 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.”
In a recent publication Zis and colleagues (2017) provide evidence that anti-TG6 antibodies are also observed in periperhal neuropathies.
6. The importance of anti-TG6 antibody determination in the differential diagnosis of ataxia
In the light of the above-mentioned context the determination of the anti-TG6 antibodies for the differential diagnosis of ataxia symptoms appears to be justified.
This is also independent of a diagnosis of a classic celiac disease with the disease-defining alterations of the small intestine (Hadjivassiluou et al., 2016). More information on “non-celiac gluten hypersensitivity” can be found in the next section.
A further justification for testing is due to the therapeutic consequence, since gluten-ataxia improves under a gluten-free diet (Hadjivassiliou et al., 2016)
7. Revisited: Pathogenesis and antibody diagnostics of classical Celiac Disease (CD; “Gluten-sensitive Enteropathy”)
There is a special aspect in the pathogenesis of celiac disease: an “external factor”, namely the grain component “gluten” (in particular “gliadin” from wheat) induces an immune reaction that is directed against a self-antigen, namely against the so-called “tissue transglutaminase (TG2)”.
In the beginning, “Celiac Disease” was described on the basis of its clinical features: namely enteric symptoms that were provoked by the consumption of cereal products and improved when the patients refrained from consumption of such products. This dependence on consumption of cereal products was the basis for disease definition and diagnosis. Later, the histologically detectable alterations in the mucosa, i.e. villous atrophy, crypt hyperplasia, and mucosal lymphocytic infiltration, were added to the disease-defining parameters.
Even later, the trigger could be defined at the molecular level: the grain component “gluten”. Therefore, the term “Gluten-sensitive Enteropathy” was coined.
Nowadays, the pathomechanism is known more precisely: the gluten component gliadin is chemically changed (deamidated) by the body’s own TG2, resulting in deamidated gliadin peptides (DGP). DGP induce an immune reaction, amongothers against the body`s own enzyme “TG2”; the immune reaction is then responsible for the pathological changes and clinical manifestations. Auto-antibodies against the self-antigen TG2 and DGP today are the major serologic biomarkers for Celiac Disease.
In Celiac Disease, involvement of other organ systems, especially in the nervous system and in the skin, is well known.
The diagnostic procedure for patients with suspected celiac disease is defined in guidelines, e.g. in the guidelines of the “American College of Gastroenterology“.
Without addressing this guideline in detail, it is important to note that in addition to a biopsy of the small intestine, with detection of the typical histological changes (“gluten enteropathy”) antibody detection is an important element of the diagnostic work-up. The antibody diagnostics are used both in the initial diagnosis and for evaluation of disease activity upon treatment.
Depending on the exact diagnostic requirements, the testing for the following antibody specificities is relevant:
- IgA or IgG autoantibodies against tissue transglutaminase
(tTG, transglutaminase 2, TG2) - Endomysium antibody (EmA)
- IgG antibodies against the gluten component gliadin;
More specifically the “deamidated gliadin peptide”
Further diagnostic procedures are (i) the determination of the total IgA in serum (to exclude a frequent IgA deficiency), and (ii) the determination of the HLA-DQ2 and DQ8 genotype, as these genotypes are linked with CD.
For historical reasons, an immunofluorescence test to detect so-called “anti-endomysium” antibodies is also recommended.
In the case of extraintestinal symptoms, antibody detection against other isoforms of transglutaminase is recommended: antibodies against transglutaminase 3 (isoform of transglutaminase in the skin, Sardy et al 2002) and antibodies against transglutaminase 6 (isoform of transglutaminase in the central nervous system, in particular in the cerebellum, see above).
In dermatological manifestations, there is also the option for immunohistological examination of a skin biopsy: in positive cases, IgA deposits are found in lesional and non-lesional skin.
A biopsy is not feasible for the diagnostic work-up of neurological manifestations so that in these cases the detection of antibodies in the serum is the sole option.
Antibody diagnostics against TG6 and TG3 are of particular diagnostic importance, since – as mentioned above – gluten-dependent diseases can also occur without the characteristic enteropathy (villous atrophy, cellular infiltrate). Furthermore, the antibody diagnostics also plays a role in the follow-up, since antibody titers decline upon appropriate antigenic abstinence. These diseases can affect various organ systems and are referred to collectively as “non-celiac gluten sensitivity” (NCGS). The NCGS is currently the subject of intensive research.
A third disease caused by wheat components, the IgE-mediated “wheat allergy” is not discussed here.
