Experimental Neurology 246 (2013) 14–25 Contents lists available at SciVerse ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr Review Overlapping molecular pathological themes link Charcot–Marie–Tooth neuropathies and hereditary spastic paraplegias Vincent Timmerman a,⁎, Virginia E. Clowes b, Evan Reid b,⁎⁎ a Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium & Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, Antwerpen, Belgium b Department of Medical Genetics and Cambridge Institute for Medical Research, University of Cambridge, UK article info abstract Article history: In this review we focus on Charcot–Marie–Tooth (CMT) neuropathies and hereditary spastic paraplegias Received 8 September 2011 (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous sys- Revised 29 December 2011 tem, both are genetically determined, progressive, long axonopathies that affect motor and sensory path- Accepted 10 January 2012 ways. This commonality suggests that there might be similarities in the molecular pathology underlying Available online 18 January 2012 these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. © 2012 Elsevier Inc. All rights reserved. Keywords: Axon degeneration Hereditary spastic paraplegia Hereditary neuropathy Contents Introduction .................................................................15 Overview of clinical features and classification .................................................15 CMT neuropathies ............................................................15 Hereditary spastic paraplegias .......................................................15 Clinical overlaps between CMT and HSP ..................................................15 Similarities and differences in the molecular and cellular pathology of CMT neuropathies and HSPs ........................15 Functional groupings that overlap in CMT and HSP .............................................15 Myelination ............................................................15 Membrane traffic .........................................................18 Cytoskeleton stability and motor proteins ..............................................19 Mitochondrial dynamics ......................................................20 Disease-specific groups of genes ......................................................20 Other pathways involved in CMT ..................................................20 Other pathways involved in HSPs ..................................................21 Conclusions and future directions .......................................................21 Acknowledgments ..............................................................21 References ..................................................................22 Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CMAP, compound muscle action potentials; CMT, Charcot–Marie–Tooth; CNS, central nervous system; ER, endoplasmic reticulum; HMN, hereditary motor neuropathy; HMSN, hereditary motor and sensory neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy; HSP, hereditary spastic paraplegia; NCV, nerve conduction velocity; PI, phosphoinositides; PNS, peripheral nervous system; SNAP, sensory nerve action potentials. ⁎ Correspondence to: V. Timmerman, Peripheral Neuropathy Group, VIB — Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerpen, Belgium. Fax: +32 3 265 10 12. ⁎⁎ Correspondence to: E. Reid, Lab 5.15, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK. Fax: +44 1223 762640. E-mail addresses: [email protected] (V. Timmerman), [email protected] (E. Reid). 0014-4886/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2012.01.010 V. Timmerman et al. / Experimental Neurology 246 (2013) 14–25 15 Introduction The clinical picture of spastic paraplegia is reflected in the neuro- pathology of HSP, which typically shows a length-dependent ‘dying In this review we focus on Charcot–Marie–Tooth (CMT) neuropa- back’ axonopathy, affecting the distal ends of sensory and motor thies and hereditary spastic paraplegias (HSPs). A key difference be- axons in the spinal cord. Strikingly, neuronal cell body loss is an infre- tween these two groups of conditions is in the target cells that they quent finding, consistent with the main site of pathology being in the primarily affect, with CMT neuropathies affecting the peripheral axon (reviewed in Reid and Rugarli, 2010). This length-dependent motor and sensory nerves, while the HSPs principally affect the cen- neurodegeneration is reminiscent of that seen in the peripheral ner- tral nervous system (CNS) axons of the corticospinal