Semin Neurol 2014; 34(03): 293-305
DOI: 10.1055/s-0034-1386767
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances

John K. Fink
1   Department of Neurology, University of Michigan; Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan
› Author Affiliations
Further Information

Publication History

Publication Date:
05 September 2014 (online)

Abstract

Hereditary spastic paraplegia (HSP) refers to inherited disorders in which spastic gait is either the only feature or is a major syndrome feature. There are more than 70 genetic types of HSP. Neuropathological studies, albeit limited to only a few genetic types of HSP, have identified axon degeneration involving the distal ends of the corticospinal tracts and fasciculus gracilis fibers. In this review, the author highlights the clinical and genetic features of HSP.

 
  • References

  • 1 Brugman F, Scheffer H, Wokke JHJ , et al. Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes. Neurology 2008; 71 (19) 1500-1505
  • 2 Arnoldi A, Tonelli A, Crippa F , et al. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat 2008; 29 (4) 522-531
  • 3 McDermott CJ, Dayaratne RK, Tomkins J , et al. Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England. Neurology 2001; 56 (4) 467-471
  • 4 Esteves T, Durr A, Mundwiller E , et al. Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. Am J Hum Genet 2014; 94 (2) 268-277
  • 5 Schwarz GA. Hereditary (familial) spastic paraplegia. AMA Arch Neurol Psychiatry 1952; 68 (5) 655-662
  • 6 Schwarz GA, Liu C-N. Hereditary (familial) spastic paraplegia; further clinical and pathologic observations. AMA Arch Neurol Psychiatry 1956; 75 (2) 144-162
  • 7 Deluca GC, Ebers GC, Esiri MM. The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol 2004; 30 (6) 576-584
  • 8 White KD, Ince PG, Lusher M , et al. Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation. Neurology 2000; 55 (1) 89-94
  • 9 Behan WM, Maia M. Strümpell's familial spastic paraplegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry 1974; 37 (1) 8-20
  • 10 Harding AE. Hereditary spastic paraplegias. Semin Neurol 1993; 13 (4) 333-336
  • 11 Sack GH, Huether CA, Garg N. Familial spastic paraplegia-clinical and pathologic studies in a large kindred. Johns Hopkins Med J 1978; 143 (4) 117-121
  • 12 Buge A, Escourolle R, Rancurel G, Gray F, Pertuiset BF. La paraplégie spasmodique familiale de Strümpell-Lorrain (P.S.F.). Une nouvelle observation anatomoclinique [in French]. Rev Neurol (Paris) 1979; 135 (4) 329-337
  • 13 Sperfeld AD, Baumgartner A, Kassubek J. Magnetic resonance investigation of the upper spinal cord in pure and complicated hereditary spastic paraparesis. Eur Neurol 2005; 54 (4) 181-185
  • 14 Dürr A, Brice A, Serdaru M , et al. The phenotype of “pure” autosomal dominant spastic paraplegia. Neurology 1994; 44 (7) 1274-1277
  • 15 Krabbe K, Nielsen JE, Fallentin E, Fenger K, Herning M. MRI of autosomal dominant pure spastic paraplegia. Neuroradiology 1997; 39 (10) 724-727
  • 16 Hedera P, Eldevik OP, Maly P, Rainier S, Fink JK. Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. Neuroradiology 2005; 47 (10) 730-734
  • 17 Hedera P, DiMauro S, Bonilla E, Wald J, Eldevik OP, Fink JK. Phenotypic analysis of autosomal dominant hereditary spastic paraplegia linked to chromosome 8q. Neurology 1999; 53 (1) 44-50
  • 18 Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013; 126 (3) 307-328
  • 19 Novarino G, Fenstermaker AG, Zaki MS , et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 2014; 343 (6170) 506-511
  • 20 Blackstone C. Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci 2012; 35: 25-47
  • 21 Fink JK. The hereditary spastic paraplegias. In: Rosenberg R, , ed. Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014
  • 22 Matsumura R, Takayanagi T, Fujimoto Y , et al. The relationship between trinucleotide repeat length and phenotypic variation in Machado-Joseph disease. J Neurol Sci 1996; 139 (1) 52-57
  • 23 Hentati A, Pericak-Vance MA, Hung W-Y , et al. Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum Mol Genet 1994; 3 (8) 1263-1267
  • 24 Muglia M, Criscuolo C, Magariello A , et al. Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus. Neurogenetics 2004; 5 (1) 49-54
  • 25 Tang BS, Chen X, Zhao GH , et al. Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases. Chin Med J (Engl) 2004; 117 (7) 1002-1005
  • 26 Wilkinson PA, Crosby AH, Turner C , et al. A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia. Neurology 2003; 61 (2) 235-238
  • 27 Tsaousidou MK, Ouahchi K, Warner TT , et al. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet 2008; 82 (2) 510-515
  • 28 Criscuolo C, Filla A, Coppola G , et al. Two novel CYP7B1 mutations in Italian families with SPG5: a clinical and genetic study. J Neurol 2009; 256 (8) 1252-1257
