CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy

Giovanni Battista Dell'Isola¹, Antonella Fattorusso², Francesco Pisani³, Mario Mastrangelo⁴, Duccio Maria Cordelli⁵, Piero Pavone⁶, Pasquale Parisi⁷, Alessandro Ferretti⁷, Francesca Felicia Operto^{8

9}, Maurizio Elia¹⁰, Marco Carotenuto¹¹, Dario Pruna¹², Sara Matricardi¹³, Elisabetta Spezia¹⁴, Alberto Spalice¹⁵, Giovanna Scorrano¹⁶, Salvatore Savasta¹⁷, Paolo Prontera¹⁸, Giuseppe Di Cara¹, Daniela Fruttini¹⁹, Vincenzo Salpietro^{16

20}, Pasquale Striano^{21

22}, Alberto Verrotti¹

Affiliations

¹ Department of Pediatrics, University of Perugia, Perugia, Italy.
² Department of Pediatrics, University of Perugia, Perugia, Italy. antonella.fattorusso@ospedale.perugia.it.
³ Child Neurology and Psychiatry Unit, Department of Human Neurosciences, Sapienza University of Rome, 00185, Rome, Italy.
⁴ Department of Women/Child Health and Urological Science, Sapienza University of Rome, Rome, Italy.
⁵ UOC Neuropsychiatry of the Pediatric Age, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
⁶ Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
⁷ Pediatrics Unit, Neuroscience, Mental Health and Sense Organs (NESMOS) Department, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189, Rome, Italy.
⁸ Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.
⁹ Department of Science of Health, School of Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy.
¹⁰ Unit of Neurology and Clinical Neurophysiopathology, Oasi Research Institute-IRCCS, Troina, Italy.
¹¹ Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, Università degli studi della Campania 'Luigi Vanvitelli', Naples, Italy.
¹² Child Neurology and Epileptology Unit, Paediatric Department, ARNAS Brotzu, Cagliari, Italy.
¹³ Department of Pediatrics, University of Chieti, Chieti, Italy.
¹⁴ Pediatric Neurology, Azienda Policlinico Modena, Modena, Italy.
¹⁵ Department of Pediatrics, "Sapienza" University of Rome, Rome, Italy.
¹⁶ Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
¹⁷ Pediatric Clinic and Rare Diseases, Microcythemic Pediatric Hospital "A. Cao", University of Cagliari, Cagliari, Italy.
¹⁸ Medical Genetics Unit, Hospital Santa Maria Della Misericordia, Perugia, Italy.
¹⁹ Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
²⁰ Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, UK.
²¹ Giannina Gaslini Institute, Scientific Institute for Research and Health Care, Genoa, Italy.
²² Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

PMID: 38874638
PMCID: PMC11319418
DOI: 10.1007/s00415-024-12421-1

Observational Study

CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy

Giovanni Battista Dell'Isola et al. J Neurol. 2024 Aug.

. 2024 Aug;271(8):5368-5377.

doi: 10.1007/s00415-024-12421-1. Epub 2024 Jun 14.

Authors

Affiliations

¹ Department of Pediatrics, University of Perugia, Perugia, Italy.
² Department of Pediatrics, University of Perugia, Perugia, Italy. antonella.fattorusso@ospedale.perugia.it.
³ Child Neurology and Psychiatry Unit, Department of Human Neurosciences, Sapienza University of Rome, 00185, Rome, Italy.
⁴ Department of Women/Child Health and Urological Science, Sapienza University of Rome, Rome, Italy.
⁵ UOC Neuropsychiatry of the Pediatric Age, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
⁶ Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
⁷ Pediatrics Unit, Neuroscience, Mental Health and Sense Organs (NESMOS) Department, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189, Rome, Italy.
⁸ Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.
⁹ Department of Science of Health, School of Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy.
¹⁰ Unit of Neurology and Clinical Neurophysiopathology, Oasi Research Institute-IRCCS, Troina, Italy.
¹¹ Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, Università degli studi della Campania 'Luigi Vanvitelli', Naples, Italy.
¹² Child Neurology and Epileptology Unit, Paediatric Department, ARNAS Brotzu, Cagliari, Italy.
¹³ Department of Pediatrics, University of Chieti, Chieti, Italy.
¹⁴ Pediatric Neurology, Azienda Policlinico Modena, Modena, Italy.
¹⁵ Department of Pediatrics, "Sapienza" University of Rome, Rome, Italy.
¹⁶ Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
¹⁷ Pediatric Clinic and Rare Diseases, Microcythemic Pediatric Hospital "A. Cao", University of Cagliari, Cagliari, Italy.
¹⁸ Medical Genetics Unit, Hospital Santa Maria Della Misericordia, Perugia, Italy.
¹⁹ Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
²⁰ Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, UK.
²¹ Giannina Gaslini Institute, Scientific Institute for Research and Health Care, Genoa, Italy.
²² Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

PMID: 38874638
PMCID: PMC11319418
DOI: 10.1007/s00415-024-12421-1

Erratum in

Correction to: CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy.
Dell'Isola GB, Fattorusso A, Pisani F, Mastrangelo M, Cordelli DM, Pavone P, Parisi P, Ferretti A, Operto FF, Elia M, Carotenuto M, Pruna D, Matricardi S, Spezia E, Spalice A, Scorrano G, Savasta S, Prontera P, Di Cara G, Fruttini D, Salpietro V, Striano P, Verrotti A. Dell'Isola GB, et al. J Neurol. 2024 Dec;271(12):7648-7649. doi: 10.1007/s00415-024-12653-1. J Neurol. 2024. PMID: 39476250 Free PMC article. No abstract available.

Abstract

CDKL5 deficiency disorder (CDD) is a complex clinical condition resulting from non-functional or absent CDKL5 protein, a serine-threonine kinase pivotal for neural maturation and synaptogenesis. 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 40,000-60,000 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-phenotype 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.

Keywords: Antiseizure medication; CDKL5 deficiency disorder; Cortical blindness; EEG; Hypermotor-tonic-spasms sequence seizures.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflict of interest to declare.

References

1. Olson HE, Demarest ST, Pestana-Knight EM et al (2019) Cyclin-dependent kinase-like 5 deficiency disorder: clinical review. Pediatr Neurol 97:18–25 - PMC - PubMed
1. Fehr S, Wong K, Chin R et al (2016) Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology 87:2206–2213 - PubMed
1. Fehr S, Downs J, Ho G et al (2016) Functional abilities in children and adults with the CDKL5 disorder. Am J Med Genet A 170:2860–2869 - PubMed
1. Hagebeuk EE, Marcelis CL, Alders M, Kaspers A, deWeerd AW (2015) Two siblings with a CDKL5 mutation: genotype and phenotype evaluation. J Child Neurol 30:1515–1519 - PubMed
1. Mangatt M, Wong K, Anderson B, Epstein A, Hodgetts S, Leonard H, Downs J (2016) Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis 11:39 - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Supplementary concepts

Actions

LinkOut - more resources

Full Text Sources
- PubMed Central
- Springer

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy

Affiliations

CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources