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Common Molecular Pathological Themes Emerge in the Hereditary Spastic Paraplegias E Reid

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Common Molecular Pathological Themes Emerge in the Hereditary Spastic Paraplegias E Reid 81 REVIEW ARTICLE J Med Genet: first published as 10.1136/jmg.40.2.81 on 1 February 2003. Downloaded from Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias E Reid ............................................................................................................................. J Med Genet 2003;40:81–86 The hereditary spastic paraplegias are a group of corticospinal tract either fail to develop normally, neurodegenerative conditions that all share the principal or show progressive degeneration after initial normal development. This review will summarise clinical feature of progressive lower limb spastic progress in identifying and characterising the paralysis, caused by either failure of development or function of genes that cause human HSPs. progressive degeneration of the corticospinal tract. The conditions are characterised by extreme genetic THE CLINICAL PHENOTYPE OF HSPs The HSPs share the principal clinical feature of heterogeneity, with at least 20 genes involved. Until progressive lower limb spastic paralysis. They are recently, no functional overlap was apparent in the conventionally subdivided into pure and compli- associated molecular pathological mechanisms. cated forms, depending on the absence or presence of additional neurological or non- However, with recent progress in hereditary spastic neurological features.2–7 Pure hereditary spastic paraplegia gene identification, common pathological paraplegia, in which spastic paraplegia occurs in themes are now emerging. relative isolation, is probably the single largest subgroup of HSP conditions.3 Histopathological .......................................................................... studies of pure HSP generally show a length dependent “dying back” of the terminal ends of A MOVING PROBLEM the corticospinal tract axons, with the longest The principal neurological pathway over which axons being involved first. Diagnostic criteria signals pass to drive a deliberate movement can have been suggested and the clinical and patho- be divided, in simple terms, into two stages. In the logical features, differential diagnosis, genetic first stage, a descending connection is made from counselling, and management have been re- neurones (often referred to clinically as “upper viewed extensively elsewhere.2–7 The complicated motor neurones”) in the motor cortex of the brain forms consist of a diverse group of individually to cells in the anterior and posterior horns of the rare conditions, and again their clinical features http://jmg.bmj.com/ spinal cord, while in the second stage “lower have been reviewed previously.236 motor neurones” in the anterior horn of the spinal cord connect to the skeletal muscles at the MOLECULAR GENETICS OF HSPs neuromuscular junction. The axons that project The hereditary spastic paraplegias are genetically from the upper motor neurone cell bodies to the complex. Autosomal dominant, autosomal reces- 1 spinal cord constitute the corticospinal tract. sive, and X linked recessive inheritance patterns These axons are exceptionally long, in some cases have been described for pure HSP.2–7 Within each over 1 metre, with axonal volumes that can be up broad inheritance pattern group, there is further on October 2, 2021 by guest. Protected copyright. to one thousand times the volume of the cell body. locus heterogeneity with, for example, eight Corticospinal tract neurones therefore provide an known loci for autosomal dominant pure HSP. extreme example of the difficulties encountered Not surprisingly for such a clinically diverse in diverse cellular processes, such as trafficking, group, the complicated HSPs also show consider- transport, and energy metabolism. able genetic heterogeneity, although with a few The corticospinal tract has great clinical important exceptions they tend to be inherited in importance. Lesions to the tract result in spastic an autosomal recessive pattern.236 The 20 HSP paralysis, a disabling clinical picture in which genes that have been mapped are summarised in weakness of muscles (paralysis) is associated table 1 and undoubtedly more remain to be with increased stiffness (hypertonicity) and over- found. Eight of these genes have now been iden- active reflexes (hyperreflexia). Depending on the tified and some interesting overlapping patho- site of lesions, spastic paralysis may affect both logical mechanisms are beginning to emerge. arms and both legs (tetraparesis or if more severe, tetraplegia), legs only (paraparesis or paraplegia), ....................... one limb (monoparesis or monoplegia), or the PATHOLOGICAL MECHANISMS limbs on one side of the body (hemiparesis