  • 29 Biancheri R, Ciccolella M, Rossi A , et al. White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1. Neuromuscul Disord 2009; 19 (1) 62-65
  • 30 De Michele G, De Fusco M, Cavalcanti F , et al. A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. Am J Hum Genet 1998; 63 (1) 135-139
  • 31 Garner CC, Garner A, Huber G, Kozak C, Matus A. Molecular cloning of microtubule-associated protein 1 (MAP1A) and microtubule-associated protein 5 (MAP1B): identification of distinct genes and their differential expression in developing brain. J Neurochem 1990; 55 (1) 146-154
  • 32 Martínez Murillo F, Kobayashi H, Pegoraro E , et al. Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13-15. Neurology 1999; 53 (1) 50-56
  • 33 Winner B, Uyanik G, Gross C , et al. Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch Neurol 2004; 61 (1) 117-121
  • 34 Vazza G, Zortea M, Boaretto F, Micaglio GF, Sartori V, Mostacciuolo ML. A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27-q28. Am J Hum Genet 2000; 67 (2) 504-509
  • 35 Hughes CA, Byrne PC, Webb S , et al. SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 2001; 56 (9) 1230-1233
  • 36 Hanein S, Martin E, Boukhris A , et al. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet 2008; 82 (4) 992-1002
  • 37 Al-Yahyaee S, Al-Gazali LI, De Jonghe P , et al. A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy. Neurology 2006; 66 (8) 1230-1234
  • 38 Alazami AM, Adly N, Al Dhalaan H, Alkuraya FS. A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18). Neurogenetics 2011; 12 (4) 333-336
  • 39 Al-Saif A, Bohlega S, Al-Mohanna F. Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. Ann Neurol 2012; 72 (4) 510-516
  • 40 Crosby AH, Patel H, Patton MA , et al. Spartin, the Troyer syndrome gene, suggests defective endosomal trafficking underlies some forms of hereditary spastic paraplegia. Am J Hum Genet 2002; 71: 516
  • 41 Cross HE, McKusick VA. The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol 1967; 16 (5) 473-485
  • 42 Patel H, Cross H, Proukakis C , et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet 2002; 31 (4) 347-348
  • 43 Proukakis C, Cross H, Patel H, Patton MA, Valentine A, Crosby AH. Troyer syndrome revisited. A clinical and radiological study of a complicated hereditary spastic paraplegia. J Neurol 2004; 251 (9) 1105-1110
  • 44 Lu J, Rashid F, Byrne PC. The hereditary spastic paraplegia protein spartin localises to mitochondria. J Neurochem 2006; 98 (6) 1908-1919
  • 45 Simpson MA, Cross H, Proukakis C , et al. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet 2003; 73 (5) 1147-1156
  • 46 Blumen SC, Bevan S, Abu-Mouch S , et al. A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32. Ann Neurol 2003; 54 (6) 796-803
  • 47 Hodgkinson CA, Bohlega S, Abu-Amero SN , et al. A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology 2002; 59 (12) 1905-1909
  • 48 Zortea M, Vettori A, Trevisan CP , et al. Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1. J Med Genet 2002; 39 (6) 387-390
  • 49 Wilkinson PA, Simpson MA, Bastaki L , et al. A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. J Med Genet 2005; 42 (1) 80-82
  • 50 Meijer IA, Cossette P, Roussel J, Benard M, Toupin S, Rouleau GA. A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1. Ann Neurol 2004; 56 (4) 579-582
  • 51 Ribai P, Stevanin G, Bouslam N , et al. A new phenotype linked to SPG27 and refinement of the critical region on chromosome. J Neurol 2006; 253 (6) 714-719
  • 52 Bouslam N, Benomar A, Azzedine H , et al. Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann Neurol 2005; 57 (4) 567-571
  • 53 Tesson C, Nawara M, Salih MA , et al. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet 2012; 91 (6) 1051-1064
  • 54 Klebe S, Azzedine H, Durr A , et al. Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain 2006; 129 (Pt 6) 1456-1462
  • 55 Dick KJ, Al-Mjeni R, Baskir W , et al. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. Neurology 2008; 71 (4) 248-252
  • 56 Dick KJ, Eckhardt M, Paisán-Ruiz C , et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat 2010; 31 (4) E1251-E1260
  • 57 Kruer MC, Paisán-Ruiz C, Boddaert N , et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 2010; 68 (5) 611-618
  • 58 Rainier S, Bui M, Mark E , et al. Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet 2008; 82 (3) 780-785
  • 59 Meilleur KG, Traoré M, Sangaré M , et al. Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19. Neurogenetics 2010; 11 (3) 313-318
  • 60 Orthmann-Murphy JL, Salsano E, Abrams CK , et al. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 2009; 132 (Pt 2) 426-438
  • 61 Dursun U, Koroglu C, Kocasoy Orhan E, Ugur SA, Tolun A. Autosomal recessive spastic paraplegia (SPG45) with mental retardation maps to 10q24.3-q25.1. Neurogenetics 2009; 10 (4) 325-331
  • 62 Boukhris A, Feki I, Elleuch N , et al. A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics 2010; 11 (4) 441-448
