Review article Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance Josef Finsterer a, b, ⁎, Wolfgang Löscher c , Stefan Quasthoff d , Julia Wanschitz c , Michaela Auer-Grumbach e , Giovanni Stevanin f a Krankenanstalt Rudolfstiftung, Wien, Austria b Danube University Krems, Krems, Austria c Neurological Department, Innsbruck Medical University, Innsbruck, Austria d Neurological Department, Medical University Graz, Graz, Austria e Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University Graz, Graz, Austria f Institut du Cerveau et de la Moelle épinière; INSERM, U975; UPMC Univ Paris-6 UMR_S975; CNRS, UMR 7225; EPHE; APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France abstract article info Article history: Received 16 February 2012 Received in revised form 25 March 2012 Accepted 29 March 2012 Available online 1 May 2012 Keywords: Spasticity Weakness Genetics Mutation Hereditary Familial Multisystem Central nervous system Imaging Antispastics Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impair- ment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of cor- ticospinal tract neurons. Among the AD-SPGs, 40–45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, de- bated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investiga- tions. Treatment is exclusively symptomatic. © 2012 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2. Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3. Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1. Pure SPG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.2. Complex (complicated) SPG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Journal of the Neurological Sciences 318 (2012) 1–18 Abbreviations: ACP33, Maspardin gene; AD, Autosomal dominant; ALS, Amyotrophic lateral sclerosis; AP, Adaptor Protein complex; AR, Autosomal recessive; ATL1, Atlastin-1 gene; BMP, Bone morphogenic protein; BSCL2, Berardinelli-Seip congenital lipodystrophy gene; CYP7B1, Oxysterol 7-alpha-hydroxylase 1 gene; ER, Endoplasmic reticulum; ERLIN2, ER lipid raft associated 2 gene; GJA12/GJC2, Gap junction protein 12; HSN1, Hereditary sensory neuropathy type 1; HSP, Hereditary spastic paraplegia; HSPD1, Heat shock 60 kDa protein 1; KIAA0196, Strumpellin gene; KIAA0415, Putative helicase gene; KIAA1840, Spatacsin gene; KIF1A, Kinesin 3; KIF5A, Kinesin heavy chain isoform 5A; LICAM, L1-cell adhesion molecule; MASA, Mental retardation, aphasia, shuffling gait, and adducted thumbs; NBIA, Neurodegeneration with brain iron accumulation; NCAM, Neural cell adhesion molecule; NGS, Next-generation sequenc- ing; NIPA1, Non-imprinted in Prader–Willi/Angelman syndrome 1 gene; NTE, Neuropathy Target Esterase; PLP1, Pproteolipid protein 1 gene; PNP, Polyneuropathy; REEP1, Receptor expression enhancing protein 1; RTN2, Reticulon 2; SLC16A2, Solute carrier family 16, member 2; SLC33A1, Solute carrier family 33; SPAST, Spastin gene; SPG, Spastic paraplegia gene; TCC, Thin corpus callosum; WMLs, White matter lesions; XL, X-linked; ZFYVE26, Zinc finger, FYVE domain containing 26; ZFYVE27, Zinc finger, FYVE domain containing 27. ⁎ Corresponding author at: Postfach 20, 1180 Vienna, Austria. Tel.: + 43 1 71165 92085; fax: + 43 1 4781711. E-mail address: fifigs1@yahoo.de (J. Finsterer). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.03.025 Contents lists available at SciVerse ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns