{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T13:01:40Z","timestamp":1793278900573,"version":"4.5.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Italian Ministry of Health"},{"DOI":"10.13039\/100012990","name":"Universit\u00e0 degli Studi di Siena","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012990","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurol Sci"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in<jats:italic>POLR3A<\/jats:italic>are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909\u2009+\u200922G\u2009&gt;\u2009A mutation in<jats:italic>POLR3A<\/jats:italic>. Here, we present 10 patients from 8 unrelated families with<jats:italic>POLR3A<\/jats:italic>-related late-onset spastic ataxia, all harboring the c.1909\u2009+\u200922G\u2009&gt;\u2009A variant. Most of them showed an ataxic-spastic picture, two a \u201cpure\u201d cerebellar phenotype, and one a \u201cpure\u201d spastic presentation. The non-neurological findings typically associated with<jats:italic>POLR3A<\/jats:italic>mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and\/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The<jats:italic>POLR3A<\/jats:italic>mutations present in this cohort were the c.1909\u2009+\u200922G\u2009&gt;\u2009A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14\u201318. Interestingly, this patient had the most \u201ccomplex\u201d presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset<jats:italic>POLR3A<\/jats:italic>-related disorders, and therefore further expand the phenotype.<\/jats:p>","DOI":"10.1007\/s10072-021-05462-1","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:02:34Z","timestamp":1626998554000},"page":"1071-1077","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients"],"prefix":"10.1007","volume":"43","author":[{"given":"Ilaria","family":"Di Donato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Gallo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Ricca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Fini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Silvestri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorella","family":"Gurrieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Cirillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Cerase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Natale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Matrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Riso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarosa Anna Beatrice","family":"Melone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Tessa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"De Michele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Federico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Filla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Dotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo Maria","family":"Santorelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"issue":"21","key":"5462_CR1","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1212\/WNL.0000000000001002","volume":"83","author":"NI Wolf","year":"2014","unstructured":"Wolf NI, Vanderver A, van Spaendonk RM et al (2014) Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology 83(21):1898\u201318905","journal-title":"Neurology"},{"issue":"19","key":"5462_CR2","doi-asserted-by":"publisher","first-page":"4302","DOI":"10.1093\/hmg\/ddw263","volume":"25","author":"DN Azmanov","year":"2016","unstructured":"Azmanov DN, Siira SJ, Chamova T et al (2016) Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement. Hum Mol Genet 25(19):4302\u20134314","journal-title":"Hum Mol Genet"},{"issue":"3","key":"5462_CR3","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1111\/ene.14646","volume":"28","author":"D Di Bella","year":"2021","unstructured":"Di Bella D, Magri S, Benzoni C et al (2021) Hypomyelinating leukodystrophies in adults: Clinical and genetic features. Eur J Neurol 28(3):934\u2013944","journal-title":"Eur J Neurol"},{"issue":"2","key":"5462_CR4","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s10048-019-00602-4","volume":"21","author":"I Harting","year":"2020","unstructured":"Harting I, Al-Saady M, Kr\u00e4geloh-Mann I et al (2020) POLR3A variants with striatal involvement and extrapyramidal movement disorder. Neurogenetics 21(2):121\u2013133","journal-title":"Neurogenetics"},{"issue":"12","key":"5462_CR5","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1038\/s41431-020-0673-1","volume":"28","author":"SG Temel","year":"2020","unstructured":"Temel SG, Ergoren MC, Manara E et al (2020) Unique combination and in silico modeling of biallelic POLR3A variants as a cause of Wiedemann-Rautenstrauch syndrome. Eur J Hum Genet 28(12):1675\u20131680","journal-title":"Eur J Hum Genet"},{"issue":"6","key":"5462_CR6","doi-asserted-by":"publisher","first-page":"e521","DOI":"10.1212\/NXG.0000000000000521","volume":"6","author":"V Zanette","year":"2020","unstructured":"Zanette V, Reyes A, Johnson M et al (2020) Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations. Neurol Genet 6(6):e521","journal-title":"Neurol Genet"},{"issue":"6","key":"5462_CR7","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1093\/brain\/awx095","volume":"140","author":"M Minnerop","year":"2017","unstructured":"Minnerop M, Kurzwelly