{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:04:55Z","timestamp":1790744695835,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Foundation-Flanders (FWO)","award":["#G049217N"],"award-info":[{"award-number":["#G049217N"]}]},{"name":"Research Foundation-Flanders (FWO)","award":["#G048220N"],"award-info":[{"award-number":["#G048220N"]}]},{"name":"Research Foundation-Flanders (FWO)","award":["#G0A2122N"],"award-info":[{"award-number":["#G0A2122N"]}]},{"name":"Research Fund of the University of Antwerp","award":["#G049217N"],"award-info":[{"award-number":["#G049217N"]}]},{"name":"Research Fund of the University of Antwerp","award":["#G048220N"],"award-info":[{"award-number":["#G048220N"]}]},{"name":"Research Fund of the University of Antwerp","award":["#G0A2122N"],"award-info":[{"award-number":["#G0A2122N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hereditary spastic paraplegia (HSP) is among the most genetically diverse of all monogenic diseases. The aim was to analyze the genetic causes of HSP among adult Serbian patients. The study comprised 74 patients from 65 families clinically diagnosed with HSP during a nine-year prospective period. A panel of thirteen genes was analyzed: L1CAM (SPG1), PLP1 (SPG2), ATL1 (SPG3A), SPAST (SPG4), CYP7B1 (SPG5A), SPG7 (SPG7), KIF5A (SPG10), SPG11 (SPG11), ZYFVE26 (SPG15), REEP1 (SPG31), ATP13A2 (SPG78), DYNC1H1, and BICD2 using a next generation sequencing-based technique. A copy number variation (CNV) test for SPAST, SPG7, and SPG11 was also performed. Twenty-three patients from 19 families (29.2%) had conclusive genetic findings, including 75.0% of families with autosomal dominant and 25.0% with autosomal recessive inheritance, and 15.7% of sporadic cases. Twelve families had mutations in the SPAST gene, usually with a pure HSP phenotype. Three sporadic patients had conclusive findings in the SPG11 gene. Two unrelated patients carried a homozygous pathogenic mutation c.233T&gt;A (p.L78*) in SPG7 that is a founder Roma mutation. One patient had a heterozygous de novo variant in the KIF5A gene, and one had a compound heterozygous mutation in the ZYFVE26 gene. The combined genetic yield of our gene panel and CNV analysis for HSP was around 30%. Our findings broaden the knowledge on the genetic epidemiology of HSP, with implications for molecular diagnostics in this region.<\/jats:p>","DOI":"10.3390\/cells11182804","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T07:05:56Z","timestamp":1662620756000},"page":"2804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Phenotypic and Genetic Heterogeneity of Adult Patients with Hereditary Spastic Paraplegia from Serbia"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-556X","authenticated-orcid":false,"given":"Stojan","family":"Peri\u0107","sequence":"first","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladana","family":"Markovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3528-2293","authenticated-orcid":false,"given":"Ay\u015fe","family":"Candayan","sequence":"additional","affiliation":[{"name":"VIB-UAntwerp Center for Molecular Neurology, VIB, 2610 Antwerpen, Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp, 2610 Antwerpen, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Els","family":"De Vriendt","sequence":"additional","affiliation":[{"name":"VIB-UAntwerp Center for Molecular Neurology, VIB, 2610 Antwerpen, 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Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Svetel","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zorica","family":"Stevi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6623-0779","authenticated-orcid":false,"given":"Ivo","family":"Bo\u017eovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0160arlota","family":"Mesaro\u0161","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-3458","authenticated-orcid":false,"given":"Jelena","family":"Drulovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Basta","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Petrovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivera","family":"Tama\u0161","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0250-597X","authenticated-orcid":false,"given":"Milija","family":"Mijajlovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Novakovi\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0226-9727","authenticated-orcid":false,"given":"Dragoslav","family":"Soki\u0107","sequence":"additional","affiliation":[{"name":"Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3833-3754","authenticated-orcid":false,"given":"Albena","family":"Jordanova","sequence":"additional","affiliation":[{"name":"VIB-UAntwerp Center for Molecular Neurology, VIB, 2610 Antwerpen, Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp, 2610 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Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1148\/radiol.14141715","article-title":"Hereditary Spastic Paraplegia: Beyond Clinical Phenotypes toward a Unified Pattern of Central Nervous System Damage","volume":"276","author":"Agosta","year":"2015","journal-title":"Radiology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Meyyazhagan, A., Kuchi Bhotla, H., Pappuswamy, M., and Orlacchio, A. (2022). The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147665"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.conb.2021.07.005","article-title":"Genetics in hereditary spastic paraplegias: Essential but not enough","volume":"72","author":"Darios","year":"2022","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e0174667","DOI":"10.1371\/journal.pone.0174667","article-title":"Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia","volume":"12","author":"Iqbal","year":"2017","journal-title":"PLoS ONE"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1093\/brain\/awab386","article-title":"Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia","volume":"145","author":"Banneau","year":"2022","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/humu.20682","article-title":"A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia","volume":"29","author":"Arnoldi","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Koh, K., Ishiura, H., Tsuji, S., and Takiyama, Y. (2018). JASPAC: Japan Spastic Paraplegia Research Consortium. Brain Sci., 8.","DOI":"10.3390\/brainsci8080153"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.expneurol.2014.06.011","article-title":"Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms","volume":"261","author":"Lombardi","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lan, M.Y., Chang, Y.Y., Yeh, T.H., Lai, S.C., Liou, C.W., Kuo, H.C., Wu, Y.R., Lyu, R.K., Hung, J.W., and Chang, Y.C. (2014). High frequency of SPG4 in Taiwanese families with autosomal dominant hereditary spastic paraplegia. BMC Neurol., 