Abstract

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs. Spasticity may occur in isolation (''pure'' HSP) or may be accompanied by other features. Although autosomal recessive HSPs usually have clinically complex phenotypes, mutations within a few genes underlie pure forms. Recently the gene (CYP7B1) responsible for SPG5, a pure recessive HSP, has been identified. The six CYP7B1 coding exons were analysed in four Italian families. Complete clinical assessment was performed in all patients. Blood CYP7B1 mRNA levels were assessed in three patients and six controls. Brain MRI and (18)F-fluoro-deoxy-glucose positron emission tomography (PET) scan were conducted in three patients. Two novel homozygous mutations were identified. Both result in a frameshift and the introduction of a premature stop codon at the C-terminal of the protein. Patients have reduced blood CYP7B1 mRNA levels, suggesting nonsense mediated RNA decay. Although clinical assessment showed a pure form of spastic paraplegia, MRI demonstrated white matter abnormalities in three patients and PET scan revealed cerebellar hypometabolism in one. Based on the results, we report the first Italian families with SPG5 molecular characterization and describe two novel truncating mutations in CYP7B1. The recessive character, the truncating nature of the mutations, and the reduced peripheral blood CYP7B1 mRNA levels suggest that the development of the disease is associated with a loss of function. SPG5 is considered a pure form of HSP, but MRI and PET findings in our patients suggest that SPG5 phenotype may be broader than the pure presentation.