8. Non-Celiac Gluten-Sensitivity“ (NCGS)
A good definition of “Non-Celiac Gluten Sensitivity” (NCGS) was given in a publication by Czaja-Bulsa (2013): “NCGS is characterized by symptoms that usually occur soon after gluten ingestion, disappear with gluten withdrawal and relapse following gluten challenge (….). Patients suffering from NCGS are a heterogeneous group, composed of several sub groups each characterized by different pathogenesis and clinical course.”
The acronym “NCGS” is used in the following.
Currently NCGS is target of intensive research; see for example: Czaja-Bulsa (2015), Asiz and Sanders (2012), Catassi et al. (2013), as well as Mansueto et al. (2014).
The clinical manifestation of the NCGS is manifold and non-specific: from chronic head, joint and muscle pain, muscle contractions, numbness in the extremities, exhaustion states (up to fatigue), unclear weight loss, anemia, to neurological / psychiatric manifestations such as disturbance of attention and depression. This is summarized in the table below.
Symptoms of Non-Celiac Gluten-Sensitivity
(“Non-celiac gluten sensitivity disorders”)
Data are from 374 patients treated at the Center for Celiac Research at the University of Maryland in 2004-2010; according to Czaja-Bulsa 2015 and Sapone et al. 2012.
Intestinal
- Abdominal pains (68%)
- Diarrhea (33%)
- Nausea
- Body mass loss
- Bloating, flatulence
Cutaneous 40%
- Erythema
- Eczema
General
- Headache (35%), bone and joint pain (11%)
- Muscle contractions (34%)
- Numbness of hands and feet (20%)
- Chronic tiredness (33%)
Haematological
- Anaemia (20%)
Behavioural
- Disturbance in attention
- Depression (22%)
- Hyperactivity
- Ataxia
Dental
- Chronic ulcerative stomatitis
Laboratory diagnostics of NCGS is also subject of scientific research and discussion. Czaja-Bulsa (2015): „There are no laboratory markers specific to NCGS. It is still a major limitation of clinical studies, making the differential diagnosis with other gluten-related disorders difficult. The only known antibodies observed in the NCGS patients are IgG anti-Gliadin antibodies (IgG-AGA) which, unfortunately, occur in only a half of the patients…”. Anti-Gliadin IgA-antibodies generally have not been observed (Catassi et al. 2013).
In the antibody-positive NCGS cases, the response of IgG anti-gliadin antibody titers to gluten-free diet shows a significant correlation with clinical improvement (Caio et al., 2014).
The anti-TG6 and anti-TG2 autoantibodies are suggested in the diagnostic work-up of neurological (TG6) and dermatological (TG2) manifestations (Catassi et al., 2013).
In summary, it can be stated that antibody determination in NCGS may be useful in some cases, but that no consensus-recommendations can be given at present.
9. Dermatitis herpetiformis Duhring: A skin disease triggered by autoantibodies against transglutaminase
Dermatitis herpetiformis Duhring is also known as Duhring’s disease or Duhring Brocq’s disease and belongs to the so-called blister-forming dermatoses (“blister-forming ski diseases). In this case, grouped skin blisters are observed, clinically similar to a herpes infe(IgA) are found at the epidermis/ dermis border, in the area of the so-called basement membrane. The deposited immunoglobulin leads to the cleft and blister formation between epidermis and dermis (“subepidemal”) via the activation of the so-called “complement cascade”.
Duhring’s disease is triggered by autoantibodies against transglutaminase 3, the so-called “epidermal transglutaminase” (Sardy et al., 2002). In contrast to the autoantibodies against transglutaminase 2 which are associated with celiac disease or the autoantibodies against transglutaminase 6 which are associated with neurological symptoms – especially gluten ataxia.
Duhring’s disease is closely related to celiac disease, Duhring’s disease is often diagnosed with celiac disease, which can also be asymptomatic. But: Not every patient with celiac disease presents with Duhring’s disease at the same time.
Clinically, however, the suspected diagnosis “Duhring’s disease” should always be considered in the case of corresponding skin symptoms in the context of celiac disease.
In the case of Morbus-Duhring, a gluten-free diet is also therapeutically in the foreground. Further anti-inflammatory agents can be part of the treatment.
The autoantibodies against epidermal transglutaminase can also be determined in the Heidelberg specialist laboratory of Prof. Kramer. This determination is listed on the request form.
10. Offer by Laboratory Prof. Kramer in Heidelberg “Transglutaminase Immunopathology Laboratory Heidelberg”
The following antibody specificities are determined in the Transglutaminase Immunopathology Laboratory Heidelberg:
- IgA-anti-Transglutaminase 6
(Gluten Ataxia, neurological symptoms in celiac disease and NCGS) - IgG anti-Transglutaminase 6
(Gluten Ataxia, neurological symptoms in celiac disease and NCGS) - IgA anti-Transglutaminase 3
(Duhring disease, cutaneous manifestations in celiac disease and NCGS)
11. Scientific references
Aziz und Sanders (2012)
Emerging Concepts: from coeliac disease to non-coeliac gluten sensitivity.
