Paraneoplastic Cerebellar Ataxia Due to Autoantibodies against a Glutamate Receptor

P, Sillevis Smitt; Kinoshita, Ayae; B, De Leeuw; Moll, W; Coesmans, Michiel; Jaarsma, Dick; Henzen‐Logmans, S. C.; Vecht, Charles J.; C, De Zeeuw; Sekiyama, Naohiro; Nakanishi, Shigetada; Shigemoto, Ryuichi

doi:10.1056/nejm200001063420104

Cited by 397 publications

(223 citation statements)

References 29 publications

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“…Anti-mGluR1 antibodies have been found in two patients with PCD and Hodgkin's disease. Passive transfer of patient anti-mGluR1 IgG into CSF of mice induced severe, transient ataxia [25].…”

Section: Antineuronal Antibodiesmentioning

confidence: 99%

“…The prognosis is better in patients with PCD associated with Hodgkin's disease and anti-Tr (PCATr) or anti-mGluR1 antibodies. With successful treatment of the tumor and/or immunotherapy, symptoms may disappear and the antibodies vanish [17,25].…”

Section: Treatment and Prognosismentioning

confidence: 99%

“…Exceptions are the neurological syndromes associated with paraneoplastic antibodies that are directed against antigens that are located at the surface of the cell (i.e., antigens that are accessible to circulating antibodies). These include not only disorders of the peripheral nervous system (LEMS, myasthenia gravis, and neuromyotonia) but also antimGluR1-associated PCD and antiamphiphysin-associated stiff-person syndrome [24,25]. Immunotherapy modalities that are recommended for these disorders include plasma exchange, immunoadsorption (extraction of patient IgG over a protein A column), steroids, and i.v.…”

Section: Treatment and Prognosismentioning

confidence: 99%

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Managing Paraneoplastic Neurological Disorders

2006

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“…Anti-mGluR1 antibodies have been found in two patients with PCD and Hodgkin's disease. Passive transfer of patient anti-mGluR1 IgG into CSF of mice induced severe, transient ataxia [25].…”

Section: Antineuronal Antibodiesmentioning

confidence: 99%

Section: Treatment and Prognosismentioning

confidence: 99%

Section: Treatment and Prognosismentioning

confidence: 99%

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Managing Paraneoplastic Neurological Disorders

2006

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“…Our work is complementary to human IgG passive-transfer models, both of LEMS (24,25) and of cerebellar ataxia associated with antibody against metabotropic glutamate receptors (26). Our work establishes the central pathogenicity of antibody against the D-III region.…”

Section: Discussionmentioning

confidence: 80%

Anti-Ca ²⁺ channel antibody attenuates Ca ²⁺ currents and mimics cerebellar ataxia in vivo

Liao

Safa²,

Chen³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-gated Ca 2؉ channels (VGCCs) are membrane proteins that determine the activity and survival of neurons, and mutations in the P/Q-type VGCCs are known to cause cerebellar ataxia. VGCC dysfunction may also underlie acquired peripheral and central nervous system diseases associated with small-cell lung cancer, including Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar ataxia (PCA). The pathogenic role of anti-VGCC antibody in LEMS is well established. Although anti-VGCC antibody is also found in a significant fraction of PCA patients, its contribution to PCA is unclear. Using a polyclonal peptide antibody against a major immunogenic region in P/Q-type VGCCs (the extracellular Domain-III S5-S6 loop), we demonstrated that such antibody was sufficient to inhibit VGCC function in neuronal and recombinant VGCCs, alter cerebellar synaptic transmission, and confer the phenotype of cerebellar ataxia. Our data support the hypothesis that anti-VGCC antibody may play a significant role in the pathogenesis of cerebellar dysfunction in PCA.Lambert-Eaton myasthenic syndrome ͉ paraneoplastic ͉ P/Q-type ͉ N-type ͉ neurotransmission T he association between anti-voltage-gated Ca 2ϩ channel (VGCC) antibody and paraneoplastic cerebellar ataxia (PCA) dates back several decades to clinical observations of the coexistence of small-cell lung cancer with either cerebellar ataxia, Lambert-Eaton myasthenic syndrome (LEMS), or both (1, 2). The majority of these cancer patients with neurological symptoms have antibody against different types of VGCCs, especially P/Q-and N-type (3-5). The presence of different antibodies may be the consequence of an autoimmune response against the cancer cells (6, 7), known to express different VGCCs (8). There is conclusive evidence that the peripheral disease LEMS is caused by anti-VGCC antibodies, which diminish the availability of P/Q-type channels of the motor nerve terminals (9, 10).In contrast, much less is known about the origin of cerebellar ataxia associated with anti-VGCC antibody, although VGCCs are prominent in cerebellar neurons (11,12), and mutations in the P/Q-type VGCC cause ataxia (13). PCA patients have a high titer of anti-VGCC antibody (14-17) and undergo a selective loss of P/Q-type VGCC-containing cerebellar neurons (2, 18). Sera from LEMS patients, known to contain anti-VGCC antibodies, reduce P/Q-type VGCC surface expression in cerebellar granule and Purkinje neurons (19), consistent with an overlap of clinical syndromes between LEMS and PCA and, possibly, of pathogenic mechanism. There is no evidence to date that passive transfer of sera from LEMS or PCA patients is sufficient to cause central nervous system disease. Based on epitope mapping of antibody repertoire in patients with paraneoplastic neurological syndromes and small-cell lung cancer, we generated an antibody against a major epitope in the P/Q-type VGCC and evaluated its ability to affect cerebellar VGCC function and motor behavior. ResultsFunctional Effects of Anti-VGCC Antibody. We looked for...

