title: Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.
abstract: 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.
authors: 1INSERM, U679, Université Pierre et Marie Curie-Paris 6, UMR S679, Paris, France.
authors: Giovanni
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authors: Stevanin
authors: Hamid
authors: H
authors: Azzedine
authors: Paola
authors: P
authors: Denora
authors: Amir
authors: A
authors: Boukhris
authors: Meriem
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authors: Tazir
authors: Alexander
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authors: Lossos
authors: Alberto Luis
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authors: Rosa
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authors: Lerer
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authors: Hamri
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authors: Alegria
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authors: Loureiro
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authors: Hannequin
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authors: Anheim
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authors: Goizet
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authors: V
authors: Gonzalez-Martinez
authors: Isabelle
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authors: Forlani
authors: Kiyoshi
authors: K
authors: Iwabuchi
authors: Vardiela
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authors: Meiner
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authors: Uyanik
authors: Anne Kjersti
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authors: Erichsen
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authors: Feki
authors: Florence
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authors: Pasquier
authors: Soreya
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authors: Belarbi
authors: Vitor T
authors: VT
authors: Cruz
authors: Christel
authors: C
authors: Depienne
authors: Jeremy
authors: J
authors: Truchetto
authors: Guillaume
authors: G
authors: Garrigues
authors: Chantal
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authors: Christine
authors: C
authors: Tranchant
authors: Masatoyo
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authors: Nishizawa
authors: José
authors: J
authors: Vale
authors: Paula
authors: P
authors: Coutinho
authors: Filippo M
authors: FM
authors: Santorelli
authors: Chokri
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authors: Mhiri
authors: Alexis
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authors: Brice
authors: Alexandra
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authors: Durr
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology; D003337:Corpus Callosum / Q000473:pathology*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology / Q000523:psychology
chemical_list: D011506:Proteins; C520412:SPG11 protein, human