Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration

Brain. 2008 Mar;131(Pt 3):772-84. doi: 10.1093/brain/awm293. Epub 2007 Dec 13.

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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Base Sequence
  • Brain / pathology
  • Child
  • Child, Preschool
  • Cognition Disorders / genetics*
  • Cognition Disorders / pathology
  • Corpus Callosum / pathology*
  • DNA Mutational Analysis / methods
  • Female
  • Genes, Recessive
  • Genetic Linkage
  • Genotype
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Magnetic Resonance Imaging
  • Male
  • Molecular Sequence Data
  • Motor Neuron Disease / genetics
  • Motor Neuron Disease / pathology
  • Mutation*
  • Pedigree
  • Phenotype
  • Proteins / genetics*
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / pathology
  • Spastic Paraplegia, Hereditary / psychology

Substances

  • Proteins
  • SPG11 protein, human