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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2018

Open Access 01-12-2018 | Research article

Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China

Authors: En-Lin Dong, Chong Wang, Shuang Wu, Ying-Qian Lu, Xiao-Hong Lin, Hui-Zhen Su, Miao Zhao, Jin He, Li-Xiang Ma, Ning Wang, Wan-Jin Chen, Xiang Lin

Published in: Molecular Neurodegeneration | Issue 1/2018

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Abstract

Background

Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population.

Methods

We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro.

Results

Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112*) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Δψm), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts.

Conclusions

Our study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP.
Appendix
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Literature
1.
Morais S, Raymond L, Mairey M, Coutinho P, Brandão E, Ribeiro P, Loureiro JL, Sequeiros J, Brice A, Alonso I, et al. Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias. Eur J Hum Genet. 2017;25:1217–28.CrossRefPubMedPubMedCentral
2.
Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42:174–83.CrossRefPubMed
3.
Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A. Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol. 2014;261:518–39.CrossRefPubMed
4.
Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 2008;7:1127–38.CrossRefPubMed
5.
de Souza PV, de Rezende Pinto WB, de Rezende Batistella GN, Bortholin T, Oliveira AS. Hereditary spastic paraplegia: clinical and genetic hallmarks. Cerebellum. 2017;16:525–51.CrossRefPubMed
6.
Tesson C, Koht J, Stevanin G. Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum Genet. 2015;134:511–38.CrossRefPubMedPubMedCentral
7.
Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, et al. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017;140:287–305.CrossRefPubMedPubMedCentral
8.
Loureiro JL, Miller-Fleming L, Thieleke-Matos C, Magalhaes P, Cruz VT, Coutinho P, Sequeiros J, Silveira I. Novel SPG3A and SPG4 mutations in dominant spastic paraplegia families. Acta Neurol Scand. 2009;119:113–8.CrossRefPubMed
9.
Schüle R, Wiethoff S, Martus P, Karle KN, Otto S, Klebe S, Klimpe S, Gallenmüller C, Kurzwelly D, Henkel D, et al. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol. 2016;79:646–58.CrossRefPubMed
10.
Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, et al. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016;139:1904–18.CrossRefPubMedPubMedCentral
11.
12.
13.
14.
McDermott CJ, Grierson AJ, Wood JD, Bingley M, Wharton SB, Bushby KM, Shaw PJ. Hereditary spastic paraparesis. Disrupted intracellular transport associated with spastin mutation. Ann Neurol. 2003;54:748–59.CrossRefPubMed
15.
Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Durr A, Wincker P, et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet. 1999;23:296–303.CrossRefPubMed
16.
Shoukier M, Neesen J, Sauter SM, Argyriou L, Doerwald N, Pantakani DV, Mannan AU. Expansion of mutation spectrum, determination of mutation cluster regions and predictivestructural classification of SPAST mutations in hereditary spastic paraplegia. Eur J Hum Genet. 2009;17:187–94.CrossRefPubMed
17.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and theAssociation for molecular pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral
18.
Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39:366–72.CrossRefPubMed
19.
Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, et al. Sequence Alterations within CYP7B1 Implicate Defective Cholesterol Homeostasis in Motor-Neuron Degeneration. Am J Hum Genet. 2008;82:510–5.
20.
Ueki I, Kimura A, Nishiyori A, Chen HL, Takei H, Nittono H, Kurosawa T. Neonatal cholestatic liver disease in an Asian patient with a homozygous mutation in the oxysterol 7alpha-hydroxylase gene. J Pediatr Gastroenterol Nutr. 2008;46:465–9.CrossRefPubMed
21.
Havlicek S, Kohl Z, Mishra HK, Prots I, Eberhardt E, Denguir N, Wend H, Plötz S, Boyer L, Marchetto MC, et al. Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients’ neurons. Hum Mol Genet. 2014;23:2527–41.CrossRefPubMed
22.
Okamoto K, Shaw JM. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet. 2005;39:503–36.CrossRefPubMed
23.
Shoshan-Barmatz V, Krelin Y, Chen Q. VDAC1 as a player in mitochondria-mediated apoptosis and target for modulating apoptosis. Curr Med Chem. 2017;24:4435–46.PubMed
24.
Arif T, Krelin Y, Shoshan-Barmatz V. Reducing VDAC1 expression induces a non-apoptotic role for pro-apoptotic proteins in cancer cell differentiation. Biochim Biophys Acta. 1857;2016:1228–42.
25.
Connolly NMC, Theurey P, Adam-Vizi V, Bazan NG, Bernardi P, Bolaños JP, Culmsee C, Dawson VL, Deshmukh M, Duchen MR, et al. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death Differ. 2018;25:542–72.CrossRefPubMed
26.
Chang J, Lee S, Blackstone C. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest. 2014;124:5249–62.CrossRefPubMedPubMedCentral
27.
Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1–222.CrossRefPubMedPubMedCentral
28.
Meijer IA, Hand CK, Cossette P, Figlewicz DA, Rouleau GA. Spectrum of SPG4 mutations in a large collection of north American families with hereditary spastic paraplegia. Arch Neurol. 2002;59:281–6.CrossRefPubMed
29.
Blair MA, Riddle ME, Wells JF, Breviu BA, Hedera P. Infantile onset of hereditary spastic paraplegia poorly predicts the genotype. Pediatr Neurol. 2007;36:382–6.CrossRefPubMed
30.
Orlacchio A, Montieri P, Babalini C, Gaudiello F, Bernardi G, Kawarai T. Late-onset hereditary spastic paraplegia with thin corpus callosum caused by a new SPG3A mutation. J Neurol. 2011;258:1361–3.CrossRefPubMed
31.
Goizet C, Boukhris A, Mundwiller E, Tallaksen C, Forlani S, Toutain A, Carriere N, Paquis V, Depienne C, Durr A, et al. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum Mutat. 2009;30:E376–85.CrossRefPubMed
32.
Muglia M, Citrigno L, D'Errico E, Magariello A, Distaso E, Gasparro AA, Scarafino A, Patitucci A, Conforti FL, Mazzei R, et al. A novel KIF5A mutation in an Italian family marked by spastic paraparesis and congenital deafness. J Neurol Sci. 2014;343:218–20.CrossRefPubMed
33.
Beetz C, Nygren AO, Schickel J, Auer-Grumbach M, Burk K, Heide G, Kassubek J, Klimpe S, Klopstock T, Kreuz F, et al. High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology. 2006;67:1926–30.CrossRefPubMed
34.
Svenson IK, Ashley-Koch AE, Gaskell PC, Riney TJ, Cumming WJ, Kingston HM, Hogan EL, Boustany RM, Vance JM, Nance MA, et al. Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. Am J Hum Genet. 2001;68:1077–85.CrossRefPubMedPubMedCentral
35.
Solowska JM, Morfini G, Falnikar A, Himes BT, Brady ST, Huang D, Baas PW. Quantitative and functional analyses of spastin in the nervous system: implications for hereditary spastic paraplegia. J Neurosci. 2008;28:2147–57.CrossRefPubMedPubMedCentral
36.
Tortosa E, Adolfs Y, Fukata M, Pasterkamp RJ, Kapitein LC, Hoogenraad CC. Dynamic Palmitoylation targets MAP6 to the axon to promote microtubule stabilization during neuronal polarization. Neuron. 2017;94(4):809–25.CrossRefPubMed
37.
38.
