{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T02:35:43Z","timestamp":1787884543355,"version":"build-2784847793"},"reference-count":21,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["2025-2027"],"award-info":[{"award-number":["2025-2027"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: The most prevalent form of neurodegeneration with brain iron accumulation (NBIA) is pantothenate kinase-associated neurodegeneration (PKAN), caused by mutations in the PANK2 gene. The hallmark of PKAN is the \u201ceye-of-the-tiger\u201d sign, which is characterized by a bilateral region of central hyperintense signal surrounded by a hypointense signal in the medial globus pallidus on T2-weighted brain magnetic resonance imaging (MRI). Methods: Whole-exome sequencing (WES) was performed in four patients who presented with dystonia, cognitive impairment and abnormalities of the globus pallidus. All patients underwent comprehensive clinical and instrumental evaluations. Results: Molecular analysis using WES revealed PANK2 variants in all four cases. Two patients were homozygous for the known pathogenic variant c.1169A &gt; T (p.N390I). The remaining two patients displayed compound heterozygotes, each carrying the novel splicing variant c.906-1G &gt; A on one allele, combined with a different second variant on the other allele: the new missense variant c.617G &gt; A (p.G206D) in one case and the known pathogenic variant c.1231G &gt; A (p.G411R) in the other. In one case, brain imaging documented the transition from initial hyperintensity of the globus pallidus to the development of the \u201ceye-of-the-tiger\u201d sign. In two cases, MRI findings clearly demonstrated the characteristic \u201ceye-of-the-tiger\u201d appearance. Ultimately, in one case, the imaging likely captured a later disease stage, in which the \u201ceye-of-the-tiger\u201d sign was no longer visible, and only the residual hypointensity remained. Conclusions: This study describes two novel likely pathogenic variants and documents the full MRI progression of globus pallidus involvement in PKAN. The sequence starts with early T2 hyperintensity, followed by the emergence of the typical \u201ceye-of-the-tiger\u201d sign, and culminates in marked hypointensity in advanced stages. Since the initial clinical presentation may mimic mitochondrial disorders or other neurometabolic conditions, these imaging features are crucial for guiding differential diagnosis and enabling accurate disease identification.<\/jats:p>","DOI":"10.3390\/genes16091008","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T14:18:49Z","timestamp":1756217929000},"page":"1008","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Focus on Clinical and Genetic Aspects of PKAN Through the Description of New Patients"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5083-1174","authenticated-orcid":false,"given":"Marika","family":"Giuliano","sequence":"first","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-7415","authenticated-orcid":false,"given":"Eugenia","family":"Borgione","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5961-0362","authenticated-orcid":false,"given":"Mariangela","family":"Lo Giudice","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2958-2927","authenticated-orcid":false,"given":"Francesco Domenico","family":"Di Blasi","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3310-782X","authenticated-orcid":false,"given":"Sandro","family":"Santa Paola","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-9692","authenticated-orcid":false,"given":"Girolamo Aurelio","family":"Vitello","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0414-1359","authenticated-orcid":false,"given":"Maurizio","family":"Elia","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"},{"name":"Department of Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Russo","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-0683","authenticated-orcid":false,"given":"Corrado","family":"Romano","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"},{"name":"Section of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5901-0041","authenticated-orcid":false,"given":"Carmela","family":"Scuderi","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wydrych, A., Paku\u0142a, B., Janikiewicz, J., Dobosz, A.M., Jakubek-Olszewska, P., Skowro\u0144ska, M., Kurkowska-Jastrz\u0119bska, I., Cwyl, M., Popielarz, M., and Pinton, P. 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Magn. Reson. Imaging"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/1008\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:33:03Z","timestamp":1760034783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/1008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,26]]},"references-count":21,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["genes16091008"],"URL":"https:\/\/doi.org\/10.3390\/genes16091008","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,26]]}}}