Stiff man syndrome: Clinical and laboratory findings in eight patients

Meinck, H.-M.; Ricker, K.; Hülser, P.-J.; Schmid, Elisabeth; Peiffer, J.; Solimena, Michele

doi:10.1007/bf00868343

Cited by 98 publications

(56 citation statements)

References 39 publications

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“…* In neurons, GAD is expressed in two isoforms, GAD65 and GAD67, which share a sequence homology of 65% at the protein level. 5 So far, GAD is the only protein known to be specific for GABAergic neurons in the central nervous system, and a dominant humoral autoimmune response directed against GAD is consistent with the notion that SMS may result from an impairment of GABAergic neurotransmission. Autoimmune mechanisms that may induce the clinical symptoms of SMS are so far unknown.…”

mentioning

confidence: 72%

Inhibition of γ‐aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff‐man syndrome

Dinkel

Meinck

Jury

et al. 1998

Annals of Neurology

215

147

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Stiff-man syndrome (SMS) is a rare disorder of the central nervous system thought to result from an impairment of gamma-aminobutyric acid (GABA)ergic neurotransmission. Autoantibodies to the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), present in about 60% of SMS patients, have suggested an autoimmune pathogenesis of SMS. By using serum or cerebrospinal fluid from 25 SMS patients, we assessed the effect of GAD autoantibodies (GAD-A) on GAD enzymatic activity in vitro; 83% of GAD-A-positive SMS sera reduced GABA production in crude rat cerebellar extracts, whereas GAD-A- sera from SMS patients or healthy blood donors did not alter the enzyme activity. Inhibition of GABA synthesis by SMS sera was dose dependent and mediated by the purified IgG fraction of the sera. Human monoclonal GAD65-A and IgG purified from serum of GAD-A-positive patients with insulin-dependent diabetes or autoimmune polyendocrine syndrome did not affect GAD activity, suggesting that a specific epitope recognition of GAD-A mediates inhibition of GAD. The disease-specific detection of GAD-inhibitory antibodies is compatible with their functional involvement in the etiopathology of SMS; the relevance of such antibodies in vivo, however, remains to be determined.

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mentioning

confidence: 72%

Inhibition of γ‐aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff‐man syndrome

Dinkel

Meinck

Jury

et al. 1998

Annals of Neurology

215

147

View full text Add to dashboard Cite

show abstract

“…Amongst patients with PAS 11 had had Type I diabetes for 2±10 years. Patients with SMS (n = 18) were diagnosed according to reported methods [7,21]. Samples from 21 prediabetic subjects, i. e. subjects who subsequently progressed to Type I diabetes during longitudinal follow-up, were analysed.…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

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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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“…Evidence for an inflammatory process with selective loss of GABAergic neurons within the cerebellum and spinal cord, or a more aggressive inflammatory picture of perivascular lymphocytic infiltration including gliosis within the spinal cord, cerebral cortex, brainstem and basal ganglia have later been reported in some patients with SPS (Warich-Kirches 1997;Meinck 1994;Mitsumoto 1991).…”

Section: Clinical Presentationmentioning

confidence: 99%

MS and clinically isolated syndromes: Shared specificity but diverging clonal patterns of virus‐specific IgG antibodies produced in vivo and by CSF B cells in vitro

Skorstad

Vandvik

Vartdal

et al. 2009

Euro J of Neurology

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Background: Intrathecal synthesis of oligoclonal IgG antibodies against measles virus (MeV), varicella zoster virus (VZV) and herpes simplex virus type‐1 (HSV‐1) is a characteristic feature multiple sclerosis (MS). Methods: We have used isoelectric focusing‐immunoblot to define the clonal patterns of IgG and of IgG antibodies to MeV, VZV and HSV‐1 in supernatants of in vitro cultures of peripheral blood lymphocytes (PBL) and cerebrospinal fluid (CSF) cells and in sera and CSF from three patients with MS and three patients with clinically isolated syndromes (CIS) suspective of demyelinating disease. Results: In vitro synthesis of IgG by PBL was not detected in any patient. In contrast, in vitro synthesis by CSF cells of oligoclonal IgG and oligoclonal IgG antibodies to one or two of the three viruses tested was observed in all six patients. The clonal patterns of the in vitro synthesized IgG and virus specific IgG differed to varying extent from those synthesized intrathecally in vivo. However, in each patient, the in vitro and in vivo intrathecally produced antibodies displayed specificity for the same viruses. The addition of B cell activating factor (BAFF) had no effect on the amounts or clonal patterns of either total IgG or virus‐specific IgG produced by CSF cells in vitro. Conclusion: Virus specific B cells capable of spontaneous IgG synthesis are clonally expanded in the CSF of patients with MS. The B‐cell repertoire in CSF samples is only partially representative of the intrathecal B‐cell repertoire.

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Stiff man syndrome: Clinical and laboratory findings in eight patients

Cited by 98 publications

References 39 publications

Inhibition of γ‐aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff‐man syndrome

Inhibition of γ‐aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff‐man syndrome

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

MS and clinically isolated syndromes: Shared specificity but diverging clonal patterns of virus‐specific IgG antibodies produced in vivo and by CSF B cells in vitro

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