Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10

Authors

  • Cyril Goizet,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
    3. Université Victor Segalen Bordeaux 2, Laboratoire de Génétique Humaine, Bordeaux, France
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    • These authors contributed equally to the work

  • Amir Boukhris,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
    3. AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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    • These authors contributed equally to the work

  • Emeline Mundwiller,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
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  • Chantal Tallaksen,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
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  • Sylvie Forlani,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
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  • Annick Toutain,

    1. Centre Hospitalier, Department of Genetics, Tours, France
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  • Nathalie Carriere,

    1. Centre Hospitalier, Department of Neurology, Clermont-Ferrand, France
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  • Véronique Paquis,

    1. Centre Hospitalier, Service de Génétique Médicale, Nice, France
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  • Christel Depienne,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
    3. AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Alexandra Durr,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
    3. AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Giovanni Stevanin,

    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
    3. AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Alexis Brice

    Corresponding author
    1. INSERM, UMR_S679, Paris, France
    2. UPMC Univ Paris 06, UMR_S679, Pitié-Salpêtrière Hospital, Paris, France
    3. AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
    • INSERM U679, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France; Tel.: +33.1.42.16.21.82; Fax: +33.1.44.24.36.58
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  • Communicated by Mireille Claustres

Abstract

Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. Only a few different mutations in the SPG10 gene, KIF5A, have been described in pure dominant forms of the disease. We sequenced the motor domain of KIF5A in a large panel of 205 European HSP patients with either pure or complicated forms of the disease. We identified eight different heterozygous missense mutations, seven novels, in eight different families of French origin. Residue R280 was a mutational hot spot. Interestingly, the patients in 7/8 families had a complex phenotype, with peripheral neuropathy, severe upper limb amyotrophy (Silver syndrome-like), mental impairment, parkinsonism, deafness and/or retinitis pigmentosa as variably associated features. We report the largest series of SPG10 families described so far, which extends both the mutational spectrum of the disease and its phenotype, which now includes complicated forms of HSP. SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that mutations in KIF5A represent the major cause of complicated AD-HSP in France. © 2008 Wiley-Liss, Inc.

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