Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many proteins contain reiterated glutamine residues, but polyglutamine of excessive length may result in human disease by conferring new properties on the protein containing it. One established property of a glutamine residue, depending on the nature of the flanking residues, is its ability to act as an amine acceptor in a transglutaminase-catalyzed reaction and to make a glutamyl-lysine cross-link with a neighboring polypeptide. To learn whether glutamine repeats can act as amine acceptors, we have made peptides with variable lengths of polyglutamine flanked by the adjacent amino acid residues in the proteins associated with spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (SCA3), or dentato-rubral pallidoluysian atrophy (DRPLA) or those residues adjacent to the preferred cross-linking site of involucrin, or solely by arginine residues. The polyglutamine was found to confer excellent substrate properties on any soluble peptide; under optimal conditions, virtually all the glutamine residues acted as amine acceptors in the reaction with glycine ethyl-ester, and lengthening the sequence of polyglutamine increased the reactivity of each glutamine residue. In the presence of transglutaminase, peptides containing polyglutamine formed insoluble aggregates with the proteins of brain extracts and these aggregates contained glutamyl-lysine cross-links. Repeated glutamine residues exposed on the surface of a neuronal protein should form cross-linked aggregates in the presence of any transglutaminase activated by the presence of Ca2+.
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PMID:Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system. 896 45

Celiac disease is much common than previously thought with a prevalence of 1/300, but most of cases are poorly symptomatic or silent. Fewer of half of patients report diarrhoea as a presenting symptom. In adults, the diagnosis should be considered, in case of isolated iron deficiency anaemia, neurological symptoms (ataxia, epilepsy), osteoporosis and arthralgia, infertility, dermatitis herpetiformis and abnormalities in liver tests. Characteristic histological features are total or subtotal villous atrophy associated with an increased number of intraepithelial lymphocytes. The most sensitive and specific circulating antibodies for the diagnosis are endomysial and transglutaminase IgA antibodies. The treatment of celiac disease requires a strict gluten free diet, but the observance to this diet is often difficult. In patients refractory to a strict gluten free diet, serious complications such as intestinal lymphoma or refractory sprue should be considered.
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PMID:[Adult celiac disease]. 1145 9

Some authors contend that patients with idiopathic neurological disease who are also anti-gliadin antibody seropositive are gluten sensitive. However, anti-gliadin antibodies lack disease specificity being found in 10% of healthy blood donors. We report a study comparing anti-gliadin antibody with other food antibodies in patients with idiopathic ataxia (20), hereditary ataxias (seven), or idiopathic peripheral neuropathy (32). Patients were HLA typed. IgA anti-tissue transglutaminase antibodies (tTG) were measured. No case was positive for IgA anti-tTG making occult coeliac disease unlikely. HLA DQ2 and HLA DQ8 were found distributed equally across all patient groups and unrelated to gliadin antibody status. HLA DQ2 expressing, anti-gliadin antibody positive cases (so called "gluten ataxia") were rare in our clinics (four cases in 2 years from a population of 2 million). We conclude that coeliac disease per se is not commonly associated with either idiopathic ataxia or idiopathic peripheral neuropathy. Our study also casts doubt on the nosological status of "gluten ataxia" as a discreet disease entity. All food antibodies tested, particularly IgG, were a common finding in both ataxia and peripheral neuropathy groups. No particular food antibody was associated with any patient group. Food antibodies were equally common in hereditary ataxias. We conclude they are a non-specific finding.
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PMID:Ataxia, peripheral neuropathy, and anti-gliadin antibody. Guilt by association? 1622 63

Gluten sensitivity is an autoimmune disease that usually causes intestinal atrophy resulting in a malabsorption syndrome known as celiac disease. However, gluten sensitivity may involve several organs and is often associated with extraintestinal manifestations. Typically, patients with celiac disease have circulating anti-tissue transglutaminase and anti-gliadin antibodies. When patients with gluten sensitivity are affected by other autoimmune diseases, other autoantibodies may arise like anti-epidermal transglutaminase in dermatitis herpetiformis, anti-thyroid peroxidase antibodies in thyroiditis, and anti-islet cells antibodies in type 1 diabetes. The most common neurological manifestation of gluten sensitivity is ataxia, the so-called gluten ataxia (GA). In patients with GA we have demonstrated that anti-gliadin and anti-tissue transglutaminase antibodies cross-react with neurons but that additional anti-neural antibodies are present. The aim of the present article is to review the knowledge on animal models of gluten sensitivity, as well as reviewing the role of anti-neural antibodies in GA.
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PMID:Gluten ataxia: passive transfer in a mouse model. 1780 60

The role and relevance of deamidated gliadin antibodies specific for celiac disease in gluten-sensitive ataxia/neuropathy is unknown. We investigated the association of celiac-specific serology with gluten-sensitive ataxia/neuropathy, in patients with and without gliadin-induced enteropathy. 51 patients with unexplained ataxia/neuropathy suspected to have gluten sensitivity were included in the study and their serum celiac-specific markers were measured. Deamidated gliadin-IgA (83% vs. 22%), deamidated gliadin-IgG (50% vs. 3%), tissue transglutaminase-IgA (78% vs. 11%), and anti-endomysial-IgA (70% vs. 0%), were significantly more positive in ataxia/neuropathy patients with celiac disease versus those without enteropathy (P<0.001). Our findings suggest that the serological profile of gluten-sensitive ataxia/neuropathy without intestinal involvement lacks the recognition of deamidated gliadin and tissue transglutaminase epitopes.
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PMID:Serology of celiac disease in gluten-sensitive ataxia or neuropathy: role of deamidated gliadin antibody. 2105 14