or ASSOCIATED WITH HSP GENES Correspondence to: Dr E Reid, Department of hemiplegia). Spastic paralysis may be the result of Cell recognition and signalling: the L1-CAM Medical Genetics, a wide variety of insults, including common con- gene University of Cambridge, ditions such as stroke, multiple sclerosis, and cer- The cell adhesion molecule L1 (L1-CAM) is a cell Box 134, Addenbrooke’s vical spinal cord injury. It may also be the result of surface membrane associated glycoprotein that is Hospital, Cambridge a member of an immunoglobulin superfamily. CB2 2QQ, UK; genetic pathology and under this heading are the [email protected] human hereditary spastic paraplegias (HSPs), Mutations in L1-CAM are found in a form of X ....................... single gene disorders in which the axons of the linked complicated (by mental retardation and www.jmedgenet.com 82 Reid Table 1 Genetic loci for HSP J Med Genet: first published as 10.1136/jmg.40.2.81 on 1 February 2003. Downloaded from Gene MIM Chromosomal Gene Key symbol number location product Phenotype references X linked SPG1 312900 Xq28 L1-CAM CHSP, XLH 8 SPG2 312920 Xq22 PLP, DM20 PHSP, CHSP, PMD 9 SPG16 300266 Xq11.2 – PHSP, CHSP 10 Dominant SPG3A 182600 14q12-q21 Atlastin PHSP 11, 12 SPG4 182601 2p21-p24 Spastin PHSP, ?CHSP 13, 14 SPG6 600363 15q11.2-q12 – PHSP 15 SPG8 603563 8q24 – PHSP 16, 17 SPG9 601162 10q23.3-q24.2 – CHSP 18 SPG10 604187 12q13 KIF5A PHSP 19, 20 SPG12 604805 19q13 – PHSP 21 SPG13 605280 2q24-q34 HSP60 PHSP 22, 23 SPG17 270685 11q12-q14 – CHSP (Silver syndrome) 24 SPG18 Pending Reserved – – – SPG19 607152 9q33-q34 – PHSP 25 Recessive SPG5 270800 8q11-q13 – PHSP 26 SPG7 602783 16q24.3 Paraplegin PHSP, CHSP 27, 28 SPG11 604360 15q13-q15 – PHSP, CHSP 29 SPG14 605229 3q27-q28 – CHSP 30 SPG15 606859 14q22-q24 – CHSP (Kjellin syndrome) 31 SPG20 275900 13q12.3 Spartin CHSP (Troyer syndrome) 32 CHSP=complicated HSP, PHSP=pure HSP, XLH=X linked hydrocephalus, PMD=Pelizaeus-Merzbacher disease. absence of the extensor pollicis longus muscle) spastic Abnormalities of myelination: the proteolipid protein paraplegia termed SPG1, in MASA (mental retardation, apha- gene sia, shuffling gait, adducted thumbs) syndrome, and in X Mutations in the proteolipid protein gene (PLP1) can cause linked hydrocephalus.833 Interestingly, the same L1-CAM pure or complicated HSP (SPG2), or the much more severe mutation may result in either an X linked hydrocephalus phe- Pelizaeus-Merzbacher disease (PMD).9 39–41 Several different notype or a MASA phenotype.33 These conditions have been missense mutations in the gene are associated with HSP, associated with over 90 different mutations, of varying forms, whereas PMD is associated with other missense mutations or, in the L1-CAM gene. Many of the mutations are predicted to more commonly, with duplications of the entire gene. eliminate expression of L1-CAM, although some missense Complete deletions or triplication of the gene have also been mutations affect particular functions of the protein.34 L1-CAM described.9 41–45 The PLP1 gene codes for two myelin proteins, is expressed throughout the nervous system on populations of PLP and DM20. There is a correlation between PLP1 gene http://jmg.bmj.com/ developing and differentiated neurones, as well as in Schwann mutation and phenotype, with point mutations that affect cells in the peripheral nervous system. In vitro studies have highly conserved DM20 amino acid residues being associated suggested that L1 interactions may mediate axon bundling with the most severe PMD phenotypes.46 The PLP and DM20 and may be involved in the processes of neurite extension and proteins are thought to play a major role in oligodendrocyte axonal guidance, along with several other functions.35 36 maturation and also form structural components of the L1-CAM knockout mice show phenotypes similar to the myelin sheath.47 The precise mechanism by which certain human L1-CAM associated conditions and, of particular missense mutations in the PLP1 gene cause spastic paraplegia relevance to the cause of spasticity in these cases, the normal is not clear. MRI studies in human SPG2 families show central on October 2, 2021 by guest. Protected copyright. anatomy of the mouse corticospinal tracts is disrupted, with nervous system white matter abnormalities similar to those impairment in axonal pathfinding resulting in failure of the found in demyelinating conditions.48 This is reminiscent of the normal crossing over of the tracts in the medulla.37 38 pathological changes found in the rumpshaker natural mouse L1-CAM sits at the centre of a complex set of extracellular mutant model of SPG2, which shows hypomyelination with and intracellular interactions.34 It binds to a wide variety of reduced levels of PLP,but not DM20.49 It seems likely that per- extracellular ligands, including other CAMs, integrins, extra- turbations
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