Hereditary spastic paraplegia caused by a mutation in the VCP gene

Abstract

Sir, The hereditary spastic paraplegias constitute a genetically and clinically heterogeneous group of disorders of which the main clinical feature is progressive lower limb spasticity due to pyramidal tract dysfunction. The cardinal signs result from a ‘dying back’ degeneration of the corticospinal tracts and dorsal column, predominantly due to disturbed axonal transport within the longest fibres that innervate the lower extremities. Currently, among the 52 known hereditary spastic paraplegia genetic loci named SPG1–52, at least 28 genes have been identified. One of the rarer autosomal dominant forms of hereditary spastic paraplegia, SPG8, is caused by mutations in the KIAA0196 gene on chromosome 8, encoding the protein strumpellin. In an interesting report in Brain by Clemen et al. (2010), strumpellin was demonstrated to interact with the valosin-containing protein (VCP), suggesting a complementary biological function. Also, strumpellin was detected in several pathological protein aggregates, including those seen in autosomal-dominant inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD; OMIM 605382) (Clemen et al. , 2010). Mutations in the human VCP gene itself cause either IBMPFD or amyotrophic lateral sclerosis with or without frontotemporal dementia (Watts et al. , 2004; Haubenberger et al. , 2005; Guyant-Marechal et al. , 2006; Gidaro et al. , 2008; Bersano et al. , 2009; Johnson et al. , 2010; Fanganiello et al. , 2011; Jesus-Hernandez et al. , 2011; Nalbandian et al. , 2011). Although the paper by Clemen et al. (2010), based on this interaction between VCP and strumpellin, could suggest that VCP mutations may perhaps lead to an hereditary spastic paraplegia phenotype, this has not yet been reported. We recently saw two brothers, both affected by a slowly progressive spastic paraplegia and Paget’s disease of bone, in whom we identified a …