Gluten-sensitive idiopathic neuropathies

Diagnosis of gluten-sensitive neuropathies without a clear cause is on the rise. These "idiopathic" neuropathies were first identified by screening for anti-gliadin IgG (AGA).cite journal | author = Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A | title = Does cryptic gluten sensitivity play a part in neurological illness? | journal = Lancet | volume = 347 | issue = 8998 | pages = 369–71 | year = 1996 | pmid = 8598704 | doi = ] 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.cite journal | author = Unsworth DJ | title = Gluten sensitivity and neurological dysfunction | journal = Lancet | volume = 347 | issue = 9005 | pages = 903–4 | year = 1996 | pmid = 8622420 | doi = ] The problem in diagnosis arises because there are precursor states prior to coeliac disease, these are called coeliac disease, early gluten-sensitive enteropathy or defined as Marsh grade 1 and 2 coeliac disease.cite journal | author = Marsh M | title = Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue') | journal = Gastroenterology | volume = 102 | issue = 1 | pages = 330–54 | year = 1992 | pmid=1727768] Coeliac disease was diagnoses by duodenal biopsy, frequently misinterpreted as negative as high as grade 3 on the Marsh scale. Anti-gliadin antibodies may precede or lag the appearance of coeliac disease. Studies in Scandinavia found an increase of pathologies in advance, as much as 10 years, of coeliac disease. These included gastrointestinal symptoms, anemia, or other autoimmune disease. In addition IgG and IgA responses sometimes accompany allergic responses to proteins. Gliadin is exceptional in that it has several proteins that, as digested peptides of considerable length, that migrate into systemic circulation.

There is a controversial subset of people with idiopathic neuropathies and anti-gliadin antibodies that fail to fit all enteropathic criteria except anti-gliadin antibodies. About 1/3rd have no DQ2 or DQ8 and an apparent abundance of HLA-DQ1. One percent of coeliacs in Europe have no DQ2 and DQ8 but have DQ1. The DQ1 serotype is very common in the normal population, over 65% of Americans have one copy, therefore the linkage is speculative. further|HLA-DQ1

Associated diseases

Gluten involvement in idiopathic neuropathies was first defined as "neurological dysfunction of an unknown cause" associated with increased anti-gliadin antibodies.cite journal |author=Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A |title=Does cryptic gluten sensitivity play a part in neurological illness? |journal=Lancet |volume=347 |issue=8998 |pages=369–71 |year=1996 |month=February |pmid=8598704 |doi= |url=] Early studies primarily focused on "gluten ataxia" and peripheral neuropathies.cite journal |author=Grossman G |title=Neurological complications of coeliac disease: what is the evidence? |journal=Pract Neurol |volume=8 |issue=2 |pages=77–89 |year=2008 |month=April |pmid=18344378 |doi=10.1136/jnnp.2007.139717 |url=] In the period preceding these early study saw the recognition of gluten's role in coeliac disease, methods of biopsy, and improved serological analysis. However, the test for gliadin antibodies included substantial false positives. Many people, 5 to 20%, have anti-gliadin antibodies. During the period prior to extensive serological testing, children were much more frequently diagnoses than adults. Many associated autoimmune diseases were not routinely tested for coeliac disease. During the subsequent period better testing for subclinical coeliac disease evolved, better antibody tests for coeliac disease became common, and a growing proportion of adults relative to children have been diagnosed with coeliac disease. Therefore the primary concern with idiopathic gluten sensitivity or gluten sensitive idiopathic disease is how carefully has the enteropathic of gluten-sensitivity has been removed.cite journal |author=Pellecchia MT, Scala R, Perretti A, "et al" |title=Cerebellar ataxia associated with subclinical celiac disease responding to gluten-free diet |journal=Neurology |volume=53 |issue=7 |pages=1606–8 |year=1999 |month=October |pmid=10534283 |doi= |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=10534283] In coeliac disease a number of neurological pathologies are associated, these can be generally linked to systemic stress (vitamin or mineral deficiencies) or secondary inflammatory conditions.cite journal |author=Mauro A, Orsi L, Mortara P, Costa P, Schiffer D |title=Cerebellar syndrome in adult celiac disease with vitamin E deficiency |journal=Acta Neurol. Scand. |volume=84 |issue=2 |pages=167–70 |year=1991 |month=August |pmid=1950453 |doi= |url=] Anti-neuronal antibodies, epilepsy and white matter lesions are all increased in celiac disease, and studies of subclinical disease finds some extra-intestinal inflammatory conditions can precede coeliac disease.cite journal |author=Volta U, De Giorgio R, Petrolini N, "et al" |title=Clinical findings and anti-neuronal antibodies in coeliac disease with neurological disorders |journal=Scand. J. Gastroenterol. |volume=37 |issue=11 |pages=1276–81 |year=2002 |month=November |pmid=12465725 |doi= |url=] cite journal |author=Wills AJ, Unsworth DJ |title=The neurology of gluten sensitivity: separating the wheat from the chaff |journal=Curr. Opin. Neurol. |volume=15 |issue=5 |pages=519–23 |year=2002 |month=October |pmid=12351994 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn= 1350-7540&volume=15&issue=5&spage=519]