14.","DOI":"10.1186\/s12883-014-0216-x"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13024-018-0269-1","article-title":"Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China","volume":"13","author":"Dong","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/15472","article-title":"Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia","volume":"23","author":"Hazan","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1212\/01.wnl.0000223315.62404.00","article-title":"UK and Irish HSP Consortium: Clinical features of hereditary spastic paraplegia due to spastin mutation","volume":"67","author":"McDermott","year":"2006","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1212\/01.wnl.0000294330.27058.61","article-title":"Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4","volume":"70","author":"Orlacchio","year":"2008","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jns.2016.10.017","article-title":"Infantile-onset ascending spastic paraplegia phenotype associated with SPAST mutation","volume":"371","author":"Bortholin","year":"2016","journal-title":"J. Neurol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.neurol.2015.02.017","article-title":"Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting","volume":"171","author":"Klebe","year":"2015","journal-title":"Rev. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1111\/j.1468-1331.2004.00888.x","article-title":"Hereditary spastic paraplegia with cerebellar ataxia: A complex phenotype associated with a new SPG4 gene mutation","volume":"11","author":"Nielsen","year":"2004","journal-title":"Eur. J. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1001\/archneur.61.6.849","article-title":"Hereditary spastic paraplegia: Clinical genetic study of 15 families","volume":"61","author":"Orlacchio","year":"2004","journal-title":"Arch. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/sj.ejhg.5201922","article-title":"Mental deficiency in three families with SPG4 spastic paraplegia","volume":"16","author":"Depienne","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.neurol.2017.03.034","article-title":"Hereditary spastic paraplegia: More than an upper motor neuron disease","volume":"173","author":"Parodi","year":"2017","journal-title":"Rev. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1007\/s00415-015-7791-7","article-title":"Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations","volume":"262","author":"Lindig","year":"2015","journal-title":"J. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1093\/brain\/aww111","article-title":"Genetic and phenotypic characterization of complex hereditary spastic paraplegia","volume":"139","author":"Kara","year":"2016","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1007\/s00415-015-7854-9","article-title":"Hereditary spastic paraplegia type 11 with a very late onset","volume":"262","author":"Rubegni","year":"2015","journal-title":"J. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jns.2015.10.045","article-title":"Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation","volume":"359","author":"Kawarai","year":"2015","journal-title":"J. Neurol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1080\/01616412.2021.1975224","article-title":"SPG11: Clinical and genetic features of seven Czech patients and literature review","volume":"44","author":"Doleckova","year":"2022","journal-title":"Neurol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s10048-007-0095-z","article-title":"SPG11: A consistent clinical phenotype in a family with homozygous spatacsin truncating mutation","volume":"8","author":"Ghezzi","year":"2007","journal-title":"Neurogenetics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/j.1468-1331.2008.02367.x","article-title":"Autosomal recessive hereditary spastic paraplegia with thin corpus callosum: A novel mutation in the SPG11 gene and further evidence for genetic heterogeneity","volume":"16","author":"Pippucci","year":"2009","journal-title":"Eur. J. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e122","DOI":"10.1212\/NXG.0000000000000122","article-title":"Clinical and genetic study of hereditary spastic paraplegia in Canada","volume":"3","author":"Chrestian","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00062-018-0665-5","article-title":"Subtle Imaging Findings Aid the Diagnosis of Adolescent Hereditary Spastic Paraplegia and Ataxia","volume":"29","author":"Wagner","year":"2019","journal-title":"Clin. Neuroradiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1093\/brain\/awm293","article-title":"SPATAX consortium. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration","volume":"131","author":"Stevanin","year":"2008","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1093\/brain\/aws240","article-title":"Spastic paraplegia gene 7 in patients with spasticity and\/or optic neuropathy","volume":"135","author":"Klebe","year":"2012","journal-title":"Brain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15012","DOI":"10.1038\/hgv.2015.12","article-title":"Predominant cerebellar phenotype in spastic paraplegia 7 (SPG7)","volume":"2","author":"Yahikozawa","year":"2015","journal-title":"Hum. Genome Var."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1093\/brain\/aws224","article-title":"Genotype-phenotype correlations in spastic paraplegia type 7: A study in a large Dutch cohort","volume":"135","author":"Kremer","year":"2012","journal-title":"Brain"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1399-0004.2012.01896.x","article-title":"SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V","volume":"83","author":"Coto","year":"2013","journal-title":"Clin. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.clineuro.2014.02.002","article-title":"Hereditary spastic paraparesis in adults. A clinical and genetic perspective from Tuscany","volume":"120","author":"Orsucci","year":"2014","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1093\/brain\/awu060","article-title":"Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance","volume":"137","author":"Pfeffer","year":"2014","journal-title":"Brain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E376","DOI":"10.1002\/humu.20920","article-title":"Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10","volume":"30","author":"Goizet","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.1399-0004.2011.01717.x","article-title":"Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2","volume":"82","author":"Crimella","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_40","unstructured":"Adam, M.P., Everman, D.B., Mirzaa, G.M., Pagon, R.A., Wallance, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (2022, September 06). Hereditary Spastic Paraplegia Overview. 2000 August 15 [Updated 2021 Feb 11], GeneReviews\u00ae [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1509\/."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/18\/2804\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:27:25Z","timestamp":1760142445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/18\/2804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":40,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["cells11182804"],"URL":"https:\/\/doi.org\/10.3390\/cells11182804","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]}}}