Journal of Shanghai Jiao Tong University (Medical Science) >

2026 , Vol. 46 >Issue 2: 256 - 264

DOI: https://doi.org/10.3969/j.issn.1674-8115.2026.02.016

Brief original article

Spastic paraplegia phenotypes associated with amyotrophic lateral sclerosis-related genes: clinical, imaging and genetic analysis

  • Cheng Xianru ,
  • Cao Yuwen ,
  • Tian Wotu ,
  • Cao Li
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  • 1.Department of Neurology, Suzhou Hospital of Anhui Medical University, Suzhou 234000, China
    2.Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai 200233, China
    3.Neurological Disorder Center, Haikou Orthopedic and Diabetes Hospital of Shanghai Sixth People's Hospital, Haikou 570311, China
Cao Li, E-mail: caoli2000@yeah.net.

Received date: 2025-10-16

  Accepted date: 2025-11-21

  Online published: 2026-02-28

Supported by

National Natural Science Foundation of China(82371255,82201398,82071258);Program for Shanghai Outstanding Academic Leaders(23XD1402500);Shanghai Science and Technology Innovation Action Plan(23DZ2291500);Program for Outstanding Medical Academic Leader of Shanghai(2022LJ011);Training Program for Research Physicians of Innovative Translational Ability(SHDC2022CRD037);Shanghai "Rising Stars of Medical Talents" Youth Development Program Youth Medical Talents-Specialist Program [SHWSRS(2025)_071];Exploratory Clinical Research Project of Shanghai Sixth People's Hospital(ynts202507);Shanghai Municipal Health Commission Clinical Research Youth Foundation(151)

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Abstract

Objective ·To analyze the clinical, imaging, and genetic characteristics of spastic paraplegia (SPG) phenotypes caused by amyotrophic lateral sclerosis (ALS)-related genes. Methods ·A total of 5 pedigrees with SPG caused by ALS-related genes, admitted to the Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, from April 2017 to September 2025, were included in the study. Detailed medical histories and imaging examinations were collected, and Sanger sequencing, family co-segregation verification, and phenotype analyses were performed. Results ·Among the 5 probands, the male-to-female ratio was 3:2. The average age at onset was (18.4±21.7) years (ranging from 1 to 51 years), and the average disease duration was (12.8±13.3) years (ranging from 3 to 33 years). Physical examination revealed increased muscle tone in the lower extremities in all patients (5/5), hyperreflexia in the lower extremities (5/5), patellar clonus in 2 patients (2/5), ankle clonus in 4 patients (4/5), positive pathological signs in the lower extremities in 4 patients (4/5), and foot deformities in 2 patients (2/5). Brain MRI examinations detected abnormalities in 2 patients, specifically cerebellar and cervical spinal cord atrophy in case 1, and a small number of abnormal signals in the splenium of the corpus callosum in case 2. Peripheral nerve electrophysiological examinations indicated that a small number of spontaneous potentials were observed in both lower extremities of 1 patient, and motor evoked potentials revealed central conduction impairment. Genetic testing identified pathogenic variants in 4 different genes, namely amyotrophic lateral sclerosis 2 (ALS2), valosin-containing protein (VCP), senataxin (SETX), and never in mitosis gene A-related kinase 1 (NEK1), in these 5 patients. Among them, 2 new variants, c.3527T>C (p.Met1176Thr) and c.1732T>C (p.Ser578Pro), were newly discovered in the ALS2 gene. Conclusion ·This article analyzes the clinical heterogeneity and genetic characteristics of SPG patients caused by ALS-related genes, providing clinical evidence for accurate diagnosis and in-depth understanding of such diseases.

Key words： spastic paraplegia; amyotrophic lateral sclerosis; ALS2; VCP; SETX; NEK1

Cite this article

Cheng Xianru , Cao Yuwen , Tian Wotu , Cao Li . Spastic paraplegia phenotypes associated with amyotrophic lateral sclerosis-related genes: clinical, imaging and genetic analysis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026 , 46(2) : 256 -264 . DOI: 10.3969/j.issn.1674-8115.2026.02.016