In addition to an increase in anti-gliadin antibodies a HLA-DQ association has been suggested. Since there is a component of latent or subclinical coeliac disease within the idiopathic population it is not surprising an association with DQ2 was found. Also suggested was a link to DQ1.

Cerebellar ataxia

In gluten ataxia, early studies of disease identified a number patients with cerebellar ataxia that had coeliac disease or signs of enteropathy.cite journal |author=Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, "et al" |title=Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia |journal=Lancet |volume=352 |issue=9140 |pages=1582–5 |year=1998 |month=November |pmid=9843103 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673698053422] cite journal |author=Bürk K, Bösch S, Müller CA, "et al" |title=Sporadic cerebellar ataxia associated with gluten sensitivity |journal=Brain |volume=124 |issue=Pt 5 |pages=1013–9 |year=2001 |month=May |pmid=11335703 |doi= |url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11335703] cite journal |author=Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P |title=Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features |journal=J. Neurol. Neurosurg. Psychiatr. |volume=66 |issue=1 |pages=32–5 |year=1999 |month=January |pmid=9886447 |pmc=1736152 |doi= |url=http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=9886447] The ataxia, which involved and often limbs, was often associated with higher anti-gliadin antibodies. Gluten sensitivity was also suggested as a rare but possible cause of cerebral ataxia in small childrencite journal | author = Gordon N | title = Cerebellar ataxia and gluten sensitivity: a rare but possible cause of ataxia, even in childhood | journal = Developmental medicine and child neurology | volume = 42 | issue = 4 | pages = 283–6 | year = 2000 | pmid = 10795570 | doi = ] Each of these studies uncovered a higher than expected number of coeliacs relative to the general population, but a subset of ataxia remained with elevated anti-gliadin antibodies.cite journal |author=Bushara KO, Goebel SU, Shill H, Goldfarb LG, Hallett M |title=Gluten sensitivity in sporadic and hereditary cerebellar ataxia |journal=Ann. Neurol. |volume=49 |issue=4 |pages=540–3 |year=2001 |month=April |pmid=11310636 |doi= |url=] This idiopathic gluten ataxia may have anti-purkinje antibodies that are not adsorbed by gliadin.cite journal | author = Hadjivassiliou M, Boscolo S, Davies-Jones GA, "et al" | title = The humoral response in the pathogenesis of gluten ataxia | journal = Neurology | volume = 58 | issue = 8 | pages = 1221–6 | year = 2002 | pmid = 11971090 | doi = ] A gluten-free diet may improve gluten ataxia in the idiopathic subset, however a percentage did not respond to the diet.cite journal |author=Hadjivassiliou M, Davies-Jones GA, Sanders DS, Grünewald RA |title=Dietary treatment of gluten ataxia |journal=J. Neurol. Neurosurg. Psychiatr. |volume=74 |issue=9 |pages=1221–4 |year=2003 |month=September |pmid=12933922 |pmc=1738682 |doi= |url=http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=12933922] Other studies find no association between anti-gliadin antibodies and idiopathic cerebral ataxia. Still other studies suggest that a gluten-free diet has no impact on the course of disease.cite journal | author = Combarros O, Infante J, López-Hoyos M, "et al" | title = Celiac disease and idiopathic cerebellar ataxia | journal = Neurology | volume = 54 | issue = 12 | pages = 2346 | year = 2000 | pmid = 10881272 | doi = ] Both the proponents and critics of gluten ataxia have produced studies that lacked the proper sample size or controls to be considered objective.

