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Mosaicism in ATP1A3-related disorders: not just a theoretical risk

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Abstract

Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS. Here, we report on two unrelated sets of full siblings with ATP1A3 mutations, (c.2116G>A) p. Gly706Arg in the first family, and (c.2266C>T) p. Arg756Cys in the second family, presenting with familial recurrence of the disease. Both families displayed parental germline mosaicism. In the first family, the brother and sister presented with severe intellectual deficiency, early onset pharmacoresistant epilepsy, ataxia, and autistic features. In the second family, both sisters demonstrated severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with ATP1A3-related disorders.

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Acknowledgments

We would like to thank the patients and their families, as well as their referring physicians (especially, DrS. Peudenier) without whom this study would not have been possible. We thank members of the pediatric neurology and medical genetics departments of Necker Enfants Malades for their thoughtful comments.

MH was responsible for conceptualization and design of the study, collected the data, analyzed and interpretated them, drafted, and revised the manuscript for intellectual content. MH had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

JR was responsible for conceptualization and design of the study, collected the data, drafted, and revised portions of the manuscript for intellectual content.

LH performed the molecular analysis and analyzed and interpreted the molecular data. LH drafted and revised portions of the manuscript for intellectual content.

NB collected all the radiological data, drafted, and revised portions of the manuscript for intellectual content.

MB performed the molecular analysis from buccal and urine samples of both parents and revised portions of the manuscript for intellectual content.

MR, ID, VCD, AM, and PdL collected the clinical data and revised portions of the manuscript for intellectual content.

LR revised the manuscript for English language.

NBB was responsible for the design and conceptualization of the study, drafted and revised portions of the manuscript for intellectual content.

CB was responsible for the design and conceptualization of the study, drafted and revised portions of the manuscript for intellectual content.

This work was partially funded by a grant to CB from the Fondation des Maladies Rares.

Author information

Authors and Affiliations

  1. Department of Pediatric Neurology, Necker Enfants Malades Hospital, APHP, 149 rue de Sèvres, 75015, Paris, France

    Marie Hully, Isabelle Desguerre & Nadia Bahi-Buisson

  2. Department of Pediatrics, University Hospital, Brest, France

    Juliette Ropars

  3. Laboratoire du Traitement de l’Information Médicale LaTIM INSERM UMR 1101, Brest, France

    Juliette Ropars

  4. Imagine Institute, Paris Descartes – Sorbonne Paris Cité University, Paris, France

    Laurence Hubert, Nathalie Boddaert, Isabelle Desguerre, Valerie Cormier-Daire, Arnold Munnich, Pascale de Lonlay, Louise Reilly, Claude Besmond & Nadia Bahi-Buisson

  5. INSERM UMR1163, Translational Genetics, Imagine Institute, Paris, France

    Laurence Hubert & Claude Besmond

  6. Department of Pediatric Radiology, Necker Enfants Malades Hospital, APHP, Paris, France

    Nathalie Boddaert

  7. INSERM U1000, UMR 1163, Institut Imagine, Paris, France

    Nathalie Boddaert

  8. Department of Medical Genetics, Necker Enfants Malades Hospital, APHP, Paris, France

    Marlene Rio, Valerie Cormier-Daire & Arnold Munnich

  9. Department of Molecular Genetics, Necker Enfants Malades Hospital, APHP, Paris, France

    Mathieu Bernardelli

  10. Reference Center of Inherited Metabolic Diseases, Necker Enfants Malades Hospital, APHP, Paris, France

    Pascale de Lonlay

  11. INSERM UMR-1163, Laboratory of Inherited Kidney Diseases, Imagine Institute, Paris, France

    Louise Reilly

  12. Paris Diderot University, 75013, Paris, France

    Louise Reilly

  13. INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Imagine Institute, Paris, France

    Nadia Bahi-Buisson

Authors
  1. Marie Hully
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  2. Juliette Ropars
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  3. Laurence Hubert
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  5. Marlene Rio
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  7. Isabelle Desguerre
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  12. Claude Besmond
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  13. Nadia Bahi-Buisson
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Corresponding author

Correspondence to Nadia Bahi-Buisson.

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The authors declare that they have no conflicts of interest.

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Claude Besmond and Nadia Bahi-Buisson contributed equally to this work.

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Hully, M., Ropars, J., Hubert, L. et al. Mosaicism in ATP1A3-related disorders: not just a theoretical risk. Neurogenetics 18, 23–28 (2017). https://doi.org/10.1007/s10048-016-0498-9

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  • DOI: https://doi.org/10.1007/s10048-016-0498-9

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