Glycine receptor modulating antibody predicting treatable stiff-person spectrum disorders

Hinson, Shannon R.; López-Chiriboga, A. Sebastian; Bower, James H.; Matsumoto, Joseph Y.; Hassan, Anhar; Basal, Eati; Lennon, Vanda A.; Pittock, Sean J.; McKeon, Andrew

doi:10.1212/nxi.0000000000000438

Cited by 67 publications

(70 citation statements)

References 17 publications

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“…The different antibodies have different management implications as they stand for different underlying pathophysiological mechanisms that reflect on links with autoimmune or paraneoplastic disease, and treatment responses (Table ) …”

Section: Diagnostic Work‐up: Clinical Spectrum Implications Of Antibmentioning

confidence: 99%

Pragmatic Treatment of Stiff Person Spectrum Disorders

Balint

Meinck

2018

Movement Disord Clin Pract

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Background Stiff person spectrum disorders (SPSD) are a group of rare conditions clinically characterized by stiffness, spasms, and heightened stimulus sensitivity. They also share a spectrum of antibodies. Methods We reviewed the literature and our own experience with the aim of providing a practical approach to the treatment of SPSD. Results Because of the rarity of SPSD, there is little evidence to guide treatment decisions. The treatment of SPSD is based on the triad of symptomatic treatment, immunotherapy, and tumor treatment where appropriate. Moreover, the management involves continuous and appropriate monitoring of the symptoms of the disease, its autoimmune associations, and potential treatment side effects. Conclusions Here we delineated a pragmatic treatment approach to SPSD, based on our experience and existing literature. We also highlighted how our understanding of neuronal antibodies and their implications reflects on management considerations.

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Section: Diagnostic Work‐up: Clinical Spectrum Implications Of Antibmentioning

confidence: 99%

Pragmatic Treatment of Stiff Person Spectrum Disorders

Balint

Meinck

2018

Movement Disord Clin Pract

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“…47 Hinson et al examined the prevalence of IgG reactive to the α-1 subunit of the glycine receptor in sera and CSF from a group of 247 patients within the spectrum of stiff person syndrome (SPS), including classical SPS, progressive encephalomyelitis with rigidity and myoclonus (PERM), stiff limb or stiff trunk syndrome, and isolated exaggerated startle (hyperekplexia). 48 SPS is classically associated with 65-kd isoform of glutamic acid decarboxylase (GAD65) antibodies, but this study explored the emerging association with glycine receptor antibodies. Seropositivity against the GlyRa1 subunit was detected in 19 of 20 patients, and in CSF in 4 of 10 patients, one of who did not have detectable antibody in serum, for an overall rate of 8.5%.…”

Section: Antibodies Directed Against Intraneuronal Antigensmentioning

confidence: 99%

“…Seropositivity against the GlyRa1 subunit was detected in 19 of 20 patients, and in CSF in 4 of 10 patients, one of who did not have detectable antibody in serum, for an overall rate of 8.5%. 48 Reminiscent of acetylcholine receptor pathophysiology in myasthenia, the authors also described development of a modulating (in addition to validation of the cell-based binding) assay, 48 and suggested that application of such second-generation or reflexive testing strategies could increase diagnostic specificity. It is important to note, however, that this test was developed and analyzed via expression of a recombinant antigen in a widely available established nonneural (HEK 293) cell line, and the effect of receptor internalization as it relates to relevant extracellular protein remains to be determined in actual neural populations in situ.…”

Section: Antibodies Directed Against Intraneuronal Antigensmentioning

confidence: 99%

Antibodies in Autoimmune Human Neurological Disease: Pathogenesis and Immunopathology

2018

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Immune-mediated processes represent a rapidly expanding categorical etiology for neurological disease manifestations spanning all subspecialties of neurology. Neural autoantibodies can be grossly divided into two main groups based on localization of the antigen: intracellular and cell membrane/synaptic antibodies. Antibodies reactive with neuronal membrane antigens have been identified in serum and cerebrospinal fluid of patients developing neurological disease either independent of or associated with cancer comorbidity, whereas antibodies directed against intracellular targets have a much higher rate of associated malignancy. Antibodies to neuronal membrane proteins such as the N-methyl-D-aspartate (NMDA) receptor are considered directly pathogenic based on disease models. Similar evidence exists for far fewer autoantibodies directed against intracellular targets. Attempts to produce an antibody-mediated animal model of human paraneoplastic disease have been unsuccessful to date. In this article, we review antineural antibodies and their clinical associations, briefly discuss recently characterized entities, and present proposed mechanisms of antibody pathogenicity.

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“…SPS patients show a similar phenotype compared to patients suffering from startle disease including stiffness and painful spasms especially in axial and proximal limb muscles ( Bhatti and Gazali, 2015 ; Dalmau et al, 2017 ). The most efficient treatment is immunotherapy but patient relapses are common ( Hinson et al, 2018 ), which demonstrates that SPS is treatable but remediless. In contrast to mutations in GlyR genes underlying startle disease, SPS patients carry GlyR autoantibodies.…”

Section: Introductionmentioning

confidence: 99%

Impaired Glycine Receptor Trafficking in Neurological Diseases

Schaefer

Roemer

Janzen

et al. 2018

Front. Mol. Neurosci.

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Ionotropic glycine receptors (GlyRs) enable fast synaptic neurotransmission in the adult spinal cord and brainstem. The inhibitory GlyR is a transmembrane glycine-gated chloride channel. The immature GlyR protein undergoes various processing steps, e.g., folding, assembly, and maturation while traveling from the endoplasmic reticulum to and through the Golgi apparatus, where post-translational modifications, e.g., glycosylation occur. The mature receptors are forward transported via microtubules to the cellular surface and inserted into neuronal membranes followed by synaptic clustering. The normal life cycle of a receptor protein includes further processes like internalization, recycling, and degradation. Defects in GlyR life cycle, e.g., impaired protein maturation and degradation have been demonstrated to underlie pathological mechanisms of various neurological diseases. The neurological disorder startle disease is caused by glycinergic dysfunction mainly due to missense mutations in genes encoding GlyR subunits (GLRA1 and GLRB). In vitro studies have shown that most recessive forms of startle disease are associated with impaired receptor biogenesis. Another neurological disease with a phenotype similar to startle disease is a special form of stiff-person syndrome (SPS), which is most probably due to the development of GlyR autoantibodies. Binding of GlyR autoantibodies leads to enhanced receptor internalization. Here we focus on the normal life cycle of GlyRs concentrating on assembly and maturation, receptor trafficking, post-synaptic integration and clustering, and GlyR internalization/recycling/degradation. Furthermore, this review highlights findings on impairment of these processes under disease conditions such as disturbed neuronal ER-Golgi trafficking as the major pathomechanism for recessive forms of human startle disease. In SPS, enhanced receptor internalization upon autoantibody binding to the GlyR has been shown to underlie the human pathology. In addition, we discuss how the existing mouse models of startle disease increased our current knowledge of GlyR trafficking routes and function. This review further illuminates receptor trafficking of GlyR variants originally identified in startle disease patients and explains changes in the life cycle of GlyRs in patients with SPS with respect to structural and functional consequences at the receptor level.

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Glycine receptor modulating antibody predicting treatable stiff-person spectrum disorders

Cited by 67 publications

References 17 publications

Pragmatic Treatment of Stiff Person Spectrum Disorders

Pragmatic Treatment of Stiff Person Spectrum Disorders

Antibodies in Autoimmune Human Neurological Disease: Pathogenesis and Immunopathology

Impaired Glycine Receptor Trafficking in Neurological Diseases

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