New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)

Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and under...

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Authors: Corral Juan, Marc, Casquero, Pilar, Giraldo Restrepo, Natalia, Laurie, Steve, Martinez Piñeiro, Alicia, Mateo Montero, Raidili Cristina, Ispierto, Lourdes, Vilas, Dolores, Tolosa, Eduardo, Volpini, Victor, Alvarez Ramo, Ramiro, Sánchez, Ivelisse, Matilla Dueñas, Antoni
Format: article
Publication Date:2022
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/184623
Online Access:https://hdl.handle.net/2445/184623
Access Level:Open access
Keyword:Cerebel
Malalties neurodegeneratives
Cerebellum
Neurodegenerative Diseases
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spelling New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)Corral Juan, MarcCasquero, PilarGiraldo Restrepo, NataliaLaurie, SteveMartinez Piñeiro, AliciaMateo Montero, Raidili CristinaIspierto, LourdesVilas, DoloresTolosa, EduardoVolpini, VictorAlvarez Ramo, RamiroSánchez, IvelisseMatilla Dueñas, AntoniCerebelMalalties neurodegenerativesCerebellumNeurodegenerative DiseasesSpinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Z(max) = 3.43; theta = 0.00; P < 3.53 x 10(-5)). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions. Corral-Juan et al. describe a novel dominantly inherited spinocerebellar ataxia subtype, SCA49, caused by SAMD9L mutation characterized by polyneuropathy, distinctive cerebral demyelination with gaze-evoked nystagmus and hyperreflexia as initial clinical signs. The study demonstrates the mitochondrial location of human SAMD9L protein triggering mitochondrial and lysosomal alterations.Oxford University Press (OUP)info:eu-repo/semantics/publishedVersion2022info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2445/184623Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1093/braincomms/fcac030Brain Communications, 2022, vol 4, num 2https://doi.org/10.1093/braincomms/fcac030cc by (c) Corral Juan, Marc et al, 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1846232026-05-27T06:46:51Z
dc.title.none.fl_str_mv New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
title New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
spellingShingle New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
Corral Juan, Marc
Cerebel
Malalties neurodegeneratives
Cerebellum
Neurodegenerative Diseases
title_short New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
title_full New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
title_fullStr New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
title_full_unstemmed New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
title_sort New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)
dc.creator.none.fl_str_mv Corral Juan, Marc
Casquero, Pilar
Giraldo Restrepo, Natalia
Laurie, Steve
Martinez Piñeiro, Alicia
Mateo Montero, Raidili Cristina
Ispierto, Lourdes
Vilas, Dolores
Tolosa, Eduardo
Volpini, Victor
Alvarez Ramo, Ramiro
Sánchez, Ivelisse
Matilla Dueñas, Antoni
author Corral Juan, Marc
author_facet Corral Juan, Marc
Casquero, Pilar
Giraldo Restrepo, Natalia
Laurie, Steve
Martinez Piñeiro, Alicia
Mateo Montero, Raidili Cristina
Ispierto, Lourdes
Vilas, Dolores
Tolosa, Eduardo
Volpini, Victor
Alvarez Ramo, Ramiro
Sánchez, Ivelisse
Matilla Dueñas, Antoni
author_role author
author2 Casquero, Pilar
Giraldo Restrepo, Natalia
Laurie, Steve
Martinez Piñeiro, Alicia
Mateo Montero, Raidili Cristina
Ispierto, Lourdes
Vilas, Dolores
Tolosa, Eduardo
Volpini, Victor
Alvarez Ramo, Ramiro
Sánchez, Ivelisse
Matilla Dueñas, Antoni
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.subject.none.fl_str_mv Cerebel
Malalties neurodegeneratives
Cerebellum
Neurodegenerative Diseases
topic Cerebel
Malalties neurodegeneratives
Cerebellum
Neurodegenerative Diseases
description Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Z(max) = 3.43; theta = 0.00; P < 3.53 x 10(-5)). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions. Corral-Juan et al. describe a novel dominantly inherited spinocerebellar ataxia subtype, SCA49, caused by SAMD9L mutation characterized by polyneuropathy, distinctive cerebral demyelination with gaze-evoked nystagmus and hyperreflexia as initial clinical signs. The study demonstrates the mitochondrial location of human SAMD9L protein triggering mitochondrial and lysosomal alterations.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/184623
url https://hdl.handle.net/2445/184623
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1093/braincomms/fcac030
Brain Communications, 2022, vol 4, num 2
https://doi.org/10.1093/braincomms/fcac030
dc.rights.none.fl_str_mv cc by (c) Corral Juan, Marc et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Corral Juan, Marc et al, 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford University Press (OUP)
publisher.none.fl_str_mv Oxford University Press (OUP)
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408744257880064
score 15.301629

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