Mutation Analysis of Spastin (SPG4) in Patients with Hereditary Spastic Paraplegia

  • Dr Himesha Vandebona, Department of Neurology/Neurogenetics, Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, Australia
  • Mr Nicholas Kerr, Australia
  • Dr Carolyn Sue, Department of Neurology/Neurogenetics, Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, Australia

    • Background:
    Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. The commonest genetic mutations are within the spastin (SPG4) gene. Spastin mutations can be associated with both complicated and uncomplicated forms of HSP. The frequency of spastin mutations is currently unknown in Australian patients, but has been reported to account for about 40% of autosomal dominant HSP cases in the United Kingdom.

    Aim:
    To determine the frequency of spastin gene mutations in our cohort of patients with HSP.

    Methods:
    We performed PCR and direct nucleotide sequencing for screening mutations in all 17 exons in SPG4 gene in 20 patients with HSP (uncomplicated HSP n=12; complicated HSP n=8). 50% had a positive family history for the disease.

    Results:
    We identified five heterozygous spastin mutations in 5 patients (25% of total). We detected two missense mutations (p.S399L in exon 9 and p.E464D in exon 11), two nonsense mutations (p.W148X in exon 2 and p.R431X in exon 10) and one splicing mutation at intron11 (c.1413+3_1413+6del). The patient with exon11 (p.E464D) mutation had complicated HSP and no family history whereas the other four all had uncomplicated HSP and a positive family history for the disease.

    Conclusions:
    We found SPG4 gene mutations in 25% of HSP patients. Most patients had uncomplicated forms of HSP and a positive family history. Patients with AD HSP should be screened for SPG4 gene mutations, especially if they present with an uncomplicated form of the disease.