GeneTable

15. HEREDITARY PARAPLEGIAS (Return to Disease group)

Disease phenotype

Item in this table

References

Gene symbol (chromosome)
protein

Spastic paraplegia 3A, autosomal dominant (Stumpell disease) - (AD)

15.1

Hazan J, Lamy C, Melki J, Munnich A, de Recondo J, Weissenbach J. Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q. Nat Genet. 1993 Oct;5(2):163-7. (15517445)

Abel, A.; Fonknechten, N.; Hofer, A.; Durr, A.; Cruaud, C.; Voit, T.; Weissenbach, J.; Brice, A.; Klimpe, S.; Auburger, G.; Hazan, J. : Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A. Neurogenetics 5: 239-243, 2004. (23483706)

Varga, R.-E., Schule, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nurnberg, G., Thiele, H., Altmuller, J., Alvarez, V., Gamez, J., Garbern, J. Y., Nurnberg, P., Zuchner, S., Beetz, C. Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia. Hum. Mutat. 34: 860-863, 2013. (8252041)

ATL1 (14q22.1)

Atlastin GTPase 1

Spastic paraplegia 4, autosomal dominant - (AD)

15.2

Hazan J, Fontaine B, Bruyn RP, Lamy C, van Deutekom JC, Rime CS, Durr A, Melki J, Lyon-Caen O, Agid Y, et al. Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p. Hum Mol Genet. 1994 Sep;3(9):1569-73. (7833913)

SPAST (2p24-p21)

Spastin

Spastic paraplegia 6, autosomal dominant - (AD)

15.3

Fink JK, Wu CT, Jones SM, Sharp GB, Lange BM, Lesicki A, Reinglass T, Varvil T, Otterud B, Leppert M. Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am J Hum Genet. 1995 Jan;56(1):188-92. (14508710)

Rainier, S.; Chai, J.-H.; Tokarz, D.; Nicholls, R. D.; Fink, J. K. : NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am. J. Hum. Genet. 73: 967-971, 2003. (7825577)

NIPA1 (15q11.2)

Non imprinted gene in Prader-Willi/Angelman syndrome chromosome region 1

Spastic paraplegia 8, autosomal dominant - (AD)

15.4

Hedera P, Rainier S, Alvarado D, Zhao X, Williamson J, Otterud B, Leppert M, Fink JK. Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. Am J Hum Genet. 1999 Feb;64(2):563-9. (17160902)

Valdmanis, P. N.; Meijer, I. A.; Reynolds, A.; Lei, A.; MacLeod, P.; Schlesinger, D.; Zatz, M.; Reid, E.; Dion, P. A.; Drapeau, P.; Rouleau, G. A. : Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am. J. Hum. Genet. 80: 152-161, 2007. (9973294)

KIAA0196 (8q24.13)

Strumpellin

Spastic paraplegia 9A, autosomal dominant - (AD)

15.5

Seri, M.; Cusano, R.; Forabosco, P.; Cinti, R.; Caroli, F.; Picco, P.; Bini, R.; Morra, V. B.; De Michele, G.; Lerone, M.; Silengo, M.; Pela, I.; Borrone, C.; Romeo, G.; Devoto, M. : Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy. Am. J. Hum. Genet. 64: 586-593, 1999. (26297558)

Panza, E., Escamilla-Honrubia, J. M., Marco-Marin, C., Gougeard, N., De Michele, G., Brescia Morra, V., Liguori, R., Salviati, L., Donati, M. A., Cusano, R., Pippucci, T., Ravazzolo, R., Nemeth, A. H., Smithson, S., Davies, S., Hurst, J. A., Bordo, D., Rubio, V., Seri, M. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. (Letter) Brain 139: e3, 2016. Note: Electronic Article. (9973297)

ALDH18A1 (10q24.1)

Aldehyde deydrogenase 18 family, member A1

Spastic paraplegia 10, autosomal dominant - (AD)

15.6

Reid E, Dearlove AM, Rhodes M, Rubinsztein DC. A new locus for autosomal dominant pure hereditary spastic paraplegia mapping to chromosome 12q13, and evidence for further genetic heterogeneity. Am J Hum Genet. 1999 Sep;65(3):757-63. (10441583)

KIF5A (12q13.13)

Kinesin family member 5A

Spastic paraplegia 12, autosomal dominant - (AD)

15.7

Reid E, Dearlove AM, Osborn O, Rogers MT, Rubinsztein DC. A locus for autosomal dominant pure hereditary spastic paraplegia maps to chromosome 19q13. Am J Hum Genet. 2000 Feb;66(2):728-32. (10677333)

Orlacchio, A.; Kawarai, T.; Rogaeva, E.; Song, Y. Q.; Paterson, A. D.; Bernardi, G.; St. George-Hyslop, P. H. : Clinical and genetic study of a large Italian family linked to SPG12 locus. Neurology 59: 1395-1401, 2002. (22232211)

Montenegro, G., Rebelo, A. P., Connell, J., Allison, R., Babalini, C., D'Aloia, M., Montieri, P., Schule, R., Ishiura, H., Price, J., Strickland, A., Gonzalez, M. A., and 13 others. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J. Clin. Invest. 122: 538-544, 2012. (12427890)

RTN2 (19q13)

Reticulon 2

Spastic paraplegia 13, autosomal dominant - (AD)

15.8

Fontaine B, Davoine CS, Durr A, Paternotte C, Feki I, Weissenbach J, Hazan J, Brice A. A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am J Hum Genet. 2000 Feb;66(2):702-7. (10677329)

Magen D, Georgopoulos C, Bross P, Ang D, Segev Y, Goldsher D, Nemirovski A, Shahar E, Ravid S, Luder A, Heno B, Gershoni-Baruch R, Skorecki K and Mandel H. Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am J Hum Genet 2008;83:30-42. (18571143)

HSPD1 (2q33.1)

Heat shock 60kDa protein 1 (chaperonin)

Spastic paraplegia 17, autosomal dominant (Silver) - (AD)

15.9

Windpassinger, C.; Auer-Grumbach, M.; Irobi, J.; Patel, H.; Petek, E.; Horl, G.; Malli, R.; Reed, J. A.; Dierick, I.; Verpoorten, N.; Warner, T. T.; Proukakis, C.; Van den Bergh, P.; Verellen, C.; Van Maldergem, L.; Merlini, L.; De Jonghe, P.; Timmerman, V.; Crosby, A. H.; Wagner, K. : Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nature Genet. 36: 271-276, 2004. (14981520)

BSCL2 (11q12-q13.5)

Seipin

Spastic paraplegia 18A7, autosomal dominant - (AD)

15.10

Rydning, S. L., Dudesek, A., Rimmele, F., Funke, C., Kruger, S., Biskup, S., Vigeland, M. D., Hjorthaug, H. S., Sejersted, Y., Tallaksen, C., Selmer, K. K., Kamm, C. A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia. Europ. J. Neurol. 25: 943-e71, 2018. [PubMed: 29528531, (29528531)

ERLIN2 (8p12-p11.21)

ER lipid raft associated 2

Spastic paraplegia 19, autosomal dominant - (AD)

15.11

Valente, E. M.; Brancati, F.; Caputo, V.; Bertini, E.; Patrono, C.; Costanti, D.; Dallapiccola, B. : Novel locus for autosomal dominant pure hereditary spastic paraplegia (SPG19) maps to chromosome 9q33-q34. Ann. Neurol. 51: 681-685, 2002. (12112072)

? - (9q33-q34)

Spastic paraplegia 29, autosomal dominant - (AD)

15.12

Orlacchio, A.; Kawarai, T.; Gaudiello, F.; St George-Hyslop, P. H.; Floris, R.; Bernardi, G.: New locus for hereditary spastic paraplegia maps to chromosome 1p31.1-1p21.1. Ann. Neurol. 58: 423-429, 2005. (16130112)

? - (1p31-p21)

Spastic paraplegia 30, autosomal dominant - (AD)

15.13

Ylikallio, E., Kim, D., Isohanni, P., Auranen, M., Kim, E., Lonnqvist, T., Tyynismaa, H. Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. Europ. J. Hum. Genet. 23: 1427-1430, 2015. [PubMed: 25585697, (25585697)

KIF1A (2q37.3)

Kinesin family member 1A

Spastic paraplegia 31, autosomal dominant - (AD)

15.14

Zuchner, S.; Kail, M. E.; Nance, M. A.; Gaskell, P. C.; Svenson, I. K.; Marchuk, D. A.; Pericak-Vance, M. A.; Ashley-Koch, A. E. : A new locus for dominant hereditary spastic paraplegia maps to chromosome 2p12. (Letter) Neurogenetics 7: 127-129, 2006(a). (16565863)

Zuchner, S.; Wang, G.; Tran-Viet, K.-N.; Nance, M. A.; Gaskell, P. C.; Vance, J. M.; Ashley-Koch, A. E.; Pericak-Vance, M. A. : Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am. J. Hum. Genet. 79: 365-369, 2006.(b) (16826527)

REEP1 (2p11.2)

Receptor accessory protein 1

Spastic paraplegia 33, autosomal dominant - (AD)

15.15

Mannan, A. U.; Krawen, P.; Sauter, S. M.; Boehm, J.; Chronowska, A.; Paulus, W.; Neesen, J.; Engel, W. : ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am. J. Hum. Genet. 79: 351-357, 2006. (16826525)

ZFYVE27 (10q24.2)

Zinc finger, FYVE domain containing 27

Spastic paraplegia 36, autosomal dominant - (AD)

15.16

Schule, R., Bonin, M., Durr, A., Forlani, S., Sperfeld, A. D., Klimpe, S., Mueller, J. C., Seibel, A., van de Warrenburg, B. P., Bauer, P., Schols, L. Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24. Neurology 72: 1893-1898, 2009. (19357379)

? - (12q23-q24)

Spastic paraplegia 37, autosomal dominant - (AD)

15.17

Hanein S, Durr A, Ribai P, Forlani S, Leutenegger AL, Nelson I, Babron MC, Elleuch N, Depienne C, Charon C, Brice A and Stevanin G. A novel locus for autosomal dominant "uncomplicated" hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3. Hum Genet 2007. (17605047)

? - (8p21.1-q13.3)

Spastic paraplegia 38, autosomal dominant - (AD)

15.18

Orlacchio A, Patrono C, Gaudiello F, Rocchi C, Moschella V, Floris R, Bernardi G, Kawarai T. Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4. Neurology. 2008 May 20;70(21):1959-66. Epub 2008 Apr 9. (18401025 )

? - (4p16-p15)

Spastic paraplegia 41, autosomal dominant - (AD)

15.19

Zhao, G., Hu, Z., Shen, L., Jiang, H., Ren, Z., Liu, X., Xia, K., Guo, P., Pan, Q., Tang, B. A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia. Chin. Med. J. 121: 430-434, 2008. (18364116)

? - (11p14.1-p11.2)

Spastic paraplegia 42, autosomal dominant - (AD)

15.20

Lin P, Li J, Liu Q, Mao F, Li J, Qiu R, Hu H, Song Y, Yang Y, Gao G, Yan C, Yang W, Shao C, Gong Y. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am J Hum Genet. 2008 Dec;83(6):752-9. (19061983)

SLC33A1 (3q25.3)

Solute carrier family 33 (acetyl- CoA transporter)

Spastic paraplegia 72, autosomal dominant - (AD)

15.21

Esteves, T., Durr, A., Mundwiller, E., Loureiro, J. L., Boutry, M., Gonzalez, M. A., Gauthier, J., El-Hachimi, K. H., Depienne, C., Muriel, M.-P., Acosta Lebrigio, R. F., Gaussen, M., and 11 others. Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. Am. J. Hum. Genet. 94: 268-277, 2014. (24388663)

REEP2 (5q31.2)

Receptor expression-enhancing proten 2

Spastic paraplegia 73, autosomal dominant - (AD)

15.22

Rinaldi, C., Schmidt, T., Situ, A. J., Johnson, J. O., Lee, P. R., Chen, K., Bott, L. C., Fado, R., Harmison, G. H., Parodi, S., Grunseich, C., Renvoise, B., and 12 others. Mutation in CPT1C associated with pure autosomal dominant spastic paraplegia. JAMA Neurol. 72: 561-570, 2015. Note: Erratum: JAMA Neurol. 72: 608 only, 2015. (25751282)

CPT1C (19q13.33)

Carnitine Palmitoyltransferase 1C

Spastic paraplegia 79, autosomal dominant - (AD)

15.23

Park, J., Tucci, A., Cipriani, V., Demidov, G., Rocca, C., Senderek, J., Butryn, M., Velic, A., Lam, T., Galanaki, E., Cali, E., Vestito, L., and 38 others. Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy. Genet. Med. 24: 2079-2090, 2022. [PubMed: 35986737, (35986737)

UCHL1 (4p13)

Ubiquitin Carboxyl-Terminal Esterase L1

Spastic paraplegia 80, autosomal dominant - (AD)

15.24

Farazi Fard, M. A., Rebelo, A. P., Buglo, E., Nemati, H., Dastsooz, H., Gehweiler, I., Reich, S., Reichbauer, J., Quintans, B., Ordonez-Ugalde, A., Cortese, A., Courel, S., and 30 others. Truncating mutations in UBAP1 cause hereditary spastic paraplegia. Am. J. Hum. Genet. 104: 767-773, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 1251 only, 2019. (30929741)

