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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/184262
Ver los metadatos del registro completo
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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 Técnicas2025-09-03T09:53:08Zoai: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:34982025-09-03 09:53:09.043CONICET 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 |
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openAccess |
rights_invalid_str_mv |
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application/pdf application/pdf |
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MDPI |
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MDPI |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.13397 |