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Novel Compound Heterozygous Mutations in TBC1D24 Cause Familial Malignant Migrating Partial Seizures of Infancy

Authors

  • Mathieu Milh,

    Corresponding author
    1. Aix-Marseille Université, Faculté de Médecine de Marseille, Marseille, France
    2. Assistance Publique Hôpitaux de Marseille, Service de Neurop'diatrie, Hôpital d'Enfants de La Timone, Marseille, France
    • Inserm, U910, Marseille, France
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    • These two authors contributed equally.

  • Antonio Falace,

    1. Department of Experimental Medicine, Section Physiology, University of Genoa, Genoa, Italy
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    • These two authors contributed equally.

  • Nathalie Villeneuve,

    1. Assistance Publique Hôpitaux de Marseille, Service de Neurop'diatrie, Hôpital d'Enfants de La Timone, Marseille, France
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  • Nicola Vanni,

    1. Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute, University of Genoa, Genoa, Italy
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  • Pierre Cacciagli,

    1. Inserm, U910, Marseille, France
    2. Aix-Marseille Université, Faculté de Médecine de Marseille, Marseille, France
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  • Stefania Assereto,

    1. Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute, University of Genoa, Genoa, Italy
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  • Rima Nabbout,

    1. Assistance Publique Hôpitaux de Paris, Centre de Référence des Epilepsies Rares de l'Enfant, Hôpital Necker Enfants Malades, Paris, France
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  • Fabio Benfenati,

    1. Department of Experimental Medicine, Section Physiology, University of Genoa, Genoa, Italy
    2. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy
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  • Federico Zara,

    1. Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute, University of Genoa, Genoa, Italy
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  • Brigitte Chabrol,

    1. Inserm, U910, Marseille, France
    2. Aix-Marseille Université, Faculté de Médecine de Marseille, Marseille, France
    3. Assistance Publique Hôpitaux de Marseille, Service de Neurop'diatrie, Hôpital d'Enfants de La Timone, Marseille, France
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  • Laurent Villard,

    1. Inserm, U910, Marseille, France
    2. Aix-Marseille Université, Faculté de Médecine de Marseille, Marseille, France
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  • Anna Fassio

    1. Department of Experimental Medicine, Section Physiology, University of Genoa, Genoa, Italy
    2. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy
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  • Additional Supporting Information may be found in the online version of this article.

  • Communicated by Lars Bertram

  • Contract grant sponsors: INSERM (Contrat d'Interface pour Hospitalier) Aix Marseille Université Assistance Publique Hôpitaux de Marseille (Contrat Hospitalier de Recherche Translationnelle) Programme Hospitalier de Recherche Clinique (PHRC); GIS institut des maladies rares (Exome sequencing), France; Consorzio Italiano di Biotecnologie, Italy; Italian Ministry of Health and Compagnia di San Paolo (Torino).

Correspondence to: Mathieu Milh, INSERM, U910, Aix-Marseille Université, Boulevard Jean Moulin, Marseille F13005, France. E-mail: mathieu.milh@ap-hm.fr

ABSTRACT

Early-onset epileptic encephalopathies (EOEEs) are a group of rare devastating epileptic syndromes of infancy characterized by severe drug-resistant seizures and electroencephalographic abnormalities. The current study aims to determine the genetic etiology of a familial form of EOEE fulfilling the diagnosis criteria for malignant migrating partial seizures of infancy (MMPSI). We identified two inherited novel mutations in TBC1D24 in two affected siblings. Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits. The screening of TBC1D24 in an additional set of eight MMPSI patients was negative. TBC1D24 loss of function has been associated to idiopathic infantile myoclonic epilepsy, as well as to drug-resistant early-onset epilepsy with intellectual disability. Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction.

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