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Recently, a group of clinically overlapping hypomyelinating leukodystrophies (HL) has been associated with mutations in RNA polymerase III enzymes (Pol III) subunits.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Case presentation<\/jats:title>\n<jats:p>In this manuscript, we describe two Italian siblings carrying a novel <jats:italic>POLR3A<\/jats:italic> genotype. MRI imaging, genetic analysis, and clinical data led to diagnosing HL type 7. The female sibling, at the age of 34, is tetra-paretic and suffers from severe cognitive regression. She had a disease onset at the age of 19, characterized by slow and progressive cognitive impairment associated with gait disturbances and amenorrhea. The male sibling was diagnosed during an MRI carried out for cephalalgia at the age of 41. After 5 years, he developed mild cognitive impairment, dystonia with 4-limb hypotonia, and moderate dysmetria with balance and gait impairment.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The present study provides the first evidence of unusually late age of onset in HL, describing two siblings with a novel <jats:italic>POLR3A<\/jats:italic> genotype which showed the first symptoms at the age of 41 and 19, respectively. This provides a powerful insight into clinical heterogeneity and genotype-phenotype correlation in <jats:italic>POLR3A<\/jats:italic> related HL.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12883-020-01835-9","type":"journal-article","created":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T08:02:38Z","timestamp":1593417758000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A novel POLR3A genotype leads to leukodystrophy type-7 in two siblings with unusually late age of onset"],"prefix":"10.1186","volume":"20","author":[{"given":"Rosa","family":"Campopiano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosangela","family":"Ferese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Zampatti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emiliano","family":"Giardina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Biagioni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Colonnese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Centonze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianna","family":"Storto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Buttari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edoardo","family":"Fraviga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vania","family":"Broccoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirco","family":"Fanelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Fornai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3727-4502","authenticated-orcid":false,"given":"Stefano","family":"Gambardella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,6,29]]},"reference":[{"key":"1835_CR1","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/ejhg.2016.183","volume":"3","author":"B Kara","year":"2017","unstructured":"Kara B, K\u00f6ro\u011flu \u00c7, Peltonen K. 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Written informed consent was obtained from the participant for the publication of this case report. Protocol ID:CGM-01 Clinical Trials ID:NCT03084224.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written consent for publication was obtained from the patient. And written consent for publication was also obtained from the proband\u2019s son and his relatives prior to genetic testing.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"258"}}