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Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy
OBJECTIVE: To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes. METHODS: We performed an international cross-sectional study on patients with genetically proven POLR3-rel...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238899/ https://www.ncbi.nlm.nih.gov/pubmed/32582862 http://dx.doi.org/10.1212/NXG.0000000000000425 |
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author | Perrier, Stefanie Gauquelin, Laurence Fallet-Bianco, Catherine Dishop, Megan K. Michell-Robinson, Mackenzie A. Tran, Luan T. Guerrero, Kether Darbelli, Lama Srour, Myriam Petrecca, Kevin Renaud, Deborah L. Saito, Michael Cohen, Seth Leiz, Steffen Alhaddad, Bader Haack, Tobias B. Tejera-Martin, Ingrid Monton, Fernando I. Rodriguez-Espinosa, Norberto Pohl, Daniela Nageswaran, Savithri Grefe, Annette Glamuzina, Emma Bernard, Geneviève |
author_facet | Perrier, Stefanie Gauquelin, Laurence Fallet-Bianco, Catherine Dishop, Megan K. Michell-Robinson, Mackenzie A. Tran, Luan T. Guerrero, Kether Darbelli, Lama Srour, Myriam Petrecca, Kevin Renaud, Deborah L. Saito, Michael Cohen, Seth Leiz, Steffen Alhaddad, Bader Haack, Tobias B. Tejera-Martin, Ingrid Monton, Fernando I. Rodriguez-Espinosa, Norberto Pohl, Daniela Nageswaran, Savithri Grefe, Annette Glamuzina, Emma Bernard, Geneviève |
author_sort | Perrier, Stefanie |
collection | PubMed |
description | OBJECTIVE: To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes. METHODS: We performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient. RESULTS: Each patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript. CONCLUSIONS: We describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology. |
format | Online Article Text |
id | pubmed-7238899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Wolters Kluwer |
record_format | MEDLINE/PubMed |
spelling | pubmed-72388992020-06-23 Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy Perrier, Stefanie Gauquelin, Laurence Fallet-Bianco, Catherine Dishop, Megan K. Michell-Robinson, Mackenzie A. Tran, Luan T. Guerrero, Kether Darbelli, Lama Srour, Myriam Petrecca, Kevin Renaud, Deborah L. Saito, Michael Cohen, Seth Leiz, Steffen Alhaddad, Bader Haack, Tobias B. Tejera-Martin, Ingrid Monton, Fernando I. Rodriguez-Espinosa, Norberto Pohl, Daniela Nageswaran, Savithri Grefe, Annette Glamuzina, Emma Bernard, Geneviève Neurol Genet Article OBJECTIVE: To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes. METHODS: We performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient. RESULTS: Each patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript. CONCLUSIONS: We describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology. Wolters Kluwer 2020-05-11 /pmc/articles/PMC7238899/ /pubmed/32582862 http://dx.doi.org/10.1212/NXG.0000000000000425 Text en Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://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 | Article Perrier, Stefanie Gauquelin, Laurence Fallet-Bianco, Catherine Dishop, Megan K. Michell-Robinson, Mackenzie A. Tran, Luan T. Guerrero, Kether Darbelli, Lama Srour, Myriam Petrecca, Kevin Renaud, Deborah L. Saito, Michael Cohen, Seth Leiz, Steffen Alhaddad, Bader Haack, Tobias B. Tejera-Martin, Ingrid Monton, Fernando I. Rodriguez-Espinosa, Norberto Pohl, Daniela Nageswaran, Savithri Grefe, Annette Glamuzina, Emma Bernard, Geneviève Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy |
title | Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy |
title_full | Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy |
title_fullStr | Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy |
title_full_unstemmed | Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy |
title_short | Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy |
title_sort | expanding the phenotypic and molecular spectrum of rna polymerase iii–related leukodystrophy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238899/ https://www.ncbi.nlm.nih.gov/pubmed/32582862 http://dx.doi.org/10.1212/NXG.0000000000000425 |
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