By Teresa Conrick
Lab results recently have shown my daughter's autoimmune condition is connected to GAD65, an autoantibody, often related to TYPE 1 DIABETES. Here is a brief description on Wiki of GAD65 :
"-Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2."
Those are two things we know a lot about with an Autism diagnosis - GLUTAMATE and GABA, in fact I wrote last year about some of the research on GLUTAMATE and how it related to Autism --- "Glutamate receptors are responsible for the glutamate-mediated post-synaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation. Furthermore, glutamate receptors are implicated in the pathologies of a number of neurodegenerative diseases due to their central role in excitotoxicity and their prevalence throughout the central nervous system."
This would then explain symptoms Meg can exhibit as her body is not converting GLUTAMATE [EXCITATORY] into GABA [INHIBITORY] and to my surprise, a very recent study showed that my daughter is NOT THE ONLY ONE with an Autism diagnosis and an autoimmune process related to GAD65:
Presence of GAD65 autoantibodies in the serum of children with autism or ADHD.
"Antibodies against glutamic acid decarboxylase 65 (GAD65) have been detected in the serum of patients with several neurological disorders....GAD65 antibodies were detected in the serum of 15% of children with autism (N = 20), 27% of children with ADHD (N = 15) and of none of the controls (N = 14).....Serum anti-GAD65 antibodies may be a common marker of subgroups of patients with autism and ADHD. Reactions of serum antibodies with the cells in the cerebellum in these patients suggest direct effects on brain function. The subgroup of children with autism and ADHD that tests positive for GAD65 antibodies needs further characterization in a larger study."
It seems that I have come face to face with an enemy in my daughter's body -- but where did it come from and what does it mean? Knowing does not make it any easier BUT is does provide a valid and viable medical road to explore. Doctors who keep telling parents like me that ----your child has autism ---- autism is based on behavioral symptoms ----- there are no medical tests --- --well, that needs to stop.
Here is a current snapshot of what I am learning and dots that connect:
Multiplicity of the antibody response to GAD65 in Type I diabetes
"Autoantibodies to GAD65 (GAD65Ab) are present in the majority of patients with Type I diabetes (TID) and serve as an important marker of the disease."
Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. http://www.ncbi.nlm.nih.gov/pubmed/20348424
"High titers of autoantibodies against glutamic acid decarboxylase (GAD) 65 are commonly observed in patients suffering from type 1 diabetes as well as stiff-person syndrome (SPS), a disorder that affects the CNS, and a variant of SPS, progressive encephalomyelitis with rigidity and myoclonus."
Epilepsy and cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies.
"Anti-glutamic acid decarboxylase (GAD) antibodies are described in stiff-person syndrome and also in other neurological syndromes, including cerebellar ataxia and epilepsy"
So it appears that GAD65 can neurologically damage and yet also damage the pancreas. More dots connecting:
"GADs catalyze the formation of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. Two forms, GAD1/GAD67 and GAD2/GAD65, have been identified in humans. They are expressed in the brain, pancreas, ovary, and oviduct. Abnormalities in GADs are related to several neurological disorders including epilepsy and schizophrenia. GAD2/GAD65 is an autoimmune target in insulin-dependent diabetes mellitus."
That is interesting as both GAD65 and GAD 67 have been shown to be impaired in those with an Autism diagnosis. Pertinent also as my daughter has developed seizures related to estrogen. If you dig to the next level of how the body begins this autoimmune process, we end up back to what we all have seen in many of our children's descent into Autism -- vaccinations -- infections -- mitochondrial dysfunction - abnormal immune response:
"The identification of clusters of cases of T1DM [ type 1 diabetes mellitus] occurring in consistent temporal time periods allowed a link between the hemophilus vaccine and T1DM to be established. The current findings indicate the there are also clusters of cases of T1DM occurring 2-4 years post-immunization with the pertussis, MMR, and BCG vaccine. The data are consistent with the occurrence of clusters following mumps infection and the progression to T1DM in patients with antipancreatic autoantibodies."
"Cohort data from Denmark in all children born from January 1, 1990 to December 31, 2000 was analyzed toassess the association between immunization and type 1 diabetes in all Danish children and in a subgroup where childrenhad a sibling with type 1 diabetes. Pediatric vaccines were associated with a statistically significant increased risk of type1 diabetes in 12 of 21 endpoints in the general population."
