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ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability

BACKGROUND: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of...

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Autores principales: Skopkova, Martina, Stufkova, Hana, Rambani, Vibhuti, Stranecky, Viktor, Brennerova, Katarina, Kolnikova, Miriam, Pietrzykova, Michaela, Karhanek, Miloslav, Noskova, Lenka, Tesarova, Marketa, Hansikova, Hana, Gasperikova, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127305/
https://www.ncbi.nlm.nih.gov/pubmed/37095554
http://dx.doi.org/10.1186/s13023-023-02689-3
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author Skopkova, Martina
Stufkova, Hana
Rambani, Vibhuti
Stranecky, Viktor
Brennerova, Katarina
Kolnikova, Miriam
Pietrzykova, Michaela
Karhanek, Miloslav
Noskova, Lenka
Tesarova, Marketa
Hansikova, Hana
Gasperikova, Daniela
author_facet Skopkova, Martina
Stufkova, Hana
Rambani, Vibhuti
Stranecky, Viktor
Brennerova, Katarina
Kolnikova, Miriam
Pietrzykova, Michaela
Karhanek, Miloslav
Noskova, Lenka
Tesarova, Marketa
Hansikova, Hana
Gasperikova, Daniela
author_sort Skopkova, Martina
collection PubMed
description BACKGROUND: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses. RESULTS: Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3–4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients. CONCLUSION: The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-023-02689-3.
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spelling pubmed-101273052023-04-26 ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability Skopkova, Martina Stufkova, Hana Rambani, Vibhuti Stranecky, Viktor Brennerova, Katarina Kolnikova, Miriam Pietrzykova, Michaela Karhanek, Miloslav Noskova, Lenka Tesarova, Marketa Hansikova, Hana Gasperikova, Daniela Orphanet J Rare Dis Research BACKGROUND: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses. RESULTS: Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3–4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients. CONCLUSION: The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-023-02689-3. BioMed Central 2023-04-24 /pmc/articles/PMC10127305/ /pubmed/37095554 http://dx.doi.org/10.1186/s13023-023-02689-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Skopkova, Martina
Stufkova, Hana
Rambani, Vibhuti
Stranecky, Viktor
Brennerova, Katarina
Kolnikova, Miriam
Pietrzykova, Michaela
Karhanek, Miloslav
Noskova, Lenka
Tesarova, Marketa
Hansikova, Hana
Gasperikova, Daniela
ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
title ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
title_full ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
title_fullStr ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
title_full_unstemmed ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
title_short ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
title_sort atad3a-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127305/
https://www.ncbi.nlm.nih.gov/pubmed/37095554
http://dx.doi.org/10.1186/s13023-023-02689-3
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