Proceedings of the Nutrition Society 71:576-580
Boscolo et al. (2010)
Anti-Transglutaminase Antibodies cause ataxia in mice.
PLoS ONE 5:e9698
Caio et al. (2014)
Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity.
BMC Gastroenterology 14: 26-34
Cascella et al. (2012)
Increased prevalence of Transglutaminase 6 antibodies in sera from schizophrenia patients.
Schizophrenia Bullettin. doi:10.1093/schbul/sbs064
Gadoth et al. (2015)
Transglutaminase 6 antibodies in the serum of patients with Amyotrophic Lateral Sclerosis.
JAMA Neurol. Doi:10.1001/jamaneurol.2015.48
Catassi et al. (2013)
Non-Celiac Gluten sensitivity: The new frontier of gluten-related disorders.
Nutrients 5: 3839-3853.
Czaja-Bulsa (2015)
Review: Non coeliac gluten sensitivity- A new disease with gluten intolerance.
Clinical Nutrition 34: 189-194
De Leo et al. (2017)
Anti-transglutaminase 6 antibody development in children with celiac disease corelats with duration of gluten exposure
Journal of Pediatric Gastroenterology and Nutrition DOI: 10.1097/MPG. 0000000000001642
Gadoth et al. (2015)
Transglutaminase 6 antibodies in the serum of patients with Amyotrophic Lateral Sclerosis.
JAMA Neurol. doi:10.1001/jamaneurol.2015.48
Hadjivassiliou et al. (2008a)
Cerebellar ataxia as a possible organ-specific autoimmune disease.
Movement Disorders. doi:10.1002/mds.22129
Hadjivassilliou et al. (2008b)
Autoantibodies in Gluten Ataxia recognize a novel neuronal transglutaminase.
Ann Neurol 64:332-343
Hadjivassiliou et al. (2013)
Transglutaminase 6 antibodies in the diagnosis of Gluten Ataxia.
Neurology 80:1-6
Hadjivassiliou et al. (2016)
Neurological dysfunction in Coeliac Disease and Non-Coeliac Gluten Sensitivity.
Am J Gastroenterol. doi:10.1038/ajg.2015.434
Leffler et al. (2012)
Open conformation tissue transglutaminase testing for celiac dietary assessment.
Dig. Liver Dis. 44:375-381
Mansueto et al. (2014)
Non-celiac gluten sensitivity: Literature review.
Journal of the American College of Nutrition 33:39-54
Sapone et al. (2012)
Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
BMC Medicine 10:13-25
Sardy et al. (2002)
Epidermal Transglutaminase (TGase 3) is the Autoantigen of Dermatitis Herpetiformis.
J. Exp. Med. 195:747-757
Stenberg et al. (2014)
Anti-Transglutaminase 6 antibodies in children and young adults with cerebral palsy.
Autoimmune Diseases. doi:10.115/2014/237107
Zis et al. (2017)
Transglutaminase 6 antibodies in gluten neuropathy
Dig. Liver Dis.: http://dx.doi.org/10.1016/j.dld.2017.08.019
12. Explanation of important terms and abbreviations
Celiac Disease
Celiac disease is a disease of the gastrointestinal tract caused by gluten intolerance; synonyma: gluten-sensitive or gluten-induced enteropathy; in adults also: non-tropical or native sprue. For details see text
CD
Celiac Disease (syn.: Coeliac Disease
More info here.
DHD
Dermatitis hepertiformis Duhring; For details see text
Ataxia
Generic term for various disorders of movement coordination; ataxia can occur with normal muscle strenghth, i.e. even if there is no paralysis (paresis).
GA
Gluten-Ataxia
Gliadin
Wheat proteins defined by being soluble in ethanol.
More info here.
Gluten
A mixture of different proteins occurring in the seeds of some types of cereals. Wheat, barley, rye and spelt have a particularly high gluten content.
More info here.
HLA
Abbreviation for “Human Leukocyte Antigen”; proteins on cell surfaces which play an important role in immune function: they are responsible for “antigen presentation” and thus are a pivotal element in the activation of antigen-specific immune response. More info here.
IgA
Immunglobulin A
IgG
Immunglobulin G
NCGS
Non-Celiac gluten-sensitivity
TTC
Tissue Transglutaminase
Transglutaminase
Enzymes that generate cross-links within a protein molecule or between two protein molecules. In humans, 8 different transglutaminases are known.
More info here.