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Hereditary spastic paraplegia

Puneet Opal, MD, PhD
Senda Ajroud-Driss, MD
Section Editor
Marc C Patterson, MD, FRACP
Deputy Editor
John F Dashe, MD, PhD


Hereditary spastic paraplegia (HSP) refers to a group of familial diseases that are characterized by progressive degeneration of the corticospinal tracts. Clinically, they present with lower limb spasticity and weakness.


HSP, also called familial spastic paraplegia, was initially referred to as Strumpell-Lorrain disease, a name given for the two physicians who in the late 19th century independently described key features of spastic paraplegia. It has become evident that HSP is not one disease but a mixed group of genetically heterogeneous conditions that result in broadly overlapping clinical features.

HSPs are clinically differentiated into "pure" forms if spastic paraplegia with bladder involvement is the only clinical finding, and "complicated" (or complex) forms if there are additional neurologic or systemic abnormalities. In the pre-genetic era, attempts were made to further classify HSP based upon age of onset, degree of spasticity, and rate of progression [1]. Today, however, the classification of HSP is increasingly based upon genetics, especially given the phenotypic heterogeneity of HSP within the same family harboring the same genetic defect.

The genetic classification of HSP is based upon mode of inheritance, chromosomal locus, and causative mutation (if known) [2]. Hereditary spastic paraplegias include autosomal dominant, autosomal recessive, and X-linked forms. The genetic loci are designated as SPG (for SPastic parapleGia) and are numbered sequentially as SPG1, SPG2, SPG3, and so on (table 1). The numbering of the SPGs is based upon the order of locus discovery and not on the mechanism of genetic transmission. The number of loci now exceeds 55 and continues to expand (see http://omim.org/phenotypicSeries/PS303350) [3].

The correlation of clinical classification (pure or complicated) with genetic classification (SPG type) is imperfect, and some genetic types of HSP are associated with both pure and complicated phenotypes [4].