UBAP1 (9p13.3)

Ubiquitin-associated protein 1

Spastic paraplegia 88, autosomal dominant - (AD)

15.25

Schob, C., Hempel, M., Safka Brozkova, D., Jiang, H., Kim, S. Y., Batzir, N. A., Orenstein, N., Bierhals, T., Johannsen, J., Uhrova Meszarosova, A., Chae, J. H., Seeman, P., Woidy, M., Fang, F., Kubisch, C., Kindler, S., Denecke, J. Dominant KPNA3 mutations cause infantile-onset hereditary spastic paraplegia. Ann. Neurol. 90: 738-750, 2021. [PubMed: 34564892, (34564892)

KPNA3 (13q14.2)

Karyopherin alpha-3

Spastic paraplegia, intellectual disability, nystagmus, and obesity - (AD)

15.26

Josifova, D. J., Monroe, G. R., Tessadori, F., de Graaff, E., van der Zwaag, B., Mehta, S. G., the DDD study, Harakalova, M., Duran, K. J., Savelberg, S. M. C., Nijman, I. J., Jungbluth, H., Hoogenraad, C. C., Bakkers, J., Knoers, N. V., Firth, H. V., Beales, P. L., van Haaften, G., van Haelst, M. M. Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity. Hum. Molec. Genet. 25: 2158-2167, 2016. (27005418)

KIDINS220 (2p25.1)

kinase D-interacting substrate, 220kDa

Spastic paraplegia 5A, autosomal recessive - (AR)

15.27

Hentati, A.; Pericak-Vance, M. A.; Hung, W.-Y.; Belal, S.; Laing, N.; Boustany, R.-M.; Hentati, F.; Ben Hamida, M.; Siddique, T. : Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum. Molec. Genet. 3: 1263-1267, 1994. (14658060)

Muglia, M.; Criscuolo, C.; Magariello, A.; De Michele, G.; Scarano, V.; D'Adamo, P.; Ambrosio, G.; Gabriele, A. L.; Patitucci, A.; Mazzei, R.; Conforti, F. L.; Sprovieri, T.; Morgante, L.; Epifanio, A.; La Spina, P.; Valentino, P.; Gasparini, P.; Filla, A.; Quattrone, A. : Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus. Neurogenetics 5: 49-54, 2004. (18252231)

Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton MA, Hentati A, Lamont PJ, Siddique T, Crosby AH. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet. 2008 Feb;82(2):510-5. Epub 2008 Jan 18. (19187859)

Tsaousidou, M. K., Ouahchi, K., Warner, T. T., Yang, Y., Simpson, M. A., Laing, N. G., Wilkinson, P. A., Madrid, R. E., Patel, H., Hentati, F., Patton, M. A., Hentati, A., Lamont, P. J., Siddique, T., Crosby, A. H. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am. J. Hum. Genet. 82: 510-515, 2008. (19224311)

Anheim M, Lagier-Tourenne C, Stevanin G, Fleury M, Durr A, Namer IJ, Denora P, Brice A, Mandel JL, Koenig M and Tranchant C. SPG11 spastic paraplegia. A new cause of juvenile parkinsonism. J Neurol 2009;256:104-8. (19439420)

Biancheri, R., Ciccolella, M., Rossi, A., Tessa, A., Cassandrini, D., Minetti, C., Santorelli, F. M. White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1. Neuromusc. Disord. 19: 62-65, 2009. (7987300)

CYP7B1 (8p12-q13)

Cytochrome P450, family 7, subfamily B, polypeptide 1

Spastic paraplegia 7, autosomal recessive - (AR)

15.28

Casari, G.; De Fusco, M.; Ciarmatori, S.; Zeviani, M.; Mora, M.; Fernandez, P.; De Michele, G.; Filla, A.; Cocozza, S.; Marconi, R.; Durr, A.; Fontaine, B.; Ballabio, A. : Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93: 973-983, 1998. (9635427)

SPG7 (16q24.3)

Paraplegin

Spastic paraplegia 9B, autosomal recessive - (AR)

15.29

Coutelier, M., Goizet, C., Durr, A., Habarou, F., Morais, S., Dionne-Laporte, A., Tao, F., Konop, J., Stoll, M., Charles, P., Jacoupy, M., Matusiak, R. and 22 others. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain 138: 2191-2205, 2015. (26026163)

ALDH18A1 (10q24.1)

Aldehyde deydrogenase 18 family, member A1

Spastic paraplegia 11, autosomal recessive - (AR)

15.30

Martinez Murillo F, Kobayashi H, Pegoraro E, Galluzzi G, Creel G, Mariani C, Farina E, Ricci E, Alfonso G, Pauli RM, Hoffman EP. Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13-15. Neurology. 1999 Jul 13;53(1):50-6. (10408536)

Stevanin, G.; Montagna, G.; Azzedine, H.; Valente, E. M.; Durr, A.; Scarano, V.; Bouslam, N.; Cassandrini, D.; Denora, P. S.; Criscuolo, C.; Belarbi, S.; Orlacchio, A.; and 27 others : Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity. Neurogenetics 7: 149-156, 2006. (16699786)

Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro JL, Elleuch N, Confavreux C, Cruz VT, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A and Brice A. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 2007;39:366-72. (17322883)

SPG11 (15q21.1)

SPG11 vesicle trafficking associated, Spatacsin

Spastic paraplegia 14, autosomal recessive - (AR)

15.31

Vazza, G.; Zortea, M.; Boaretto, F.; Micaglio, G. F.; Sartori, V.; Mostacciuolo, M. L. : 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. 67: 504-509, 2000. (10877981)

? - (3q27-q28)

Spastic paraplegia 15, autosomal recessive (Kjellin syndrome) - (AR)

15.32

Hughes, C. A.; Byrne, P. C.; Webb, S.; McMonagle, P.; Patterson, V.; Hutchinson, M.; Parfrey, N. A. : SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 56: 1230-1233, 2001. (11342696)

Elleuch N, Bouslam N, Hanein S, Lossos A, Hamri A, Klebe S, Meiner V, Birouk N, Lerer I, Grid D, Bacq D, Tazir M, Zelenika D, Argov Z, Durr A, Yahyaoui M, Benomar A, Brice A, Stevanin G. Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families. Neurogenetics. 2007 Nov;8(4):307-15. Epub 2007 Jul 28. (18394578)

Hanein S, Martin E, Boukhris A, Byrne P, Goizet C, Hamri A, Benomar A, Lossos A, Denora P, Fernandez J, Elleuch N, Forlani S, Durr A, Feki I, Hutchinson M, Santorelli FM, Mhiri C, Brice A, Stevanin G. 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 Apr;82(4):992-1002. (17661097)

ZFYVE26 (14q24.1)