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“…In these instances, autoantibodies are produced against neuronal antigens, specifically the metabotropic glutamate receptors (mGluR1). 50 The mGluR1 receptors are located at the perisynaptic site of the Purkinje cell dendritic spines, which form excitatory synapses with parallel fibers or climbing fibers. 51 The ␦2 subunit of the ionotropic glutamate receptor (GluR␦2) plays an important role in the stabilization of developing parallel fiber-Purkinje cell synapses to form functionally mature synapses.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Cerebellar Ataxia in Coton de Tulear Dogs

Coates¹,

O’Brien

Kline

et al. 2002

Veterinary Internal Medicne

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A neonatal ataxia syndrome was observed in Coton de Tulear dogs. Seven affected pups (32%; 7/22) of both genders came from 5 different litters with phenotypically normal parents. Neurologic examination revealed normal mental status, head titubation, intention tremors, and severe gait, stance, and ocular ataxia beginning at 2 weeks of age. One of the pups was able to walk with assistance, but most of the affected pups were unable to stand and used propulsive movements (''swimming'') for goal-oriented activities. They frequently would fall to lateral recumbency with subsequent decerebellate posturing and paddling. Ocular motor abnormalities included fine vertical tremors at rest and saccadic dysmetria. The condition was nonprogressive at least until 4 months of age. No specific abnormalities were identified in routine laboratory screening of blood and urine. Cerebrospinal fluid (CSF) analysis was normal in 1 dog, and a mild increase in protein concentration was observed in a second dog. CSF organic and amino acid concentrations were within normal limits. Magnetic resonance imaging and computed tomography of the brain, electromyography, motor nerve conduction studies, and brain stem auditory-evoked potentials were within normal limits. Postmortem examinations were performed on 5 affected dogs between 2 and 4 months of age. Routine light microscopic and immunocytochemical examination of brain, spinal cord, peripheral nerve, and muscle did not disclose any gross or histologic lesions. Compared with the cerebellum from an age-matched normal dog, the cerebellum from an affected dog showed synaptic abnormalities, including loss of presynaptic terminals and organelles associated with parallel fiber varicosities within the molecular layer and increased numbers of lamellar bodies in Purkinje cells. An autosomal recessive trait affecting development of the cerebellum is suspected.

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Paraneoplastic Cerebellar Ataxia Due to Autoantibodies against a Glutamate Receptor

Cited by 397 publications

References 29 publications

Managing Paraneoplastic Neurological Disorders

Managing Paraneoplastic Neurological Disorders

Anti-Ca ²⁺ channel antibody attenuates Ca ²⁺ currents and mimics cerebellar ataxia in vivo

Neonatal Cerebellar Ataxia in Coton de Tulear Dogs

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Paraneoplastic Cerebellar Ataxia Due to Autoantibodies against a Glutamate Receptor

Cited by 397 publications

References 29 publications

Managing Paraneoplastic Neurological Disorders

Managing Paraneoplastic Neurological Disorders

Anti-Ca 2+ channel antibody attenuates Ca 2+ currents and mimics cerebellar ataxia in vivo

Neonatal Cerebellar Ataxia in Coton de Tulear Dogs

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Anti-Ca ²⁺ channel antibody attenuates Ca ²⁺ currents and mimics cerebellar ataxia in vivo