Peripheral neuropathies

The link of peripheral neuropathies with gluten-sensitive enteropathy is considerably stronger than with gluten ataxia. Coeliacs complain of burning, tingling or numbness in the hands or feet with some sensory loss.cite journal |author=Chin RL, Sander HW, Brannagan TH, "et al" |title=Celiac neuropathy |journal=Neurology |volume=60 |issue=10 |pages=1581–5 |year=2003 |month=May |pmid=12771245 |doi= |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12771245] In addition axonopathy, nultifocal axonal polynephropathy, small-fiber neuropathy, motor neuropathy and anti-ganglioside antibody are found in coeliac disease. A few studies report idiopathic neuropathies which were not defined as enteropathic and fewer studies report the presence of anti-gliadin antibodies.cite journal |author=Chin RL, Tseng VG, Green PH, Sander HW, Brannagan TH, Latov N |title=Multifocal axonal polyneuropathy in celiac disease |journal=Neurology |volume=66 |issue=12 |pages=1923–5 |year=2006 |month=June |pmid=16801661 |doi=10.1212/01.wnl.0000208413.40583.6c |url=] cite journal |author=De Sousa EA, Hays AP, Chin RL, Sander HW, Brannagan TH |title=Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy |journal=J. Neurol. Neurosurg. Psychiatr. |volume=77 |issue=8 |pages=983–5 |year=2006 |month=August |pmid=16844956 |doi=10.1136/jnnp.2006.091074 |url=] Other studies found a normal occurrence of AGA in idiopathic peripheral neuropathies.cite journal |author=Rosenberg NR, Vermeulen M |title=Should coeliac disease be considered in the work up of patients with chronic peripheral neuropathy? |journal=J. Neurol. Neurosurg. Psychiatr. |volume=76 |issue=10 |pages=1415–9 |year=2005 |month=October |pmid=16170088 |doi=10.1136/jnnp.2004.048413 |url=] Even among those that advocate gluten-sensitive neuropathies, the effective treatment rate on gluten-free diet is low.cite journal |author=Chin RL, Latov N |title=Peripheral Neuropathy and Celiac Disease |journal=Curr Treat Options Neurol |volume=7 |issue=1 |pages=43–48 |year=2005 |month=January |pmid=15610706 |doi= |url=http://www.treatment-options.com/1092-8480/7/43] In instances where vitamin or mineral deficiencies are involved the recovery rate is substantially higher, however within the coeliac subset of neuropathies and within the idiopathic gluten-sensitive subset the response rate to gluten abstinence is low. One possibility is that enteropathy or gluten sensitivity is causing an autoimmune condition that once triggered becomes irreversiblecite journal |author=Volta U, De Giorgio R, Petrolini N, "et al" |title=Clinical findings and anti-neuronal antibodies in coeliac disease with neurological disorders |journal=Scand. J. Gastroenterol. |volume=37 |issue=11 |pages=1276–81 |year=2002 |month=November |pmid=12465725 |doi= |url=] , the other possibility is that transient malnutrition causes damage that is irreversible, and a final possibility is that atypical anti-gliadin antibodies are damaging the nervous system; however such damage should quickly abate on a gluten-free diet.

