{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T19:09:47Z","timestamp":1754161787158,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>ATP13A2 is a gene localized on chromosome 1p36.13 and coding for a transmembrane protein found in the lysosomes and late endosomes, which is involved in many cellular metabolic activities. Pathogenetic variants of <jats:italic>ATP13A2<\/jats:italic> are associated with a wide range of neurodegenerative disorder including Kufor Rakeb syndrome (KRS), a rare autosomal recessive form of levodopa responsive juvenile onset parkinsonism (MxMD-<jats:italic>ATP13A2<\/jats:italic>), characterized by rapidly progressive muscular stiffness, bradykinesia, spasticity, pyramidal findings, dementia and supranuclear gaze palsy. The aim of this study is to provide detailed clinical descriptions of two siblings, carriers of novel biallelic <jats:italic>ATP13A2<\/jats:italic> variants. One of them showed KRS levodopa-responsive motor dystonic features at the age of 10\u00a0years preceded by moderate cognitive impairment, while the other only showed mild cognitive impairment at our last evaluation at 11\u00a0years of age. Additionally, we reviewed the previously published cases, focusing on early signs and symptoms, clinical evolution and response to therapy. To our knowledge, this is the only work that groups all reported KRS patients and compares their clinical and molecular features.<\/jats:p>","DOI":"10.3389\/fgene.2025.1588812","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T10:07:43Z","timestamp":1753783663000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Novel ATP13A2 pathogenic variants associated with early-onset parkinsonism and a mini-review"],"prefix":"10.3389","volume":"16","author":[{"given":"Leonardo","family":"Affronte","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Pini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Pizzoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Coccia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Mazzone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arber","family":"Golemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melania","family":"Giannotta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duccio Maria","family":"Cordelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerio","family":"Carelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Vaisfeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia","family":"Palombo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1002\/mdc3.12353","article-title":"Exome sequencing identifies a novel homozygous missense ATP13A2 mutation","volume":"4","author":"Abbas","year":"2016","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B2","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1002\/mdc3.13034","article-title":"Psychiatric manifestations of ATP13A2 mutations","volume":"7","author":"Balint","year":"2020","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1002\/mds.22996","article-title":"Clinical spectrum of kufor-rakeb syndrome in the Chilean kindred with ATP13A2 mutations","volume":"25","author":"Behrens","year":"2010","journal-title":"Mov. Disord."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1001\/archneurol.2010.281","article-title":"Recessively inherited parkinsonism: effect of ATP13A2 mutations on the clinical and neuroimaging phenotype","volume":"67","author":"Br\u00fcggemann","year":"2010","journal-title":"Arch. Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1002\/ajmg.b.31214","article-title":"ATP13A2 variability in Taiwanese parkinson's disease","author":"Chen","year":"2011","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.parkreldis.2010.10.011","article-title":"Juvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2 frameshift mutation","volume":"17","author":"Crosiers","year":"2011","journal-title":"Park. Relat. Disord."},{"key":"B7","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.parkreldis.2020.06.001","article-title":"Ataxia-myoclonus syndrome due to a novel homozygous ATP13A2 mutation","volume":"76","author":"De Michele","year":"2020","journal-title":"Park. Relat. Disord."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1212\/01.wnl.0000260963.08711.08","article-title":"ATP13A2 missense mutations in juvenile parkinsonism and young onset parkinson disease","volume":"68","author":"Di Fonzo","year":"2007","journal-title":"Neurology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1002\/mds.22728","article-title":"ATP13A2 variants in early-onset parkinson's disease patients and controls","volume":"24","author":"Djarmati","year":"2009","journal-title":"Mov. Disord."},{"key":"B10","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1111\/j.1399-0004.2011.01745.x","article-title":"Novel mutation in ATP13A2 widens the spectrum of kufor-rakeb syndrome (PARK9)","volume":"82","author":"Eiberg","year":"2012","journal-title":"Clin. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1093\/brain\/aww307","article-title":"Loss-of-function mutations in the ATP13A2\/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)","volume":"140","author":"Estrada-Cuzcano","year":"2017","journal-title":"Brain"},{"key":"B12","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.ejpn.2011.01.001","article-title":"Juvenile parkinsonism associated with heterozygous frameshift ATP13A2 gene mutation","volume":"15","author":"Fong","year":"2011","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s10545-014-9723-6","article-title":"Parkinsonism and inborn errors of metabolism","volume":"37","author":"Garcia-Cazorla","year":"2014","journal-title":"J. Inherit. Metab. Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s12098-019-03167-0","article-title":"Kufor-rakeb syndrome\/parkinson disease type 9","volume":"87","author":"Gowda","year":"2020","journal-title":"Indian J. Pediatr."},{"key":"B15","doi-asserted-by":"publisher","first-page":"343","DOI":"10.14802\/jmd.23098","article-title":"Dystonic opisthotonus in kufor-rakeb syndrome: expanding the phenotypic and genotypic spectrum","volume":"16","author":"Gurram","year":"2023","journal-title":"J. Mov. Disord."},{"key":"B16","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3233\/JPD-181360","article-title":"Kufor-rakeb Syndrome\/PARK9: one novel and one possible recurring Ashkenazi ATP13A2 mutation","volume":"8","author":"Inzelberg","year":"2018","journal-title":"J. Park. Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.injms.2016.09.002","article-title":"Kufor\u2013rakeb syndrome (KRS): clinico-radiological phenotype of a probable sporadic case with \u201ceye of tiger\u201d sign","volume":"7","author":"Jain","year":"2016","journal-title":"Indian J. Med. Specialities"},{"key":"B18","doi-asserted-by":"publisher","first-page":"S257","DOI":"10.1016\/j.pmrj.2016.07.470","article-title":"Poster 298 ataxia and dysarthria in two siblings with kufor rakeb syndrome: a case report","volume":"8","author":"Kaul","year":"2016","journal-title":"PM R."},{"key":"B19","doi-asserted-by":"publisher","first-page":"147167","DOI":"10.1016\/j.brainres.2020.147167","article-title":"Novel mutations in ATP13A2 associated with mixed neurological presentations and iron toxicity due to nonsense-mediated decay","volume":"1750","author":"K\u0131r\u0131mtay","year":"2021","journal-title":"Brain Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1002\/mdc3.13518","article-title":"Kufor rakeb syndrome with novel mutation and the role of deep brain stimulation","volume":"9","author":"Kola","year":"2022","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B21","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1002\/mds.28982","article-title":"Nomenclature of genetic movement disorders: recommendations of the international parkinson and movement disorder society task force - an update","volume":"37","author":"Lange","year":"2022","journal-title":"Mov. Disord."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1212\/01.wnl.0000335167.72412.68","article-title":"Novel ATP13A2 variant associated with parkinson disease in Taiwan and Singapore","volume":"71","author":"Lin","year":"2008","journal-title":"Neurology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.neulet.2014.06.023","article-title":"Identification of p.Gln858* in ATP13A2 in two EOPD patients and presentation of their clinical features","volume":"577","author":"Malakouti-Nejad","year":"2014","journal-title":"Neurosci. Lett."},{"key":"B24","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1002\/mdc3.13260","article-title":"Ataxia and action myoclonus related to novel mutations in ATP13A2 gene","volume":"8","author":"Manrique","year":"2021","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3341","DOI":"10.1080\/15384101.2015.1093420","article-title":"Unlocking ATP13A2\/PARK9 activity","volume":"14","author":"Martin","year":"2015","journal-title":"Cell Cycle"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1016\/j.parkreldis.2015.09.036","article-title":"Juvenile dystonia-parkinsonism syndrome caused by a novel p.S941Tfs1X ATP13A2 (PARK9) mutation","volume":"21","author":"Martino","year":"2015","journal-title":"Park. Relat. Disord."},{"key":"B27","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1080\/13554794.2019.1625928","article-title":"Successful treatment of psychosis in a patient with kufor-rakeb syndrome with low dose aripiprazole: a case report","volume":"25","author":"McNeil-Gauthier","year":"2019","journal-title":"Neurocase"},{"key":"B28","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1111\/j.1600-0404.1994.tb02645.x","article-title":"Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: kufor-rakeb syndrome","volume":"89","author":"Najim al-Din","year":"1994","journal-title":"Acta Neurol. Scand."