Spastizin

Spastic paraplegia 18, autosomal recessive - (AR)

15.33

Al-Yahyaee, S., Al-Gazali, L. I., De Jonghe, P., Al-Barwany, H., Al-Kindi, M., De Vriendt, E., Chand, P., Koul, R., Jacob, P. C., Gururaj, A., Sztriha, L., Parrado, A., Van Broeckhoven, C., Bayoumi, R. A. A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy. Neurology 66: 1230-1234, 2006. (16636240)

Alazami, A. M., Adly, N., Al Dhalaan, H., Alkuraya, F. S. A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18). Neurogenetics 12: 333-336, 2011. (21796390)

Al-Saif, A., Bohlega, S., Al-Mohanna, F. Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. Ann. Neurol. 72: 510-516, 2012. (23109145)

ERLIN2 (8p12-p11.21)

ER lipid raft associated 2

Spastic paraplegia 20, autosomal recessive (Troyer syndrome) - (AR)

15.34

Patel, H.; Cross, H.; Proukakis, C.; Hershberger, R.; Bork, P.; Ciccarelli, F. D.; Patton, M. A.; McKusick, V. A.; Crosby, A. H. : SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nature Genet. 31: 347-348, 2002. (12134148)

SPG20 (13q12.3)

Spartin

Spastic paraplegia 21, autosomal recessive (Mast syndrome) - (AR)

15.35

Simpson, M. A.; Cross, H.; Proukakis, C.; Pryde, A.; Hershberger, R.; Chatonnet, A.; Patton, M. A.; Crosby, A. H. : Maspardin is mutated in Mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am. J. Hum. Genet. 73: 1147-1156, 2003. (14564668)

SPG21 (15q21-q22)

Maspardin

Spastic paraplegia 23, autosomal recessive (Lison) - (AR)

15.36

Blumen, S. C.; Bevan, S.; Abu-Mouch, S.; Negus, D.; Kahana, M.; Inzelberg, R.; Mazarib, A.; Mahamid, A.; Carasso, R. L.; Slor, H.; Withers, D.; Nisipeanu, P.; Navon, R.; Reid, E. : A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32. Ann. Neurol. 54: 796-803, 2003. (14681889)

? - (1q24-q32)

Spastic paraplegia 24, autosomal recessive - (AR)

15.37

Hodgkinson, C. A.; Bohlega, S.; Abu-Amero, S. N.; Cupler, E.; Kambouris, M.; Meyer, B. F.; Bharucha, V. A. : A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology 59: 1905-1909, 2002. (12499481)

? - (13q14)

Spastic paraplegia 25, autosomal recessive - (AR)

15.38

Zortea, M.; Vettori, A.; Trevisan, C. P.; Bellini, S.; Vazza, G.; Armani, M.; Simonati, A.; Mostacciuolo, M. L. : Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1. J. Med. Genet. 39: 387-390, 2002. (12070243)

? - (6q23.3-q24.1)

Spastic paraplegia 26, autosomal recessive - (AR)

15.39

Wilkinson, P. A.; Simpson, M. A.; Bastaki, L.; Patel, H.; Reed, J. A.; Kalidas, K.; Samilchuk, E.; Khan, R.; Warner, T. T.; Crosby, A. H. : A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. (Letter) J. Med. Genet. 42: 80-82, 2005. (15635080)

Boukhris, A., Schule, R., Loureiro, J. L., Lourenco, C. M., Mundwiller, E., Gonzalez, M. A., Charles, P., Gauthier, J., Rekik, I., Acosta Lebrigio, R. F., Gaussen, M., Speziani, F., and 21 others. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am. J. Hum. Genet. 93: 118-123, 2013. (23746551)

B4GALNT1 (12q13.3)

Beta-1,4-N-acetyl-galactosaminyl transferase 1

Spastic paraplegia 27, autosomal recessive - (AR)

15.40

Meijer, I. A.; Cossette, P.; Roussel, J.; Benard, M.; Toupin, S.; Rouleau, G. A. : A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1. Ann. Neurol. 56: 579-582, 2004. (15455396)

? - (10q22.1-q24.1)

Spastic paraplegia 28, autosomal recessive - (AR)

15.41

Bouslam, N.; Benomar, A.; Azzedine, H.; Bouhouche, A.; Namekawa, M.; Klebe, S.; Charon, C.; Durr, A.; Ruberg, M.; Brice, A.; Yahyaoui, M.; Stevanin, G. : Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann. Neurol. 57: 567-571, 2005. (15786464)

Tesson, C., Nawara, M., Salih, M. A. M., Rossignol, R., Zaki, M. S., Al Balwi, M., Schule, R., Mignot, C., Obre, E., Bouhouche, A., Santorelli, F. M., Durand, C. M., and 30 others. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1051-1064, 2012. (23176821)

DDHD1 (14q21)

DDHD domain containing 1

Spastic paraplegia 30, autosomal recessive - (AR)

15.42

Klebe, S.; Azzedine, H.; Durr, A.; Bastien, P.; Bouslam, N.; Elleuch, N.; Forlani, S.; Charon, C.; Koenig, M.; Melki, J.; Brice, A.; Stevanin, G. : Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain 129: 1456-1462, 2006. (16434418)

Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res. 2011 May;21(5):658-64. Epub 2011 Apr 12. (21487076)

KIF1A (2q37.3)

Kinesin family member 1A

Spastic paraplegia 32, autosomal recessive - (AR)

15.43

Stevanin G, Paternotte C, Coutinho P, Klebe S, Elleuch N, Loureiro JL, Denis E, Cruz VT, Durr A, Prud'homme JF, Weissenbach J, Brice A and Hazan J. A new locus for autosomal recessive spastic paraplegia (SPG32) on chromosome 14q12-q21. Neurology 2007;68:1837-40. (17515546)

? - (14q12-q21)

Spastic paraplegia 35, autosomal recessive - (AR)

15.44

Dick KJ, Al-Mjeni R, Baskir W, Koul R, Simpson MA, Patton MA, Raeburn S, Crosby AH. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. Neurology. 2008 Jul 22;71(4):248-52. Epub 2008 May 7. (18463364)

FA2H (16q21-q23.1)

Fatty acid 2-hydroxylase

Spastic paraplegia 39, autosomal recessive - (AR)

15.45

Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L, Delaney C, Richardson RJ, Albers JW, Matsunami N, Stevens J, Coon H, Leppert M, Fink JK. Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet. 2008 Mar;82(3):780-5. Epub 2008 Feb 28. (18313024)

PNPLA6 (19p13.3-p13.2)

Patatin-like phospholipase domain containing 6

Spastic paraplegia 43, autosomal recessive - (AR)