References

[1] Rimoin D L, Connor J M, Pyeritz R, et al. Emery & Rimoin's principles and practice of medical genetics[M]. New York: Churchill Livingstone, 2002.
[2] Parodi L, Fenu S, Stevanin G, et al. Hereditary spastic paraplegia: more than an upper motor neuron disease[J]. Rev Neurol, 2017, 173(5): 352-360.
[3] Fullam T, Statland J. Upper motor neuron disorders: primary lateral sclerosis, upper motor neuron dominant amyotrophic lateral sclerosis, and hereditary spastic paraplegia[J]. Brain Sci, 2021, 11(5): 611.
[4] Harding A E. Classification of the hereditary ataxias and paraplegias[J]. Lancet, 1983, 1(8334): 1151-1155.
[5] Fink J K, Heiman-Patterson T, Bird T, et al. Hereditary spastic paraplegia: advances in genetic research[J]. Neurology, 1996, 46(6): 1507-1514.
[6] Fink J K. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms[J]. Acta Neuropathol, 2013, 126(3): 307-328.
[7] Fink J K. Advances in hereditary spastic paraplegia[J]. Curr Opin Neurol, 1997, 10(4): 313-318.
[8] Richards S, Aziz N, Bale S, 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 the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424.
[9] Pan X Y, Dutta D, Lu S Z, et al. Sphingolipids in neurodegenerative diseases[J]. Front Neurosci, 2023, 17: 1137893.
[10] Schreij A M, Fon E A, McPherson P S. Endocytic membrane trafficking and neurodegenerative disease[J]. Cell Mol Life Sci, 2016, 73(8): 1529-1545.
[11] Berth S H, Lloyd T E. Disruption of axonal transport in neurodegeneration[J]. J Clin Invest, 2023, 133(11): e168554.
[12] Hartmann H, Ho W Y, Chang J C, et al. Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon?[J]. FEBS J, 2022, 289(24): 7688-7709.
[13] Paschen W, Mengesdorf T. Endoplasmic reticulum stress response and neurodegeneration[J]. Cell Calcium, 2005, 38(3/4): 409-415.
[14] Dubey J, Ratnakaran N, Koushika S P. Neurodegeneration and microtubule dynamics: death by a thousand cuts[J]. Front Cell Neurosci, 2015, 9: 343.
[15] Liao P L, Yuan Y C, Liu Z, et al. Association of variants in the KIF1A gene with amyotrophic lateral sclerosis[J]. Transl Neurodegener, 2022, 11(1): 46.
[16] Simone M, Trabacca A, Panzeri E, et al. KIF5A and ALS2 variants in a family with hereditary spastic paraplegia and amyotrophic lateral sclerosis[J]. Front Neurol, 2018, 9: 1078.
[17] Theuriet J, Pegat A, Leblanc P, et al. Phenoconversion from spastic paraplegia to ALS/FTD associated with CYP7B1 compound heterozygous mutations[J]. Genes, 2021, 12(12): 1876.
[18] Teyssou E, Chartier L, Amador M D, et al. Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis[J]. Neurobiol Aging, 2017, 58: 239.e11-239.e20.
[19] Kume K, Kamada M, Shimatani Y, et al. Novel monoallelic variant in ERLIN2 causes spastic paraplegia converted to amyotrophic lateral sclerosis[J]. J Neurol Sci, 2021, 430: 119984.
[20] Khosravi S, Amini E, Emamikhah M, et al. Motor neuron involvement in two ATP13A2-related families: ALS and HSP-like phenotypes[J]. Mov Disord Clin Pract, 2025, 12(6): 852-857.
[21] Clemen C S, Tangavelou K, Strucksberg K H, et al. Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases[J]. Brain, 2010, 133(10): 2920-2941.
[22] Musacchio T, Zaum A K, ü?eyler N, et al. ALS and MMN mimics in patients with BSCL2 mutations: the expanding clinical spectrum of SPG17 hereditary spastic paraplegia[J]. J Neurol, 2017, 264(1): 11-20.
[23] Kim J, Kim S, Nahm M, et al. ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival[J]. J Cell Biol, 2021, 220(5): e202007112.
[24] Hadano S, Kunita R, Otomo A, et al. Molecular and cellular function of ALS2/alsin:implication of membrane dynamics in neuronal development and degeneration [J]. Neurochem Int, 2007, 51(2-4): 74-84.
