Hereditary spastic paraplegia type 4 (SPG4): clinical and molecular-genetic characteristics

Rudenskaia G.E.; Sermiagina I.G.; Illarioshkin S.N.; Sidorova O.P.; Fedotov V.P.; Poliakov A.V.

doi:https://doi.org/

Rudenskaia G.E.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN

Sermiagina I.G.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN

Illarioshkin S.N.

Nauchnyĭ tsentr nevrologii RAMN

Sidorova O.P.

Moskovskiĭ oblastnoĭ nauchno-issledovatel'skiĭ klinicheskiĭ institut

Fedotov V.P.

Voronezhskaia mezhoblastnaia mediko-geneticheskaia konsul'tatsiia

Poliakov A.V.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN, Moskva

Hereditary spastic paraplegia type 4 (SPG4): clinical and molecular-genetic characteristics

Authors:

Rudenskaia G.E., Sermiagina I.G., Illarioshkin S.N., Sidorova O.P., Fedotov V.P., Poliakov A.V.

More about the authors

Journal: S.S. Korsakov Journal of Neurology and Psychiatry. 2010;110(6): 12‑19

Read: 5198 times

Download PDF (RU)

Contact the author

Table of contents

To cite this article:

Rudenskaia GE, Sermiagina IG, Illarioshkin SN, Sidorova OP, Fedotov VP, Poliakov AV. Hereditary spastic paraplegia type 4 (SPG4): clinical and molecular-genetic characteristics. S.S. Korsakov Journal of Neurology and Psychiatry. 2010;110(6):12‑19. (In Russ.)

Подписка 2026 Журнал неврологии и психиатрии им. С.С. Корсакова (S.S. Korsakov Journal of Neurology and Psychiatry)

Использование инфографики авторами научных работ

Close metadata

Recommended articles:

Socio-demographic portrait of a patient with endometriosis using artificial intelligence (original material). Russian Journal of Human Reproduction. 2025;(5):84-88

News in molecular biology. Digest of scientific publications. Issue 1. Laboratory Service. 2025;(3):5-7

Epidural spinal cord stimulation in hereditary spastic paraplegia: preliminary results. Burdenko's Journal of Neurosurgery. 2026;(2):62-69

News in molecular biology. Digest of scientific publications. Issue 3. Laboratory Service. 2026;(1):5-7

Abstract:

Hereditary spastic paraplegia (HSP), type 4, or SPG4, caused by various mutations in the spastin gene (SPAST) is the most common disorder in a heterogeneous group of autosomal dominant HSP's. We performed a search of SPAST mutations by routine methods (SSCP and subsequent direct sequencing of fragments with modified electrophoretic mobility) in a sample of 26 families with autosomal dominant HSP from different Russian regions. In six families, five of Russian and one of Tatar ethnicity, different SPAST mutations were detected. Three of the mutations, Arg431Stop, Gln280Arg FsX9 and Asn386Ser, were reported previously; the remaining three, Asp555Tyr, Thr369Thr and Asn184Thr, were novel. In the family with the Arg431Stop mutation, a linkage to SPG4 locus was also established, lod scores were 1,66 for D2S352 marker and 1,51 for D2S367. Another large family also showed a linkage to the SPG4 locus (lod scores 1,68 for D2S352 и 2,17 for D2S367) but the mutation was not found which may be due to atypical SPAST mutations (large deletions etc) undetectable by routine methods of DNA analysis. Including this family, the proportion of the SPG4 in the sample is 27%, which is less than average literature data (40-45%). Most of our patients presented relatively late-onset "uncompicated" HSP, which was typical for SPG4, though different additional features in SPG4 patients were also known. One of our patients had very early-onset HSP and concomitant epilepsy. In two pedigrees, in which all available relatives were examined, some patients had mild signs of SPG4, even late in life.

Keywords:

hereditary spastic paraplegia

SPG4

DNA diagnostics

SPAST mutations

phenotype

Authors:

Rudenskaia G.E.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN

Sermiagina I.G.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN

Illarioshkin S.N.

Nauchnyĭ tsentr nevrologii RAMN

Sidorova O.P.

Moskovskiĭ oblastnoĭ nauchno-issledovatel'skiĭ klinicheskiĭ institut

Fedotov V.P.

