Molecular Genetics of Hereditary Spastic Paraplegias


Hereditary spastic paraplegias (HSPs), also known as Strümpell–Lorrain disease, are rare neurological conditions characterised by gradual spasticity and weakness of the lower limbs caused by developmental failure and/or degeneration of motor neuron axons in the corticospinal tract. The course is generally slowly progressive, with considerable variation in age at onset and severity of spasticity. There are also complex forms of HSPs, with additional neurological features or extraneurological signs. HSPs are transmitted according to all classical modes of inheritance and are extremely heterogeneous genetically as >80 causative genes or loci have been identified. The altered cellular functions include mainly intracellular trafficking, endoplasmic reticulum shaping, lipid metabolism and mitochondrial functions. The multiple inheritance modes and phenotypic presentation of several HSP genes together with the clinical and genetic overlap of HSPs with other neurological disorders complicate greatly their diagnosis in clinical practice.

Key Concepts

  • Hereditary spastic paraplegias are among the most highly heterogeneous neurodegenerative disorders.
  • The clinical presentation in patients can be pure or complex, variably associating additional, neurological and nonneurological signs.
  • Mutations or genomic rearrangements in >80 genes/loci can lead to spastic paraplegia.
  • Their diagnosis in clinical practice is complicated by (1) their heterogeneity, (2) the multiple inheritance modes of some of the genes involved and (3) by their overlap with other neurological disorders in terms of phenotype and causative genes, calling for a new nosology.
  • A relatively small number of functions are altered in these diseases, mainly intracellular trafficking, endoplasmic reticulum shaping, lipid metabolism and mitochondrial functions.
  • Only few biological markers can be used in clinical practice for follow‐up and diagnosis confirmation.

Keywords: hereditary spastic paraplegia; spasticity; intracellular transport; mitochondria; trafficking; lipid metabolism; motor neuron diseases

Figure 1. Illustration of the overlapping phenotypes according to the first and secondary motor neuron lesions. ALS, amyotrophic lateral sclerosis; PLS, primary lateral sclerosis; SMA, spinal muscular atrophy.


Boukhris A, Stevanin G, Feki I, et al. (2009) Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity. Clinical Genetics 75: 527–536.

Bouhlal Y, Amouri R, El Euch‐Fayeche G, et al. (2011) Autosomal recessive spastic ataxia of Charlevoix‐Saguenay: an overview. Parkinsonism & Related Disorders 17: 418–422.

Boutry M, Branchu J, Lustremant C, et al. (2018) Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration. Cell Rep 23: 3813–3826.

Caballero Oteyza A, Battaloğlu E, Ocek L, et al. (2014) Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology 82: 2007–2016.

Chang J, Lee S and Blackstone C (2014) Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. Journal of Clinical Investigation 124: 5249–5262.

Cheon CK, Lim SH, Kim YM, et al. (2017) Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene. Scientific Reports 7: 12527.

Citterio A, Arnoldi A, Panzeri E, et al. (2015) Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. Journal of Neurology 262: 2684–2690.

Coutelier M, Goizet C, Durr A, et al. (2015) Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain 138: 2191–2205.

Coutelier M, Hammer MB, Stevanin G, et al. (2018) Efficacy of exome‐targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurology 75 (5): 591–599. DOI: 10.1001/jamaneurol.2017.5121.

Coutinho P, Ruano L, Loureiro JL, et al. (2013) Hereditary ataxia and spastic paraplegia in Portugal: a population‐based prevalence study. JAMA Neurology 70: 746–755.

Ebbing B, Mann K, Starosta A, et al. (2008) Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Human Molecular Genetics 17: 1245–1252.

Edvardson S, Hama H, Shaag A, et al. (2008) Mutations in the fatty acid 2‐hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. American Journal of Human Genetics 83: 643–648.

Esteves T, Durr A, Mundwiller E, et al. (2014) Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. American Journal of Human Genetics 91: 1051–1064.

Evans K, Keller C, Pavur K, et al. (2006) Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proceedings of the National academy of Sciences of the United States of America 103: 10666–10671.

Falk J, Rohde M, Bekhite MM, et al. (2014) Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology. Human Mutation 35: 497–504.

Ferreirinha F, Quattrini A, Pirozzi M, et al. (2004) Axonal degeneration in paraplegin‐deficient mice is associated with abnormal mitochondria and impairment of axonal transport. Journal of Clinical Investigation 113: 231–242.

Goizet C, Boukhris A, Durr A, et al. (2009) CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain 132: 1589–1600.

Gregianin E, Vazza G, Scaramel E, et al. (2013) A novel SACS mutation results in non‐ataxic spastic paraplegia and peripheral neuropathy. European Journal of Neurology 20: 1486–1491.

Harlalka GV, Lehman A, Chioza B, et al. (2013) Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain 136: 3618–3624.

Hammer MB, Eleuch‐Fayache G, Schottlaender LV, et al. (2013) Mutations in GBA2 cause autosomal‐recessive cerebellar ataxia with spasticity. American Journal of Human Genetics 92: 245–251.

Hehr U, Bauer P, Winner B, et al. (2007) Long‐term course and mutational spectrum of spatacsin‐linked spastic paraplegia. Annals of Neurology 62: 656–665.

Hirst J, Edgar JR, Esteves T, et al. (2015) Loss of AP‐5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Human Molecular Genetics 24: 4984–4996.

Ivanova N, Claeys KG, Deconinck T, et al. (2007) Hereditary spastic paraplegia 3A associated with axonal neuropathy. Archives of Neurology 64: 706–713.

Klebe S, Depienne C, Gerber S, et al. (2012) Spastic paraplegia gene 7 in patients with spasticity and/or optic atrophy. Brain 135: 2980–2993.

Klemm RW, Norton JP, Cole RA, et al. (2013) A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Reports 3: 1465–1475.

Marelli C, Lamari F, Rainteau D, et al. (2018) Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain 141: 72–84.

Martin E, Yanicostas C, Rastetter A, et al. (2012) Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish. Neurobiology of Disease 48: 299–308.

Martin E, Schüle R, Smets K, et al. (2013) Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. American Journal of Human Genetics 92: 238–244.

Montecchiani C, Pedace L, Lo Giudice T, et al. (2016) ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot‐Marie‐Tooth disease. Brain 139: 73–85.

Orlacchio A, Babalini C, Borreca A, et al. (2010) SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133: 591–598.

Orso G, Martinuzzi A, Rossetto MG, et al. (2005) Disease‐related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. Journal of Clinical Investigation 115: 3026–3034.

Orso G, Pendin D, Liu S, et al. (2009) Homotypic fusion of ER membranes requires the dynamin‐like GTPase atlastin. Nature 460: 978–983.

Orthmann‐Murphy JL, Salsano E, Abrams CK, et al. (2009) Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 132: 426–438.

Papadopoulos C, Orso G, Mancuso G, et al. (2015) Spastin binds to lipid droplets and affects lipid metabolism. PLoS Genetics 11: e1005149.

Pirozzi M, Quattrini A, Andolfi G, et al. (2006) Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia. Journal of Clinical Investigation 116: 202–208.

Rainier S, Bui M, Mark E, et al. (2008) Neuropathy target esterase gene mutations cause motor neuron disease. American Journal of Human Genetics 82: 780–785.

Renvoisé B, Stadler J, Singh R, et al. (2012) Spg20−/− mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling. Human Molecular Genetics 21: 3604–3618.

Ribai P, Depienne C, Fedirko E, et al. (2008) Mental deficiency in three families with SPG4 spastic paraplegia. European Journal of Human Genetics 16: 97–104.

Roda RH, Schindler AB and Blackstone C (2017) Multigeneration family with dominant SPG30 hereditary spastic paraplegia. Annals of Clinical Translational Neurology 4: 821–824.

Roll‐Mecak A and Vale RD (2008) Structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin. Nature 451: 363–367.

Schickel J, Pamminger T, Ehrsam A, et al. (2007) Isoform‐specific increase of spastin stability by N‐terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. European Journal of Neurology 14: 1322–1328.

Schöls L, Rattay TW, Martus P, et al. (2017) Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain 140: 3112–3127.

Smith BN, Bevan S, Vance C, et al. (2009) Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra‐familial variability in age of onset and complex phenotype. Clinical Genetics 75: 485–489.

Stevanin G, Azzedine H, Denora P, et al. (2008) Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain 131: 772–784.

Synofzik M, Gonzalez MA, Lourenco CM, et al. (2014) PNPLA6 mutations cause Boucher‐Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain 137: 69–77.

Tarrade A, Fassier C, Courageot S, et al. (2006) A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Human Molecular Genetics 15: 3544–3558.

Trotta N, Orso G, Rossetto MG, et al. (2004) The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Current Biology 14: 1135–1147.

Tsang HT, Edwards TL, Wang X, et al. (2009) The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling. Human Molecular Genetics 18: 3805–3821.

White SR, Evans KJ, Lary J, et al. (2007) Recognition of C‐terminal amino acids in tubulin by pore loops in spastin is important for microtubule severing. Journal of Cell Biology 176: 995–1005.

Wood JD, Landers JA, Bingley M, et al. (2006) The microtubule‐severing protein spastin is essential for axon outgrowth in the zebrafish embryo. Human Molecular Genetics 15: 2763–2771.

Further Reading

Allison R, Edgar JR, Pearson G, et al. (2017) Defects in ER‐endosome contacts impact lysosome function in hereditary spastic paraplegia. Journal of Cell Biology 216: 1337–1355.

Blackstone C (2012) Cellular pathways of hereditary spastic paraplegia. Annual Review of Neuroscience 35: 25–47.

Cai H, Shim H, Lai C, et al. (2008) ALS2/alsin knockout mice and motor neuron diseases. Neurodegenerative Diseases 5: 359–366.

De Vos KJ, Grierson AJ, Ackerley S and Miller CC (2008) Role of axonal transport in neurodegenerative diseases. Annual Review of Neuroscience 31: 151–173.

OMIM: Online Mendelian Inheritance in Man, OMIM (TM) (2010) McKusick‐Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD).

Pagon RA, Bird TC, Dolan CR and Stephens K (eds) (2009) GeneReviews [Internet]. Seattle, WA: University of Washington 1993–2008 March 27 [updated 2009 September 03].

Salinas S, Proukakis C, Crosby A and Warner TT (2008) Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurology 7: 1127–1138.

Synofzik M and Schüle R (2017) Overcoming the divide between ataxias and spastic paraplegias: shared phenotypes, genes, and pathways. Movement Disorders 32: 332–345.

Tallaksen CM, Dürr A and Brice A (2001) Recent advances in hereditary spastic paraplegia. Current Opinion in Neurology 14: 457–463.

Tesson C, Koht J and Stevanin G (2015) Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Human Genetics 134: 511–538.

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Boutry, Maxime, and Stevanin, Giovanni(Aug 2018) Molecular Genetics of Hereditary Spastic Paraplegias. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022419.pub2]