  • 63 Blumkin L, Lerman-Sagie T, Lev D, Yosovich K, Leshinsky-Silver E. A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum. J Neurol Sci 2011; 305 (1-2) 67-70
  • 64 Słabicki M, Theis M, Krastev DB , et al. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol 2010; 8 (6) e1000408
  • 65 Oz-Levi D, Ben-Zeev B, Ruzzo EK , et al. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet 2012; 91 (6) 1065-1072
  • 66 Verkerk AJ, Schot R, Dumee B , et al. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet 2009; 85 (1) 40-52
  • 67 Najmabadi H, Hu H, Garshasbi M , et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011; 478 (7367) 57-63
  • 68 Moreno-De-Luca A, Helmers SL, Mao H , et al. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J Med Genet 2011; 48 (2) 141-144
  • 69 Abou Jamra R, Philippe O, Raas-Rothschild A , et al. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet 2011; 88 (6) 788-795
  • 70 Dell'Angelica EC, Mullins C, Bonifacino JS. AP-4, a novel protein complex related to clathrin adaptors. J Biol Chem 1999; 274 (11) 7278-7285
  • 71 Hirst J, Bright NA, Rous B, Robinson MS. Characterization of a fourth adaptor-related protein complex. Mol Biol Cell 1999; 10 (8) 2787-2802
  • 72 Zivony-Elboum Y, Westbroek W, Kfir N , et al. A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. J Med Genet 2012; 49 (7) 462-472
  • 73 Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ , et al; FORGE Canada Consortium. Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet 2012; 91 (6) 1073-1081
  • 74 Shimazaki H, Takiyama Y, Ishiura H , et al; Japan Spastic Paraplegia Research Consortium (JASPAC). A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). J Med Genet 2012; 49 (12) 777-784
  • 75 Antonicka H, Ostergaard E, Sasarman F , et al. Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am J Hum Genet 2010; 87 (1) 115-122
  • 76 Beetz C, Johnson A, Schuh AL , et al. Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. Proc Natl Acad Sci U S A 2013; 110 (13) 5091-5096
  • 77 Dor T, Cinnamon Y, Raymond L , et al. KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction. J Med Genet 2014; 51 (2) 137-142
  • 78 Mitchell S, Bundey S. Symmetry of neurological signs in Pakistani patients with probable inherited spastic cerebral palsy. Clin Genet 1997; 51 (1) 7-14
  • 79 McHale DP, Mitchell S, Bundey S , et al. A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. Am J Hum Genet 1999; 64 (2) 526-532
  • 80 Lynex CN, Carr IM, Leek JP , et al. Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person syndrome and other movement disorders. BMC Neurol 2004; 4 (1) 20
  • 81 Macedo-Souza LI, Kok F, Santos S , et al. Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13. Ann Neurol 2005; 57 (5) 730-737
  • 82 Bouhouche A, Benomar A, Bouslam N, Ouazzani R, Chkili T, Yahyaoui M. Autosomal recessive mutilating sensory neuropathy with spastic paraplegia maps to chromosome 5p15.31-14.1. Eur J Hum Genet 2006; 14 (2) 249-252
  • 83 Bouhouche A, Benomar A, Bouslam N, Chkili T, Yahyaoui M. Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia. J Med Genet 2006; 43 (5) 441-443
  • 84 Jouet M, Rosenthal A, Armstrong G , et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 1994; 7 (3) 402-407
  • 85 Kobayashi H, Hoffman EP, Marks HG. The rumpshaker mutation in spastic paraplegia. Nat Genet 1994; 7 (3) 351-352
  • 86 Hudson LD. Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. J Child Neurol 2003; 18 (9) 616-624
  • 87 Saugier-Veber P, Munnich A, Bonneau D , et al. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 1994; 6 (3) 257-262
  • 88 Cambi F, Tang XM, Cordray P, Fain PR, Keppen LD, Barker DF. Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. Neurology 1996; 46 (4) 1112-1117
  • 89 Steinmüller R, Lantigua-Cruz A, Garcia-Garcia R, Kostrzewa M, Steinberger D, Müller U. Evidence of a third locus in X-linked recessive spastic paraplegia. [letter] Hum Genet 1997; 100 (2) 287-289
  • 90 Tamagaki A, Shima M, Tomita R , et al. Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2. Am J Med Genet 2000; 94 (1) 5-8
  • 91 Marx J. Alzheimer's research moves to mice. Science 1991; 253 (5017) 266-267
  • 92 Allan W, Herndon CN, Dudley FC. Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am J Ment Defic 1944; 48: 325-334
  • 93 Bialer MG, Lawrence L, Stevenson RE , et al. Allan-Herndon-Dudley syndrome: clinical and linkage studies on a second family. Am J Med Genet 1992; 43 (1-2) 491-497
  • 94 Macedo-Souza LI, Kok F, Santos S , et al. Reevaluation of a large family defines a new locus for X-linked recessive pure spastic paraplegia (SPG34) on chromosome Xq25. Neurogenetics 2008; 9 (3) 225-226
  • 95 Verny C, Guegen N, Desquiret V , et al. Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation. Mitochondrion 2011; 11 (1) 70-75