Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review
- 43 Downloads
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.
KeywordsSPG35 FA2H Complicated hereditary spastic paraplegia
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.
- 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.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.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.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
- 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.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
- 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
- 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.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.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