Autosomal recessive spastic paraplegias types 7 and 76

Cover Page

Abstract

Introduction. Since 2017, the Research Centre for Medical Genetics has been conducting the first clinical and molecular study in Russia of a heterogeneous spastic paraplegia group based on the MPS high throughput sequencing method. Our group of molecularly diagnosed SPGs (types with known genes) includes 122 families with 22 SPG types. This article continues the publication series on the study results.

The study aimed to determine the proportion and analyze the clinical, molecular, and genetic characteristics of two autosomal recessive forms, SPG7 and SPG76, in a group of identified SPGs.

Materials and methods. We assessed three non-inbred Russian families: two with SPG7 (a non-familial and a familial case) and one with SPG76 (a non-familial cases). Molecular genetic methods included massive parallel sequencing (MPS) panel for spastic paraplegia, Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA)).

Results. SPG7 was detected in 2 families and accounted for 1.6% of the entire SPG group and 8.7% of the autosomal recessive subgroup (less than in several other studies). The compound heterozygous genotypes in both families included the most frequent mutation in the SPG7 gene, c.1529C>T (p.Ala510Val); the allelic mutation in one case was a 4-exon deletion not previously described, while the other was a known mutation, c.228T>C (p.Ile743Thr). Despite a similar age at onset (end of the 3rd–4th decade), the symptoms were different: ‘uncomplicated’ spastic paraplegia in the non-familial case, while in the affected brothers prevailed ataxia; in both families, brain MRI showed cerebellar atrophy. The SPG76 case is a rare one, especially in a non-inbred family, and the first in Eastern Europe. A total of 28 families, mostly inbred, have been described worldwide. Two new mutations were found in the CAPN1 gene in the compound heterozygous state: c.398_399insAGTGGTTCCGCCGGCC (p. Arg133Glnfs*39) and c.1535G>A (p.Arg512His). Clinical features of the 30-year-old patient were typical, with onset at 20 years of age, spastic paraplegia and ataxia, and without brain MRI abnormalities.

Conclusion. The range of autosomal recessive SPGs in Russian patients includes both common and very rare forms occurring in non-inbred families. Of the 5 mutations found in the SPG7 and CAPN1 genes, 3 have not been previously described. Our observations demonstrate the close relationship between spastic paraplegia and ataxia and the significance of MPS and MLPA technologies in the diagnostics of SPG.

 

About the authors

Galina E. Rudenskaya

Research Centre for Medical Genetics

Author for correspondence.
Email: rudenskaya@med-gen.ru
Russian Federation, Moscow