Ahmad FJ, He Y, Myers KA, Hasaka TP, Francis F, Black MM, Baas PW. Effects of dynactin disruption and dynein depletion on axonal microtubules. Traffic. 2006;7:524–37.CrossRefPubMed
39.
40.
Abrahamsen G, Fan Y, Matigian N, Wali G, Bellette B, Sutharsan R, Raju J, Wood SA, Veivers D, Sue CM, et al. A patient-derived stem cell model of hereditary spastic paraplegia with SPASTmutations. Dis Model Mech. 2013;6:489–502.CrossRefPubMed
41.
Denton KR, Lei L, Grenier J, Rodionov V, Blackstone C, Li XJ. Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia. Stem Cells. 2014;32:414–23.CrossRefPubMedPubMedCentral
42.
Wharton SB, McDermott CJ, Grierson AJ, Wood JD, Gelsthorpe C, Ince PG, Shaw PJ. The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. J Neuropathol Exp Neurol. 2003;62:1166–77.CrossRefPubMed
43.
Paisan-Ruiz C, Nath P, Wood NW, Singleton A, Houlden H. Clinical heterogeneity and genotype-phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11). Eur J Neurol. 2008;15:1065–70.CrossRefPubMed
44.
Samaranch L, Riverol M, Masdeu JC, Lorenzo E, Vidal-Taboada JM, Irigoyen J, Pastor MA, de Castro P, Pastor P. SPG11 compound mutations in spastic paraparesis with thin corpus callosum. Neurology. 2008;71(5):332–6.CrossRefPubMed
45.
Choquet K, Tetreault M, Yang S, La Piana R, Dicaire MJ, Vanstone MR, Mathieu J, Bouchard JP, Rioux MF, Rouleau GA, et al. SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases. Eur J Hum Genet. 2016;24:1016–21.CrossRefPubMed
46.
Klebe S, Depienne C, Gerber S, Challe G, Anheim M, Charles P, Fedirko E, Lejeune E, Cottineau J, Brusco A, et al. Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain. 2012;135:2980–93.CrossRefPubMedPubMedCentral
47.
Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M, Forlani S, Guyant-Maréchal L, Fontaine B, et al. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain. 2009;132:1589–600.CrossRefPubMed
48.
R S, Brandt E, Karle KN, Tsaousidou M, Klebe S, Klimpe S, Auer-Grumbach M, Crosby AH, Hübner CA, Schöls L, et al. Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia. Neurogenetics. 2009;10:97–104.CrossRef
49.
Stevanin G, Azzedine H, Denora P, Boukhris A, Tazir M, Lossos A, Rosa AL, Lerer I, Hamri A, Alegria P, et al. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain. 2008;131:772–84.CrossRefPubMed
50.
Renvoise B, Chang J, Singh R, Yonekawa S, FitzGibbon EJ, Mankodi A, Vanderver A, Schindler A, Toro C, Gahl WA, et al. Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11. Ann Clin Transl Neurol. 2014;1:379–89.CrossRefPubMedPubMedCentral
51.
Vantaggiato C, Crimella C, Airoldi G, Polishchuk R, Bonato S, Brighina E, Scarlato M, Musumeci O, Toscano A, Martinuzzi A, et al. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. Brain. 2013;136:3119–39.CrossRefPubMedPubMedCentral
52.
53.
Pérez-Brangulí F, Mishra HK, Prots I, Havlicek S, Kohl Z, Saul D, Rummel C, Dorca-Arevalo J, Regensburger M, Graef D, et al. Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum Mol Genet. 2014;23:4859–74.CrossRefPubMedPubMedCentral
54.
Varga RE, Khundadze M, Damme M, Nietzsche S, Hoffmann B, Stauber T, Koch N, Hennings JC, Franzka P, Huebner AK, et al. In vivo evidence for lysosome depletion and impaired Autophagic clearance in hereditary spastic paraplegia type SPG11. PLoS Genet. 2015;11:e1005454.CrossRefPubMedPubMedCentral
55.
Metadata
Title
Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China
Authors
En-Lin Dong
Chong Wang
Shuang Wu
Ying-Qian Lu
Xiao-Hong Lin
Hui-Zhen Su
Miao Zhao
Jin He
Li-Xiang Ma
Ning Wang
Wan-Jin Chen
Xiang Lin
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-018-0269-1

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