},{"key":"B29","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.parkreldis.2019.06.025","article-title":"Juvenile parkinsonism: differential diagnosis, genetics, and treatment","volume":"67","author":"Niemann","year":"2019","journal-title":"Park. Relat. Disord."},{"key":"B30","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1002\/mdc3.12567","article-title":"Kufor-rakeb syndrome due to a novel ATP13A2 mutation in 2 Chinese-American brothers","volume":"5","author":"Noch","year":"2017","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B31","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1002\/humu.21527","article-title":"Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing kufor-rakeb syndrome, a form of early-onset parkinsonism","volume":"32","author":"Park","year":"2011","journal-title":"Hum. Mutat."},{"key":"B32","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/mds.10644","article-title":"Diagnostic considerations in juvenile parkinsonism","volume":"19","author":"Paviour","year":"2004","journal-title":"Mov. Disord."},{"key":"B33","doi-asserted-by":"publisher","first-page":"285","DOI":"10.5114\/fn.2019.88459","article-title":"Clinical and ultrastructural findings in an ataxic variant of kufor-rakeb syndrome","volume":"57","author":"Pietrzak","year":"2019","journal-title":"Folia Neuropathol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1002\/mdc3.12175","article-title":"First report of kufor-rakeb syndrome (PARK 9) from India, and a novel nonsense mutation in ATP13A2 gene","volume":"2","author":"Prashanth","year":"2015","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1038\/ng1884","article-title":"Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase","volume":"38","author":"Ramirez","year":"2006","journal-title":"Nat. Genet."},{"key":"B36","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/mdc3.12570","article-title":"Action myoclonus and seizure in kufor-rakeb syndrome","volume":"5","author":"Rohani","year":"2017","journal-title":"Mov. Disord. Clin. Pract."},{"key":"B37","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s10048-010-0259-0","article-title":"Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability","volume":"12","author":"Santoro","year":"2011","journal-title":"Neurogenetics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"3723","DOI":"10.1007\/s10072-023-06899-2","article-title":"Kufor rakeb syndrome without gaze palsy and pyramidal signs due to novel ATP13A2 mutations","volume":"44","author":"Satolli","year":"2023","journal-title":"Neurol. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1002\/mds.22947","article-title":"ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation","volume":"25","author":"Schneider","year":"2010","journal-title":"Mov. Disord."},{"key":"B40","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/S1474-4422(06)70411-2","article-title":"Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism","volume":"5","author":"Schrag","year":"2006","journal-title":"Lancet. Neurol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e0193228","DOI":"10.1371\/journal.pone.0193228","article-title":"Parkinson disease related ATP13A2 evolved early in animal evolution","volume":"13","author":"S\u00f8rensen","year":"2018","journal-title":"PLoS One"},{"key":"B42","doi-asserted-by":"publisher","first-page":"48","DOI":"10.3389\/fnmol.2014.00048","article-title":"Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson\u2019s disease and other neurological disorders","volume":"7","author":"Van Veen","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"6954820","DOI":"10.1155\/2020\/6954820","article-title":"ATP13A2 gene variants in patients with Parkinson\u2019s disease in Xinjiang","volume":"2020","author":"Wang","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1002\/mds.20511","article-title":"Kufor rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia","volume":"20","author":"Williams","year":"2005","journal-title":"Mov. Disord."},{"key":"B45","doi-asserted-by":"publisher","first-page":"6338","DOI":"10.3390\/ijms24076338","article-title":"Genetic evidence for endolysosomal dysfunction in parkinson\u2019s disease: a critical overview","volume":"24","author":"Yahya","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"371256","DOI":"10.1155\/2014\/371256","article-title":"Mutations in the ATP13A2 gene and parkinsonism: a preliminary review","volume":"2014","author":"Yang","year":"2014","journal-title":"Biomed. Res. Int."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1588812\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T10:07:44Z","timestamp":1753783664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1588812\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":46,"alternative-id":["10.3389\/fgene.2025.1588812"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1588812","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,29]]},"article-number":"1588812"}}