Eight Novel Mutations in SPG4 in a Large Sample of Patients With Hereditary Spastic Paraplegia

Background

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs. Mutations in theSPG4gene, which encodes spastin protein, are responsible for up to 45% of autosomal dominant cases.

Objective

To search for disease-causing mutations in a large series of Italian patients with HSP.

Design

Samples of DNA were analyzed by direct sequencing of all exons inSPG4. Samples from a subset of patients were also analyzed by direct sequencing of all exons inSPG3A, SPG6, SPG10, andSPG13.

Setting

Molecular testing facility in Italy.

Patients

Sixty unrelated Italian patients with pure (n = 50) and complicated (n = 10) HSP.

Main Outcome Measures

Mutations inSPG4, SPG3A, SPG6, SPG10, andSPG13.

Results

We identified 12 different mutations, 8 of which were novel, in 13 patients. No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in theSPG4gene.

Conclusions

The overall rate of mutation in theSPG4gene within our sample was 22%, rising to 26% when only patients with pure HSP were considered. The negative result obtained in 15 patients without mutations inSPG4in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, andSPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.