Chinese patients with hereditary spastic paraplegias (HSPs): a protocol for a hospital-based cohort study

Yu-Sen Qiu, Yi-Heng Zeng, Ru-Ying Yuan, Zhi-Xian Ye, Jin Bi, Xiao-Hong Lin, Yi-Jun Chen, Meng-Wen Wang, Ying Liu, Shao-Bo Yao, Yi-Kun Chen, Jun-Yi Jiang, Yi Lin, Xiang Lin, Ning Wang, Ying Fu, Wan-Jin Chen, Yu-Sen Qiu, Yi-Heng Zeng, Ru-Ying Yuan, Zhi-Xian Ye, Jin Bi, Xiao-Hong Lin, Yi-Jun Chen, Meng-Wen Wang, Ying Liu, Shao-Bo Yao, Yi-Kun Chen, Jun-Yi Jiang, Yi Lin, Xiang Lin, Ning Wang, Ying Fu, Wan-Jin Chen

Abstract

Introduction: Hereditary spastic paraplegias (HSPs) are uncommon but not rare neurodegenerative diseases. More than 100 pathogenic genes and loci related to spastic paraplegia symptoms have been reported. HSPs have the same core clinical features, including progressive spasticity in the lower limbs, though HSPs are heterogeneous (eg, clinical signs, MRI features, gene mutation). The age of onset varies greatly, from infant to adulthood. In addition, the slow and variable rates of disease progression in patients with HSP represent a substantial challenge for informative assessment of therapeutic efficacy. To address this, we are undertaking a prospective cohort study to investigate genetic-clinical characteristics, find surrogates for monitoring disease progress and identify clinical readouts for treatment.

Methods and analysis: In this case-control cohort study, we will enrol 200 patients with HSP and 200 healthy individuals in parallel. Participants will be continuously assessed for 3 years at 12-month intervals. Six aspects, including clinical signs, genetic spectrum, cognitive competence, MRI features, potential biochemical indicators and nerve electrophysiological factors, will be assessed in detail. This study will observe clinical manifestations and disease severity based on different molecular mechanisms, including oxidative stress, cholesterol metabolism and microtubule dynamics, all of which have been proposed as potential treatment targets or modalities. The analysis will also assess disease progression in different types of HSPs and cellular pathways with a longitudinal study using t tests and χ2 tests.

Ethics and dissemination: The study was granted ethics committee approval by the first affiliated hospital of Fujian Medical University (MRCTA, ECFAH of FMU (2019)194) in 2019. Findings will be disseminated via presentations and peer-reviewed publications. Dissemination will target different audiences, including national stakeholders, researchers from different disciplines and the general public.

Trial registration number: NCT04006418.

Keywords: neurogenetics; neurology; neuroradiology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Clinical diagnosis procedure of HSP. DRPLA, dentatorubral-pallidoluysian atrophy; FRDA, Friedreich’s ataxia; HSP, hereditary spastic paraplegia; SCA, spinocerebellar ataxia.

References

    1. Novarino G, Fenstermaker AG, Zaki MS, et al. . Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 2014;343:506–11. 10.1126/science.1247363
    1. Shribman S, Reid E, Crosby AH, et al. . Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol 2019;18:1136–46. 10.1016/S1474-4422(19)30235-2
    1. Ruano L, Melo C, Silva MC, et al. . The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 2014;42:174–83. 10.1159/000358801
    1. Schüle R, Schöls L. Genetics of hereditary spastic paraplegias. Semin Neurol 2011;31:484–93. 10.1055/s-0031-1299787
    1. Dong E-L, Wang C, Wu S, et al. . Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China. Mol Neurodegener 2018;13:36. 10.1186/s13024-018-0269-1
    1. Vaz FM, McDermott JH, Alders M, et al. . Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia. Brain 2019;142:3382–97. 10.1093/brain/awz291
    1. Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet 1983;1:1151–5. 10.1016/S0140-6736(83)92879-9
    1. Harding AE. Hereditary spastic paraplegias. Semin Neurol 1993;13:333–6. 10.1055/s-2008-1041143
    1. Kara E, Tucci A, Manzoni C, et al. . Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain 2016;139:1904–18. 10.1093/brain/aww111
    1. Schüle R, Wiethoff S, Martus P, et al. . Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol 2016;79:646–58. 10.1002/ana.24611
    1. Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013;126:307–28. 10.1007/s00401-013-1115-8
    1. Blackstone C. Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci 2012;35:25–47. 10.1146/annurev-neuro-062111-150400
    1. Wang Y-guang, Du J, Wang J-ling, et al. . Six cases of SCA3/MJD patients that mimic hereditary spastic paraplegia in clinic. J Neurol Sci 2009;285:121–4. 10.1016/j.jns.2009.06.027
    1. Diniz de Lima F, Faber I, Servelhere KR, et al. . Randomized trial of botulinum toxin type A in hereditary spastic paraplegia - the SPASTOX trial. Mov Disord 2021;36:1654–63. 10.1002/mds.28523
    1. Schüle R, Holland-Letz T, Klimpe S, et al. . The spastic paraplegia rating scale (SPRS): a reliable and valid measure of disease severity. Neurology 2006;67:430–4. 10.1212/01.wnl.0000228242.53336.90
    1. Chrestian N, Dupré N, Gan-Or Z, et al. . Clinical and genetic study of hereditary spastic paraplegia in Canada. Neurol Genet 2017;3:e122. 10.1212/NXG.0000000000000122
    1. Brureau A, Blanchard-Bregeon V, Pech C, et al. . NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration. Neurobiol Dis 2017;104:73–84. 10.1016/j.nbd.2017.04.007
    1. Vassall KA, Bamm VV, Harauz G. MyelStones: the executive roles of myelin basic protein in myelin assembly and destabilization in multiple sclerosis. Biochem J 2015;472:17–32. 10.1042/BJ20150710
    1. Avila J, Lucas JJ, Perez M, et al. . Role of tau protein in both physiological and pathological conditions. Physiol Rev 2004;84:361–84. 10.1152/physrev.00024.2003
    1. Zhao M, Chen Y-J, Wang M-W, et al. . Genetic and clinical profile of Chinese patients with autosomal dominant spastic paraplegia. Mol Diagn Ther 2019;23:781–9. 10.1007/s40291-019-00426-w
    1. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25:1754–60. 10.1093/bioinformatics/btp324
    1. McKenna A, Hanna M, Banks E, et al. . The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010;20:1297–303. 10.1101/gr.107524.110
    1. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164. 10.1093/nar/gkq603
    1. Caspar SM, Dubacher N, Kopps AM, et al. . Clinical sequencing: from raw data to diagnosis with lifetime value. Clin Genet 2018;93:508–19. 10.1111/cge.13190
    1. Stenson PD, Ball EV, Mort M, et al. . Human gene mutation database (HGMD): 2003 update. Hum Mutat 2003;21:577–81. 10.1002/humu.10212
    1. Ning Wang YL, Ye Z, Lin Y, et al. . Cross sign T2 hyperintensities in atrophic spinal cord of hereditary spastic paraplegia type 5. Available:
    1. Tavares V, Prata D, Ferreira HA. Comparing SPM12 and CAT12 segmentation pipelines: a brain tissue volume-based age and Alzheimer's disease study. J Neurosci Methods 2019;334:108565. 10.1016/j.jneumeth.2019.108565
    1. Coppola G, Petolicchio B, Di Renzo A, et al. . Cerebral gray matter volume in patients with chronic migraine: correlations with clinical features. J Headache Pain 2017;18:115. 10.1186/s10194-017-0825-z