D, Wagner H et al (2017) Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain 140(6):1561\u20131578","journal-title":"Brain"},{"issue":"1","key":"5462_CR8","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/brain\/awx290","volume":"141","author":"L Gauquelin","year":"2018","unstructured":"Gauquelin L, T\u00e9treault M, Thiffault I et al (2018) POLR3A variants in hereditary spastic paraplegia and ataxia. Brain 141(1):e1","journal-title":"Brain"},{"issue":"1","key":"5462_CR9","doi-asserted-by":"publisher","first-page":"e2","DOI":"10.1093\/brain\/awx291","volume":"141","author":"M Minnerop","year":"2018","unstructured":"Minnerop M, Kurzwelly D, Rattay TW et al (2018) Reply: POLR3A variants in hereditary spastic paraplegia and ataxia. Brain 141(1):e2","journal-title":"Brain"},{"issue":"4","key":"5462_CR10","doi-asserted-by":"publisher","first-page":"e13","DOI":"10.1093\/brain\/awz042","volume":"142","author":"M Minnerop","year":"2019","unstructured":"Minnerop M, Kurzwelly D, Wagner H, Sch\u00fcle R, Ramirez A (2019) Reply: biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis. Brain 142(4):e13","journal-title":"Brain"},{"issue":"4","key":"5462_CR11","doi-asserted-by":"publisher","first-page":"e12","DOI":"10.1093\/brain\/awz041","volume":"142","author":"SL Rydning","year":"2019","unstructured":"Rydning SL, Koht J, Sheng Y et al (2019) Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis. Brain 142(4):e12","journal-title":"Brain"},{"issue":"2","key":"5462_CR12","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1007\/s00415-019-09574-9","volume":"267","author":"J Infante","year":"2020","unstructured":"Infante J, Serrano-C\u00e1rdenas KM, Corral-Juan M et al (2020) POLR3A-related spastic ataxia: new mutations and a look into the phenotype. J Neurol 267(2):324\u2013330","journal-title":"J Neurol"},{"issue":"9","key":"5462_CR13","doi-asserted-by":"crossref","first-page":"e1341","DOI":"10.1002\/mgg3.1341","volume":"8","author":"JA Morales-Rosado","year":"2020","unstructured":"Morales-Rosado JA, Macke EL, Cousin MA et al (2020) Interpretation challenges of novel dual-class missense and splice-impacting variant in POLR3A-related late-onset hereditary spastic ataxia. Mol Genet Genomic Med 8(9):e1341","journal-title":"Mol Genet Genomic Med"},{"key":"5462_CR14","doi-asserted-by":"publisher","DOI":"10.1111\/ene.14868","author":"V Riso","year":"2021","unstructured":"Riso V, Galatolo D, Barghigiani M et al (2021) A next generation sequencing-based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21. Eur J Neurol. https:\/\/doi.org\/10.1111\/ene.14868","journal-title":"Eur J Neurol"},{"issue":"1","key":"5462_CR15","doi-asserted-by":"publisher","first-page":"e122","DOI":"10.1212\/NXG.0000000000000122","volume":"3","author":"N Chrestian","year":"2016","unstructured":"Chrestian N, Dupr\u00e9 N, Gan-Or Z et al (2016) Clinical and genetic study of hereditary spastic paraplegia in Canada. Neurol Genet 3(1):e122","journal-title":"Neurol Genet"},{"issue":"3","key":"5462_CR16","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1111\/ene.14094","volume":"27","author":"M Lieto","year":"2020","unstructured":"Lieto M, Riso V, Galatolo D et al (2020) The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families. Eur J Neurol 27(3):498\u2013505","journal-title":"Eur J Neurol"},{"issue":"D1","key":"5462_CR17","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47(D1):D886\u2013D894","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"5462_CR18","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S et al (2015) 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. Genet Med 17(5):405\u2013424","journal-title":"Genet Med"},{"issue":"11","key":"5462_CR19","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1002\/acn3.51221","volume":"7","author":"L Ruggiero","year":"2020","unstructured":"Ruggiero L, Iovino A, Dubbioso R et al (2020) Multimodal evaluation of an Italian family with a hereditary spastic paraplegia and POLR3A mutations. Ann Clin Transl Neurol 7(11):2326\u20132331","journal-title":"Ann Clin Transl Neurol"},{"key":"5462_CR20","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s13023-015-0279-9","volume":"10","author":"M Gutierrez","year":"2015","unstructured":"Gutierrez M, Thiffault I, Guerrero K et al (2015) Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy. Orphanet J Rare Dis 10:69","journal-title":"Orphanet J Rare Dis"}],"container-title":["Neurological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10072-021-05462-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10072-021-05462-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10072-021-05462-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T10:52:10Z","timestamp":1699267930000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10072-021-05462-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,23]]},"references-count":20,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["5462"],"URL":"https:\/\/doi.org\/10.1007\/s10072-021-05462-1","relation":{},"ISSN":["1590-1874","1590-3478"],"issn-type":[{"value":"1590-1874","type":"print"},{"value":"1590-3478","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,23]]},"assertion":[{"value":"26 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"None.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}