15.46

Meilleur KG, Traoré M, Sangaré M, Britton A, Landouré G, Coulibaly S, Niaré B, Mochel F, La Pean A, Rafferty I, Watts C, Shriner D, Littleton-Kearney MT, Blackstone C, Singleton A, Fischbeck KH. Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19. Neurogenetics. 2010 Jul;11(3):313-8. Epub 2009 Dec 29. (20039086)

Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum. Mutat. 34: 1357-1360, 2013. (23857908)

C19orf12 (19q12)

Chromosome 19 open reading frame 12

Spastic paraplegia 44, autosomal recessive - (AR)

15.47

Orthmann-Murphy, J. L., Salsano, E., Abrams, C. K., Bizzi, A., Uziel, G., Freidin, M. M., Lamantea, E., Zeviani, M., Scherer, S. S., Pareyson, D. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 132: 426-438, 2009 (1905680)

GJC2 (1q42.13)

gap junction protein, gamma 2, 47kDa

Spastic paraplegia 45, autosomal recessive - (AR)

15.48

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 Oct;10(4):325-31. Epub 2009 May 5. (19415352)

Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014 (24482476)

NT5C2 (10q24-q32)

5'-nucleotidase, cytosolic II

Spastic paraplegia 46, autosomal recessive - (AR)

15.49

Boukhris, A., Feki, I., Elleuch, N., Miladi, M. I., Boland-Auge, A., Truchetto, J., Mundwiller, E., Jezequel, N., Zelenika, D., Mhiri, C., Brice, A., Stevanin, G. 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 11: 441-448, 2010 (20593214)

Martin, E., Schule, R., Smets, K., Rastetter, A., Boukhris, A., Loureiro, J. L., Gonzalez, M. A., Mundwiller, E., Deconinck, T., Wessner, M., Jornea, L., Oteyza, A. C., and 10 others. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am. J. Hum. Genet. 92: 238-244, 2013. (23332916)

Hammer, M. B., Eleuch-Fayache, G., Schottlaender, L. V., Nehdi, H., Gibbs, J. R., Arepalli, S. K., Chong, S. B., Hernandez, D. G., Sailer, A., Liu, G., Mistry, P. K., Cai, H., Shrader, G., Sassi, C., Bouhlal, Y., Houlden, H., Hentati, F., Amouri, R., Singleton, A. B. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am. J. Hum. Genet. 92: 245-251, 2013. (23332917)

GBA2 (9p13.3)

Glucosidase, beta (bile acid) 2

Spastic paraplegia 47, autosomal recessive - (AR)

15.50

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 Jun 15;305(1-2):67-70. Epub 2011 Mar 25. (21440262)

Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am. J. Hum. Genet. 88: 788-795, 2011 (21620353)

Bauer, P., Leshinsky-Silver, E., Blumkin, L., Schlipf, N., Schroder, C., Schicks, J., Lev, D., Riess, O., Lerman-Sagie, T., Schols, L.Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47). Neurogenetics 13: 73-76, 2012 (22290197)

AP4B1 (1p13.2)

adaptor-related protein complex 4, beta 1 subunit

Spastic paraplegia 48, autosomal recessive - (AR)

15.51

Stabicki M, Theis M, Krastev DB, Samsonov S, Mundwiller E, Junqueira M, Paszkowski-Rogacz M, Teyra J, Heninger AK, Poser I, Prieur F, Truchetto J, Confavreux C, Marelli C, Durr A, Camdessanche JP, Brice A, Shevchenko A, Pisabarro MT, Stevanin G, Buchholz F. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 2010 Jun 29;8(6):e1000408. (20613862)

AP5Z1 (7p22.2)

Hypothetical protein LOC9907 ?

Spastic paraplegia 49, autosomal recessive - (AR)

15.52

Oz-Levi, D., Ben-Zeev, B., Ruzzo, E. K., Hitomi, Y., Gelman, A., Pelak, K., Anikster, Y., Reznik-Wolf, H., Bar-Joseph, I., Olender, T., Alkelai, A., Weiss, M., Ben-Asher, E., Ge, D., Shianna, K. V., Elazar, Z., Goldstein, D. B., Pras, E., Lancet, D. Mutation in TECPR2reveals a role for autophagy in hereditary spastic paraparesis. Am. J. Hum. Genet. 91: 1065-1072, 2012 (23176824)

TECPR2 (14q32)

Tectonin beta-propeller repeat containing 2

Spastic paraplegia 50, autosomal recessive - (AR)

15.53

Verkerk, A. J. M. H., Schot, R., Dumee, B., Schellekens, K., Swagemakers, S., Bertoli-Avella, A. M., Lequin, M. H., Dudink, J., Govaert, P., van Zwol, A. L., Hirst, J., Wessels, M. W., and 9 others. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am. J. Hum. Genet. 85: 40-52, 2009. (19559397)

AP4M1 (7q22.1)

Adaptor-related protein complex 4, mu 1 subunit

Spastic paraplegia 51, autosomal recessive - (AR)

15.54

Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J. Med. Genet. 48: 141-144, 2011. (20972249)

AP4E1 (15q21.2)

Adaptor-related protein complex 4, epsilon-1 subunit

Spastic paraplegia 52, autosomal recessive - (AR)

15.55

AP4S1 (14q12)

Adaptor-related protein complex 4, sigma 1 subunit

Spastic paraplegia 53, autosomal recessive - (AR)

15.56

Zivony-Elboum, Y., Westbroek, W., Kfir, N., Savitzki, D., Shoval, Y., Bloom, A., Rod, R., Khayat, M., Gross, B., Samri, W., Cohen, H., Sonkin, V., Freidman, T., Geiger, D., Fattal-Valevski, A., Anikster, Y., Waters, A. M., Kleta, R., Falik-Zaccai, T. C. A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. J. Med. Genet. 49: 462-472, 2012. (22717650)

VPS37A (8p22)

Vacuolar protein sorting-associated protein 37A

Spastic paraplegia 54, autosomal recessive - (AR)

15.57

Schuurs-Hoeijmakers, J. H. M., Geraghty, M. T., Kamsteeg, E.-J., Ben-Salem, S., de Bot, S. T., Nijhof, B., van de Vondervoort, I. I. G. M., van der Graaf, M., Nobau, A. C., Otte-Holler, I., Vermeer, S., Smith, A. C., and 29 others. Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1073-1081, 2012 (23176823)

Gonzalez, M., Nampoothiri, S., Kornblum, C., Oteyza, A. C., Walter, J., Konidari, I., Hulme, W., Speziani, F., Schols, L., Zuchner, S., Schule, R. Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54).Europ. J. Hum. Genet. 21: 1214-1218, 2013 (23486545)

DDHD2 (8p11.23)

DDHD domain containing protein 2

Spastic paraplegia 55, autosomal recessive - (AR)

