neurogenetics

, Volume 19, Issue 2, pp 123–130 | Cite as

Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review

  • Francesco Mari
  • Beatrice Berti
  • Alessandro Romano
  • Jacopo Baldacci
  • Riccardo Rizzi
  • M. Grazia Alessandrì
  • Alessandra Tessa
  • Elena Procopio
  • Anna Rubegni
  • Charles Marques Lourenḉo
  • Alessandro Simonati
  • Renzo Guerrini
  • Filippo Maria Santorelli
Short Communication
  • 173 Downloads

Abstract

Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation. While we reviewed the pertinent literature, we also report three new patients with SPG35, highlighting the possible absence of white matter lesions even after a long neuroimaging follow-up. Three-dimensional modeling of the mutated proteins was helpful to elucidate the role of the site of mutations and the correlation with the residual enzyme activity as determined in cultured skin fibroblasts.

Keywords

SPG35 FA2H Complicated hereditary spastic paraplegia 

Notes

Acknowledgments

The authors thank Doctor Catherine J. Wrenn who provided expert editorial assistance. This research was supported in part by the E-RARE-3 Joint Transnational Call grant “Preparing therapies for autosomal recessive ataxias” (PREPARE) (MoH; project 3398 to FMS).

Compliance with ethical standards

This study was approved by the Tuscany Regional Pediatric Ethics committee. All the procedures complied with the Helsinki Declaration of 1975. Genetic studies were performed after parental written informed consent.

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

10048_2018_538_Fig4_ESM.gif (215 kb)
Supplementary Fig. S1

(GIF 214 kb)

10048_2018_538_MOESM1_ESM.tif (166 kb)
High resolution image (TIFF 165 kb)
10048_2018_538_Fig5_ESM.gif (143 kb)
Supplementary Fig. S2

(GIF 143 kb)

10048_2018_538_MOESM2_ESM.tif (643 kb)
High resolution image (TIFF 643 kb)
10048_2018_538_MOESM3_ESM.xls (42 kb)
Supplementary Table S1 (XLS 42 kb)
10048_2018_538_MOESM4_ESM.docx (30 kb)
Supplementary Table S2 (DOCX 30 kb)
10048_2018_538_MOESM5_ESM.docx (39 kb)
ESM 1 (DOCX 38 kb)

