Gluten-sensitive idiopathic neuropathies

Diagnosis of gluten-sensitive neuropathies without a clear cause is on the rise. These idiopathic neuropathies were first identified by anti-gliadin IgG (AGA) screening of patients.^[1] The criteria has been critiqued because of the large misdiagnosis rate of coeliac disease (CD), and because AGA exist in the normal population at >12%, far more abundant than cases of neuropathy.^[2]

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Establishing criteria

In these studies, less than 65% of AGA positive patients did not have CD indicating, based on the normal random occurrence of AGA, that less that 50% of the idiopathic neuropathy/AGA+ set were idiopathic with regard to anti-gliadin antibodies.^[3] Some of these cases are the result of underdiagnosis of coeliac disease or inability to diagnose Marsh grade 1 and 2 CD (subclinical diseases, gluten sensitive enteropathy). An additional critique pointed out that several cases of latent GSE, where associated with neuropathies that appeared as a result of avitaminosis, and were unlikely due to AGA.^[4], but are secondary consequences of GSE. Therefore ~15% of GSE who were neuropathic could be missed due to AGA-/GSE+ exceptions. The same team that introduced these AGA phenomena has also found patients with Neuropathy that are AGA negative but still had CD. Therefore AGA+ may not be directly involved.

Associated diseases

IGS Cerebral Ataxia

First suggested as a rare but possible cause in small children^[5], gluten has been implicated as being a cause in a large percent of idiopathic ataxia.^[6]. Some cerebral ataxia that are gluten sensitive are due to GSE, in one study of the 12 individuals the demonstrated gluten sensitivity 7 had some indication of GSE.^[7]. There appear to be some differences since idiopathic gluten sensitivity appears to have anti-purkinje antibodies that are not adsorbed by gliadin, as with GSE. ^[8]

Cerebral Palsy

A recent study of children with severe cerebral palsy suggest a high percentage have anti-gliadin antibodies^[9]

IGS Myopathies (neurological)

A study of patients with neurological myopathies demonstrated large percent were 'gluten sensitive' and many responded favorably with no other treatment. ^[10]

Schizophrenia, Psychosis

Reductions and remissions of schizophrenic symptoms on gluten free diet have been noted in a subset of schizophrenic patients.^[11][12][13]. Many of these definitions were done when the ability to define Marsh 1 and 2 grades CD was poor, and given the "brain calcification" association with GSE, it is likely that some cases of schizophrenia can be explained by GSE. The associations that remain, in terms of treatment results, appear to be weak.

Peripheral Neuropathies

Some peripheral idiopathic neuropathies that are GS are due to GSE, in one study of the 12 individuals the demonstrated GS neuropathies 7 had some indication of GSE.^[7]. Peripheral neuropathy is reported as a common element in idiopathic neuropathy with AGA, and critics of that claims suggest peripheral neuropathies are common to many neuropathies not specifically GS neuropathies. (See: GSEA Peripehera neuropathies)

Chronic fatigue

Chronic fatigue in patients with elevated Anti-gliadin antibodies is elevated.^[14] However the study was conducted at a time when it was difficult to diagnose all grades of enteropathy.

Pathophysiology

Recently, Synapsin I has been identified as an autoimmune target of crossreactive anti-gliadin antibodies, and possible links to patients with peripheral neuropathies or cerebral ataxia.^[15] Fifteen percent of people with elevated antigliadin antibodies do not have CD, and also may not have enteropathy. In cases where enteropathy is subclinical or underdiagnosed, avitaminosis may play a role. Paralleling the neuropathological gliadin issue, it has been recently shown that removing wheat as well as other allergens identified by RAST testing in autoimmune arthritis patients results in the reduction of certain indicators or disease. With wheat, unidentified allergenic motifs can potentially elicit crossreactive autoantibodies. Another possibility that has precedence in EIA is the possible action of glutens directly on nerves or a combination of IgE or IgA and gluten on these neuronal tissues. There are instances of large scale neurological sensitivities to wheat products, such as in North Dakota, and suggest some neuropathies may be due to contamination of wheat with other chemicals or antigens, such as mites.^[16]

Genetics and Serology

Several diagnostic groups report a significance of finding HLA-DQ1, this finding is virtually absent in the peer-reviewed primary science literature. In the USA, caucasian population DQ1 (DQ5 and DQ6) is quite common. A survey of 1899 European derived Americans revealed 30 DR-DQ1 genetic haplotypes, with a combined allele frequency of 40.07%. Hardy-Weinberg principle suggest the random phenotype frequency is 64.1%; however since balancing selection acts on HLA-DQ the phenotype frequency may be slightly higher. DQ1 freqeuncy in affected individuals would need to be quite high to obtain a significance for frequency greater than 64%. (see: Is DQ1 associated with IGS?)

The British team that looked at DQ and IGS neuropathies also looked at DQ and idiopathic Ataxia with somewhat more clarity in their data.^[17] Like the previous study allele and phenotype frequencies were not fully disclosed, but an effort was made to identify GSE+ individuals by duodenal biopsy and IEL determinations (although immunohistochemistry with anti-tTG was not done) most GSE (17 of N = 68) should have been identified. Within the same 68, the DQ2 phenotype was present in 49, DQ8 in 4 and DQ1 in the remainder. Approximately 15 DQ2 and 2 DQ8 could be likely eliminated as GSEA Ataxia, leaving 34 DQ2, 2 DQ8 and 15 DQ1 (Homozygotes and 2nd serotypes not reported). By Fisher's exact test there appears to be a significant association of DQ2 with IGS Ataxia (p ~ 10E-5). However, there is population data for Britain^[18] with a given allele frequency for DQ2 of 26.2% (N=101) and using Hardy-weinberg assessment arrived at 46:55 phenotype frequency for DQ2:DQX in Britain suggesting a probability of random DQ2 (N = 34 or more) at 0.012. This indicates by both the authors controls and the general controls that if GSE was carefully assessed in gluten-sensitive ataxia then DQ2 is positively associated with IGS Ataxia.

References