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The location of DCX mutations predicts malformation severity in X-linked lissencephaly

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Abstract

Lissencephaly spectrum (LIS) is one of the most severe neuronal migration disorders that ranges from agyria/pachygyria to subcortical band heterotopia. Approximately 80% of patients with the LIS spectrum carry mutations in either the LIS1 or DCX (doublecortin) genes which have an opposite gradient of severity. The aim of the study was to evaluate in detail the phenotype of DCX-associated lissencephaly and to look for genotype–phenotype correlations. Of the 180 male patients with DCX-related lissencephaly, 33 males (24 familial cases and nine cases with de novo mutations) were found with hemizygous DCX mutations and were clinically and genetically assessed here. DCX mutation analysis revealed that the majority of mutations were missense (79.2%), clustered in the two evolutionary conserved domains, N-DC and C-DC, of DCX. The most prominent radiological phenotype was an anteriorly predominant pachygyria or agyria (54.5%) although DCX-associated lissencephaly encompasses a complete range of LIS grades. The severity of neurological impairment was in accordance with the degree of agyria with severe cognitive impairment in all patients, inability to walk independently in over half and refractory epilepsy in more than a third. For genotype–phenotype correlations, patients were divided in two groups according to the location of DCX missense mutations. Patients with mutations in the C-DC domain tended to have a less severe lissencephaly (grade 4–5 in 58.3%) compared with those in the N-DC domain (grade 4–5 in 36.3%) although, in this dataset, this was not statistically significant (p = 0.12). Our evaluation suggests a putative correlation between phenotype and genotype. These data provide further clues to deepen our understanding of the function of the DCX protein and may give new insights into the molecular mechanisms that could influence the consequence of the mutation in the N-DC versus the C-DC domain of DCX.

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Acknowledgements

The authors wish to thank all the families and clinicians Valérie Lieko, Marie Ange N’Guyen Morel, Isabelle Caubel, Pierre Angelo Vegiotti, Laurence Faivre Olivier, Bertrand Sotos, Anna Kaminska, Isabelle Desguerre and Sylvie Odent whose cooperation made this study possible. We thank David Keays and Drs M. Eisermann, Dr Soufflet and P Plouin for their helpful discussions and their help in the EEG analysis. This work was supported by the Société d'Etudes et de Soins pour les Enfants Paralysés et Polymalformés (CESEP).

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Authors and Affiliations

  1. Service de Neurologie Pédiatrique, Département de Pédiatrie, Hopital Necker Enfants Malades, AP-HP, Université Paris Descartes, 149 rue de Sevres, 75015, Paris, France

    Pierre-Louis Leger & Nadia Bahi-Buisson

  2. Laboratoire de Génétique Moléculaire Pavillon Cassini Hopital Cochin AP-HP, Université Paris Descartes, Paris, France

    Isabelle Souville, Jamel Chelly & Cherif Beldjord

  3. Service de Radiologie Pédiatrique, Hopital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France

    Nathalie Boddaert

  4. Inserm, U797-INSERM-CEA, Service Hospitalier Frédéric Joliot, CEA, 4, place du General Leclerc, 91406, Orsay, France

    Nathalie Boddaert

  5. Unité de Bioinformatique, Hopital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France

    Caroline Elie

  6. Service de Neurologie Pédiatrique, Hopital Raymond Poincaré AP-HP, Garches, France

    Jean Marc Pinard

  7. Laboratoire de Neurophysiologie Hopital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France

    Perrine Plouin

  8. Service de Neurologie Pédiatrique, Hopital Trousseau AP-HP, Paris, France

    Marie Laure Moutard

  9. Service de Neuropédiatrie Centre Hospitalo, Universitaire de Lyon, Lyon, France

    Vincent des Portes

  10. Center for Human Genetics, University Hospital Leuven, Leuven, Belgium

    Hilde Van Esch

  11. Service de Neuropédiatrie Clinique Hopital Jeanne de Flandres Centre Hospitalo-Universitaire de Lille, Lille, France

    Sylvie Joriot

  12. Service de Neurologie, HIA Val-de-Grâce, Paris, France

    Jean Louis Renard

  13. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France

    Jamel Chelly, Fiona Francis, Cherif Beldjord & Nadia Bahi-Buisson

  14. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Inserm U867, Paris, France

    Jamel Chelly, Fiona Francis, Cherif Beldjord & Nadia Bahi-Buisson

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  1. Pierre-Louis Leger
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  2. Isabelle Souville
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Correspondence to Nadia Bahi-Buisson.

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Leger, PL., Souville, I., Boddaert, N. et al. The location of DCX mutations predicts malformation severity in X-linked lissencephaly. Neurogenetics 9, 277–285 (2008). https://doi.org/10.1007/s10048-008-0141-5

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  • DOI: https://doi.org/10.1007/s10048-008-0141-5

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