Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG

Josephe A. Honorat, A. Sebastian Lopez-Chiriboga, Thomas J. Kryzer, Lars Komorowski, Madeleine Scharf, Shannon R. Hinson, Vanda A Lennon, Sean J Pittock, Christopher Jon Klein, Andrew McKeon

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3). METHODS: Archived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin-immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively. RESULTS: Serum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24-58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3-94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA). CONCLUSION: AP3B2 (previously named β-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.

Original languageEnglish (US)
Pages (from-to)e954-e963
JournalNeurology
Volume93
Issue number10
DOIs
StatePublished - Sep 3 2019

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Gait
Immunoglobulin G
Western Blotting
Cerebellar Ataxia
Proteins
Autoimmunity
Fluorescent Antibody Technique
Mass Spectrometry
Serum
Gait Ataxia
Staining and Labeling
Spinocerebellar Ataxias
Antigens
Nerve Tissue
Sympathetic Ganglia
Synaptic Vesicles
Autoantigens
Capsid Proteins
Spinal Ganglia
Peripheral Nervous System Diseases

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Honorat, J. A., Lopez-Chiriboga, A. S., Kryzer, T. J., Komorowski, L., Scharf, M., Hinson, S. R., ... McKeon, A. (2019). Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG. Neurology, 93(10), e954-e963. https://doi.org/10.1212/WNL.0000000000008061

Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG. / Honorat, Josephe A.; Lopez-Chiriboga, A. Sebastian; Kryzer, Thomas J.; Komorowski, Lars; Scharf, Madeleine; Hinson, Shannon R.; Lennon, Vanda A; Pittock, Sean J; Klein, Christopher Jon; McKeon, Andrew.

In: Neurology, Vol. 93, No. 10, 03.09.2019, p. e954-e963.

Research output: Contribution to journalArticle

Honorat, JA, Lopez-Chiriboga, AS, Kryzer, TJ, Komorowski, L, Scharf, M, Hinson, SR, Lennon, VA, Pittock, SJ, Klein, CJ & McKeon, A 2019, 'Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG', Neurology, vol. 93, no. 10, pp. e954-e963. https://doi.org/10.1212/WNL.0000000000008061
Honorat JA, Lopez-Chiriboga AS, Kryzer TJ, Komorowski L, Scharf M, Hinson SR et al. Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG. Neurology. 2019 Sep 3;93(10):e954-e963. https://doi.org/10.1212/WNL.0000000000008061
Honorat, Josephe A. ; Lopez-Chiriboga, A. Sebastian ; Kryzer, Thomas J. ; Komorowski, Lars ; Scharf, Madeleine ; Hinson, Shannon R. ; Lennon, Vanda A ; Pittock, Sean J ; Klein, Christopher Jon ; McKeon, Andrew. / Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG. In: Neurology. 2019 ; Vol. 93, No. 10. pp. e954-e963.
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abstract = "OBJECTIVE: To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3). METHODS: Archived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin-immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively. RESULTS: Serum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24-58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3-94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA). CONCLUSION: AP3B2 (previously named β-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.",
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AU - Honorat, Josephe A.

AU - Lopez-Chiriboga, A. Sebastian

AU - Kryzer, Thomas J.

AU - Komorowski, Lars

AU - Scharf, Madeleine

AU - Hinson, Shannon R.

AU - Lennon, Vanda A

AU - Pittock, Sean J

AU - Klein, Christopher Jon

AU - McKeon, Andrew

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N2 - OBJECTIVE: To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3). METHODS: Archived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin-immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively. RESULTS: Serum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24-58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3-94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA). CONCLUSION: AP3B2 (previously named β-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.

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