Brain Advance Access originally published online on December 13, 2007
Brain 2008 131(3):772-784; doi:10.1093/brain/awm293
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Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration
1INSERM, U679, 2Université Pierre et Marie Curie - Paris 6, UMR S679, 3APHP, Département de Génétique et Cytogénétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, 4Centre de Référence de Neurogénétique, CHU d’Angers, France, 5Unit of Molecular Medicine, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy; 6Service de Neurologie, Hôpital Habib Bourguiba, Sfax, Tunisia, 7Service de Neurologie, Hôpital Mustapha, Algiers, Algeria, 8Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 9Laboratorio de Biologia Cellular y Molecular, Fundacion Allende and Sanatorio Allende, Cordoba, Argentina, 10Department of Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 11Hôpital Benbadis, Constantine, Algeria 12Serviço Neurologia, Hospital De Egas Moniz, Lisboa, 13Departamento de Neurologia, Hospital S. Sebastiao, Santa Maria da Feira, Portugal, 14Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan, 15Department of Neurology, Rouen University Hospital and 16INSERM, U614, Rouen, France, 17Neurology Department, Hôpital Civil, Strasbourg, France, 18Service de Génétique, Hôpital Pellegrin, Bordeaux, France, 19Service de Neurologie, CHU de Montpellier, Hôpital Gui de Chauliac, Montpellier, France, 20Neurological Clinic of Yokohama, Yamate, Japan, 21Department of Neurology, University of Regensburg, Germany, 22Ulleval University Hospital, Oslo, Norway and 23Centre Hospitalier Régional Universitaire, EA2691, Lille, France
Correspondence to: Prof Alexis Brice, INSERM U679, IFR de Neurosciences, Pitié-Salpêtrière Group, 47 Bd de l'Hôpital, 75013 Paris, France E-mail: brice{at}ccr.jussieu.fr
Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 ± 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.
Key Words: spastic paraplegias; SPG11; thin corpus callosum; mental retardation; lower motor neuron degeneration
Abbreviations: AR, autosomal recessive; HSP, hereditary spastic paraplegias; IQ, intellectual quotient; LL, lower limbs; MMSE, Mini Mental State Evaluation; UL, upper limbs; SPG, spastic paraplegia gene; TCC, thin corpus callosum; WMA, white matter abnormalities
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Received September 28, 2007. Revised November 3, 2007. Accepted November 8, 2007.
*The first three authors contributed equally to this work.
The members of the SPATAX consortium are listed in the Appendix.
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