Document Detail

Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.
MedLine Citation:
PMID:  18079167     Owner:  NLM     Status:  MEDLINE    
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.
Giovanni Stevanin; Hamid Azzedine; Paola Denora; Amir Boukhris; Meriem Tazir; Alexander Lossos; Alberto Luis Rosa; Israela Lerer; Abdelmadjid Hamri; Paulo Alegria; José Loureiro; Masayoshi Tada; Didier Hannequin; Mathieu Anheim; Cyril Goizet; Victoria Gonzalez-Martinez; Isabelle Le Ber; Sylvie Forlani; Kiyoshi Iwabuchi; Vardiela Meiner; Goekhan Uyanik; Anne Kjersti Erichsen; Imed Feki; Florence Pasquier; Soreya Belarbi; Vitor T Cruz; Christel Depienne; Jeremy Truchetto; Guillaume Garrigues; Chantal Tallaksen; Christine Tranchant; Masatoyo Nishizawa; José Vale; Paula Coutinho; Filippo M Santorelli; Chokri Mhiri; Alexis Brice; Alexandra Durr;
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Publication Detail:
Type:  Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't     Date:  2007-12-13
Journal Detail:
Title:  Brain : a journal of neurology     Volume:  131     ISSN:  1460-2156     ISO Abbreviation:  Brain     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-02-22     Completed Date:  2008-05-01     Revised Date:  2011-11-24    
Medline Journal Info:
Nlm Unique ID:  0372537     Medline TA:  Brain     Country:  England    
Other Details:
Languages:  eng     Pagination:  772-84     Citation Subset:  AIM; IM    
1INSERM, U679, Université Pierre et Marie Curie-Paris 6, UMR S679, Paris, France.
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MeSH Terms
Age of Onset
Base Sequence
Brain / pathology
Child, Preschool
Cognition Disorders / genetics*,  pathology
Corpus Callosum / pathology*
DNA Mutational Analysis / methods
Genes, Recessive
Genetic Linkage
Intellectual Disability / genetics,  pathology
Magnetic Resonance Imaging
Molecular Sequence Data
Motor Neuron Disease / genetics,  pathology
Proteins / genetics*
Spastic Paraplegia, Hereditary / genetics*,  pathology,  psychology
Grant Support
Reg. No./Substance:
0/Proteins; 0/SPG11 protein, human

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