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Central nervous system: Paediatric and neurodevelopmental disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Other neurodegenerative disorders must be carefully excluded before the diagnosis is made, especially if the diagnosis has not been confirmed through finding a pathogenic MECP2 mutation. Rett syndrome may be confused clinically with Angelman syndrome, especially if the early history is not available, and some other Rett-like and Angelman-like disorders may also have overlapping clinical features. CDKL5-related disease causes a developmental disturbance with microcephaly, autistic behaviours and (often) a severe epileptic disorder. The epilepsy typically has onset within the first 6 months, may cause infantile spasms and, in the long term, is often resistant to treatment. Mutations in FOXG1, or deletions of chromosome 9 including or adjacent to the gene and recognised on aCGH, cause ‘congenital-onset Rett syndrome’. This misnomer (it really is a contradiction in terms, as the early development of girls with Rett syndrome must, by definition, at least appear to have been normal) has many similarities to Rett syndrome except that there is no period of normal early development and it affects boys and girls equally.
Rett Syndrome around the world
Published in Rosa Angela Fabio, Tindara Caprì, Gabriella Martino, Understanding Rett Syndrome, 2019
Rosa Angela Fabio, Tindara Caprì, Gabriella Martino
A large amount of work has been performed by EuroRETT laboratories to understand neuronal dysfunction caused by MeCP2, CDKL5, or FOXG1 dysfunction. Alteration of the stability of microtubules and of neuronal trafficking was found, together with deficits of chromatin architecture, neuronal excitability, and morphology, or abnormal micro-RNA regulations in MeCP2deficient cells or tissues. Two EuroRETT laboratories performed in-depth studies of CDKL5 function, while others developed new mouse models.
Learnings in developmental and epileptic encephalopathies: what do we know?
Published in Expert Review of Neurotherapeutics, 2023
Martina Giorgia Perinelli, Antonella Riva, Elisabetta Amadori, Roberta Follo, Pasquale Striano
One study [34] included 108 females and 16 males whose data were collected from the International CDKL5 Disorder Database. Nearly a quarter of females could walk ten steps and sit on the floor. Most females could pick up a large object compared to males. CDKL5-DEE patients have difficulties with language features in both receiving and expressing domains. These symptoms are associated with neuro-developmental delay and cortical visual impairments (CVI). The development of CVI is one of the main characteristics impacting these patients. Different studies demonstrate that CVI can be a biomarker and predictive factor for developmental delays [35,36]. Moreover, females communicate using a wide variety of gestures while males use other forms of non-verbal communication systems [34]. Szafranski and collaborators [37] also proposed that learning difficulties, hyperactivity and autistic traits, developmental delays, and macrocephaly are some manifestations of increased CDKL5 dosage which perturbed synaptic plasticity and neuronal development by the global output of the CDKL5 kinase’s interactions with its substrates.
Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2016–2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Carlos Roca, Nuria E. Campillo
GSK-3 is still a key target in a great amount of diseases. In this sense, the search of patents during the period of 2016–2019 has allowed to identify different new therapeutic uses. Cyclin-dependent kinase-like 5 (CDKL5) disorder is a neurodevelopment disease characterized by epileptic seizures, development delay and intellectual disability. Fuchs et al. showed an increased activity of GSK-3β, using a Cdkl5 knockout (KO) mouse model together with the associated defects of the disorder [52]. Treatment with Tideglusib (Figure 1) during the juvenile period improved hippocampal development and hippocampus-dependent behaviors in Cdkl5 KO mice. Ciani et al. from Alma Mater Studiorum of U. di Bologna claims the use of Tideglusib as treatment of CDKL5 disorders [53].
Epilepsy: key experimental therapeutics in early clinical development
Published in Expert Opinion on Investigational Drugs, 2020
Claude Steriade, Jacqueline French, Orrin Devinsky
Ganaxolone is an analog of the neurosteroid allopregnanolone. It modulates GABAA receptors [11], and has efficacy in multiple epilepsy models, but can exacerbate seizures in absence seizure models [11,12]. Focal epilepsy studies showed good tolerability but no significant reduction in seizure frequency [13]. Ganaxolone development has switched to studies of genetic epileptic encephalopathies, with phase II studies underway in children with protocadherin 19 (PCDH19) and CDKL5 deficiency disorder syndromes [14]. An initial open-label phase II study of PCDH19 deficiency subjects showed a 25% median seizure reduction. A post hoc analysis stratifying subjects according to baseline allopregnanolone-sulfate levels (Allo-S) revealed that high Allo-S levels predicted lack of response, and as a result a future phase III study in PCDH19 deficiency disorder will focus on patients with low Allo-S levels [15]. A phase II study of children with CDKL5 deficiency disorder found a 43% median seizure reduction, supporting advancement to a phase III trial [16].