Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stiff-man syndrome (Moersch-Woltman syndrome) is a rare disorder of motor function characterized by involuntary stiffness of axial muscles and superimposed painful muscle spasms, which are often induced by startle or emotional stimuli. The standard treatment has been benzodiazepines. An association has been reported between stiff-man syndrome and epilepsy, insulin-dependent diabetes, and a variety of organ-specific autoimmune disorders. Antibodies directed against glutamic acid decarboxylase and against pancreatic islet cells have been detected in the serum and cerebrospinal of patients with stiff-man syndrome. These findings suggest that stiff-man syndrome may be an autoimmune disease. Preliminary reports indicate that patients with stiff-man syndrome have a favorable response to plasma exchange and corticosteroid therapy.
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PMID:Stiff-man syndrome. 167 74

The pancreatic islet beta-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mellitus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). Pancreatic beta cells and a subpopulation of central nervous system neurons express high levels of this enzyme. Autoantibodies against glutamic acid decarboxylase with a higher titre and increased epitope recognition compared with those usually associated with IDDM are found in stiff-man syndrome, a rare neurological disorder characterized by a high coincidence with IDDM.
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PMID:Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. 169 48

Glutamic acid decarboxylase (GAD; glutamate decarboxylase, L-glutamate 1-carboxy-lyase, EC 4.1.1.15), which catalyzes formation of gamma-aminobutyric acid from L-glutamic acid, is detectable in different isoforms with distinct electrophoretic and kinetic characteristics. GAD has also been implicated as an autoantigen in the vastly differing autoimmune disease stiff-man syndrome and insulin-dependent diabetes mellitus. Despite the differing GAD isoforms, only one type of GAD cDNA (GAD-1), localized to a syntenic region of chromosome 2, has been isolated from rat, mouse, and cat. Using sequence information from GAD-1 to screen a human pancreatic islet cDNA library, we describe the isolation of an additional GAD cDNA (GAD-2), which was mapped to the short arm of human chromosome 10. Genomic Southern blotting with GAD-2 demonstrated a hybridization pattern different from that detected by GAD-1. GAD-2 recognizes a 5.6-kilobase transcript in both islets and brain, in contrast to GAD-1, which detects a 3.7-kilobase transcript in brain only. The deduced 585-amino acid sequence coded for by GAD-2 shows less than 65% identity to previously published, highly conserved GAD-1 brain sequences, which show greater than 96% deduced amino acid sequence homology among the three species. The function of this additional islet GAD isoform and its importance as an autoantigen in insulin-dependent diabetes remain to be determined.
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PMID:Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. 192 93

We report partial nucleotide sequences of the human enzyme glutamic acid decarboxylase (GAD) from brain and pancreatic islets which encode the middle 180 amino acids of GAD. The brain and islet GAD sequences display a high degree of sequence homology with the equivalent region of other mammalian brain GAD cDNAs. Alignment of the brain and islet GAD sequences showed that there were 45 nucleotide differences which, at the translational level, would result in seven amino acid substitutions. These results which suggest that different isomeric forms of human GAD exist in brain and pancreas may be relevant to the pathogenesis of stiff man syndrome (SMS) and insulin-dependent diabetes mellitus (IDDM), respectively, two distinct but associated clinical disorders in which GAD is the target of autoantibodies.
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PMID:Cloning and partial nucleotide sequence of human glutamic acid decarboxylase cDNA from brain and pancreatic islets. 203 9

Stiff-man syndrome is a rare disorder of the central nervous system of unknown pathogenesis. We have previously reported the presence of autoantibodies against glutamic acid decarboxylase (GAD) in a patient with stiff-man syndrome, epilepsy, and insulin-dependent diabetes mellitus. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) and in pancreatic beta cells. We subsequently observed autoantibodies to GABA-ergic neurons in 20 of 33 patients with stiff-man syndrome. GAD was the principal autoantigen. In the group of patients positive for autoantibodies against GABA-ergic neurons, there was a striking association with organ-specific autoimmune diseases, primarily insulin-dependent diabetes mellitus. These findings support the hypothesis that stiff-man syndrome is an autoimmune disease and suggest that GAD is the primary autoantigen involved in stiff-man syndrome and the associated insulin-dependent diabetes mellitus. Our findings also indicate that autoantibodies directed against GABA-ergic neurons are a useful marker in the diagnosis of the disease.
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PMID:Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. 213 82

Autoantibodies that reacted with cell bodies and axon terminals of gamma-aminobutyric acid (GABA)ergic neurons were present in the serum and cerebrospinal fluid in a patient with stiff-man syndrome with type I diabetes. Immunoblot experiments using this patient's serum and cerebrospinal fluid did not corroborate an earlier observation that these autoantibodies are directed against the GABAergic cytosolic enzyme, L-glutamic acid decarboxylase. While L-glutamic acid decarboxylase autoantibodies may be associated with this syndrome, they do not appear to be easily demonstrated.
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PMID:Stiff-man syndrome: a GABAergic autoimmune disorder with autoantigenic heterogeneity. 226 Aug 59

