A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course
An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and altera...
Published in: | European Journal of Human Genetics |
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Online Access: | https://portal.findresearcher.sdu.dk/da/publications/21dffa26-5dba-4b2f-8f1b-aef8f931437d https://doi.org/10.1038/s41431-018-0204-5 |
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ftsydanskunivpub:oai:sdu.dk:publications/21dffa26-5dba-4b2f-8f1b-aef8f931437d 2023-05-15T16:10:57+02:00 A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course Grønborg, Sabine Risom, Lotte Ek, Jakob Larsen, Karen Bonde Scheie, David Petkov, Yanko Larsen, Vibeke André Dunø, Morten Joensen, Fróði Østergaard, Elsebet 2018-06 https://portal.findresearcher.sdu.dk/da/publications/21dffa26-5dba-4b2f-8f1b-aef8f931437d https://doi.org/10.1038/s41431-018-0204-5 eng eng info:eu-repo/semantics/closedAccess Grønborg , S , Risom , L , Ek , J , Larsen , K B , Scheie , D , Petkov , Y , Larsen , V A , Dunø , M , Joensen , F & Østergaard , E 2018 , ' A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course ' , European Journal of Human Genetics , vol. 26 , no. 10 , pp. 1512-1520 . https://doi.org/10.1038/s41431-018-0204-5 article 2018 ftsydanskunivpub https://doi.org/10.1038/s41431-018-0204-5 2022-08-14T10:04:51Z An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the α-/β-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.[3099C>G]; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroese population (2.6%). The patients had similar age of onset as the previously reported patients (n = 24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples. Article in Journal/Newspaper Faroe Islands University of Southern Denmark Research Portal Faroe Islands European Journal of Human Genetics 26 10 1512 1520 |
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University of Southern Denmark Research Portal |
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ftsydanskunivpub |
language |
English |
description |
An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the α-/β-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.[3099C>G]; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroese population (2.6%). The patients had similar age of onset as the previously reported patients (n = 24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples. |
format |
Article in Journal/Newspaper |
author |
Grønborg, Sabine Risom, Lotte Ek, Jakob Larsen, Karen Bonde Scheie, David Petkov, Yanko Larsen, Vibeke André Dunø, Morten Joensen, Fróði Østergaard, Elsebet |
spellingShingle |
Grønborg, Sabine Risom, Lotte Ek, Jakob Larsen, Karen Bonde Scheie, David Petkov, Yanko Larsen, Vibeke André Dunø, Morten Joensen, Fróði Østergaard, Elsebet A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course |
author_facet |
Grønborg, Sabine Risom, Lotte Ek, Jakob Larsen, Karen Bonde Scheie, David Petkov, Yanko Larsen, Vibeke André Dunø, Morten Joensen, Fróði Østergaard, Elsebet |
author_sort |
Grønborg, Sabine |
title |
A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course |
title_short |
A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course |
title_full |
A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course |
title_fullStr |
A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course |
title_full_unstemmed |
A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course |
title_sort |
faroese founder variant in tbcd causes early onset, progressive encephalopathy with a homogenous clinical course |
publishDate |
2018 |
url |
https://portal.findresearcher.sdu.dk/da/publications/21dffa26-5dba-4b2f-8f1b-aef8f931437d https://doi.org/10.1038/s41431-018-0204-5 |
geographic |
Faroe Islands |
geographic_facet |
Faroe Islands |
genre |
Faroe Islands |
genre_facet |
Faroe Islands |
op_source |
Grønborg , S , Risom , L , Ek , J , Larsen , K B , Scheie , D , Petkov , Y , Larsen , V A , Dunø , M , Joensen , F & Østergaard , E 2018 , ' A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course ' , European Journal of Human Genetics , vol. 26 , no. 10 , pp. 1512-1520 . https://doi.org/10.1038/s41431-018-0204-5 |
op_rights |
info:eu-repo/semantics/closedAccess |
op_doi |
https://doi.org/10.1038/s41431-018-0204-5 |
container_title |
European Journal of Human Genetics |
container_volume |
26 |
container_issue |
10 |
container_start_page |
1512 |
op_container_end_page |
1520 |
_version_ |
1765996087111319552 |