Gluten-sensitive idiopathic neuropathies
Encyclopedia
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). The criteria has been critiqued because of the large misdiagnosis rate of coeliac disease
(CD), and because AGA exists in the normal population at >12%, far more abundant than cases of neuropathy. The problem in diagnosis arises because there are precursor states prior to coeliac disease. These are called subclinical coeliac disease and early gluten-sensitive enteropathy and are defined as Marsh grade 1 and 2 coeliac disease. Coeliac disease was diagnosed 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 as much as 10 years in advance 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 which remain peptides of considerable length after digestion, and 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 1/3 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.
involvement in idiopathic neuropathies was first defined as neurological dysfunction of an unknown cause associated with increased anti-gliadin antibodies
. Early studies primarily focused on "gluten ataxia
" and peripheral neuropathies. In the period preceding these early studies saw the recognition of gluten's role in coeliac disease, the development of 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 diagnosed than adults. Many patients suffering from associated autoimmune diseases were not routinely tested for celiac 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 the enteropathic cohort of gluten-sensitivity has been removed. 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.
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.
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.
or signs of enteropathy. The ataxia, which involved gait 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 children 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. This idiopathic gluten ataxia may have anti-purkinje antibodies that are not adsorbed by gliadin. A gluten-free diet
may improve gluten ataxia in the idiopathic subset, however a percentage did not respond to the diet. 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. Both the proponents and critics of gluten ataxia have produced studies that lacked the proper sample size or controls to be considered objective.
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. 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. Other studies found a normal occurrence of AGA in idiopathic peripheral neuropathies. Even among those that advocate gluten-sensitive neuropathies, the effective treatment rate on gluten-free diet is low. 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 irreversible, 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.
, particularly temporal lobe epilepsy, was found in coeliac disease patients. In the mid 1980s, studies conducted in Southern Europe noticed an association between epilepsy, occipital calcifications, and folic acid deficiency. Such calcifications are also seen in dementia. There is a growing body of evidence suggesting that subclinical cases in older adults will typically progress toward dementia, 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.
can be caused or aggravated by opioid peptide
s that are metabolic products of gluten
. Several treatments based on this hypothesis are widely promoted. 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.
A recent review of the benefit of gluten-elimination diets indicates studies lack large scale, good quality randomised controlled trials
to 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. 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. Recent studies indicate that GSE is not associated with multiple sclerosis. And other studies question the association with idiopathic disease.
A recent study of children with severe cerebral palsy
suggest a high percentage have anti-gliadin antibodies A study of patients with neurological myopathies demonstrated large percent were 'gluten sensitive' and many responded favorably with no other treatment.
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.
I has been identified as an autoimmune target of crossreactive anti-gliadin antibodies, and possible links to patients with peripheral neuropathies or cerebral ataxia. 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.
positive patients did not have CD indicating, based on the normal random occurrence of AGA, that less than 50% of the idiopathic neuropathy/AGA+ set were idiopathic with regard to anti-gliadin antibodies
. 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., 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.
, 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.
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
(AGA). The criteria has been critiqued because of the large misdiagnosis rate of coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
(CD), and because AGA exists in the normal population at >12%, far more abundant than cases of neuropathy. The problem in diagnosis arises because there are precursor states prior to coeliac disease. These are called subclinical coeliac disease and early gluten-sensitive enteropathy and are defined as Marsh grade 1 and 2 coeliac disease. Coeliac disease was diagnosed 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 as much as 10 years in advance of coeliac disease. These included gastrointestinal symptoms, anemia or other autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
. In addition IgG and IgA responses sometimes accompany allergic responses to proteins. Gliadin is exceptional in that it has several proteins which remain peptides of considerable length after digestion, and 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 1/3 have no DQ2
HLA-DQ2
HLA-DQ2 is a serotype group within HLA-DQ serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles,...
or DQ8
HLA-DQ8
HLA-DQ8 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302....
and an apparent abundance of HLA-DQ1. One percent of coeliacs in Europe have no DQ2 and DQ8 but have DQ1. The DQ1 serotype
Serotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...
is very common in the normal population, over 65% of Americans have one copy, therefore the linkage is speculative.
Associated diseases
GlutenGluten
Gluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
involvement in idiopathic neuropathies was first defined as neurological dysfunction of an unknown cause associated with increased anti-gliadin antibodies
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
. Early studies primarily focused on "gluten ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
" and peripheral neuropathies. In the period preceding these early studies saw the recognition of gluten's role in coeliac disease, the development of methods of biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
, and improved serological analysis
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
. 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 diagnosed than adults. Many patients suffering from associated autoimmune diseases were not routinely tested for celiac 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 the enteropathic cohort of gluten-sensitivity has been removed. 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.
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.
