Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction.

OBJECTIVE: Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. METHODS: A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. RESULTS: Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues 29 A to 62 G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. INTERPRETATION: Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.

Chronic inflammation and accelerated atherosclerosis as important cofactors in nephrogenic systemic fibrosis following intravenous gadolinium exposure.

Nephrogenic systemic fibrosis (NSF) is a rare disorder in patients with chronic kidney disease characterized by an increased tissue deposition of collagen. Its pathogenesis remains unclear. Prior studies indirectly suggested a possible impact of chronic inflammation and accelerated atherosclerosis--a common feature in kidney diseased patients--whereas recent data focused almost exclusively on gadolinium (Gd)-based MR contrast agents. Usually NSF develops a maximum of 2-3 months after Gd. Longer intervals have not yet been described. Therefore, we present the first case with an extraordinary long time course in terms of chronic inflammation. A 52-year-old Caucasian woman with end-stage renal disease was admitted to our hospital with progressive muscle weakness and skin induration resulting in growing immobility. Her past medical history revealed a secondary HPT, multiple vascular complications, a seronegative rheumatoid arthritis, and a pituitary gland adenoma. The latter conditions led to multiple MR examinations with Gd-based contrast agents, the last one more than 4 years ago. Numerous laboratory tests were performed including ESR, CRP, intact parathyroid hormone (iPTH), serum ferritin, cyclic-citrullinated peptide antibodies (CCP), ANA, ANCA, immunoelectrophoresis, and serology for hepatitis as well as human immunodeficiency virus. Eventually a skin biopsy of her left thigh was obtained. The laboratory investigation showed persistently elevated levels of CRP, ESR, serum ferritin, and iPTH, whereas all other parameters were inconspicuous. The hisology displayed typical signs of nephrogenic systemic fibrosis. NSF can occur at any time after Gd exposure in the long term. Gd is a necessary, but not the sole cause of NSF. Certain other cofactors such as chronic inflammation and accelerated atherosclerosis seem to be involved.