Epilepsy

As early as the 1960s it had been noticed that individuals with coeliac disease have neurological problems sometimes resembling epilepsycite journal |author=Cooke WT, Smith WT |title=Neurological disorders associated with adult coeliac disease |journal=Brain |volume=89 |issue=4 |pages=683–722 |year=1966 |month=December |pmid=4163580 |doi= |url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=4163580] Subsequently epilepsy, particularly temporal lobe epilepsy, was found in coeliac disease patients.cite journal | author = Chapman RW, Laidlow JM, Colin-Jones D, Eade OE, Smith CL | title = Increased prevalence of epilepsy in coeliac disease | journal = British medical journal | volume = 2 | issue = 6132 | pages = 250–1 | year = 1978 | pmid = 678891 | doi = ] In the mid 1980s, studies conducted in Southern Europe noticed an association between epilepsy, occipital calcifications, and folic acid deficiency. [Sammaritano M, Andermann F, Malanson D, Guberman A, Tinuper P, Gausaut H. "The syndrome of intractable epilepsy, bilateral occipital calcifications, and folic acid calcification deficiency". Neurology 1988; 38 (Suppl. 1):239.] Such calcifications are also seen in dementia. cite journal | author = Molteni N, Bardella MT, Baldassarri AR, Bianchi PA | title = Celiac disease associated with epilepsy and intracranial calcifications: report of two patients | journal = Am. J. Gastroenterol. | volume = 83 | issue = 9 | pages = 992–4 | year = 1988 | pmid = 3414652 | doi = ] cite journal | author = Gobbi G, Ambrosetto P, Zaniboni MG, Lambertini A, Ambrosioni G, Tassinari CA | title = Celiac disease, posterior cerebral calcifications and epilepsy | journal = Brain Dev. | volume = 14 | issue = 1 | pages = 23–9 | year = 1992 | pmid = 1590524 | doi = ] There is a growing body of evidence suggesting that subclinical cases in older adults will typically progress toward dementiacite journal | author = Hu WT, Murray JA, Greenaway MC, Parisi JE, Josephs KA | title = Cognitive impairment and celiac disease | journal = Arch. Neurol. | volume = 63 | issue = 10 | pages = 1440–6 | year = 2006 | pmid = 17030661 | doi = 10.1001/archneur.63.10.1440] , a large number of studies in Italy and Spain have documented earlier onset cases. Though the autoimmune condition is not known, folic acid malabsorption may be the cause. A number of studies have shown a link between gluten and brain calcifications that are either linked to epileptic disease such as Sturge-Weber syndrome, to a risk of epilepsy, or to visual or auditory problems caused by rare forms of epilepsy. Some of the studies have found celiac disease, while others have found increased anti-gliadin IgA, and still others have found remission or more easily treated disease with the removal of gluten. In the case of epileptic diseases the role of avitaminosis appears to be the key to restoring gastrointestinal function and folic acid and vitamin B12 metabolism. However, there is a gap in the literature as to the extent to which neuropathology is either caused by enteropathy or is the result of anti-gliadin IgA. The involvement of gluten in epilepsy is minor: Aside from the normal risk, the increase of coeliac disease incidence in epilepsy is small, and the idiopathic gluten-sensitive component is smaller still. The increased risk of epilepsy in coeliac disease is also small, but there appear to be substantive differences in the types of epilepsy coeliacs have, and this may extend to people who have idiopathic gluten-sensitivity.