"Antigens of pathogenic microbes that mimic autoantigens are thought to be responsible for the activation of autoreactive T cells. Viral infections have been associated with the development of the neuroendocrine autoimmune diseases type 1 diabetes and stiff-man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoantigen.....a pathogenic association between these autoimmune diseases is conceivable. Molecular mimicry has been postulated to represent the environmental cause of autoimmune diseases. Both type 1 diabetes and SMS have been associated with microbial infections."
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease with a predominantly non-hereditary etiology that results in a destruction of pancreatic beta cells by autoaggressive T lymphocytes. Our results demonstrate that mono- and polyclonal GAD65-specific T cells from IDDM patients can be stimulated by viral and bacterial peptides with little apparent sequence homology with autoantigenic epitopes.
"Since the rate-limiting step in GABA biosynthesis is the decarboxylation of glutamate by GAD, it is important to understand how GAD is regulated. So far, we know that GAD is regulated at the transcriptional level by alternate splicing and at the post-translational level by protein phosphorylation, palmitoylation and activity-dependent cleavage. Here, we present new evidence of the presence of GAD65 associated with mitochondria in the axon terminal and project a model in which ATP generated by mitochondrial GAD65 may serve an important function in providing energy for GAD65 mediated GABA biosynthesis and packaging into synaptic vesicles by vesicular GABA transporter (VGAT)."
"Mitochondrial metabolism plays a pivotal role in the pancreatic beta cell by generating signals that couple glucose sensing to insulin secretion. We have demonstrated previously that mitochondrially derived glutamate participates directly in the stimulation of insulin exocytosis. The aim of the present study was to impose altered cellular glutamate levels by overexpression of glutamate decarboxylase (GAD) to repress elevation of cytosolic glutamate."
ABNORMAL IMMUNE RESPONSE
"Treatments that tolerize, deviate, or alter the anti-GAD65 response in NOD mice typically delay or prevent insulitis and diabetes..... Part of the charm of the molecular mimicry model is the provision of a single epitope as the initiator, which could likely manifest as a sequential pattern of autoimmunity as described in the evolution of autoimmunity in young NOD [nonobese diabetic] mice."
"That autoimmune mechanisms are involved in the pathogenesis of IDDM [Type 1 (insulin-dependent) diabetes mellitus] is supported by the ﬁndings of experimental studies which showed that monoclonal antibodies for rubella virus capsid protein recognise B-cell epitopes on human and rat islet cells),and that T-cell clones from patients with congenital rubella elicit cytotoxic responses to GAD65, a B-cell autoantigen."
So there seems to be quit a bit of evidence showing that it is possible for GAD65 to be an important avenue of research to both Autism, Diabetes and autoimmunity. It was interesting that the American Academy of Pediatrics published a study in 1999:
Previous Exposure to Measles, Mumps, and Rubella—but Not Vaccination During Adolescence—Correlates to the Prevalence of Pancreatic and Thyroid Autoantibodies
"ABSTRACT. Objective. This study was designed to determine whether a relationship exists between previous exposure to measles, mumps, and rubella (MMR) by natural infection or vaccination or by new immunization with MMR vaccine, and either the presence or levels of autoantibodies against thyroid cell and pancreatic b-cell antigens. Methods. Antibodies against MMR and autoantibodies
against thyroglobulin, thyroid peroxidase, pancreas islet cells (ICA), islet cell surface, glutamic acid decarboxylase 65k autoantibodies, and insulin were studied before, and 3 months after, vaccination with combined MMR vaccine in 386 school children between 11 and 13 years of age....The vaccination changed neither the prevalence nor the level of autoantibodies."
It seems that vaccination of MMR ---during adolescence---- would be missing the point as most babies receive their first dose of MMR after their first birthday. Megan received her's at 15 months, had fever, rash for over 10 days, then AUTISM developed, and now, 18 years later, her measles, mumps and rubella titers are abnormally high and above the normal range of immunity. Is it possible that these high viral titers are an indication of how or why she now has developed an autoimmune diagnosis? Will she develop Diabetes in addition to her Autism diagnosis? When will we get some honest answers and real help for our very ill children?
"Our data suggest that the prevalence of autism spectrum disorder in children with type 1 diabetes attending the Diabetes Clinic at The Hospital for Sick Children, Toronto, may be greater than that in the general population (0.9% [95% CI 0.3–1.5] vs. 0.34–0.67). Certain factors may account for this finding, including a common autoimmune pathogenesis."
Teresa Conrick is Contributing Editor for Age of Autism.