Varvara A. Kadnikova

Research Centre for Medical Genetics, Moscow

Email: rudenskaya@med-gen.ru
Russian Federation

Oksana P. Ryzhkova

Research Centre for Medical Genetics, Moscow

Email: rudenskaya@med-gen.ru
Russian Federation

Nina A. Dyomina

Research Centre for Medical Genetics, Moscow

Email: rudenskaya@med-gen.ru
Russian Federation

Inna V. Sharkova

Research Centre for Medical Genetics, Moscow

Email: rudenskaya@med-gen.ru
Russian Federation

Alexander V. Polyakov

Research Centre for Medical Genetics, Moscow

Email: rudenskaya@med-gen.ru
Russian Federation

References

  1. Galatolo D., Tessa A., Filla A., Santorelli F.M. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018; 19(1): 1–8. doi: 10.1007/s10048-017-0532-6. PMID: 28209898.
  2. Boutry M., Morais S., Stevanin G. Update on the genetics of spastic paraplegias. Curr Neurol Neurosci Rep. 2019; 19(4): 18. doi: 10.1007/s11910-019-0930-2. PMID: 30820684
  3. Kadnikova V., Rudenskaya G., Stepanova A. et al. Mutational spectrum of SPAST (SPG4) and ATL1 (SPG3A) genes in Russian patients with hereditary spastic paraplegia. Sci. Rep. 2019; 9(1): 14412. doi: 10.1038/s41598-019-50911-9. PMID: 31594988.
  4. Rudenskaya G.E., Kadnikova V.A., Sidorova O.P. et al. Hereditary spastic paraplegia type 4 in Russian patients. Zhurn. Nevrolologii i Psikhiatriii im S.S. Korsakova. 2019; 11: 11–20. doi: 10.17116/jnevro201911911111. PMID: 31851166. (In Russ.)
  5. Rudenskaya G.E., Kadnikova V.A, Chukhrova A.L. et al. Rare autosomal recessive spastic paraplegias. Meditsinskaya genetika. 2019; 11: 26–35. doi: 10.25557/2073-7998.2019.11.26-3-35. (In Russ.)
  6. Chukhrova A.L., Akimova I.A., Shchagina O.A. et al. A new case of infantile-onset hereditary spastic paraplegia with complicated phenotype (SPG61) in a consanguineous Russian family. Eur J Neurol. 2019; 26(5): e61–e62. doi: 10.1111/ene.13880. PMID: 30980493.
  7. Rudenskaya G.E., Kadnikova V.A., Ryzhkova O.P. Spastic ataxia of Charlevoix–Saguenay (ARSACS): first Russian case and review. Zh Nevrolol Psikhiatr im S S Korsakova. 2020; 120(2): 85–91. doi: 10.17116/jnevro202012002185 PMID: 32307416. (In Russ.)
  8. Rudenkaya G.E., Kadnikova V.A., Beetz С. et al. Clinical, molecular, and genetic characteristics of the hereditary spastic paraplegia type 3 (SPG3). Annaly klinicheskoi i eksperimental’noy nevrologii 2020; 1: 44–54. doi: 10.25692/ACEN.2020.1.5. (In Russ).
  9. Rudenskaya G.E., Kadnikova V.A., Ryzhkova O.P. et al. KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families. BMC Neurology. 2020; 20(1): 290. doi: 10.1186/s12883-020-01872-4. PMID: 32746806.
  10. Schagina O.A., Tverskaya S.M., Kadnikova V.A., Polyakov A.V. DNA diagnostics of periodic disease. Meditsinskaya genetika. 2006; 10: 29–32. (In Russ).
  11. Ryzhkova O.P., Kardymon O.L., Prohorchuk E.B. et al. Guidelines for the interpretation of data on human DNA sequencing obtained by methods of massive parallel sequencing (MPS) (Ed.2018, version 2). Meditsinskaya genetika. 2019; 18(8): 3–23. (In Russ.)
  12. Chrestian N., Dupré N., Gan-Or Z. et al. Clinical and genetic study of hereditary spastic paraplegia in Canada. Neurol Genet. 2016; 3(1): doi: 10.1212/NXG.0000000000000122. PMID: 27957547.
  13. Balicza P., Grosz Z., Gonzalez M.A. et al. Genetic background of the hereditary spastic paraplegia phenotypes in Hungary an analysis of 58 probands. J Neurol Sci. 2016; 364: 116–121. doi: 10.1016/j.jns.2016.03.018. PMID: 27084228.