In addition to an increase in anti-gliadin antibodies a HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
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 idiopathic cerebellar ataxia that had coeliac diseaseCoeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
or signs of enteropathy. The ataxia, which involved gait and often limbs, was often associated with higher anti-gliadin antibodies
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
. Gluten sensitivity
Gluten sensitivity
Gluten sensitivity belongs to a spectrum of disorders in which gluten has an adverse effect on the body. It can be defined as a non-allergic and non-autoimmune condition in which the consumption of gluten can lead to symptoms similar to those observed in coeliac disease or wheat allergy .Gluten...
was also suggested as a rare but possible cause of cerebral ataxia in small children 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. This idiopathic gluten ataxia may have anti-purkinje antibodies that are not adsorbed by gliadin. A gluten-free diet
Gluten-free diet
A gluten-free diet is a diet that excludes foods containing gluten. Gluten is a protein found in wheat , barley, rye, malts and triticale. It is used as a food additive in the form of a flavoring, stabilizing or thickening agent, often as "dextrin"...
may improve gluten ataxia in the idiopathic subset, however a percentage did not respond to the diet. Other studies find no association between anti-gliadin antibodies
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
and idiopathic cerebral ataxia. Still other studies suggest that a gluten-free diet has no impact on the course of disease. 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 neuropathiesPeripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
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. 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. Other studies found a normal occurrence of AGA in idiopathic peripheral neuropathies. Even among those that advocate gluten-sensitive neuropathies, the effective treatment rate on gluten-free diet is low. 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 irreversible, 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 epilepsy Subsequently epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, particularly temporal lobe epilepsy, was found in coeliac disease patients. In the mid 1980s, studies conducted in Southern Europe noticed an association between epilepsy, occipital calcifications, and folic acid deficiency. Such calcifications are also seen in dementia. There is a growing body of evidence suggesting that subclinical cases in older adults will typically progress toward dementia, a large number of studies in Italy and Spain have documented earlier onset cases. Though the autoimmune condition is not known, folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
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 autismAutism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
can be caused or aggravated by opioid peptide
Opioid peptide
Opioid peptides are short sequences of amino acids that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Opioid peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble opiates...
s that are metabolic products of gluten
Gluten
Gluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
. Several treatments based on this hypothesis are widely promoted. Popular diets eliminate foods containing gluten, often in combination with casein
Casein
Casein is the name for a family of related phosphoprotein proteins . These proteins are commonly found in mammalian milk, making up 80% of the proteins in cow milk and between 60% and 65% of the proteins in human milk....
; studies supporting these diets have had significant flaws, so the data are inadequate to guide autism treatment recommendations.
A recent review of the benefit of gluten-elimination diets indicates studies lack large scale, good quality randomised controlled trials
Other possible associations
Reductions and remissions of schizophrenic symptoms on a gluten-free diet have been noted in a subset of schizophrenic patients. 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
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
are often elevated in Chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
; however, the study was conducted at a time when it was difficult to diagnose all grades of enteropathy. Significantly increased levels of IgA and IgG antibodies against gliadin
Gliadin
Gliadin is a glycoprotein present in wheat and several other cereals within the grass genus Triticum. Gliadins are prolamins and are separated on the basis of electrophoretic mobility and isoelectric focusing.- Types :...
and gluten
Gluten
Gluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
were found in multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
compared with controls. IgA antibodies
Immunoglobulin A
Immunoglobulin A is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined; between three and five grams are secreted into the intestinal lumen each day....
against casein
Casein
Casein is the name for a family of related phosphoprotein proteins . These proteins are commonly found in mammalian milk, making up 80% of the proteins in cow milk and between 60% and 65% of the proteins in human milk....
were significantly increased. Anti-endomycium and anti-transglutaminase antibodies were negative. Recent studies indicate that GSE is not associated with multiple sclerosis. And other studies question the association with idiopathic disease.
A recent study of children with severe cerebral palsy
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
suggest a high percentage have anti-gliadin antibodies A study of patients with neurological myopathies demonstrated large percent were 'gluten sensitive' and many responded favorably with no other treatment.
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, SynapsinSynapsin
The synapsins are a family of proteins that have long been implicated in the regulation of neurotransmitter release at synapses. Specifically, they are thought to be involved in regulating the number of synaptic vesicles available for release via exocytosis at any one time.Current studies suggest...
I has been identified as an autoimmune target of crossreactive anti-gliadin antibodies, and possible links to patients with peripheral neuropathies or cerebral ataxia. 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
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different 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 AGAAnti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
positive patients did not have CD indicating, based on the normal random occurrence of AGA, that less than 50% of the idiopathic neuropathy/AGA+ set were idiopathic with regard to anti-gliadin antibodies
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
. 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., 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-DQ1HLA-DQ1
HLA-DQ1 is a serotype that covers a broad range of HLA-DQ haplotypes. Historically it was identified as a DR-like alpha chain called DC1, later, it was among 3 types DQw1 , DQw2 and DQw3. Of these three serotyping specificities only DQw1 recognized DQ alpha chain. The serotype is positive in...
, this finding is virtually absent in the peer-reviewed primary literature. In the USA, Caucasian population DQ1 (DQ5
HLA-DQ5
HLA-DQ4 is a human leukocyte antigen serotype subgroup within HLA-DQ serotypes. The serotype is determined by the antibody recognition of β5.x subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ5 are encoded by the HLA-DQB1*05 allele group. This group currently contains 4...
and DQ6
HLA-DQ6
HLA-DQ6 is a human leukocyte antigen serotype within HLA-DQ serotype group. The serotype is determined by the antibody recognition of β6 subset of DQ β-chains. The β-chain of DQ isoforms are encoded by HLA-DQB1 locus and DQ6 are encoded by the HLA-DQB1*06 allele group. This group currently...
) 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
Hardy-Weinberg principle
The Hardy–Weinberg principle states that both allele and genotype frequencies in a population remain constant—that is, they are in equilibrium—from generation to generation unless specific disturbing influences are introduced...
suggest the random phenotype frequency is 64.1%; however since balancing selection
Balancing selection
Balancing selection refers to a number of selective processes by which multiple alleles are actively maintained in the gene pool of a population at frequencies above that of gene mutation. This usually happens when the heterozygotes for the alleles under consideration have a higher adaptive value...
acts on HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
the phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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.