Autoantibodies to GABA-ergic Neurons and Pancreatic Beta Cells in Stiff-Man Syndrome

Solimena, Michele; Folli, Franco; Aparisi, R; Pozza, G.; Camilli, Pietro De

doi:10.1056/nejm199005313222202

Cited by 613 publications

(358 citation statements)

References 30 publications

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“…Although GAD has initially been regarded as an important -cell antigen able to induce type 1 diabetes in non-obese diabetic (NOD) mice, its pathogenic role in the initiation of type 1 diabetes remains controversial (6). Anti-GAD antibodies are also detected in Stiff-person syndrome (SPS), a rare neurological disorder characterized by muscle rigidity and painful spasms, implicating their involvement in neurological diseases in central nervous system (CNS) (7). We report herein a very rare case presenting with type 1 diabetes and drug-resistant epilepsy with a high titer of anti-GAD antibodies in serum and cerebrospinal fluid (CSF).…”

Section: Introductionmentioning

confidence: 99%

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Yoshimoto¹,

Doi²,

Fukai³

et al. 2005

Intern. Med.

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A 55-year-old man who was diagnosed as having type 1 diabetes mellitus (DM) at the age of 50 years was started on insulin therapy. At 54 years old of age, he suddenly developed complex partial seizures, which frequently occurred despite intensive anti-epileptic drug therapy. Neurological examination on admission revealed hyporeflexia in bilateral upper and lower extremities without any muscle rigidity, painful spasm or cerebellar ataxia. Laboratory examination showed poor glycemic control with increased glycated hemoglobin levels. Positive anti-thyroglobulin antibodies and anti-thyroid peroxidase (TPO) antibodies and slight elevation of TSH levels are consistent with subclinical hypothyroidism due to Hashimoto's thyroiditis. A high titer of anti-glutamic acid decarboxylase (GAD) antibodies was detected in the patient's serum and cerebrospinal fluid (CSF). Electroencephalography showed temporal spikes, consistent with complex partial seizure. This is a very rare case presenting with concomitant type 1 diabetes and drugresistant epilepsy associated with high titers of circulating and CSF anti-GAD antibodies.

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Section: Introductionmentioning

confidence: 99%

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Yoshimoto¹,

Doi²,

Fukai³

et al. 2005

Intern. Med.

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“…pear in sera from patients with the rare neurological disorder stiff-man syndrome (SMS) [7,8] and in a third group of patients, in which various autoimmune endocrinopathies coincide in diverse combinations. A minor group of these patients with autoimmune polyendocrine syndrome (PAS) develop Type I diabetes at a later stage (PAS + diabetes) whereas others do not (PAS ± diabetes).…”

mentioning

confidence: 99%

Epitope spreading and a varying but not disease-specific GAD65 antibody response in Type I diabetes

et al. 2000

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The g-amino butyric acid (GABA) synthesising enzyme glutamic acid decarboxylase (GAD) is a common target of the humoral immune response in Type I (insulin-dependent) diabetes mellitus. Studies in first-degree relatives [1,2], twins [3] and school-children [4,5] have shown that GAD autoantibodies (GAD65-ab) can be present years or even decades before the clinical diagnosis of Type I diabetes. They have been used for prediction of diabetes development especially in combination with other diabetesrelated autoantibodies [6]. These GAD65-ab also ap- Diabetologia (2000) Abstract Aims/hypothesis. The aim of this study was to analyse the conformational and linear epitope profiles of glutamic acid decarboxylase antibody (GAD65-ab)-positive sera to find disease-specific epitope profiles and to study, whether GAD65-ab epitope recognition changes or spreads during the prediabetic period and, thus, can provide markers to differentiate early from later stages of progression to diabetes. Methods. Sera from subjects before (n = 21), at onset (n = 44), or at increased risk of Type I (insulin-dependent) diabetes mellitus (n = 20) and from patients with stiff-man syndrome (SMS, n = 18) or polyendocrine autoimmune syndrome (PAS, n = 21) were analysed for conformational and linear GAD65 epitope recognition by an immunohistochemical blocking test based on human monoclonal GAD65-ab (MICA 1±10) and western blotting of a GAD65 epitope-cDNA-library. Results. A redundant reactivity of many GAD65-ab positive sera to three major conformational (EP-1, EP-2, EP-3) and two dominant linear epitope clusters (amino acid 1±124 and 535±585) was observed in diabetes, polyendocrine autoimmune syndrome and stiff-man syndrome and no disease-specific epitopes or epitope-profiles were detected. Epitope recognition broadened with higher titres and with the vulnerability of patients to acquire additional autoimmune diseases apart from diabetes. Low GAD65-ab serum titres ( < 1200 arbitrary units) and EP-1 recognition in the absence of EP-2 binding characterised the early immune response. Changing epitope profiles combined stable recognition of EP-1 with gain or loss of reactivity to C-terminal epitopes during follow-up. Conclusion/interpretation. A maturing autoantibody response, which could spread from EP-1-recognition to other regions of GAD65, resulted in titre-related rather than disease-specific epitope profiles which were not sufficient to predict whether GAD65-ab positive subjects will progress to Type I diabetes, autoimmune polyendocrine syndrome or stiff-man syndrome. [Diabetologia (2000) 43: 210±217]

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“…In other GAD65Ab-positive phenotypes such as SMS, approximately 25% of these rare patients also develop Type 1 diabetes [34,35]. In the four non-diabetic SMS patients in this study, there was no difference in binding between wild-type GAD65 and GAD65-E517P, regardless of the antibody dilution (Fig.…”

Section: Discussionmentioning

confidence: 55%

“…35 S-labelled GAD65, its variant molecules, and islet antigen-2 (IA-2) were prepared by in vitro transcription/translation …”

Section: Pcr-mediated Mutagenesismentioning

confidence: 99%

Conformation-dependent GAD65 autoantibodies in diabetes

et al. 2004

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Aims/hypothesis. Conformation-dependent autoantibodies directed against GAD65 are markers of Type 1 diabetes. In this study we aimed to determine whether the substitution of GAD65 with GAD67 amino acids would affect the binding of conformation-dependent GAD65 autoantibodies. Methods. We used PCR-based site-directed mutagenesis to generate a series of mutated GAD65 cDNA constructs in which specific GAD65 coding sequences for regions of the protein critical for autoantibody binding were replaced with GAD67 coding sequences. Results. The introduction of a point mutation at position 517, substituting glutamic acid with proline, markedly reduced the binding of disease-associated GAD65 antibodies. The binding of GAD65 antibodies to the E517P mutant was reduced in the sera of all newly diagnosed Type 1 diabetes patients (n=85) by a mean of 72% (p<0.0001) compared with binding to wild-type GAD65. Patients with latent autoimmune diabetes in adults (n=24) showed a similar reduction

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Autoantibodies to GABA-ergic Neurons and Pancreatic Beta Cells in Stiff-Man Syndrome

Cited by 613 publications

References 30 publications

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Epitope spreading and a varying but not disease-specific GAD65 antibody response in Type I diabetes

Conformation-dependent GAD65 autoantibodies in diabetes

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