Voronezhskaia mezhoblastnaia mediko-geneticheskaia konsul'tatsiia

Poliakov A.V.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN, Moskva

Close metadata

References:

Illarioshkin S.N., Rudenskaya G.E., Ivanova-Smolenskaya I.A. i dr. Nasledstvennye ataksii i paraplegii. M 2006; 415.
Alber B., Pernauer M., Schwan A. et al. Spastin related hereditary spastic paraplegia with dysplastic corpus callosum. J Neurol Sci 2005; 236: 9-12.
Aridon P., Ragonese P., De Fusco M. et al. Autosomal dominant hereditary spastic paraplegia: report of a large Italian family with R581X spastin mutation. J Neurol Sci 2007; 28:171-174.
Beetz C., Nygren A., Schickel J. et al. High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology 2006; 67:1926-1930.
Beetz C., Zuchner S., Ashley-Koch A. et al. Linkage to a known gene but no mutation identified: comprehensive reanalysis of SPG4 HSP pedigrees reveals large deletions as the sole cause. Hum Mutat 2007; 28: 739-740.
Bertelli M., Cecchin S., Lorusso L. et al. Identification of a novel mutation in the spastin gene (SPG4) in an Italian family with hereditary spastic paresis. Panminerva Med 2006; 48: 193-197.
Braschinsky M., Lüüs S., Gross-Paju K., Haldre S. The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia. Neuroepidemiology 2008; 32: 89-93.
Brugman F., Wokke J., Scheffer H. et al. Spastin mutations in sporadic adult-onset upper motor neuron syndromes. Ann Neurol 2005; 58: 865-869.
Byrne P., McMonagle P., Webb S. et al. Age-related cognitive decline in hereditary spastic paraplegia linked to chromosome 2p. Neurology 2000; 54: 1510-1517.
Chinnery P., Keers S., Holden M. et al. Infantile hereditary spastic paraparesis due to codominant mutations in the spastin gene. Neurology 2004; 63: 710-712.
Crippa F., Panzeri C., Martinuzzi A. et al. Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. Arch Neurol 2006; 63: 750-755.
Depienne C., Fedirko E., Bricka B. et al. Mutation spectrum and clinical features pf SPG4 HSP. Eur J Hum Genet 2007; 15: Suppl 1: 90.
Depienne C., Fedirko E., Faucheux J. et al. A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP. Neurogenetics 2007; 8: 231-233.
Depienne C., Fedirko E., Forlani S. et al. Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. J Med Genet 2007; 44: 281-284.
Depienne C., Tallaksen C., Lephay J. 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: 259-265.
Dürr A., Davoine C., Paternotte C. et al. Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2. Brain 1996; 119: 1487-1496.
Erichsen A., Inderhaug E., Mattingsdal M. et al. Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia. Eur J Neurol 2007; 14: 809-814.
Gal A., Mede K., Remenyi V. et al. Synergistic effect of spastin gene mutations in a Hungarian patient with hereditary spastic paraplegia (HSP). Eupop J Hum Genet 2009; 17: Suppl 2: 327.
Heinzlef O., Paternotte C., Mahieux F. et al. Mapping of a complicated familial spastic paraplegia to a locus SPG4 on chromosome 2p. J Med Genet 1998; 35: 89-93.
Human Gene Mutation Database, Cardiff (HGMD) http://www.hgmd.cf.ac.uk
Ivanova N., Lofgren A., Tournev I. et al. Spastin gene mutations in Bulgarian patients with hereditary spastic paraplegia. Clin Genet 2006; 70: 490-495.
Iwanaga H., Tsujino A., Shirabe S. et al. Large deletion involving the 5'-UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia. Am J Med Genet 2005; 133A: 13-17.
Loureiro J., Miller-Fleming L., Thieleke-Matos C. et al. Novel SPG3A and SPG4 mutations in dominant spastic paraplegia families. Acta Neurol Scand 2009; 119: 113-118.
Ma D., Chia S., Tang Y. et al. Spastin in the human and mouse central nervous system with special reference to its expression in the hippocampus of mouse pilocarpine model of status epilepticus and temporal lobe epilepsy. Neurochem Int 2006; 49: 651-664.
Magariello A., Muglia M., Patitucci A. et al. Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia. Neuromusc Disord 2006; 16:387-390
Magariello A., Muglia M., Patitucci A. et al. Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia. J Neurol Sci 2009.
McDermott C., Burness C., Kirby J. et al. Clinical features of hereditary spastic paraplegia due to spastin mutation. Neurology 2006; 67: 45-51.
McMonagle P., Hutchinson M., Lawlor B. Hereditary spastic paraparesis and psychosis. Eur J Neurol 2006; 13: 874-879.