    1. Zhao C, Zhu J, Liu X, et al. . Structural and functional brain abnormalities in schizophrenia: a cross-sectional study at different stages of the disease. Prog Neuropsychopharmacol Biol Psychiatry 2018;83:27–32. 10.1016/j.pnpbp.2017.12.017
    1. Spalthoff R, Gaser C, Nenadić I. Altered gyrification in schizophrenia and its relation to other morphometric markers. Schizophr Res 2018;202:195–202. 10.1016/j.schres.2018.07.014
    1. Mascalchi M, Salvadori E, Toschi N, et al. . DTI-derived indexes of brain WM correlate with cognitive performance in vascular MCI and small-vessel disease. A TBSS study. Brain Imaging Behav 2019;13:594–602. 10.1007/s11682-018-9873-5
    1. Castellano A, Papinutto N, Cadioli M, et al. . Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy: in vivo assessment of structural changes. Brain 2016;139:1735–46. 10.1093/brain/aww068
    1. De Leener B, Lévy S, Dupont SM, et al. . Sct: spinal cord toolbox, an open-source software for processing spinal cord MRI data. Neuroimage 2017;145:24–43. 10.1016/j.neuroimage.2016.10.009
    1. Dupont SM, De Leener B, Taso M, et al. . Fully-integrated framework for the segmentation and registration of the spinal cord white and gray matter. Neuroimage 2017;150:358–72. 10.1016/j.neuroimage.2016.09.026
    1. Gros C, De Leener B, Badji A, et al. . Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks. Neuroimage 2019;184:901–15. 10.1016/j.neuroimage.2018.09.081
    1. Moccia M, Prados F, Filippi M, et al. . Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral. Ann Neurol 2019;86:704–13. 10.1002/ana.25571
    1. Benedict RH, DeLuca J, Phillips G, et al. . Validity of the symbol digit modalities test as a cognition performance outcome measure for multiple sclerosis. Mult Scler 2017;23:721–33. 10.1177/1352458517690821
    1. Elwood RW. The California verbal learning test: psychometric characteristics and clinical application. Neuropsychol Rev 1995;5:173–201. 10.1007/BF02214761
    1. Pliskin JI, DeDios Stern S, Resch ZJ, et al. . Comparing the psychometric properties of eight embedded performance validity tests in the Rey auditory verbal learning test, Wechsler memory scale logical memory, and brief visuospatial memory test-revised recognition trials for detecting invalid neuropsychological test performance. Assessment 2021;28:1871–81. 10.1177/1073191120929093
    1. Calamia M, Markon K, Denburg NL, et al. . Developing a short form of Benton’s judgment of line orientation test: an item response theory approach. Clin Neuropsychol 2011;25:670–84. 10.1080/13854046.2011.564209
    1. Sumerall SW, Timmons PL, James AL, et al. . Expanded norms for the controlled oral word association test. J Clin Psychol 1997;53:517–21. 10.1002/(SICI)1097-4679(199708)53:5<517::AID-JCLP14>;2-H
    1. Tombaugh TN. A comprehensive review of the paced auditory serial addition test (PASAT). Arch Clin Neuropsychol 2006;21:53–76. 10.1016/j.acn.2005.07.006
    1. Bo Q, Mao Z, Li X, et al. . Use of the MATRICS consensus cognitive battery (MCCB) to evaluate cognitive deficits in bipolar disorder: a systematic review and meta-analysis. PLoS One 2017;12:e0176212. 10.1371/journal.pone.0176212
    1. Zhang N, Li YJ, Fu Y, et al. . Cognitive impairment in Chinese neuromyelitis optica. Mult Scler 2015;21:1839–46. 10.1177/1352458515576982
    1. Shi C, Kang L, Yao S, et al. . What is the optimal neuropsychological test battery for schizophrenia in China? Schizophr Res 2019;208:317–23. 10.1016/j.schres.2019.01.034
    1. Shi C, Kang L, Yao S, et al. . The MATRICS consensus cognitive battery (MCCB): Co-norming and standardization in China. Schizophr Res 2015;169:109–15. 10.1016/j.schres.2015.09.003
    1. Zhang Y, Zhu D, Zhang P, et al. . Neural mechanisms of AVPR1A RS3-RS1 haplotypes that impact verbal learning and memory. Neuroimage 2020;222:117283. 10.1016/j.neuroimage.2020.117283
    1. Liao Z, Bu Y, Li M, et al. . Remote ischemic conditioning improves cognition in patients with subcortical ischemic vascular dementia. BMC Neurol 2019;19:206. 10.1186/s12883-019-1435-y
    1. Sun XY, Li YX, Yu CQ, et al. . [Reliability and validity of depression scales of Chinese version: a systematic review]. Zhonghua Liu Xing Bing Xue Za Zhi 2017;38:110–6. 10.3760/cma.j.issn.0254-6450.2017.01.021

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