  14. Orsucci D., Petrucci L., Ienco E.C. et al. Hereditary soastic paraparesis in adults. A clinical and genetic perspective from Tuscany. Clin Neurol Neurosurg. 2014; 120: 14–19. doi: 10.1016/j.clineuro.2014.02.002. PMID: 24731568.
  15. Schüle R., Wiethoff S., Martus P. et al. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol. 2016; 79(4): 646–658. doi: 10.1002/ana.24611. PMID: 26856398.
  16. van Gassen K.L., van der Heijden C.D., de Bot S.T. et al. Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. Brain. 2012; 135(Pt 10): 2994–3004. doi: 10.1093/brain/aws224. PMID: 22964162.
  17. 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(3): 257–262. doi: 10.1111/j.1399-0004.2012.01896.x. PMID: 22571692.
  18. Kara E., Tucci A., Manzoni C. et al. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016; 139(Pt 7): 1904–1918. doi: 10.1093/brain/aww111. PMID: 27227339.
  19. Klebe S., Depienne C., Gerber S. et al. Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain. 2012; 135(Pt 10): 2980–2993. doi: 10.1093/brain/aws240. PMID: 23065789.
  20. Roxburgh R.H., Marquis-Nicholson R., Ashton F. et al. The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol. 2013; 260(5): 1286–1294. doi: 10.1007/s00415-012-6792-z. PMID: 23269439.
  21. Wedding I.M., Koht J., Tran G.T. et al. Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions. PLoS One. 2014; 9(1): e86340. doi: 10.1371/journal.pone.0086340. PMID: 2446603.
  22. Pfeffer G., Pyle A., Griffin H. et al. SPG7 mutations are a common cause of undiagnosed ataxia. Neurology. 2015; 84(11): 1174–1176. doi: 10.1212/WNL.0000000000001369. PMID: 25681447.
  23. Choquet K., Tetreault M., Yang S. et al. SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases. Eur J Hum Genet. 2016; 24(7): 1016–1021. doi: 10.1038/ejhg.2015.240. PMID: 26626314.
  24. Rydning S.L., Wedding I.M., Koht J. et al. A founder mutation p.H701P identified as a major cause of SPG7 in Norway. Eur J Neurol. 2016; 23(4): 763–771. doi: 10.1111/ene.12937. PMID: 26756429.
  25. Zhang L., McFarland K.N., Subramony S.H. et al. SPG7 and impaired emotional communication. Cerebellum. 2017; 16(2): 595–598. doi: 10.1007/s12311-016-0818-5. PMID: 27557734.
  26. De la Casa-Fages B., Fernández-Eulate G., Gamez J. et al. Parkinsonism and spastic paraplegia type 7: expanding the spectrum of mitochondrial parkinsonism. Mov Disord. 2019; 34(10): 1547–1561. doi: 10.1002/mds.27812. PMID: 31433872.
  27. Hewamadduma H.A., Hoggard N., O'MalleyR. et al. Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations. Neurol Genet 2018: 4(6): e279. doi: 10.1212/NXG.0000000000000279. PMID: 30533525.
  28. Mancini C., Giorgio E., Rubegni A. et al. Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy. Eur J Neurol. 2019; 26(1): 80–86. doi: 10.1111/ene.13768. PMID: 30098094.
  29. Casari G., Marconi R., Adam M.P. et al. Spastic paraplegia 7. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1107. PMID: 20301286.
  30. Yoon G., Baskin B., Tarnopolsky M. et al. Autosomal recessive hereditary spastic paraplegia — clinical and genetic characteristics of a well-defined cohort. Neurogenetics. 2013; 14: 181–188. doi: 10.1007/s10048-013-0366-9. PMID: 23733235.
  31. Pfeffer G., Gorman G.S., Griffin H. et al. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain. 2014; 137(Pt 5): 1323–1336. doi: 10.1093/brain/awu060. PMID: 24727571.