A patient who developed generalized autoimmune myasthenia gravis six years after the spontaneous remission of a stiff-man syndrome is described. He also suffered from chronic active hepatitis and had radiological evidence of a thymoma. He did not have diabetes mellitus. Besides anti-nicotinic acetylcholine receptor antibodies, anti-nuclear, anti-DNA, anti-mitochondrial and anti-skeletal muscle antibodies were found in his serum, while islet-cell antibodies were absent. Immunocytochemistry studies failed to demonstrate autoantibodies to GABA-ergic nerve terminals, although an aspecific neuronal immunostaining was observed. The clinical and immunological features of this case support the hypothesis of a dysimmune pathogenesis of SMS, also in cases not associated with autoimmunity to GABA-ergic nerve terminals. Furthermore, a relationship between thymoma and the neurological syndromes discussed could be considered.
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PMID:Autoimmune myastenia gravis with thymoma following the spontaneous remission of stiff-man syndrome. 236 54

Stiff-man syndrome is a rare disorder of the central nervous system consisting of progressive, fluctuating muscle rigidity with painful spasms. It is occasionally associated with endocrine disorders, including insulin-dependent diabetes, and with epilepsy. We investigated the possible existence of autoimmunity against the nervous system in a patient with stiff-man syndrome associated with epilepsy and Type I diabetes mellitus. Levels of IgG, which had an oligoclonal pattern, were elevated in the cerebrospinal fluid. The serum and the cerebrospinal fluid produced an identical, intense staining of all gray-matter regions when used to stain brain sections according to an indirect light-microscopical immunocytochemical procedure. The staining patterns were identical to those produced by antibodies to glutamic acid decarboxylase (the enzyme responsible for the synthesis of gamma-aminobutyric acid). A band comigrating with glutamic acid decarboxylase in sodium dodecyl sulfate-polyacrylamide gels appeared to be the only nervous-tissue antigen recognized by cerebrospinal fluid antibodies, and the predominant antigen recognized by serum antibodies. These findings support the idea that an impairment of neuronal pathways that operate through gamma-aminobutyric acid is involved in the pathogenesis of stiff-man syndrome, and they raise the possibility of an autoimmune pathogenesis.
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PMID:Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. 328 Oct 11

Glutamic acid decarboxylase (GAD) is a major islet cell autoantigen in insulin-dependent diabetes mellitus (IDDM), and autoantibodies are found in high frequencies in patients with recent-onset IDDM, stiff-man syndrome (SMS), and autoimmune polyendocrine syndrome type I (APS I). Antigens in autoimmune disorders are often enzymes, and autoantibody binding frequently inhibit their activity. In this study, we examined the reactivity of anti-GAD-containing sera from 7 patients with IDDM, 4 patients with SMS, and 5 patients with APS I. All sera immunoprecipitated GAD from [35S]methionine-labeled rat islet lysates and the sera from patients with SMS and APS I, but none of the IDDM patients' sera, identified the GAD protein in Western blots. Two of four SMS patients' sera and 5 of 5 APS I patients' sera, in contrast to 0 of 7 IDDM patients' sera, inhibited the enzymatic activity of GAD. When the various sera were tested with the GAD65 and GAD67 isoforms, produced separately by transient expression in COS cells, the enzymatic activity of GAD65 was inhibited by sera from patients with SMS and APS I, whereas no effect on the GAD67 activity was observed. Taken together, the results demonstrate that the GAD autoantibodies in these three disorders display marked differences in epitope recognition and indicate that, during the development of the diseases, the autoantigen is being presented to the immune system through separate pathogenetic mechanisms.
Diabetes 1994 Jan
PMID:GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes. 750 44

The frequency of antibodies to GAD (anti-GAD) in insulin-dependent diabetes mellitus (IDDM) varies greatly according to the type of assay employed. We therefore examined the immunoassay characteristics of diabetic sera using GAD purified from porcine brain and shown to contain both isoforms. Sera from 38 patients with IDDM, including 1 patient with both stiff-man syndrome (SMS) and IDDM, were studied for anti-GAD by radioimmunoprecipitation (RIP), Western blotting, and dot-blotting. The sera were selected according to reactivity in the RIP assay. There was a good correlation between potency of the RIP reaction at the screening dilution of 1:2 and the endpoint dilution in the assay which ranged from 1:2 to 1:30,000 for IDDM sera, and 1:300,000 for the SMS serum. Of the 38 sera positive for anti-GAD by RIP, only 6 had antibodies detectable by Western blotting, and all gave an RIP titer of at least 1:250. The low frequency of antibodies by Western blotting was explicable by denaturation of the antigen. Thus, using a dot-blotting assay in which reactivity to untreated "native" GAD was compared with reactivity to GAD after denaturation by reduction with 2-mercaptoethanol and boiling, 20 of the 38 IDDM sera reacted unequivocally with the native GAD compared with only 2 that reacted with denatured GAD after reduction and boiling. The sera were tested for their capacity to inhibit the catalytic activity of GAD, but only the high-titer serum from the patient with SMS did so. Our study further validates the RIP assay for anti-GAD and establishes that anti-GAD exists in IDDM over a wide range of titers that correlate with other assay characteristics, and also indicates that the conformational autoantibody epitope on GAD is susceptible to alteration under denaturing conditions.
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PMID:Autoantigenic properties of native and denatured glutamic acid decarboxylase: evidence for a conformational epitope. 751 Oct 84


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