15.58

Shimazaki, H., Takiyama, Y., Ishiura, H., Sakai, C., Matsushima, Y., Hatakeyama, H., Honda, J., Sakoe, K., Naoi, T., Namekawa, M., Fukuda, Y., Takahashi, Y., Goto, J., Tsuji, S., Goto, Y., Nakano, I., Japan Spastic Paraplegia Research Consortium (JASPAC). A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). J. Med. Genet. 49: 777-784, 2012 (23188110)

Buchert, R., Uebe, S., Radwan, F., Tawamie, H., Issa, S., Shimazaki, H., Henneke, M., Ekici, A. B., Reis, A., Abou Jamra, R. Mutations in the mitochondrial gene C12ORF65 lead to syndromic autosomal recessive intellectual disability and show genotype phenotype correlation. Europ. J. Med. Genet. 56: 599-602, 2013. (24080142)

C12orf65 (12q24.31)

Chomosome 12 open reading frame 65

Spastic paraplegia 56, autosomal recessive - (AR)

15.59

CYP2U1 (4q25)

Cytochrome P450, family 2, subfamily U, polypeptide 1

Spastic paraplegia 57, autosomal recessive - (AR)

15.60

Beetz, C., Johnson, A., Schuh, A. L. et al. 2013. Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. Proc. Nat. Acad. Sci. 110: 5091-5096. (23479643)

TFG (3q13)

TRK-fused gene

Spastic paraplegia 61, autosomal recessive - (AR)

15.61

ARL6IP1 (16p12.3)

ADP-ribosylation factor-like 6 interacting protein 1

Spastic paraplegia 62 autosomal recessive - (AR)

15.62

ERLIN1 (10q24.31)

Endoplasmic reticulum lipid raft-associated protein 1 (Erlin-1)

Spastic paraplegia 63, autosomal recessive - (AR)

15.63

AMPD2 (1p13.3)

Adenosine monophosphate deaminase 2

Spastic paraplegia 64, autosomal recessive - (AR)

15.64

ENTPD1 (10q24.1)

Ectonucleoside triphosphate diphosphohydrolase 1

Spastic paraplegia 70, autosomal recessive - (AR)

15.65

Okamoto, N., Miya, F., Tsunoda, T., Kanemura, Y., Saitoh, S., Kato, M., Yanagi, K., Kaname, T., Kosaki, K. Four pedigrees with aminoacyl-tRNA synthetase abnormalities. Neurol. Sci. 43: 2765-2774, 2022.[PubMed: 34585293] (34585293)

MARS1 (12q13.3)

Methionyl-tRNA synthetase

Spastic paraplegia 72, autosomal recessive - (AR)

15.66

REEP2 (5q31.2)

Receptor expression-enhancing proten 2

Spastic paraplegia 74, autosomal recessive - (AR)

15.67

Lossos, A., Stumpfig, C., Stevanin, G., Gaussen, M., Zimmerman, B.-E., Mundwiller, E., Asulin, M., Chamma, L., Sheffer, R., Misk, A., Dotan, S., Gomori, J. M., Ponger, P., Brice, A., Lerer, I., Meiner, V., Lill, R. Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology 84: 659-667, 2015. (25609768)

IBA57 (1q42.13)

IBA57 homolog, iron-sulfur cluster assembly

Spastic paraplegia 75, autosomal recessive - (AR)

15.68

Lossos, A., Elazar, N., Lerer, I., Schueler-Furman, O., Fellig, Y., Glick, B., Zimmerman, B.-E., Azulay, H., Dotan, S., Goldberg, S., Gomori, J. M., Ponger, P., and 10 others. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. Brain 138: 2521-2536, 2015. (26179919)

MAG (19q13.12)

Myelin associated glycoprotein

Spastic paraplegia 76, autosomal recessive - (AR)

15.69

Gan-Or, Z., Bouslam, N., Birouk, N., Lissouba, A., Chambers, D. B., Verlepe, J., Androschuk, A., Laurent, S. B., Rochesfort, D., Spiegelman, D., Dionne-Laporte, A., Szuto, A., and 15 others. Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia. Am. J. Hum. Genet. 98: 1038-1046, 2016. Note: Erratum: Am. J. Hum. Genet. 98: 1271 only, 2016. (27153400)

CAPN1 (11q13.1)

Calpain 1

Spastic paraplegia 77, autosomal recessive - (AR)

15.70

Yang, Y., Liu, W., Fang, Z., Shi, J., Che, F., He, C., Yao, L., Wang, E., Wu, Y. A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia. Hum. Mutat. 37: 165-169, 2016. (26553276)

FARS2 (6p25.1)

Phenylalanine-tRNA synthetase 2

Spastic paraplegia 78, autosomal recessive - (AR)

15.71

Kara, E., Tucci, A., Manzoni, C., Lynch, D. S., Elpidorou, M., Bettencourt, C., Chelban, V., Manole, A., Hamed, S. A., Haridy, N. A., Federoff, M., Preza, E., and 17 others. genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain 139: 1904-1918, 2016. (27217339)

ATP13A2 (1q36.13)

ATPase, type 13A2

Spastic paraplegia 79, autosomal recessive - (AR)

15.72

Bilguvar, K., Tyagi, N. K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M., Delil, S., Caglayan, A. O., Baranoski, J. F., Erturk, O., Yalcinkaya, C., Karacorlu, M., and 9 others. Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc. Nat. Acad. Sci. 110: 3489-3494, 2013. (23359680)

UCHL1 (4p13)

Ubiquitin Carboxyl-Terminal Esterase L1

Spastic paraplegia 81, autosomal recessive - (AR)

15.73

Ahmed, M. Y., Al-Khayat, A., Al-Murshedi, F., Al-Futaisi, A., Chioza, B. A., Fernandez-Murray, J. P., Self, J. E., Salter, C. G., Harlalka, G. V., Rawlins, L. E., Al-Zuhaibi, S., Al-Azri, F., and 10 others. A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis. Brain 140: 547-554, 2017. [PubMed: 28052917, (28052917)

SELENOI (2p23.3)

Selenoprotein I

Spastic paraplegia 82, autosomal recessive - (AR)

15.74

Vaz, F. M., McDermott, J. H., Alders, M., Wortmann, S. B., Kolker, S., Pras-Raves, M. L., Vervaart, M. A. T., van Lenthe, H., Luyf, A. C. M., Elfrink, H. L., Metcalfe, K., Cuvertino, S., and 13 others. Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia. Brain 142: 3382-3397, 2019.[PubMed: 31637422, (31637422)

PCYT2 (17q25.3)

Phosphate cytidylyltransferase 2, ethanolamine

Spastic paraplegia 83, autosomal recessive - (AR)