  32. Yahikozawa H., Yoshida K., Sato S. et al. Predominant cerebellar phenotype in spastic paraplegia 7 (SPG7). Hum Genome Var. 2015; 2: 15012. doi: 10.1038/hgv.2015.12. PMID: 27081526
  33. Thal D.R., Züchner S., Gierer S. et al. Abnormal paraplegin expression in swollen neurites, τ- and α-synuclein pathology in a case of hereditary spastic paraplegia SPG7 with an Ala510Val mutation. Int J Mol Sci. 2015; 16(10): 25050–25066. doi: 10.3390/ijms161025050. PMID: 26506339.
  34. van de Warrenburg B.P., Schouten M.I., de Bot S.T. et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2016; 24(10): 1460–1466. doi: 10.1038/ejhg.2016.42. PMID: 27165006.
  35. Bhattacharjee S., Beauchamp N., Murray B.E., Lynch T. Case series of autosomal recessive hereditary spastic paraparesis with novel mutation in SPG7 gene. Neurosciences (Riyadh). 2017; 22(4): 303–307. doi: 10.17712/nsj.2017.4.20170253. PMID: 29057857.
  36. Synofzik M., Schüle R. Overcoming the divide between ataxias and spastic paraplegias: shared phenotypes, genes, and pathways. Mov Disord. 2017; 32(3): 332–345. DOI; 10.1002/mds.26944. PMID: 28195350.
  37. Coarelli G., Schule R., van de Warrenburg B. et al. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7 Neurology 2019; 92(23): e2679–e2690. doi: 10.1212/WNL.0000000000007606. PMID: 31068484.
  38. Nuzhny E.P. [Clinical and genetic characterisics of autosomal recessive ataxias in adult patients: PhD Thesis]. Moscow, 2019. (In Russ).
  39. Martinuzzi A., Montanaro D., Vavla M. et al. Clinical and paraclinical indicators of motor system impairment in hereditary spastic paraplegia: a pilot study. PLoS One. 2016; 11(4): e0153283. doi: 10.1371/journal.pone.0153283. PMID: 27077743.
  40. Mahoney C.J., Dharmadasa T., Huynh W. et al. A novel phenotype of hereditary spastic paraplegia type 7 associated with a compound heterozygous mutation in paraplegin. Muscle Nerve. 2020; 62(1): E44–E45. doi: 10.1002/mus.26882. PMID: 32270516.
  41. Lupo M., Olivito G., Clausi S. et al. Cerebello-cortical alterations linked to cognitive and social problems in patients with spastic paraplegia type 7: a preliminary study. Front Neurol. 2020; 11: 82. doi: 10.3389/fneur.2020.00082. PMID: 32161564.
  42. Verdura E., Schlüter A., Fernández-Eulate G. et al. A deep intronic splice variant advises reexamination of presumably dominant SPG7 cases. Ann Clin Transl Neurol. 2020; 7(1): 105–111. doi: 10.1002/acn3.50967. PMID: 31854126.
  43. Osmanovic A., Widjaja M., Förster A. et al. SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia. J Neurol. 2020; 267(9): 2732–2743. doi: 10.1007/s00415-020-09861-w. PMID: 32447552.
  44. Forman O.P., De Risio L., Mellersh C.S. Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed. PLoS One. 2013; 8: e64627. doi: 10.1371/journal.pone.0064627. PMID: 23741357.
  45. Wang Y., Hersheson J., Lopez D. et al. Defects in the CAPN1 gene result in alterations in cerebellar development and cerebellar ataxia in mice and humans. Cell Rep. 2016; 16(1): 79–91. doi: 10.1016/j.celrep.2016.05.044. PMID: 27320912.
  46. Gan-Or Z., Bouslam N., Birouk N. et al Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia Am J Hum Genet. 2016; 98(5): 1038–1046. doi: 10.1016/j.ajhg.2016.04.002. PMID: 27153400.
  47. Travaglini L., Bellacchio E., Aiello C. et al. Expanding the clinical phenotype of CAPN1-associated mutations: a new case with congenital-onset pure spastic paraplegia. J Neurol Sci. 2017; 378: 210–212. doi: 10.1016/j.jns.2017.05.014 PMID: 28566166.