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Literature review current through: Nov 2017. | This topic last updated: Jul 18, 2017.
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  1. Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet 1983; 1:1151.
  2. Fink JK. Hereditary spastic paraplegia overview. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1509/ (Accessed on May 29, 2014).
  3. Novarino G, Fenstermaker AG, Zaki MS, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 2014; 343:506.
  4. Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013; 126:307.
  5. Denora PS, Santorelli FM, Bertini E. Hereditary spastic paraplegias: one disease for many genes, and still counting. Handb Clin Neurol 2013; 113:1899.
  6. Chase A. Genetics: Exome sequencing sheds light on hereditary spastic paraplegia. Nat Rev Neurol 2014; 10:124.
  7. Coutinho P, Ruano L, Loureiro JL, et al. Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study. JAMA Neurol 2013; 70:746.
  8. Depienne C, Stevanin G, Brice A, Durr A. Hereditary spastic paraplegias: an update. Curr Opin Neurol 2007; 20:674.
  9. Loureiro JL, Brandão E, Ruano L, et al. Autosomal dominant spastic paraplegias: a review of 89 families resulting from a portuguese survey. JAMA Neurol 2013; 70:481.
  10. McDermott CJ, Burness CE, Kirby J, et al. Clinical features of hereditary spastic paraplegia due to spastin mutation. Neurology 2006; 67:45.
  11. Züchner S. The genetics of hereditary spastic paraplegia and implications for drug therapy. Expert Opin Pharmacother 2007; 8:1433.
  12. Haberlová J, Claeys KG, Zámecník J, et al. Extending the clinical spectrum of SPG3A mutations to a very severe and very early complicated phenotype. J Neurol 2008; 255:927.
  13. Ivanova N, Claeys KG, Deconinck T, et al. Hereditary spastic paraplegia 3A associated with axonal neuropathy. Arch Neurol 2007; 64:706.
  14. Fusco C, Frattini D, Farnetti E, et al. Very early onset and severe complicated phenotype caused by a new spastic paraplegia 3A gene mutation. J Child Neurol 2012; 27:1348.
  15. Al-Maawali A, Rolfs A, Klingenhaeger M, Yoon G. Hereditary spastic paraplegia associated with axonal neuropathy: a novel mutation of SPG3A in a large family. J Clin Neuromuscul Dis 2011; 12:143.
  16. Zhao X, Alvarado D, Rainier S, et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet 2001; 29:326.
  17. Webb S, Coleman D, Byrne P, et al. Autosomal dominant hereditary spastic paraparesis with cognitive loss linked to chromosome 2p. Brain 1998; 121 ( Pt 4):601.
  18. Nielsen JE, Johnsen B, Koefoed P, et al. Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. Eur J Neurol 2004; 11:817.
  19. Meyer T, Schwan A, Dullinger JS, et al. Early-onset ALS with long-term survival associated with spastin gene mutation. Neurology 2005; 65:141.
  20. Orlacchio A, Kawarai T, Totaro A, et al. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol 2004; 61:849.
  21. Chelban V, Tucci A, Lynch DS, et al. Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 2017; 88:681.
  22. Svenson IK, Kloos MT, Gaskell PC, et al. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics 2004; 5:157.
  23. Hazan J, Fonknechten N, Mavel D, et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 1999; 23:296.
  24. Solowska JM, Baas PW. Hereditary spastic paraplegia SPG4: what is known and not known about the disease. Brain 2015; 138:2471.
  25. Rainier S, Chai JH, Tokarz D, et al. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet 2003; 73:967.
  26. Du J, Hu YC, Tang BS, et al. Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1. Clin Neurol Neurosurg 2011; 113:480.
  27. Svenstrup K, Møller RS, Christensen J, et al. NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy. Eur J Neurol 2011; 18:1197.
  28. Valdmanis PN, Meijer IA, Reynolds A, et al. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet 2007; 80:152.
  29. Blair MA, Ma S, Hedera P. Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia. Neurogenetics 2006; 7:47.
  30. Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 2009; 132:8.
  31. Windpassinger C, Auer-Grumbach M, Irobi J, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 2004; 36:271.
  32. Beetz C, Schüle R, Deconinck T, et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 2008; 131:1078.
  33. Züchner S, Wang G, Tran-Viet KN, et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 2006; 79:365.
  34. Pensato V, Castellotti B, Gellera C, et al. Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48. Brain 2014; 137:1907.
  35. Biancheri R, Ciccolella M, Rossi A, et al. White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1. Neuromuscul Disord 2009; 19:62.
  36. Wilkinson PA, Crosby AH, Turner C, et al. A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia. Neurology 2003; 61:235.
  37. 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; 256:1252.
  38. 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; 82:510.
  39. Warnecke T, Duning T, Schirmacher A, et al. A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects. Mov Disord 2010; 25:413.
  40. Klebe S, Depienne C, Gerber S, et al. Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain 2012; 135:2980.
  41. van Gassen KL, van der Heijden CD, de Bot ST, et al. Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. Brain 2012; 135:2994.
  42. 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; 63:135.
  43. Sánchez-Ferrero E, Coto E, Beetz C, et al. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Clin Genet 2013; 83:257.
  44. Stevanin G, Santorelli FM, Azzedine H, et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 2007; 39:366.
  45. 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; 61:117.
  46. França MC Jr, Yasuda CL, Pereira FR, et al. White and grey matter abnormalities in patients with SPG11 mutations. J Neurol Neurosurg Psychiatry 2012; 83:828.
  47. Goizet C, Boukhris A, Maltete D, et al. SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 2009; 73:1111.
  48. 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; 82:992.
  49. Proukakis C, Cross H, Patel H, et al. Troyer syndrome revisited. A clinical and radiological study of a complicated hereditary spastic paraplegia. J Neurol 2004; 251:1105.
  50. Cross HE, McKusick VA. The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol 1967; 16:473.
  51. Patel H, Cross H, Proukakis C, et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet 2002; 31:347.
  52. Cross HE, McKusick VA. The mast syndrome. A recessively inherited form of presenile dementia with motor disturbances. Arch Neurol 1967; 16:1.
  53. 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; 73:1147.
  54. Orthmann-Murphy JL, Salsano E, Abrams CK, et al. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 2009; 132:426.
  55. 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; 7:402.
  56. Kenwrick S, Watkins A, De Angelis E. Neural cell recognition molecule L1: relating biological complexity to human disease mutations. Hum Mol Genet 2000; 9:879.
  57. Diehl HJ, Schaich M, Budzinski RM, Stoffel W. Individual exons encode the integral membrane domains of human myelin proteolipid protein. Proc Natl Acad Sci U S A 1986; 83:9807.
  58. Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005; 6:1.
  59. Depienne C, Tallaksen C, Lephay JY, et al. Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases. J Med Genet 2006; 43:259.
  60. Bajaj NP, Waldman A, Orrell R, et al. Familial adult onset of Krabbe's disease resembling hereditary spastic paraplegia with normal neuroimaging. J Neurol Neurosurg Psychiatry 2002; 72:635.
  61. de Bot ST, Willemsen MA, Vermeer S, et al. Reviewing the genetic causes of spastic-ataxias. Neurology 2012; 79:1507.
  62. Schüle R, Wiethoff S, Martus P, et al. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol 2016; 79:646.