Novel and recurrent spastin mutations in a large series of SPG4 Italian families

Hereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders, genetically classified according to the identified disease gene or locus. Clinically, HSP are distinguished in pure and complicated forms. Mutations in the spastin gene (SPAST) are responsible for SPG4 and account approximately for 50% of the dominantly inherited paraplegias with a pure HSP phenotype.

Molecular screening of the SPAST gene allowed the identification of 31 Italian mutation carriers, from 19 unrelated families. Genetic testing was performed by direct sequencing and multiplex ligation-dependent probe amplification. Subjects carrying SPAST mutations were retrospectively evaluated for clinical phenotype and disability score assessment.

We found 12 recurrent mutations, and 7 novel SPAST mutations. Twenty-eight patients exhibited a pure spastic paraplegia phenotype, while 3 subjects were asymptomatic mutation carriers. Four patients were sporadic cases. Age at onset ranged from 10 to 61 years. Disability score increased with age at examination and disease duration. Patients with onset >38 years presented a faster disease progression, and a higher disability functional index, than the patients with earlier onset (p<0.04).

Our study enlarges the number of pathogenic SPAST mutations, and confirms the association with a pure spastic paraplegia phenotype. Age at onset was highly variable and correlates with the rate of disease progression. Future longitudinal clinical studies are needed to confirm these observations.