Autism

In the early 1990s it was hypothesized that autism can be caused or aggravated by opioid peptides that are metabolic products of gluten. [cite journal |author= Reichelt KL, Knivsberg A-M, Lind G, Nødland M |title= Probable etiology and possible treatment of childhood autism |journal= Brain Dysfunct |year=1991 |volume=4 |pages=308–19] Several treatments based on this hypothesis are widely promoted. [cite journal | author = Kidd PM | title = Autism, an extreme challenge to integrative medicine. Part II: medical management | journal = Altern Med Rev | volume = 7 | issue = 6 | pages = 472–99 | year = 2002 | pmid = 12495373 | url = http://www.thorne.com/altmedrev/.fulltext/7/6/472.pdf | format = PDF ] Popular diets eliminate foods containing gluten, often in combination with casein; studies supporting these diets have had significant flaws, so the data are inadequate to guide autism treatment recommendations.cite journal | author = Christison GW, Ivany K | title = Elimination diets in autism spectrum disorders: any wheat amidst the chaff? | journal = Journal of developmental and behavioral pediatrics : JDBP | volume = 27 | issue = 2 Suppl | pages = S162–71 | year = 2006 | pmid = 16685183 | doi = ] A recent review of the benefit of gluten-elimination diets indicates studies lack large scale, good quality randomised controlled trials cite journal |author=Millward C, Ferriter M, Calver S, Connell-Jones G |title=Gluten- and casein-free diets for autistic spectrum disorder |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD003498 |year=2008 |pmid=18425890 |doi=10.1002/14651858.CD003498.pub3 |url=]

Other possible associations

Reductions and remissions of schizophrenic symptoms on a gluten-free diet have been noted in a subset of schizophrenic patients.cite journal | author = Dohan FC | title = Is celiac disease a clue to the pathogenesis of schizophrenia? | journal = Mental hygiene | volume = 53 | issue = 4 | pages = 525–9 | year = 1969 | pmid = 5344577 | doi = ] cite journal | author = Ross-Smith P, Jenner FA | title = Diet (gluten) and schizophrenia | journal = Journal of human nutrition | volume = 34 | issue = 2 | pages = 107–12 | year = 1980 | pmid = 6989901 | doi = ] cite journal | author = Kalaydjian AE, Eaton W, Cascella N, Fasano A | title = The gluten connection: the association between schizophrenia and celiac disease | journal = Acta Psychiatrica Scandinavica | volume = 113 | issue = 2 | pages = 82–90 | year = 2006 | pmid = 16423158 | doi = 10.1111/j.1600-0447.2005.00687.x] . Many of these definitions were developed 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, appearto be weak.

Anti-gliadin antibodies are often elevated in Chronic fatigue syndrome; however, the study was conducted at a time when it was difficult to diagnose all grades of enteropathy.cite journal | author = Arnason JA, Gudjónsson H, Freysdóttir J, Jónsdóttir I, Valdimarsson H | title = Do adults with high gliadin antibody concentrations have subclinical gluten intolerance? | journal = Gut | volume = 33 | issue = 2 | pages = 194–7 | year = 1992 | pmid = 1541415 | doi = ] Significantly increased levels of IgA and IgG antibodies against gliadin and gluten were found in multiple sclerosis compared with controls. IgA antibodies against casein were significantly increased. Anti-endomycium and anti-transglutaminase antibodies were negative.cite journal | author = Reichelt KL, Jensen D | title = IgA antibodies against gliadin and gluten in multiple sclerosis | journal = Acta Neurol. Scand. | volume = 110 | issue = 4 | pages = 239–41 | year = 2004 | pmid = 15355487 | doi = 10.1111/j.1600-0404.2004.00303.x] Recent studies indicate that GSE is not associated with multiple sclerosis.cite journal |author=Ludvigsson JF, Olsson T, Ekbom A, Montgomery SM |title=A population-based study of coeliac disease, neurodegenerative and neuroinflammatory diseases |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=11 |pages=1317–27 |year=2007 |month=June |pmid=17509100 |doi=10.1111/j.1365-2036.2007.03329.x |url=] cite journal |author=Bodil Roth E, Theander E, Londos E, "et al" |title=Pathogenesis of autoimmune diseases: antibodies against transglutaminase, peptidylarginine deiminase and protein-bound citrulline in primary Sjögren's syndrome, multiple sclerosis and Alzheimer's disease |journal=Scand. J. Immunol. |volume=67 |issue=6 |pages=626–31 |year=2008 |month=June |pmid=18476880 |doi=10.1111/j.1365-3083.2008.02115.x |url=] And other studies question the association with idiopathic disease.cite journal |author=Borhani Haghighi A, Ansari N, Mokhtari M, Geramizadeh B, Lankarani KB |title=Multiple sclerosis and gluten sensitivity |journal=Clin Neurol Neurosurg |volume=109 |issue=8 |pages=651–3 |year=2007 |month=October |pmid=17537569 |doi=10.1016/j.clineuro.2007.04.011 |url=] A recent study of children with severe cerebral palsy suggest a high percentage have anti-gliadin antibodiescite journal | author = Stenberg R, Schollin J | title = Is there a connection between severe cerebral palsy and increased gluten sensitivity? | journal = Acta Paediatr. | volume = 96 | issue = 1 | pages = 132–4 | year = 2007 | pmid = 17187621 | doi = 10.1111/j.1651-2227.2007.00027.x] A study of patients with neurological myopathies demonstrated large percent were 'gluten sensitive' and many responded favorably with no other treatment. cite journal | author = Hadjivassiliou M, Chattopadhyay AK, Grünewald RA, "et al" | title = Myopathy associated with gluten sensitivity | journal = Muscle Nerve | volume = 35 | issue = 4 | pages = 443–50 | year = 2007 | pmid = 17143894 | doi = 10.1002/mus.20709] Single studies with no corroborating studies or approaches are often difficult to use as evidence of association. Coeliac disease can cause a broad spectrum of problems, but associating non-enteropathic sensitivity is considerably less certain.

