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The disorder manifests primarily as developmental epileptic encephalopathy, with associated neurological phenotypes, such as hypotonia, movement disorders, visual impairment, and gastrointestinal issues. Its prevalence is estimated at 1 in 40,000\u201360,000 live births, and it is more prevalent in females due to the lethality of germline mutations in males during fetal development. This Italian multi-center observational study focused on 34 patients with CDKL5-related epileptic encephalopathy, aiming to enhance the understanding of the clinical and molecular aspects of CDD. The study, conducted across 14 pediatric neurology tertiary care centers in Italy, covered various aspects, including phenotypic presentations, seizure types, EEG patterns, treatments, neuroimaging findings, severity of psychomotor delay, and variant-phenotype correlations. The results highlighted the heterogeneity of seizure patterns, with hypermotor-tonic-spasms sequence seizures (HTSS) noted in 17.6% of patients. The study revealed a lack of clear genotype\u2013phenotype correlation within the cohort. The presence of HTSS or HTSS-like at onset resulted a negative prognostic factor for the presence of daily seizures at long-term follow-up in CDD patients. Despite extensive polypharmacotherapy, including medications such as valproic acid, clobazam, cannabidiol, and others, sustained seizure freedom proved elusive, affirming the inherent drug-resistant nature of CDD. The findings underscored the need for further research to explore response rates to different treatments and the potential role of non-pharmacological interventions in managing this challenging disorder.<\/jats:p>","DOI":"10.1007\/s00415-024-12421-1","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T12:02:09Z","timestamp":1718366529000},"page":"5368-5377","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy"],"prefix":"10.1007","volume":"271","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2302-1029","authenticated-orcid":false,"given":"Giovanni Battista","family":"Dell\u2019Isola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Fattorusso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Pisani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Mastrangelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duccio Maria","family":"Cordelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Pavone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Parisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Ferretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Felicia","family":"Operto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Elia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Carotenuto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Pruna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Matricardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Spezia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Spalice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Scorrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Savasta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Prontera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Di Cara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Fruttini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Salpietro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Verrotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,14]]},"reference":[{"key":"12421_CR1","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.pediatrneurol.2019.02.015","volume":"97","author":"HE Olson","year":"2019","unstructured":"Olson HE, Demarest ST, Pestana-Knight EM et al (2019) Cyclin-dependent kinase-like 5 deficiency disorder: clinical review. 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