  48. Cotti Piccinelli S., Bassi M., Citterio A. et al. A novel CAPN1 mutation causes a pure hereditary spastic paraplegia in an Italian family. Front Neurol 2019; 10: 580. doi: 10.3389/fneur.2019.00580. PMID: 31231303.
  49. Lambe J., Monaghan B., Munteanu T., Redmond J. CAPN1 mutations broadening the hereditary spastic paraplegia/spinocerebellar ataxia phenotype. Pract Neurol. 2018; 18(5): 369–372. doi: 10.1136/practneurol-2017-001842. PMID: 29678961.
  50. Tadic V., Klein C., Hinrichs F. et al. CAPN1 mutations are associated with a syndrome of combined spasticity and ataxia. J Neurol. 2017; 264(5): 1008–1010. doi: 10.1007/s00415-017-8464-5. PMID: 28321562.
  51. Kocoglu C., Gundogdu A., Kocaman G. et al. Homozygous CAPN1 mutations causing a spastic-ataxia phenotype in 2 families. Neurol Genet. 2018; 4(1): e218. doi: 10.1212/NXG.0000000000000218. PMID: 29379883.
  52. Shetty A., Ashtiani S., Gan-Or Z. et al. CAPN1 mutations: еxpanding the CAPN1-related phenotype: from hereditary spastic paraparesis to spastic ataxia. Eur J Med Genet. 2019; 62(12): 103605. doi: 10.1016/j.ejmg.2018.12.010. PMID: 30572172.
  53. Bidgoli M., Javanparast L., Rohani M. et al. CAPN1 and hereditary spastic paraplegia: a novel variant in an Iranian family and overview of the genotype-phenotype correlation. Int J Neurosci. 2020 May 13; 1–13. doi: 10.1080/00207454.2020.1763344. PMID: 32352326.
  54. Peng F., Sun Y.M., Quan C. et al. Two novel homozygous mutations of CAPN1 in Chinese patients with hereditary spastic paraplegia and literatures review. Orphanet J Rare Dis. 2019; 14(1): 83. doi: 10.1186/s13023-019-1053-1. PMID: 31023339.
  55. Chen Y., Cen Z., Zheng X. et al. A novel homozygous CAPN1 pathogenic variant in a Chinese patient with pure hereditary spastic paraplegia. 2019; 15(2): 271–272. doi: 10.3988/jcn.2019.15.2.271. PMID: 30938113.
  56. Xia Z.C., Liu Z.H., Zhou X.X. et al. Mutation analysis of CAPN1 in Chinese populations with spastic paraplegia and related neurodegenerative diseases. J Neurol Sci. 2020; 411: 116691. doi: 10.1016/j.jns.2020.116691. PMID: 31982778.
  57. Kim А., Kumar K., Davis R. et al. Increased diagnostic yield of spastic paraplegia with or without cerebellar ataxia through whole-genome sequencing. Cerebellum. 2019; 8(4):781–790. doi: 10.1007/s12311-019-01038-0. PMID: 31104286.
  58. Melo U.S., Freua F., Lynch D.S. et al. Clinical aspects of hereditary spastic paraplegia 76 and novel CAPN1 mutations. Clin Genet. 2018; 94(5): 482–483. doi: 10.1111/cge.13428 PMID: 30198554.
  59. Souza P., Badia B., Farias I. et al. An extremely rare hereditary spastic paraplegia with a new expanding complicated phenotype. Rev Neurol (Paris). 2019; 175(9): 572–574. doi: 10.1016/j.neurol.2019.01.397. PMID: 31147273.
  60. Garcia-Berlanga J.E., Moscovich M., Palacios J.I. et al. CAPN1 variants as cause of hereditary spastic paraplegia type 76. Case Rep Neurol Med 2019; 7615605. doi: 10.1155/2019/7615605. PMID: 31355030.
  61. Rudenskaya G.E., Zakharova E.Yu. [Hereditary neurometabolic diseases of young and adult age]. Moscow, Geotar-Media: 2018. 383 p. (in Russ).

Statistics

Views

Abstract: 379

PDF (Russian): 241

Article Metrics

Metrics Loading ...

Dimensions

PlumX


Copyright (c) 2021 Rudenskaya G.E., Kadnikova V.A., Ryzhkova O.P., Dyomina N.A., Sharkova I.V., Polyakov A.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies