SPAST mutations in Australian patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is often caused by mutations in the SPAST gene. The frequency of SPAST mutations causing HSP in Australian patients is currently unknown. AIM: We aimed to determine the frequency of SPAST gene mutations in our cohort of HSP patients.
METHODS: We recruited 30 unrelated patients with HSP for clinical and genetic assessment. DNA or RNA was extracted from patients' samples to perform direct DNA sequencing of the SPAST gene, multiplex ligation-dependent probe amplification (MLPA) and/or cDNA analysis.
RESULTS: We identified 13 heterozygous SPAST mutations in 16 unrelated patients. Most mutations (75%) were detected by DNA sequence analysis. We identified nine-point mutations (n = 9), insertion (n = 1), one type of splice site mutation (n = 2), one type of exonic deletion (n = 2) and one type of exonic amplification (n = 2). Missense mutations (n = 7) were the most frequent mutation type (44%). Heterozygous exonic deletion (n = 2) and heterozygous exonic amplification (n = 2) were identified by MLPA and cDNA screening (25%). We also identified the single heterozygous p.Ser44Leu polymorphism in two other patients without pathogenic mutations in SPAST.
CONCLUSION: We conclude that SPAST mutations are responsible for the majority of HSP in Australia. Most of the patients with SPAST mutations had pure forms of HSP and a positive family history to suggest autosomal dominant (AD) HSP. Not all mutations were identified by direct sequencing of the SPAST gene, necessitating further molecular analysis. Given that SPAST mutations cause AD-HSP, these findings are important when providing genetic counselling for affected patients.