15.75

Husain, R. A., Grimmel, M., Wagner, M., Hennings, J. C., Marx, C., Feichtinger, R. G., Saadi, A., Rostasy, K., Radelfahr, F., Bevot, A., Dobler-Neumann, M., Hartmann, H., and 34 others. Bi-allelic HPDL variants cause a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraplegia. Am. J. Hum. Genet. 107: 364-373, 2020.[PubMed: 32707086 (32707086)

HPDL (1p34.1)

4-hydroxyphenylpyruvate dioxygenase-like

Spastic paraplegia 84, autosomal recessive - (AR)

15.76

Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy. Brain 144: 2659-2669, 2021.[PubMed: 34415322 (34415322)

PI4KA (22q11.21)

Phosphatidylinositol 4-kinase, alpha

Spastic paraplegia 85, autosomal recessive - (AR)

15.77

Wagner, M., Osborn, D. P. S., Gehweiler, I., Nagel, M., Ulmer, U., Bakhtiari, S., Amouri, R., Boostani, R., Hentati, F., Hockley, M. M., Holbling, B., Schwarzmayr, T., and 17 others. Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. Nature Commun. 10: 4790, 2019.[PubMed: 31636353, (31636353)

RNF170 (8p11.21)

Ring finger protein 170

Spastic paraplegia 86, autosomal recessive - (AR)

15.78

Yahia, A., Elsayed, L. E. O., Valter, R., Hamed, A. A. A., Mohammed, I. N., Elseed, M. A., Salih, M. A., Esteves, T., Auger, N., Abubaker, R., Koko, M., Abozar, F., and 17 others. Pathogenic variants in ABHD16A cause a novel psychomotor developmental disorder with spastic paraplegia. Front. Neurol. 12: 720201, 2021.[PubMed: 34489854, (34489854)

ABHD16A (6p21.33)

Abhydrolase domain-containing protein 16a, phospholipase

Spastic paraplegia 87, autosomal recessive - (AR)

15.79

Tabara, L. C., Al-Salmi, F., Maroofian, R., Al-Futaisi, A. M., Al-Murshedi, F., Kennedy, J., Day, J. O., Courtin, T., Al-Khayat, A., Galedari, H., Mazaheri, N., Protasoni, M., and 19 others. TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia. Brain 145: 3095-3107, 2022. Note: Erratum: Brain: 145: e103, 2022.[PubMed: 35718349, (35718349)

TMEM63C (14q324.3)

Transmembrane protein 63c

Sjögren-Larsson syndrome - (AR)

15.80

Pigg M, Jagell S, Sillen A, Weissenbach J, Gustavson KH, Wadelius C. The Sjogren-Larsson syndrome gene is close to D17S805 as determined by linkage analysis and allelic association. Nat Genet. 1994 Dec;8(4):361-4. Erratum in: Nat Genet 1995 Apr;9(4):451. (7894487)

De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Steinert PM, Compton JG, Markova N, Rizzo WB. Related Articles, Links Sjogren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet. 1996 Jan;12(1):52-7. (8528251)

ALDH3A2 (17p11.2)

Aldehyde dehydrogenase 3A2

Infantile-onset ascending spastic paraplegia - (AR)

15.81

Eymard-Pierre, E.; Lesca, G.; Dollet, S.; Santorelli, F. M.; di Capua, M.; Bertini, E.; Boespflug-Tanguy, O. : Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am. J. Hum. Genet. 71: 518-527, 2002. (12145748)

ALS2 (2q33.2)

Alsin Rho guanine nucleotide exchange factor 2

Spastic paraplegia, optic atrophy, and neuropathy - (AR)

15.82

Melo, U. S., Macedo-Souza, L. I., Figueiredo, T., Muotri, A. R., Gleeson, J. G., Coux, G., Armas, P., Calcaterra, N. B., Kitajima, J. P., Amorim, S., Olavio, T. R., Griesi-Oliveira, K., Coatti, G. C., Rocha, C. R. R., Martins-Pinheiro, M., Menck, C. F. M., Zaki, M. S., Kok, F., Zatz, M., Santos, S. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Hum. Molec. Genet. 24: 6877-6885, 2015. (26385635)

KLC2 (11q13.2)

Kinesin light chain 2

Spastic paraplegia and psychomotor retardation with or without seizures - (AR)

15.83

Hollstein, R., Parry, D. A., Nalbach, L., Logan, C. V., Strom, T. M., Hartill, V. L., Carr, I. M., Korenke, G. C., Uppal, S., Ahmed, M., Wieland, T., Markham, A. F., Bennett, C. P., Gillessen-Kaesbach, G., Sheridan, E. G., Kaiser, F. J., Bonthron, D. T. HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J. Med. Genet. 52: 797-803, 2015. (26424145)

Akawi, N., McRae, J., Ansari, M., Balasubramanian, M., Blyth, M., Brady, A. F., Clayton, S., Cole, T., Deshpande, C., Fitzgerald, T. W., Foulds, N., Francis, R., and 30 others. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nature Genet. 47: 1363-1369, 2015. (26437029)

HACE1 (6q16.3)

Hect domain- and Ankyrin repeat- contaiing E3 Ubiquitin protein ligase 1

MASA syndrome - (XR)

15.84

Kenwrick S, Ionasescu V, Ionasescu G, Searby C, King A, Dubowitz M, Davies KE. Linkage studies of X-linked recessive spastic paraplegia using DNA probes. Hum Genet. 1986 Jul;73(3):264-6. (3460961)

Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, Metzenberg A, Ionasescu V, Temple K, Kenwrick S. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet. 1994 Jul;7(3):402-7. (7920659)

L1CAM (Xq28)

L1 cell adhesion molecule

Spastic paraplegia 2, X-linked - (XR)

15.85

Keppen LD, Leppert MF, O'Connell P, Nakamura Y, Stauffer D, Lathrop M, Lalouel JM, White R. Etiological heterogeneity in X-linked spastic paraplegia. Am J Hum Genet. 1987 Nov;41(5):933-43. (3479019)

Kobayashi H, Hoffman EP, Marks HG. The rumpshaker mutation in spastic paraplegia. Nat Genet. 1994 Jul;7(3):351-2. (7522741)

Saugier-Veber P, Munnich A, Bonneau D, Rozet JM, Le Merrer M, Gil R, Boespflug-Tanguy O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet. 1994 Mar;6(3):257-62. (8012387)

PLP1 (Xq22)

Proteolipid protein 1

Spastic paraplegia 16, X-linked, complicated - (XR)

15.86

Steinmuller, R.; Lantigua-Cruz, A.; Garcia-Garcia, R.; Kostrzewa, M.; Steinberger, D.; Muller, U. : Evidence of a third locus in X-linked recessive spastic paraplegia. Hum. Genet. 100: 287-289, 1997. (9254866)

? - (Xq11.2-q23)

Spastic paraplegia 34, X-linked - (XLR)

