Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology

Autores
Marsili, Luca; Sharma, Jennifer; Espay, Alberto J.; Migazzi, Alice; Abdelghany, Elhusseini; Hill, Emily J.; Duque, Kevin R.; Hagen, Matthew C.; Stephen, Christopher D.; Kovacs, Gabor G.; Lang, Anthony E.; Hadjivassiliou, Marios; Basso, Manuela; Kauffman, Marcelo Andres; Sturchio, Andrea
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The gold standard for classification of neurodegenerative diseases is postmortem histopathol-ogy; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new het-erozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.
Fil: Marsili, Luca. University of Cincinnati; Estados Unidos
Fil: Sharma, Jennifer. University of Cincinnati; Estados Unidos
Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos
Fil: Migazzi, Alice. Universita degli Studi di Trento; Italia
Fil: Abdelghany, Elhusseini. University of Cincinnati; Estados Unidos
Fil: Hill, Emily J.. University of Cincinnati; Estados Unidos
Fil: Duque, Kevin R.. University of Cincinnati; Estados Unidos
Fil: Hagen, Matthew C.. University of Cincinnati; Estados Unidos
Fil: Stephen, Christopher D.. Harvard Medical School; Estados Unidos
Fil: Kovacs, Gabor G.. University of Toronto; Canadá
Fil: Lang, Anthony E.. University of Toronto; Canadá
Fil: Hadjivassiliou, Marios. University Of Sheffield (university Of Sheffield);
Fil: Basso, Manuela. Universita degli Studi di Trento; Italia
Fil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Sturchio, Andrea. University of Cincinnati; Estados Unidos
Materia
CEREBELLAR ATAXIA
MOVEMENT DISORDERS
NEUROGENETICS
POSTMORTEM
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/184262
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosologyMarsili, LucaSharma, JenniferEspay, Alberto J.Migazzi, AliceAbdelghany, ElhusseiniHill, Emily J.Duque, Kevin R.Hagen, Matthew C.Stephen, Christopher D.Kovacs, Gabor G.Lang, Anthony E.Hadjivassiliou, MariosBasso, ManuelaKauffman, Marcelo AndresSturchio, AndreaCEREBELLAR ATAXIAMOVEMENT DISORDERSNEUROGENETICSPOSTMORTEMhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3The gold standard for classification of neurodegenerative diseases is postmortem histopathol-ogy; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new het-erozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.Fil: Marsili, Luca. University of Cincinnati; Estados UnidosFil: Sharma, Jennifer. University of Cincinnati; Estados UnidosFil: Espay, Alberto J.. University of Cincinnati; Estados UnidosFil: Migazzi, Alice. Universita degli Studi di Trento; ItaliaFil: Abdelghany, Elhusseini. University of Cincinnati; Estados UnidosFil: Hill, Emily J.. University of Cincinnati; Estados UnidosFil: Duque, Kevin R.. University of Cincinnati; Estados UnidosFil: Hagen, Matthew C.. University of Cincinnati; Estados UnidosFil: Stephen, Christopher D.. Harvard Medical School; Estados UnidosFil: Kovacs, Gabor G.. University of Toronto; CanadáFil: Lang, Anthony E.. University of Toronto; CanadáFil: Hadjivassiliou, Marios. University Of Sheffield (university Of Sheffield);Fil: Basso, Manuela. Universita degli Studi di Trento; ItaliaFil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Sturchio, Andrea. University of Cincinnati; Estados UnidosMDPI2021-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/184262Marsili, Luca; Sharma, Jennifer; Espay, Alberto J.; Migazzi, Alice; Abdelghany, Elhusseini; et al.; Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology; MDPI; International Journal of Molecular Sciences; 22; 14; 7-2021; 1-81661-65961422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3390/ijms22147292info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:51:52Zoai:ri.conicet.gov.ar:11336/184262instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:51:52.607CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
title Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
spellingShingle Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
Marsili, Luca
CEREBELLAR ATAXIA
MOVEMENT DISORDERS
NEUROGENETICS
POSTMORTEM
title_short Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
title_full Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
title_fullStr Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
title_full_unstemmed Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
title_sort Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology
dc.creator.none.fl_str_mv Marsili, Luca
Sharma, Jennifer
Espay, Alberto J.
Migazzi, Alice
Abdelghany, Elhusseini
Hill, Emily J.
Duque, Kevin R.
Hagen, Matthew C.
Stephen, Christopher D.
Kovacs, Gabor G.
Lang, Anthony E.
Hadjivassiliou, Marios
Basso, Manuela
Kauffman, Marcelo Andres
Sturchio, Andrea
author Marsili, Luca
author_facet Marsili, Luca
Sharma, Jennifer
Espay, Alberto J.
Migazzi, Alice
Abdelghany, Elhusseini
Hill, Emily J.
Duque, Kevin R.
Hagen, Matthew C.
Stephen, Christopher D.
Kovacs, Gabor G.
Lang, Anthony E.
Hadjivassiliou, Marios
Basso, Manuela
Kauffman, Marcelo Andres
Sturchio, Andrea
author_role author
author2 Sharma, Jennifer
Espay, Alberto J.
Migazzi, Alice
Abdelghany, Elhusseini
Hill, Emily J.
Duque, Kevin R.
Hagen, Matthew C.
Stephen, Christopher D.
Kovacs, Gabor G.
Lang, Anthony E.
Hadjivassiliou, Marios
Basso, Manuela
Kauffman, Marcelo Andres
Sturchio, Andrea
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CEREBELLAR ATAXIA
MOVEMENT DISORDERS
NEUROGENETICS
POSTMORTEM
topic CEREBELLAR ATAXIA
MOVEMENT DISORDERS
NEUROGENETICS
POSTMORTEM
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The gold standard for classification of neurodegenerative diseases is postmortem histopathol-ogy; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new het-erozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.
Fil: Marsili, Luca. University of Cincinnati; Estados Unidos
Fil: Sharma, Jennifer. University of Cincinnati; Estados Unidos
Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos
Fil: Migazzi, Alice. Universita degli Studi di Trento; Italia
Fil: Abdelghany, Elhusseini. University of Cincinnati; Estados Unidos
Fil: Hill, Emily J.. University of Cincinnati; Estados Unidos
Fil: Duque, Kevin R.. University of Cincinnati; Estados Unidos
Fil: Hagen, Matthew C.. University of Cincinnati; Estados Unidos
Fil: Stephen, Christopher D.. Harvard Medical School; Estados Unidos
Fil: Kovacs, Gabor G.. University of Toronto; Canadá
Fil: Lang, Anthony E.. University of Toronto; Canadá
Fil: Hadjivassiliou, Marios. University Of Sheffield (university Of Sheffield);
Fil: Basso, Manuela. Universita degli Studi di Trento; Italia
Fil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Sturchio, Andrea. University of Cincinnati; Estados Unidos
description The gold standard for classification of neurodegenerative diseases is postmortem histopathol-ogy; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new het-erozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.
publishDate 2021
dc.date.none.fl_str_mv 2021-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/184262
Marsili, Luca; Sharma, Jennifer; Espay, Alberto J.; Migazzi, Alice; Abdelghany, Elhusseini; et al.; Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology; MDPI; International Journal of Molecular Sciences; 22; 14; 7-2021; 1-8
1661-6596
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/184262
identifier_str_mv Marsili, Luca; Sharma, Jennifer; Espay, Alberto J.; Migazzi, Alice; Abdelghany, Elhusseini; et al.; Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology; MDPI; International Journal of Molecular Sciences; 22; 14; 7-2021; 1-8
1661-6596
1422-0067
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms22147292
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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