Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice

Mazziotti, Raffaele; Lupori, Leonardo; Sagona, Giulia; Gennaro, Mariangela; Sala, Grazia Della; Putignano, Elena; Pizzorusso, Tommaso

doi:10.1093/hmg/ddx119

Cited by 54 publications

(83 citation statements)

References 41 publications

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“…Because of their potential association, CVI and developmental impairment deserve consideration as outcomes in future clinical trials that specifically target epilepsy. Furthermore, this may have utility in preclinical models creating parity between preclinical models and meaningful disease outcomes in patients . More detailed future exploration of this relationship is important, including evaluation of this population with visual evoked potentials and a more detailed evaluation of the severity of CVI.…”

Section: Discussionmentioning

confidence: 99%

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

et al. 2019

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Objective The cyclin‐dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure‐free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. Methods This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. Results Ninety‐two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0‐11.0). Eighty‐one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor‐tonic‐spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty‐three percent of patients experienced a seizure‐free period ranging from 1 to >12 months, but only 6% were still seizure‐free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. Significance The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.

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Section: Discussionmentioning

confidence: 99%

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

et al. 2019

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“…To clarify the role of CDKL5 in brain development and in the etiology of CDKL5 disorder, we and others generated and characterized constitutive Cdkl5 knockout (KO) mouse models (Wang et al ., ; Amendola et al ., ; Okuda et al ., ). Although deficiency of Cdkl5 in mice does not lead to spontaneous seizures, Cdkl5 KO mice show several behavioral abnormalities that resemble CDKL5‐like phenotypes, such as hind‐limb clasping, hypoactivity, impaired learning and memory, and visual attention/acuity deficits (Wang et al ., ; Amendola et al ., ; Fuchs et al ., , ; Mazziotti et al ., ). These defects are associated with neuroanatomical alterations, such as dendritic hypotrophy and impairment in neural circuit communication, indicating that CDKL5 loss of function severely impairs brain development (Amendola et al ., ; Fuchs et al ., ; Della Sala et al ., ; Pizzo et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Treatment with the GSK3‐beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice

Fuchs

Fustini

Trazzi

et al. 2018

Eur J of Neuroscience

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Cyclin-dependent kinase-like 5 (CDKL5) disorder is a severe neurodevelopmental disorder characterized by early-onset epileptic seizures, severe developmental delay, and intellectual disability. To date, no effective pharmacological treatments are available to improve the neurological phenotype that is due to mutations in the CDKL5 gene. Murine models of CDKL5 disorder have recently been generated, making the preclinical testing of pharmacological interventions possible. Using a Cdkl5 knockout (KO) mouse model, we recently demonstrated that deficiency of Cdkl5 causes defects in postnatal hippocampal development and hippocampus-dependent learning and memory. These defects were accompanied by an increased activity of GSK3β, an important inhibitory regulator of many neuronal functions. Pharmacological inhibition of GSK3β activity was able to recover hippocampal defects and cognitive performance in juvenile Cdkl5 KO mice, suggesting that GSK3β inhibitors might be a potential therapeutic option for CDKL5 disorder. As GSK3β inhibitors have been shown to have differential medication responses in young people and adults, this study was designed to examine whether GSK3β is a possible therapeutic target both in juvenile and in adult CDKL5 patients. We found that treatment with the GSK3β inhibitor Tideglusib during the juvenile period improved hippocampal development and hippocampus-dependent behaviors in Cdkl5 KO mice, while treatment later on in adulthood had no positive effects. These results suggest that pharmacological interventions aimed at normalizing impaired GSK3β activity might have different age-dependent outcomes in CDKL5 disorder. This is of utmost importance in the development of therapeutic approaches in CDKL5 patients and in the design of rational clinical trials.

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“…In CDD individuals, defective sensory processing in primary cortical areas is thought to be involved in the loss of purposeful hands movement and the progressive appearance of dyspraxia or apraxia, until walking is completely prevented (Bahi-Buisson and Bienvenu, 2011). Sensory defects such visual and auditory impairments were recently revealed in CDD mouse models (Wang et al, 2012;Amendola et al, 2014;Trazzi et al, 2016;Mazziotti et al, 2017). Moreover, CDD mouse models exhibit autistic-like features such as profoundly altered social interaction (Wang et al, 2012;Jhang et al, 2017;Yennewar et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…CDKL5 mouse models offer a valuable opportunity to assess the cellular and molecular mechanisms underlying abnormal computation of sensory inputs in CDD (Wang et al, 2012;Amendola et al, 2014;Trazzi et al, 2016;Mazziotti et al, 2017). CDKL5 is a serine/threonine kinase that is highly expressed in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder

et al. 2020

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Highlights • CDKL5 deficiency disrupts the synaptic organization of thalamo-cortical (TC) and cortico-cortical (CC) connections in the barrel cortex (BC) • CDKL5 deficiency leads to BC hypoactivation • CDKL5 deficiency causes atypical whisker-mediated behavioural responses • CDKL5 deficiency does not prevent TC circuitry to undergo experience-dependent structural plasticity • Enhanced sensory stimulation restores cortical connectivity, BC activation levels and whisker-related behavioural responses ABSTRACT Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental syndrome where patients exhibit early-onset seizures, intellectual disability, stereotypies, limited or absent speech, autism-like symptoms and sensory impairments. Mounting evidences indicate that disrupted sensory perception and processing represent core signs also in mouse models of CDD, however we have very limited knowledge on their underlying causes. In this study, we investigated how CDKL5 deficiency affects synaptic organization and experience-dependent plasticity in the thalamo-cortical (TC) pathway carrying whisker-related tactile information to the barrel cortex (BC). By using synapse-specific antibodies and confocal microscopy, we found that Cdkl5-KO mice display a lower density of TC synapses in the BC that was paralleled by a reduction of cortico-cortical (CC) connections compared to wild-type mice. These synaptic defects were accompanied by reduced BC activation, as shown by a robust decrease of c-fos immunostaining, and atypical behavioural responses to whisker-mediated tactile stimulation. Notably, a two-day paradigm of enriched whisker stimulation rescued both number and configuration of TC and CC synapses in Cdkl5-KO mice, and restored cortical activity as well as behavioural responses to control levels. Our findings disclose an important role of CDKL5 in controlling the organization and experience-induced modifications of excitatory connections in the BC and indicate how mutations of CDKL5 produce failures in higher-order processing of somatosensory stimuli.

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Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice

Cited by 54 publications

References 41 publications

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

Treatment with the GSK3‐beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice

Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder

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