{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T16:15:09Z","timestamp":1767197709128,"version":"3.48.0"},"reference-count":71,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pathogenic variants in the PAK1 gene are linked to neurodevelopmental and neurodegenerative disorders by disrupting neuronal signaling and function. Despite increasing recognition, the mechanisms underlying these conditions remain incompletely understood, limiting therapeutic options. Here, we report a novel de novo PAK1 variant, c.396C&gt;A (p.Asn132Lys), in a 5-year-old girl with Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). The patient presented with mild intellectual disability, delayed speech, macrocephaly, hypotonia, gait ataxia, autism-like behaviors, and focal epileptiform activity. Trio exome sequencing confirmed the variant as likely pathogenic, absent in her parents and population databases. This finding expands the phenotypic spectrum of PAK1-related disorders and underscores the critical role of the autoinhibitory domain in neurodevelopment. In addition, we performed a comprehensive literature review of PAK1 variants affecting both the autoregulatory and kinase domains, summarizing associated clinical features and pathogenic mechanisms. Our study highlights the importance of identifying PAK1 pathogenic variants for accurate diagnosis, refined genotype-phenotype correlations, and the development of potential targeted therapeutic strategies. By integrating novel case data with existing literature, this work advances understanding of PAK1-related neurodevelopmental disorders and supports the application of genetic analysis in rare pediatric NDD cases.<\/jats:p>","DOI":"10.3390\/ijms27010439","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T16:08:00Z","timestamp":1767197280000},"page":"439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PAK1 (p21-Activated Kinase 1) and Its Role in Neurodevelopmental Disorders\u2014New Case Report and a Comprehensive Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3213-7330","authenticated-orcid":false,"given":"Natasza","family":"Blek","sequence":"first","affiliation":[{"name":"Institute of Clinical Sciences, Maria Sklodowska-Curie Medical Academy in Warsaw, Pl. \u017belaznej Bramy 10, 00-136 Warsaw, Poland"},{"name":"Neurosphera Epilepsy, Neurology and Psychiatry Centre, 02-829 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0094-2934","authenticated-orcid":false,"given":"Miko\u0142aj","family":"Pielas","sequence":"additional","affiliation":[{"name":"Neurosphera Epilepsy, Neurology and Psychiatry Centre, 02-829 Warsaw, Poland"},{"name":"Department of Neurology and Epileptology, The Children\u2019s Memorial Health Institute, 04-730 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9875-7209","authenticated-orcid":false,"given":"Volodymyr","family":"Kharytonov","sequence":"additional","affiliation":[{"name":"Neurosphera Epilepsy, Neurology and Psychiatry Centre, 02-829 Warsaw, Poland"},{"name":"Clinical Hospital \u201cPsychiatry\u201d, 04080 Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-2593","authenticated-orcid":false,"given":"Karolina","family":"Rutkowska","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6936-9645","authenticated-orcid":false,"given":"Joanna","family":"Rusecka","sequence":"additional","affiliation":[{"name":"Institute of Outcomes Research, Maria Sklodowska-Curie Medical Academy in Warsaw, Pl. \u017belaznej Bramy 10, 00-136 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0539-0680","authenticated-orcid":false,"given":"S\u0142awomir","family":"Lewicki","sequence":"additional","affiliation":[{"name":"Institute of Outcomes Research, Maria Sklodowska-Curie Medical Academy in Warsaw, Pl. \u017belaznej Bramy 10, 00-136 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-5526","authenticated-orcid":false,"given":"Rafa\u0142","family":"P\u0142oski","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Zwoli\u0144ski","sequence":"additional","affiliation":[{"name":"Neurosphera Epilepsy, Neurology and Psychiatry Centre, 02-829 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.31887\/DCNS.2020.22.1\/macrocq","article-title":"Neurodevelopmental Disorders-the History and Future of a Diagnostic Concept","volume":"22","author":"Crocq","year":"2020","journal-title":"Dialogues Clin. 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