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Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease

OBJECTIVES: To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia. METHODS: We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause. RESULTS: Both siblings presented...

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Autores principales: Burnyte, Birute, Vilimiene, Ramune, Grigalioniene, Kristina, Adomaitiene, Irina, Utkus, Algirdas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088641/
https://www.ncbi.nlm.nih.gov/pubmed/37057294
http://dx.doi.org/10.1212/NXG.0000000000200068
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author Burnyte, Birute
Vilimiene, Ramune
Grigalioniene, Kristina
Adomaitiene, Irina
Utkus, Algirdas
author_facet Burnyte, Birute
Vilimiene, Ramune
Grigalioniene, Kristina
Adomaitiene, Irina
Utkus, Algirdas
author_sort Burnyte, Birute
collection PubMed
description OBJECTIVES: To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia. METHODS: We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause. RESULTS: Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) in PNPLA8. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function. DISCUSSION: Our findings support the theory that biallelic loss-of-function PNPLA8 variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood.
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spelling pubmed-100886412023-04-12 Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease Burnyte, Birute Vilimiene, Ramune Grigalioniene, Kristina Adomaitiene, Irina Utkus, Algirdas Neurol Genet Clinical/Scientific Note OBJECTIVES: To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia. METHODS: We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause. RESULTS: Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) in PNPLA8. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function. DISCUSSION: Our findings support the theory that biallelic loss-of-function PNPLA8 variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood. Wolters Kluwer 2023-04-10 /pmc/articles/PMC10088641/ /pubmed/37057294 http://dx.doi.org/10.1212/NXG.0000000000200068 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Clinical/Scientific Note
Burnyte, Birute
Vilimiene, Ramune
Grigalioniene, Kristina
Adomaitiene, Irina
Utkus, Algirdas
Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease
title Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease
title_full Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease
title_fullStr Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease
title_full_unstemmed Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease
title_short Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease
title_sort cerebellar ataxia and peripheral neuropathy in a family with pnpla8-associated disease
topic Clinical/Scientific Note
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088641/
https://www.ncbi.nlm.nih.gov/pubmed/37057294
http://dx.doi.org/10.1212/NXG.0000000000200068
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