15.87

Macedo-Souza, L. I., Kok, F., Santos, S., Licinio, L., Lezirovitz, K., Nascimento, R. M. P., Bueno, C., Martyn, M., Leao, E. K. E. A., Zatz, M. Reevaluation of a large family defines a new locus for X-linked recessive pure spastic paraplegia (SPG34) on chromosome Xq25. Neurogenetics 9: 225-226, 2008. (18463901)

? - (Xq24-q25)

Spastic ataxia 1 - (AD)

15.88

Meijer, I. A.; Hand, C. K.; Grewal, K. K.; Stefanelli, M. G.; Ives, E. J.; Rouleau, G. A. : A locus for autosomal dominant hereditary spastic ataxia, SAX1, maps to chromosome 12p13. Am. J. Hum. Genet. 70: 763-769, 2002. (11774073)

Bourassa, C. V., Meijer, I. A., Merner, N. D., Grewal, K. K., Stefanelli, M. G., Hodgkinson, K., Ives, E. J., Pryse-Phillips, W., Jog, M., Boycott, K., Grimes, D. A., Goobie, S., Leckey, R., Dion, P. A., Rouleau, G. A. VAMP1 mutation causes dominant hereditary spastic ataxia in Newfoundland families. Am. J. Hum. Genet. 91: 548-552, 2012. (22958904)

VAMP1 (12p13)

Vesicle associated membrane protein (synaptobrevin 1)

Spastic ataxia 2 - (AR)

15.89

Bouslam N, Bouhouche A, Benomar A, Hanein S, Klebe S, Azzedine H, Di Giandomenico S, Boland-Auge A, Santorelli FM, Durr A, Brice A, Yahyaoui M and Stevanin G. A novel locus for autosomal recessive spastic ataxia on chromosome 17p. Hum Genet 2007;121:413-20. (17273843)

Dor, T., Cinnamon, Y., Raymond, L., Shaag, A., Bouslam, N., Bouhouche, A., Gaussen, M., Meyer, V., Durr, A., Brice, A., Benomar, A., Stevanin, G., Schuelke, M., Edvardson, S. KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction. J. Med. Genet. 51: 137-142, 2014. (24482476)

KIF1C (17p13.2)

kinesin family member 1C

Spastic ataxia 3 with leukoencephalopathy - (AR)

15.90

Thiffault I, Rioux MF, Tetreault M, Jarry J, Loiselle L, Poirier J, Gros-Louis F, Mathieu J, Vanasse M, Rouleau GA, Bouchard JP, Lesage J, Brais B. A new autosomal recessive spastic ataxia associated with frequent white matter changes maps to 2q33-34. Brain. 2006 Sep;129(Pt 9):2332-40. Epub 2006 May 3. (16672289)

Bayat, V., Thiffault, I., Jaiswal, M., Tetreault, M., Donti, T., Sasarman, F., Bernard, G., Demers-Lamarche, J., Dicaire, M.-J., Mathieu, J., Vanasse, M., Bouchard, J.-P., Rioux, M.-F., Lourenco, C. M., Li, Z., Haueter, C., Shoubridge, E. A., Graham, B. H., Brais, B., Bellen, H. J. Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLos Biol. 10: e1001288, 2012. Note: Electronic Article. (22448145)

MARS2 (2q33-34)

Methionyl-tRNA synthetase 2, mitochondrial

Spastic ataxia 4 autosomal recessive - (AR)

15.91

Crosby, A. H., Patel, H., Chioza, B. A., Proukakis, C., Gurtz, K., Patton, M. A., Sharifi, R., Harlalka, G., Simpson, M. A., Dick, K., Reed, J. A., Al-Memar, A., Chrzanowska-Lightowlers, Z. M. A., Cross, H. E., Lightowlers, R. N. Defective mitochondrial mRNA maturation is associated with spastic ataxia. Am. J. Hum. Genet. 87: 655-660, 2010. (20970105)

MTPAP (10p12.1)

Mitochondrial poly(A) polymerase

Spastic ataxia 5 autosomal recessive - (AR)

15.92

Pierson, T. M., Adams, D., Bonn, F., Martinelli, P., Cherukuri, P. F., Teer, J. K., Hansen, N. F., Cruz, P., Mullikin, J. C., Blakesley, R. W., Golas, G., Kwan, J., and 9 others. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet. 7: e1002325, 2011. Note: Electronic Article. (22022284)

AFG3L2 (18p11-q11)

AFG3 ATPase family gene 3-like 2 (S. cerevisiae) 1

Spastic ataxia Charlevoix-Saguenay type - (AR)

15.93

Bouchard JP, Richter A, Mathieu J, Brunet D, Hudson TJ, Morgan K, Melancon SB. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neuromuscul Disord. 1998 Oct;8(7):474-9. (10610707)

Engert, J. C.; Dore, C.; Mercier, J.; Ge, B.; Betard, C.; Rioux, J. D.; Owen, C.; Berube, P.; Devon, K.; Birren, B.; Melancon, S. B.; Morgan, K.; Hudson, T. J.; Richter, A. : Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): high-resolution physical and transcript map of the candidate region in chromosome region 13q11. Genomics 62: 156-164, 1999. (9829277)

Engert JC, Berube P, Mercier J, Dore C, Lepage P, Ge B, Bouchard JP, Mathieu J, Melancon SB, Schalling M, Lander ES, Morgan K, Hudson TJ, Richter A. ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet. 2000 Feb;24(2):120-5. (10655055)

SACS (13q12)

Sacsin

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy - (AR)

15.94

Chelban, V., Patel, N., Vandrovcova, J., Zanetti, M. N., Lynch, D. S., Ryten, M., Botia, J. A., Bello, O., Tribollet, E., Efthymiou, S., Davagnanam, I., SYNAPSE Study Group, Bashiri, F. A., Wood, N. W., Rothman, J. E., Alkuraya, F. S., Houlden, H. Mutations in NKX6-2 cause progressive spastic ataxia and hypomyelination. Am. J. Hum. Genet. 100: 969-977, 2017. (28575651)

NKX6-2 (10q26.3)

NK6 homeobox 2

Spastic ataxia 9, autosomal recessive - (AR)

15.95

Mendoza-Ferreira, N., Coutelier, M., Janzen, E., Hosseinibarkooie, S., Lohr, H., Schneider, S., Milbradt, J., Karakaya, M., Riessland, M., Pichlo, C., Torres-Benito, L., Singleton, A., Zuchner, S., Brice, A., Durr, A., Hammerschmidt, M., Stevanin, G., Wirth, B. Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function. :Neurol. Genet. 4: e209, 2018. Note: Electronic Article. [PubMed: 29379881, related citations] (29379881)

CHP1 (15q15.1)

Calcineurin-like EF-hand protein 1

GeneTable of Neuromuscular Disorders