Pathophysiology

Unlike coeliac disease, there is no developed pathophysiology for gluten-sensitive idiopathic neuropathies. Many studies rely either on the diagnosis of elevated anti-gliadin antibodies or an improvement with the removal of gluten. In either case the disease pathway is unclear. There is currently no consensus whether antigliadin antibodies can cause disease, with the exception of IgE in which it is known that omega-gliadin can mediate anaphylaxis and urticaria. 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.cite journal |author=Alaedini A, Okamoto H, Briani C, "et al" |title=Immune cross-reactivity in celiac disease: anti-gliadin antibodies bind to neuronal synapsin I |journal=J. Immunol. |volume=178 |issue=10 |pages=6590–5 |year=2007 |pmid=17475890] Other studies show that antigliadin antibodies can cross react with tissue-transglutaminase. These studies have to be considered in light of idiopathic sensitivity, where gluten in removed and anti-gliadin antibodies remain. The key to enteropathy is in the T-cell responses, not antibody responses. Fifteen percent of people with elevated anti-gliadin antibodies do not have coeliac disease, 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. The bottom-line on idiopathic sensitivity is there can be many causes from different pathways, most of which have not been thoroughly investigated.

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.cite journal |author=Lock RJ, Tengah DP, Williams AJ, "et al" |title=Cerebellar ataxia, peripheral neuropathy, "gluten sensitivity" and anti-neuronal autoantibodies |journal=Clin. Lab. |volume=52 |issue=11-12 |pages=589–92 |year=2006 |pmid=17175889 |doi=] 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.cite journal | author = Mitchell M, Robinson TJ | title = Gluten sensitivity and neurological dysfunction | journal = Lancet | volume = 347 | issue = 9005 | pages = 904 | year = 1996 | pmid = 8622422 | doi = ] , 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.

Genetics and Serology

Several diagnostic groups report a significance of finding HLA-DQ1, this finding is virtually absent in the peer-reviewed primary 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. There appears to be an uncontestable and elevated DQ2 involved in a few studies, routine testing of idiopathic neuropathies with high resolution DR or DQ typing has not been done.

Links

[http://www.celiac.com/articles/21637/1/Tg6-Antibody-Plays-a-Key-Role-in-Celiac-Disease-Related-Neurological-Disorders/Page1.html Tg6 Antibody Plays a Key Role in Celiac-Related Neurological Disorders Celiac.com 09/02/2008 ]

References