tract and dorsal vous system (PNS) in some CMT patients. columns. However, CMT neuropathies and HSPs also share many fea- As with CMT, the HSPs show extreme genetic heterogeneity. AD tures, for example, both are genetically determined long axonopa- and AR inheritance patterns are found in pure and complex types of thies that affect motor and sensory pathways and which can be HSP, although X-linked recessive inheritance is rare. Sporadic cases later-onset and are typically progressive. This commonality suggests are also found, and these have a number of genetic explanations, in- that there might be similarities in the molecular pathology underly- cluding singleton AR cases, de novo mutations and non-penetrant ing these conditions, and here we compare and contrast the AD mutations in a parent. Currently nearly 50 HSP loci have been molecular genetics and cellular pathology of the two groups of neuro- mapped and more than 20 causative genes (termed SPG — spastic degenerative diseases. paraplegia or spastic gait) have been identified, leading to an expand- ing genetic classification of HSP disorders (Table 1). Overview of clinical features and classification Clinical overlaps between CMT and HSP CMT neuropathies Peripheral neuropathy can be a feature of some types of HSP. The most obvious example is Silver syndrome, a complicated HSP caused CMT neuropathy can be divided into demyelinating (referred as by mutations in the Berardinelli–Seip congenital lipodystrophy 2 CMT1), axonal (CMT2) and intermediate clinical variants. These gene (BSCL2; SPG17). Dominant mutations in this gene present with CMT phenotypes are grouped within the hereditary motor and senso- neurological features on a spectrum ranging from HSP to CMT, with ry neuropathies (HMSN) according to clinical, electrophysiological a significant subset of patients having an overlap condition termed and neuropathological criteria (Dyck et al., 2005). Other CMT related Silver syndrome (Windpassinger et al., 2004; Irobi et al., 2004a; neuropathies have been classified, depending on the nerves involved, Auer-Grumbach et al., 2005). An axonal peripheral neuropathy may as hereditary motor neuropathies (HMN) or hereditary sensory and be a feature of HSP families with atlastin-1 (SPG3A) mutations autonomic neuropathies (HSAN) (Dyck and Ohta, 1975; Harding (Ivanova et al., 2007), and mutations in this gene also cause heredi- and Thomas, 1980). More recently, genotype–phenotype correlation tary sensory neuropathy type I (HSN-I). Mutations in the SPG10 studies have revealed several more complex CMT neuropathies, in- gene KIF5A were first found in a family with pure HSP, but the pheno- volving other tissues such as the CNS, muscle, bone and skin. typic spectrum associated with mutations in this gene has expanded The modern classification of CMT neuropathies and related disor- to include peripheral neuropathy, with the patients often having a ders is based on genetics. This new era started with the discovery of phenotype reminiscent of Silver syndrome (Goizet et al., 2009). the 1.4 megabase tandem duplication at chromosome 17p11.2 associ- REEP1 (SPG33) mutations are rarely accompanied by amyotrophy, pe- ated with autosomal dominant demyelinating CMT1A (Raeymaekers ripheral nerve involvement and bulbar palsy (Hewamadduma et al., et al., 1991; Lupski et al., 1991; Timmerman et al., 1992). This geno- 2009). NIPA1 (SPG6) and spastin (SPG4) mutation may also be associ- mic mutation is the most frequent cause of CMT disease (Nelis et al., ated with peripheral nerve involvement (Schulte et al., 2003; Liu et 1996). Since then all of the Mendelian inheritance patterns have al., 2008). This clinical overlap hints at commonalities in the molecu- been described for CMT and 52 loci and 50 genes have been identified lar pathology underlying the two groups of conditions, and these are (Table 1). Autosomal dominant (AD) inheritance is the most fre- discussed below. quently observed in families with CMT1, CMT2, or intermediate forms (DI-CMT). Dominant X-linked inheritance is observed in Similarities and differences in the molecular and cellular CMTX families, but some rare recessive X-linked CMT forms have pathology of CMT neuropathies and HSPs also been reported. Autosomal recessive (AR) CMT accounts for less than 10% of patients, although this may be an underestimation due The spectacular advances in gene identification over the last de- to the small size of sibships, and many AR-CMT patients may remain cade have allowed functional classes of CMT and HSP genes to be unrecognised or considered to