Dermatitis herpetiformis is an autoimmune blistering disease that appears as a cutaneous manifestation of gluten intolerance. It is one of a group of disorders that have gluten sensitivity in common, including celiac disease and gluten ataxia. Patients with dermatitis herpetiformis present with a pruritic papulovesicular rash on extensor surfaces and on the buttocks. Immunological studies demonstrate the presence of specific immunoglobulin (Ig) A anti-endomysial and anti-transglutaminase antibodies. The finding of granular deposits of IgA along the dermal-epidermal junction is pathognomonic of dermatitis herpetiformis. Treatment of dermatitis herpetiformis is based on a life-long, strict gluten-free diet, which improves all clinical aspects of gluten sensitivity, and dapsone, a drug that is only effective for the skin manifestations.
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PMID:[Clinical guidelines for the diagnosis and treatment of dermatitis herpetiformis]. 2115 58

A 25-year-old female presented to a university neurology clinic with a 1-month history of progressive ataxia, downbeat nystagmus and spastic tetraparesis. Personal history revealed polyarthralgias and weight loss. Family history was negative. Following thorough history, laboratory, neurophysiological and MRI investigations, a diagnosis of cerebellar ataxia due to coeliac disease was done. The patient was treated with strict gluten-free diet and intravenous administration of immunoglobulins. Although there are many controversies about neurological manifestations of coeliac disease, this case pointed to strong association between these two disorders. The findings of elevated protein content in the cerebrospinal fluid with positive oligoclonal bands suggested an immune-mediated process, further supported by positive anti-endomysium antibodies and anti-transglutaminase antibodies in the cerebrospinal fluid.
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PMID:Downbeat nystagmus, ataxia and spastic tetraparesis due to coeliac disease. 2139 May 33

Gluten can cause extraintestinal manifestations with or without gastrointestinal symptoms and elevated antitissue transglutaminase 2 (tTG2) autoantibodies. Organ-specific gluten reaction involves immune response toward other transglutaminase (TG) isoforms including tTG3 (expressed in the skin, leading to dermatitis herpetiformis) and tTG6 (expressed in the brain, causing gluten ataxia). This analysis focuses on tTG6 antibodies, which have never been studied before in schizophrenia (SZ) and its relationships to tTG2 and to antigliadin antibodies. We previously showed an increased prevalence of tTG2 antibodies in gluten sensitive SZ patients compared with healthy controls (HC) that was not paralleled by an increased prevalence of antiendomysial antibody. To elucidate this discrepancy, we examined those tTG2 positive SZ patients for the presence of tTG6 antibody. We also searched for tTG6 antibodies in our sample of antigliadin (AGA) positive and AGA and tTG2 negative SZ patients. Seventy-four tTG2 positive SZ patients were compared with 148 age and gender-matched HC. Of the 74 tTG2 positive SZ patients, 16 were positive for tTG6 IgA for a prevalence of 22%. Only 4 HC were positive for tTG6 IgA for a prevalence of 2.7%. Among the AGA positive SZ patients, the prevalence of tTG6 IgA was 21.3% while 13.1% of the AGA and tTG2 negative SZ patients were positive for tTG6 IgA. The HC had a prevalence of 6%. Our results indicate a higher prevalence of tTG6 antibodies in SZ that may represent a biomarker useful to identify SZ patients who would benefit from a gluten-free diet.
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PMID:Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. 2251 48

A 4-year-old boy presented with occipital seizures but normal initial neuroimaging and proved refractory to antiepileptic medications. On repeat neuroimaging after 1 year, he had developed bi-occipital calcification and was then found to have positive coeliac serology. He was diagnosed with coeliac disease, epilepsy, and cerebral calcifications (CEC) and became seizure free after starting the gluten-free diet. Positive antibody binding to neurons and glia was demonstrated on indirect immunofluorescence. High levels of immunoglobulin-A directed against transglutaminase isoenzyme 6 (TG6) were found in the patient's serum. The positive response to the diet, TG6 antibodies, and neuronal antibody binding suggest that CEC might be autoimmune in nature, as in other extra-intestinal manifestations of gluten-related diseases, such as gluten ataxia.
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PMID:Coeliac disease, epilepsy, and cerebral calcifications: association with TG6 autoantibodies. 2284 73

A common feature of polyglutamine (polyQ) diseases is the presence of aggregates in neuronal cells caused by expanded polyglutamine tracts. PolyQ proteins are the substrates of transglutaminase 2, and the increased activity of transglutaminase in polyQ diseases suggests that transglutaminase may be directly involved in the formation of the aggregates. We previously identified the transglutaminase 6 gene to be causative of spinocerebellar ataxia type 35 (SCA35), and we found that SCA35-associated mutants exhibited reduced transglutaminase activity. Here we report that transglutaminase 6 interacts and co-localizes with both normal and expanded polyQ proteins in HEK293 cells. Moreover, the overexpression of transglutaminase 6 promotes the formation of polyQ aggregates and the conversion of soluble polyQ into insoluble polyQ aggregates. However, SCA35-associated mutants do not affect their interactions with polyQ proteins. These data suggest that transglutaminase 6 could be involved in polyQ diseases and there may exist a common pathological link between polyQ associated SCA and SCA35.
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PMID:Transglutaminase 6 interacts with polyQ proteins and promotes the formation of polyQ aggregates. 2380 Apr 13


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