[25] 朱子豪, 华冉, 姜俊红, 等. ALS2基因突变致婴儿起病型上行性遗传性痉挛性截瘫家系2例报道[J]. 中国优生与遗传杂志, 2025, 33(2): 363-372.
  Zhu Z H, Hua R, Jiang J H, et al. 2 cases of infantile ascending hereditary spastic paraplegia caused by mutation in ALS2 gene[J]. Chinese Journal of Birth Health & Heredity, 2025, 33(2): 363-372.
[26] Miceli M, Exertier C, Cavaglià M, et al. ALS2-related motor neuron diseases: from symptoms to molecules[J]. Biology, 2022, 11(1): 77.
[27] Zaki M S, Sharaf-Eldin W E, Rafat K, et al. Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS[J]. Clin Genet, 2023, 104(2): 238-244.
[28] Nogueira E, Alarcón J, Garma C, et al. ALS2-related disorders in Spanish children[J]. Neurol Sci, 2021, 42(5): 2091-2094.
[29] Orrell R W. ALS2-related disorder[M/OL]//Adam M P, Bick S, Mirzaa G M, et al. GeneReviews?. Seattle: University of Washington, 1993?2026[2025-09-30]. https://www.ncbi.nlm.nih.gov/books/NBK1243/.
[30] Sprute R, Jergas H, ?lmez A, et al. Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations[J]. Am J Med Genet A, 2021, 185(2): 344-354.
[31] Yoganathan S, Kumar M, Aaron R, et al. Phenotype and genotype of children with ALS2 gene-related disorder[J]. Neuropediatrics, 2025, 56(1): 20-28.
[32] Weihl C C, Pestronk A, Kimonis V E. Valosin-containing protein disease: inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia[J]. Neuromuscul Disord, 2009, 19(5): 308-315.
[33] de Bot S T, Schelhaas H J, Kamsteeg E J, et al. Hereditary spastic paraplegia caused by a mutation in the VCP gene[J]. Brain, 2012, 135(Pt 12): e223.
[34] Erzurumlu Y, Kose F A, Gozen O, et al. A unique IBMPFD-related P97/VCP mutation with differential binding pattern and subcellular localization[J]. Int J Biochem Cell Biol, 2013, 45(4): 773-782.
[35] Shmara A, Gibbs L, Mahoney R P, et al. Prevalence of frontotemporal dementia in females of 5 Hispanic families with R159H VCP multisystem proteinopathy[J]. Neurol Genet, 2023, 9(1): e200037.
[36] van der Zee J, Pirici D, van Langenhove T, et al. Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His[J]. Neurology, 2009, 73(8): 626-632.
[37] de Ridder W, Azmi A, Clemen C S, et al. Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation: a tale of the unexpected[J]. Neurology, 2020, 94(8): e785-e796.
[38] Ling S C, Polymenidou M, Cleveland D W. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis[J]. Neuron, 2013, 79(3): 416-438.
[39] Rudnik-Sch?neborn S, Arning L, Epplen J T, et al. SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy[J]. Neuromuscul Disord, 2012, 22(3): 258-262.
[40] Ma L M, Shi Y Y, Chen Z C, et al. A novel SETX gene mutation associated with juvenile amyotrophic lateral sclerosis[J]. Brain Behav, 2018, 8(9): e01066.
[41] Chen X C, Chen X D, Lin X Y, et al. Unveiling ten novel SETX mutations: implications for ALS pathogenesis and clinical diversity[J]. Somatosens Mot Res, 2025: 1-8.
[42] Sberna S, Filipuzzi M, Bianchi N, et al. Senataxin prevents replicative stress induced by the Myc oncogene[J]. Cell Death Dis, 2025, 16(1): 187.
[43] Chen Y Z, Bennett C L, Huynh H M, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)[J]. Am J Hum Genet, 2004, 74(6): 1128-1135.
[44] Nguyen H P, van Broeckhoven C, van der Zee J. ALS genes in the genomic era and their implications for FTD[J]. Trends Genet, 2018, 34(6): 404-423.
[45] Brenner D, Müller K, Wieland T, et al. NEK1 mutations in familial amyotrophic lateral sclerosis[J]. Brain, 2016, 139(Pt 5): e28.
[46] Riva N, Pozzi L, Russo T, et al. NEK1 variants in a cohort of Italian patients with amyotrophic lateral sclerosis[J]. Front Neurosci, 2022, 16: 833051.
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