Op-brai120109 1..3

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 pathogenic mutation in the VCP gene (NM_007126.3) c.475 C4T (p.Arg159Cys). The Arg159Cys mutation affects an arginine residue highly conserved during evolution, located in the N-terminal (CDC48) domain, which is involved in substrate binding (e.g. ubiquitin) and lies within the mutational hot spot (Watts et al., 2004). To date, this missense mutation has only been identified in a sporadic Italian patient with the above mentioned phenotype of adult-onset inclusion body myopathy, who developed frontotemporal dementia 18 years after inclusion body myopathy onset (Bersano et al., 2009). The two Dutch brothers described here developed a slowly progressive gait impairment in their sixth decade (ages at onset: 54 and 57 years, respectively), limiting their maximum walking distance. Around the same time, Paget’s disease of bone was diagnosed. Sensory complaints or sphincter disturbances were not reported, and neither were dysarthria, dysphagia, behavioural changes or cognitive decline (confirmed by their relatives). The family history revealed another, older brother with Paget’s disease of bone, who became wheelchair-bound at age 57 after 10 years of gait impairment, but unfortunately refused any medical examination or investigation. One younger brother with Paget’s disease of bone just started to notice some gait problems. Their deceased father was said to have had gait problems for a long time, attributed to his diagnosis of Paget disease of bone, but he did show lower limb weakness and was wheelchair-bound for the last 25 years of his life. He died at age 75 without signs of swallowing difficulties or respiratory problems. Two of their father’s brothers had gait impairment without a clear diagnosis. Neurological doi:10.1093/brain/aws201 Brain 2012: Page 1 of 3 | e1