336 Recently, paraplegin and spastin have been found to be mutated in two autosomal forms of hereditary spastic paraplegia. Both proteins harbour a common ATPase domain that expresses a chaperone function. Paraplegin is a nuclear- encoded mitochondrial metalloprotease, while the exact role and subcellular localisation of spastin are still unclear. Addresses *Human Molecular Genetics Unit, Stem Cells Research Institute (SCRI), Dibit —San Raffaele Hospital, Via Olgettina 58, 20132 Milan, Italy; e-mail: casari.giorgio@hsr.it † Telethon Institute of Genetics and Medicine (TIGEM), via P Castellino 111, 80131 Napoli, Italy; e-mail: rugarli@tigem.it Current Opinion in Genetics & Development 2001, 11:336–342 0959-437X/01/$ —see front matter © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations HSP hereditary spastic paraplegia L1CAM L1 cell adhesion molecule PLP proteolipid protein PMD Pelizaeus–Merzbacher disease Introduction Hereditary spastic paraplegia (HSP) comprises a heteroge- neous group of disorders characterised by progressive lower-limb weakness and spasticity, with or without blad- der disturbances, and subtle impairment of the vibratory sense [1–3]. Age of onset is quite variable — generally between 10 and 40 years old. First described by Strumpell in 1880, HSP has been classified traditionally as ‘pure’ or ‘complicated’, depending on whether spastic paraplegia is the only symptom or whether it is found in association with other neurological abnormalities, such as optic neuropathy, retinopathy, extrapyramidal symptoms, dementia, ataxia, mental retardation and deafness [4]. Neuropathological analyses of tissues from a small num- ber of individuals with pure HSP have shown axonal degeneration involving the more distal portions of the longest motor and sensory axons of the central nervous system (CNS) (i.e. the crossed and uncrossed corticospinal tracts, the fasciculus gracilis and the spinocerebellar tracts) [5,6]. These studies showed that the neuronal cell bodies of the degenerating axons are intact; no degenera- tion of the dorsal root ganglia, dorsal roots or peripheral nerves was found, and there was no evidence of primary demyelination. The pathogenetic mechanism for this ‘dying back’ axonopathy and why it is confined to defined axonal tracts is still unknown and represents an engaging biological question. HSP is a genetically heterogeneous condition that can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner [7]. So far, 15 loci have been mapped (known as SPG1–SPG15, see Table 1), but only four genes have been cloned so far. These encode L1 cell adhesion molecule (L1CAM), proteolipid protein (PLP), paraplegin and spastin. L1CAM and PLP are responsible for two X-linked complicated forms of HSP, paraplegin is involved in autosomal recessive pure and complicated HSP, and spastin is mutated in most autosomal dominant cases. In this review. we will focus on the most recent advances in understanding the molecular pathogenesis of HSP, and will discuss novel findings involving these known HSP genes. This research has stimulated an understanding of several different aspects of the biology of corticospinal axons and highlights the relevance of distinct — and possibly interconnected — pathways for pathogenesis of HSP. HSP caused by impaired development of the corticospinal tract SPG1 results from mutations in L1CAM [8], and may man- ifest as pure HSP or, more often, in association with complex disorders, referred to either as MASA syndrome (mental retardation, adducted thumbs, spasticity and apha- sia) or CRASH syndrome (corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) [9]. L1CAM is a transmembrane gly- coprotein with extracellular immunoglobulin and fibronectin type III repeats [10]. It is expressed during development on the surface of long axons and growth cones, including those of the corticospinal tract [11]. L1 mediates cell adhesion, neurite outgrowth, axon path- finding, and fasciculation through homophilic and heterophilic binding with a variety of extracellular and transmembrane molecules, to activate signal transduction pathways [12,13]. Spastic paraplegia is a common finding in patients with altered L1 function. In all cases in which neuropathologi- cal studies have been performed, the pyramids, which are two elongated swellings on the ventral aspect of the medulla containing the corticospinal axons, were found to be absent or severely reduced in size [14], suggesting that abnormal development of the corticospinal tract is respon- sible for paraplegia in these patients. Consistently, spastic paraplegia in SPG1 begins in the first two decades of life, with delayed acquisition of motor milestones and slow progression of symptoms. The role of L1 in corticospinal tract formation has been substantiated by analysis of transgenic animals [15–18]. Loss of L1 function impairs guidance of corticospinal axons across the pyramidal decussation in mice, so that a substantial proportion of axons fail to cross the midline and therefore descend ipsilaterally. In addition, projection of the axons below cervical levels is severely reduced. Very recently, L1CAM has been associated with the complex Molecular basis of inherited spastic paraplegias Giorgio Casari* and Elena Rugarli †