Mead S., Proukakis C., Wood N. et al. A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin (SPG4) gene: association with multiple sclerosis in two affected siblings and epilepsy in other affected family members. J Neurol Neurosurg Psychiat 2001; 71: 788-791.
Meijer I., Dupré N., Brais B. et al. SPG4 founder effect in French Canadians with hereditary spastic paraplegia. Can J Neurol Sci 2007; 34: 211-214.
Meijer I., Hand C., Cossette P. Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Arch Neurol 2002; 59: 281-286.
Mitne-Neto M., Kok F., Beetz C. et al. A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large Brazilian pedigree. Eur J Hum Genet 2007; 15: 1276-1279.
Münch C., Rolfs A., Meyer T. Heterozygous S44L missense change of the spastin gene in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2008; 9:251-253.
Murphy S., Gorman G., Beetz C. et al. Dementia in SPG4 hereditary spastic paraplegia: clinical, genetic, and neuropathologic evidence. Neurology 2009; 73:378-384.
Nielsen J., 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: 817-824.
Orlacchio A., Gaudiello F., Totaro A. et al. A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts. Neurology 2004; 62: 1875-1878.
Orlacchio A., Kawarai T., Gaudiello F. et al. Clinical and genetic study of a large SPG4 Italian family. Mov Disord 2005; 20: 1055-1059.
Orlacchio A., Kawarai T., Totaro A. et al. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol 2004; 61: 830-833.
Orlacchio A., Patrono C., Gaudiello F. et al. Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4. Neurology 2008; 70: 1959-1966.
Pak S., Ki C., Kim H. et al. Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia. Arch Neurol 2005; 62: 1118-1121.
Pantakani D., Zechner U., Arygriou L. et al. Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia. Clin Genet 2008; 73: 268-272.
Patrono C., Scarano V., Cricchi F. et al. Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations. Hum Mutat 2005; 25: 506.
Reddy P., Seltzer W., Grewal R. Possible anticipation in hereditary spastic paraplegia type 4 (SPG4). Can J Neurol Sci 2007; 34: 208-210.
Reid E., Grayson C., Rubinsztein D. et al. Subclinical cognitive impairment in autosomal dominant pure' hereditary spastic paraplegia. J Med Genet 1999; 36: 797-798.
Ribaï P., Depienne C., Fedirko E. et al. Mental deficiency in three families with SPG4 spastic paraplegia. Eur J Hum Genet 2008; 16: 97-104.
Salameh J., Shenoy A., David W. Novel SPG3A and SPG4 mutations in two patients with Silver syndrome. J Clin Neuromuscul Dis 2009; 11: 57-59.
Salinas S., Carazo-Salas R., Proukakis C. et al. Spastin and microtubules: Functions in health and disease. J Neurosci Res 2007; 85: 2778-2882.
Sauter S., Miterski B., Klimpe S. et al. Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum Mutat 2002; 20:127-132.
Schickel J., Beetz C., Frömmel C. et al. Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 (spastin). Neurology 2006; 66: 421-423.
Schickel J., Pamminger T., Ehrsam A. et al. Isoform-specific increase of spastin stability by N-terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. Eur J Neurol 2007; 14: 1322-1328.
Scuderi C., Fichera M., Calabrese G. et al. Posterior fossa abnormalities in hereditary spastic paraparesis with spastin mutations. J Neurol Neurosurg Psychiat 2009; 80: 440-443.
Shoukier M., Neesen J., Sauter S. et al. Expansion of mutation spectrum, determination of mutation cluster region and predictive structural classification on SPAST mutations in hereditary spastic paraplegia. Eur J Hum Genet 2009; 17: 187-194.
Svenson I., Kloos M., Gaskell P. et al. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics 2004; 5: 157-164.
Svenstrup K., Bross P., Koefoed P. et al. Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia. J Neurol Sci 2009; 284:90-95.
Tallaksen C., Guichart-Gomez E., Verpillat P. Subtle cognitive impairment but no dementia in patients with spastin mutations. Arch Neurol 2003; 60: 1113-1118.
Tang B., Zhao G., Xia K. et al. Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia. Arch Neurol 2004; 61: 49-55.
Webb S., Flanagan N., Callaghan N., Hutchinson M. A family with hereditary spastic paraparesis and epilepsy. Epilepsia 1997; 38: 495-499.
White K., Ince P., Lusher M. et al. Clinical and pathological findings in hereditary spastic paraplegia with spastin mutation. Neurology 2000; 55: 89-94.