Update in Autoimmune Movement Disorders: Newly Described Antigen Targets in Autoimmune and Paraneoplastic Cerebellar Ataxia

Garza, Madeline; Piquet, Amanda L.

doi:10.3389/fneur.2021.683048

Cited by 17 publications

(15 citation statements)

References 45 publications

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“…Our novel finding of neurochondrin autoantibodies in conjunction with AD dementia seems surprising at first glance, as neurochondrin autoimmunity has only been reported so far in association with vestibulocerebellar syndromes ( 1 , 7 – 9 ) and movement disorders ( 2 , 10 ) and only rarely with cognitive dysfunction in children ( 3 ). Neurochondrin is required during embryogenesis, as embryos lacking the neurochondrin gene die early during their embryogenesis ( 11 ).…”

Section: Discussionmentioning

confidence: 80%

Case Report: Alzheimer's Dementia Associated With Cerebrospinal Fluid Neurochondrin Autoantibodies

Hansen

Malchow²,

Teegen³

et al. 2022

Front. Neurol.

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BackgroundNeurochondrin autoimmunity is a rare disorder mainly associated with cerebellar and vestibular syndromes. Our report aims to enlarge its phenotypic spectrum to encompass major cognitive disorder with very late onset never before reported in conjunction with neurochondrin antibodies.MethodsWe describe the case of an 85-year-old woman who presented in our memory clinic. Retrospective analysis of patient records included cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), and neuropsychological testing using the CERAD-plus.ResultsBecause of her unknown onset of progressive cognitive dysfunction in conjunction with speech and language problems, we decided to take an extensive differential diagnostic approach including a search for neural autoantibodies potentially involved in cognitive impairment. Our patient presented serum and CSF neurochondrin autoantibodies. Further CSF analysis revealed elevated tau and ptau 181 protein as well as a reduced Aß42/40 ratio in CSF, thus matching a biomarker profile of Alzheimer's disease (AD). Neuropsychological tests revealed predominant and severe deficits in verbal and visual memory. Her MRI showed reduced parietal and cerebellar brain volume.DiscussionTaken together, this case reveals the novelty of a patient with a CSF-based and typical clinical and imaging profile of AD. She is also likely to have neurochondrin autoimmunity, as we detected neurochondrin autoantibodies in her CSF; we therefore diagnosed AD dementia associated with neurochondrin antibodies. Our case expands the spectrum of neurochondrin autoimmunity to disorders involving major cognitive disorder such as AD dementia. Furthermore, we speculate that neurochondrin autoimmunity might have triggered an acceleration of AD symptoms as its onset was reported only after a short 6-month interval via a synergistic or negatively additive hybrid mechanism of action between neurodegeneration and autoimmunity.

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Section: Discussionmentioning

confidence: 80%

Case Report: Alzheimer's Dementia Associated With Cerebrospinal Fluid Neurochondrin Autoantibodies

Hansen

Malchow²,

Teegen³

et al. 2022

Front. Neurol.

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“…Cerebellar Purkinje cells highly express a scaffold molecule Homer-3, and its antibodies also induce cerebellitis and ataxia [157,158]. Furthermore, antibodies against glutamic acid decarboxylase (GAD), GluD2, Caspr2, mGluR2, AP3B2, ITPR1, and NIF are also suggested to link with immune-mediated ataxia, although the mechanism remains poorly understood [159][160][161][162]. Several environmental factors, including exposure to toxic chemicals, gluten-containing diets, and diseases, such as cancer, affect the formation of autoantibodies [163].…”

Section: Cerebellar Atrophy and Host Autoimmunitymentioning

confidence: 99%

Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology

Parvez

Ohtsuki

2022

Brain Sciences

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The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of cerebellar ataxia. In our animal model of the acute inflammation of the cerebellar cortex, animals did not show any ataxia but hyperexcitability in the cerebellar cortex and depression-like behaviors. In contrast, animal models with neurodegeneration of the cerebellar Purkinje cells and hypoexcitability of the neurons show cerebellar ataxia. The suppression of the Ca2+-activated K+ channels in vivo is associated with a type of ataxia. Therefore, there is a gap in our interpretation between the very early phase of cerebellar inflammation and the emergence of cerebellar ataxia. In this review, we discuss the hypothesized scenario concerning the emergence of cerebellar ataxia. First, compared with genetically induced cerebellar ataxias, we introduce infection and inflammation in the cerebellum via aberrant immunity and glial responses. Especially, we focus on infections with cytomegalovirus, influenza virus, dengue virus, and SARS-CoV-2, potential relevance to mitochondrial DNA, and autoimmunity in infection. Second, we review neurophysiological modulation (intrinsic excitability, excitatory, and inhibitory synaptic transmission) by inflammatory mediators and aberrant immunity. Next, we discuss the cerebellar circuit dysfunction (presumably, via maintaining the homeostatic property). Lastly, we propose the mechanism of the cerebellar ataxia and possible treatments for the ataxia in the cerebellar inflammation.

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“…Recent studies have shown that selective antibodies against molecules of the mGluR1 pathway are often present in patients with Autoimmune Cerebellar Ataxia. Importantly, many of these antigens are also associated with the pathogenesis of spinocerebellar ataxias [ 113 , 114 , 115 ]. This clinical evidence suggests that the mGluR1 signaling pathway may be a common pathophysiological mechanism not only in SCAs but also in other conditions with signs of cerebellar ataxia.…”

Section: Shared Mglur1-pkcγ Signaling Pathway In Scasmentioning

confidence: 99%

The Emerging Key Role of the mGluR1-PKCγ Signaling Pathway in the Pathogenesis of Spinocerebellar Ataxias: A Neurodevelopmental Viewpoint

Kapfhammer

2022

IJMS

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Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive disorders with degeneration and dysfunction of the cerebellum. Although different subtypes of SCAs are classified according to the disease-associated causative genes, the clinical syndrome of the ataxia is shared, pointing towards a possible convergent pathogenic pathway among SCAs. In this review, we summarize the role of SCA-associated gene function during cerebellar Purkinje cell development and discuss the relationship between SCA pathogenesis and neurodevelopment. We will summarize recent studies on molecules involved in SCA pathogenesis and will focus on the mGluR1-PKCγ signaling pathway evaluating the possibility that this might be a common pathway which contributes to these diseases.

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Update in Autoimmune Movement Disorders: Newly Described Antigen Targets in Autoimmune and Paraneoplastic Cerebellar Ataxia

Cited by 17 publications

References 45 publications

Case Report: Alzheimer's Dementia Associated With Cerebrospinal Fluid Neurochondrin Autoantibodies

Case Report: Alzheimer's Dementia Associated With Cerebrospinal Fluid Neurochondrin Autoantibodies

Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology

The Emerging Key Role of the mGluR1-PKCγ Signaling Pathway in the Pathogenesis of Spinocerebellar Ataxias: A Neurodevelopmental Viewpoint

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