References

  1. 1.
    Harding A (1993) Hereditary spastic paraplegias. Semin Neurol 13(04):333–336.  https://doi.org/10.1055/s-2008-1041143 CrossRefPubMedGoogle Scholar
  2. 2.
    Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A (2014) Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol 261:518–539CrossRefPubMedGoogle Scholar
  3. 3.
    Klebe S, Stevanin G, Depienne C (2015) Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. Rev Neurol (Paris) 171:505–530CrossRefGoogle Scholar
  4. 4.
    Fink JK (2013) Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 126(3):307–328.  https://doi.org/10.1007/s00401-013-1115-8 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Alderson NL, Rembiesa BM, Walla MD, Bielawska A, Bielawski J, Hama H (2004) The human FA2H gene encodes a fatty acid 2-hydroxylase. J Biol Chem 279(47):48562–48568.  https://doi.org/10.1074/jbc.M406649200 CrossRefPubMedGoogle Scholar
  6. 6.
    Hama H (2010) Fatty acid 2-hydroxylation in mammalian sphingolipid biology. Biochim Biophys Acta-Mol Cell Biol Lipids 1801(4):405–414.  https://doi.org/10.1016/j.bbalip.2009.12.004 CrossRefGoogle Scholar
  7. 7.
    Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V et al (2010) Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat 31(4):E1251–E1260.  https://doi.org/10.1002/humu.21205 CrossRefPubMedGoogle Scholar
  8. 8.
    Edvardson S, Hama H, Shaag A, Gomori JM, Berger I, Soffer D, Korman SH, Taustein I, Saada A, Elpeleg O (2008) Mutations in the fatty acid 2-hydroxylase gene are associated with Leukodystrophy with spastic Paraparesis and dystonia. Am J Hum Genet 83(5):643–648.  https://doi.org/10.1016/j.ajhg.2008.10.010 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kruer MC, Paisán-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, Malandrini A, Woltjer RL, Munnich A, Gobin S, Polster BJ, Palmeri S, Edvardson S, Hardy J, Houlden H, Hayflick SJ (2010) Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 68(5):611–618.  https://doi.org/10.1002/ana.22122 CrossRefPubMedGoogle Scholar
  10. 10.
    Pierson TM, Simeonov DR, Sincan M, Adams DA, Markello T, Golas G, Fuentes-Fajardo K, Hansen NF, Cherukuri PF, Cruz P, Blackstone C, Tifft C, Boerkoel CF et al (2012) Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. Eur J Hum Genet 20(4):476–479.  https://doi.org/10.1038/ejhg.2011.222 CrossRefPubMedGoogle Scholar
  11. 11.
    Cao L, Huang XJ, Chen CJ, Di Chen S (2013) A rare family with hereditary spastic paraplegia type 35 due to novel FA2H mutations: a case report with literature review. J Neurol Sci 329(1-2):1–5.  https://doi.org/10.1016/j.jns.2013.02.026 CrossRefPubMedGoogle Scholar
  12. 12.
    Garone C, Pippucci T, Cordelli DM, Zuntini R, Castegnaro G, Marconi C, Graziano C, Marchiani V, Verrotti A, Seri M, Franzoni E (2011) FA2H-related disorders: A novel c.270+3A>T splice-site mutation leads to a complex neurodegenerative phenotype. Dev Med Child Neurol 53:958–961CrossRefPubMedGoogle Scholar
  13. 13.
    Pensato V, Castellotti B, Gellera C, Pareyson D, Ciano C, Nanetti L, Salsano E, Piscosquito G, Sarto E, Eoli M, Moroni I, Soliveri P, Lamperti E, Chiapparini L, di Bella D, Taroni F, Mariotti C (2014) Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48. Brain 137(7):1907–1920.  https://doi.org/10.1093/brain/awu121 CrossRefPubMedGoogle Scholar
  14. 14.
    Tessa A, Battini R, Rubegni A, Storti E, Marini C, Galatolo D, Pasquariello R, Santorelli FM (2016) Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families. Eur J Neurol 23(10):1580–1587.  https://doi.org/10.1111/ene.13085 CrossRefPubMedGoogle Scholar
  15. 15.
    Guerois R, Nielsen JE, Serrano L (2002) Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 320(2):369–387.  https://doi.org/10.1016/S0022-2836(02)00442-4 CrossRefPubMedGoogle Scholar
  16. 16.
    Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A 98(18):10037–10041.  https://doi.org/10.1073/pnas.181342398 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Pires DE, Blundell TL, Ascher DB (2016) mCSM-lig: quantifying the effects of mutations on protein-small molecule affinity in genetic disease and emergence of drug resistance. Sci Rep 6(1):29575.  https://doi.org/10.1038/srep29575 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dick KJ, Al-Mjeni R, Baskir W, Koul R, Simpson MA, Patton MA, Raeburn S, Crosby AH (2008) A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. Neurology 71(4):248–252.  https://doi.org/10.1212/01.wnl.0000319610.29522.8a CrossRefPubMedGoogle Scholar
  19. 19.
    Zaki MS, Selim L, Mansour L, Mahmoud IG, Fenstermaker AG, Gabriel SB, Gleeson JG (2015) Mutations in FA2H in three Arab families with a clinical spectrum of neurodegeneration and hereditary spastic paraparesis. Clin Genet 88(1):95–97.  https://doi.org/10.1111/cge.12516 CrossRefPubMedGoogle Scholar
  20. 20.
    Donkervoort S, Dastgir J, Hu Y, Zein WM, Marks H, Blackstone C, Bönnemann CG (2014) Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia. Clin Genet 85(4):393–395.  https://doi.org/10.1111/cge.12185 CrossRefPubMedGoogle Scholar
  21. 21.
    Liao X, Luo Y, Zhan Z, Du J, Hu Z, Wang J, Guo J, Yan X (2015) SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations. Clin Genet 87(1):85–89.  https://doi.org/10.1111/cge.12336 CrossRefPubMedGoogle Scholar
  22. 22.
    Tonelli A, D’Angelo MG, Arrigoni F, Brighina E, Arnoldi A, Citterio A, Bresolin N, Bassi MT (2012) Atypical adult onset complicated spastic paraparesis with thin corpus callosum in two patients carrying a novel FA2H mutation. Eur J Neurol 19:e127–e129CrossRefPubMedGoogle Scholar
  23. 23.
    Rupps R, Hukin J, Balicki M, Mercimek-Mahmutoglu S, Rolfs A, Dias C (2013) Novel mutations in FA2H -associated neurodegeneration. J Child Neurol 28(11):1500–1504.  https://doi.org/10.1177/0883073812458538 CrossRefPubMedGoogle Scholar
  24. 24.
    Aguirre-Rodriguez FJ, Lucenilla MIR, Alvarez-Cubero MJ, Mata C, Entrala-Bernal C, Fernandez-Rosado F (2015) Novel FA2H mutation in a girl with familial spastic paraplegia. J Neurol Sci 357(1-2):332–334.  https://doi.org/10.1016/j.jns.2015.07.042 CrossRefPubMedGoogle Scholar
  25. 25.
    Soehn AS, Rattay TW, Beck-Wödl S, Schäferhoff K, Monk D, Döbler-Neumann M, Hörtnagel K, Schlüter A, Ruiz M, Pujol A, Züchner S, Riess O, Schüle R, Bauer P, Schöls L (2016) Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families. Neurology 87(2):186–191.  https://doi.org/10.1212/WNL.0000000000002843 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LVP, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H (2016) Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain 139(7):1904–1918.  https://doi.org/10.1093/brain/aww111 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Magariello A, Russo C, Citrigno L, Züchner S, Patitucci A, Mazzei R, Conforti FL, Ferlazzo E, Aguglia U, Muglia M (2017) Exome sequencing reveals two FA2H mutations in a family with a complicated form of hereditary spastic paraplegia and psychiatric impairments. J Neurol Sci 372:347–349.  https://doi.org/10.1016/j.jns.2016.11.069 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Francesco Mari
    • 1
  • Beatrice Berti
    • 1
  • Alessandro Romano
    • 2
  • Jacopo Baldacci
    • 3
  • Riccardo Rizzi
    • 1
  • M. Grazia Alessandrì
    • 3
  • Alessandra Tessa
    • 3
  • Elena Procopio
    • 1
  • Anna Rubegni
    • 3
  • Charles Marques Lourenḉo
    • 4
  • Alessandro Simonati
    • 5
  • Renzo Guerrini
    • 1
    • 3
  • Filippo Maria Santorelli
    • 3
  1. 1.Pediatric Neurology Unit, Children’s Hospital A. MeyerUniversity of FirenzeFlorenceItaly
  2. 2.Neuropathology Unit, Institute of Experimental Neurology and Division of NeuroscienceIRCCS San Raffaele Scientific InstituteMilanItaly
  3. 3.IRCCS Stella MarisPisaItaly
  4. 4.Neurogenetics Division, Clinics Hospital of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  5. 5.Department of Neuroscience, Biomedicine and MovementUniversity of VeronaVeronaItaly

Personalised recommendations