RARE DISEASE
CDKL5-deficiency disorder
CDKL5-deficiency disorder
CDKL5-deficiency disorder
Synonyms: CDD
Synonyms: CDD
Synonyms: CDD
Drug discovery
6
drugs
With orphan designations
Overview
CDKL5 deficiency disorder (CDD) is a rare X-linked neurodevelopmental condition caused by pathogenic variants in the CDKL5 gene, characterized by early-onset drug-resistant epilepsy (beginning within weeks of birth) and severe global developmental delays. Key features include hypotonia, cortical visual impairment, motor disabilities, and stereotypic hand movements. Over 90% of patients experience daily seizures refractory to multiple antiseizure medications, with comorbidities including gastrointestinal dysfunction, sleep disturbances, and respiratory issues [1][2][6][7][12].
Burden
Median 5-30 seizures/week, requiring lifelong caregiver support. >75% require enteral feeding due to dysphagia, 40% have suboptimal growth. Hospitalization rates exceed general epilepsy populations, with 22-26% experiencing aspiration pneumonia [4][5][7][9][17]. Caregivers report significant impacts on mental health and employment [5][7].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
178 drug discovery papers about CDKL5-deficiency disorder, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
178 drug discovery papers about CDKL5-deficiency disorder, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-24 | Microtubule-associated protein 1S phosphorylation regulates dynein-driven transport in the brain and synaptogenesis in neurons.
Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine kinase enriched in the mammalian brain whose loss of function causes a severe developmental and epileptic encephalopathy named CDKL5 Deficiency Disorder. We previously showed that CDKL5 phosphorylates the microtubule-associated protein MAP1S, but how this regulates microtubule-dependent functions is not well understood. To address this question, we generated MAP1S phosphomutant mice in which the CDKL5 phosphorylation sites S786 and S812 were mutated to alanine (MAP1S S786/812A; MAP1S SA). Using a microtubule cosedimentation assay, we found that dynein binding to microtubules was reduced in MAP1S SA and CDKL5 knockout (KO) brain lysates, and time-lapse imaging showed impaired dynein motility in dendrites from both genotypes. MAP1S SA mice also exhibited reduced AMPA receptor transport, dendritic spine density, and excitatory synapses, accompanied by anxiety-like behavior and motor, social, and memory deficits relevant to CDD. Mechanistically, MAP1S SA and CDKL5 KO neurons showed increased microtubule stability and reduced tubulin tyrosination, consistent with excessive MAP1S-mediated stabilization. Restoring tubulin tyrosination by expressing tubulin-tyrosine ligase rescued dynein transport defects. Together, these findings identify MAP1S phosphorylation as a critical regulator of microtubule dynamics and dynein-dependent transport.
2026-05-26 | From Sea to Therapy: Development and Analytical Control of Recombinant Human CDKL5 Production in the Marine Bacterium Pseudoalteromonas haloplanktis TAC125.
Marine bacteria are increasingly explored as alternative microbial platforms for the production of high-value biopharmaceuticals. In this study, we investigate the Antarctic marine bacterium Pseudoalteromonas haloplanktis TAC125 (PhTAC125), an unconventional host capable of yielding soluble and biologically active human cyclin-dependent kinase-like 5 (hCDKL5). This serine/threonine kinase plays a crucial role in neuronal development, and its deficiency causes CDKL5 Deficiency Disorder, a severe and currently untreatable neurodevelopmental disease. Recombinant production of hCDKL5 is a prerequisite for the development of enzyme replacement therapy; however, current manufacturing processes remain insufficient for industrial translation, particularly in terms of product quality and functional consistency. To address these limitations, we developed dedicated analytical strategies: protein accumulation was quantified using a customised sandwich Enzyme-Linked Immunosorbent Assay (ELISA) designed to selectively detect full-length hCDKL5, while protein functionality was assessed by mass spectrometry-based quantification of autophosphorylation, a critical determinant of kinase activation. These complementary tools were applied to characterise hCDKL5 production under different growth conditions. Overall, this work establishes an integrated analytical framework aligned with a Quality by Design approach, enabling the simultaneous assessment of yield, structural integrity, and functional activation, and providing a robust basis for rational process optimisation towards scalable hCDKL5 manufacturing.
2025-07-18 | A Cross-Correction Gene Therapy Approach for CDKL5 Deficiency Disorder Improves the Pathological Phenotype of CDD Patient-Derived Cortical Organoids
Efficient delivery of biological material to the central nervous system (CNS) remains a key limitation of conventional gene therapies. Recently, we developed a novel strategy based on a secretable and cell-penetrating TATk-CDKL5 fused protein which enhances the brain biodistribution and the therapeutic efficiency of the gene therapy approach in a mouse model of CDKL5 Deficiency Disorder (CDD). Here, to compare the efficacy of the TATk-CDKL5 gene therapy with a conventional approach in correcting the CDD pathological phenotype, we employed cortical organoids generated from CDD patient-derived iPSCs as a human model of CDD. We found greater therapeutic efficacy of the recombinant TATk-CDKL5 protein compared to the CDKL5 protein alone in improving or ameliorating defects caused by the absence of CDKL5, such as abnormal hyperexcitability evaluated with microelectrode arrays (MEA). Interestingly, CDD cortical organoids exhibited reduced cell proliferation and increased neuronal cell death compared to control cortical organoids; defects that were only restored by the expression of the recombinant TATk-CDKL5 protein. These findings suggest the superior efficiency of a gene therapy based on a cross-correction approach for treating CDD.
2024-08-29 | CDKL5's role in microtubule-based transport and cognitive function
Abstract Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine kinase highly enriched in mammalian neurons. CDKL5 is located on the X-chromosome and its loss-of-function leads to a severe neurodevelopmental disorder called CDKL5 deficiency disorder (CDD). CDKL5 phosphorylates microtubule-associated protein MAP1S and regulates its binding to microtubules. How MAP1S phosphorylation affects microtubule function is not well understood. To address this question, we generated MAP1S phosphomutant mice, in which the CDKL5 phosphorylation sites S786 and S812 are mutated to Alanine (MAP1S S786/812A or MAP1S SA). Using a microtubule co-sedimentation assay, we showed that dynein binding to microtubules is severely reduced in CDKL5 knockout (KO) and MAP1S SA brains. Time-lapse imaging in primary neurons showed impaired dynein motility in both Cdkl5 KO and MAP1S SA. Dynein-driven cargo transport was affected in mutant neuron dendrites, including the delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We next studied tubulin tyrosination in Cdkl5 KO and MAP1S SA neurons and found that both mutants had a reduced tubulin tyrosination when compared to WT neurons. Since dynein-dynactin has a higher affinity for tyrosinated microtubules, we hypothesized that reduced tyrosination in MAP1S phosphomutant mice could be the mechanistic cause of impaired dynein motility. In support of this, we show that upon expression of tubulin tyrosine kinase TTL, we rescued dynein motility defects in MAP1S phosphomutant neurons. Hippocampal neurons derived from MAP1S SA mice revealed a significant reduction in spine density and synapses, and altered spine morphology. Finally, behavioral phenotyping of MAP1S phosphomutant mice showed increased anxiety, impaired motor performance, social and memory deficits, mirroring to some extent the clinical manifestations present in CDD patients. Our results reveal MAP1S phosphorylation to be an important contributor to dynein-mediated transport and synapse formation. Graphical abstract
2024-02-08 | Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder
Abstract Background Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer’s disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expressions, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD. Methods We used SH- CDKL5 -KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects. Results We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl 5 KO mice, resulting in limited behavioral benefit. Conclusions At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.
small molecules
2026-08-26 | Nationwide Survey of Association Between Fever and Epileptic Seizure in CDKL5 Deficiency Disorder Revealed Therapeutic Implications.
CDKL5 deficiency disorder (CDD) is a rare, severe developmental and epileptic encephalopathy. There is a pressing need to develop effective and sustainable therapeutic strategies. We aimed to investigate the causal association between febrile episodes and epileptic seizures for therapeutic implications in CDD patients. The study was a nationwide, cross-sectional survey on CDD patients in China (ClinicalTrials.gov, NCT06663163). Detailed phenotypic and genotypic data were collected through an online questionnaire with uploaded original medical records, genetic testing results, and peri-fever seizure diaries. The primary outcome was changes in epileptic seizure frequency during and post-fever phases compared to a 1-month pre-fever phase based on seizure diaries. Between October 2024 and December 2024, we received 131 questionnaires. Forty-seven questionnaires were removed after excluding duplicates and missing data. Ultimately, 84 eligible participants with complete uploads were included, from 26 of 34 (76.5%) province-level regions in China. Among these, 47 (56.0%) patients had significant decreased seizure frequency only during febrile episodes, and 27 (32.1%) patients with daily seizures achieved at least a seizure-free day. Notably, 20 patients (23.8%) exhibited post-fever seizure reduction: 12 (25.5%) for 3 days to 1 week, and 6 (12.8%) for more than 2 weeks (maximum > 40 days). The effect was independent of patients' clinical and genetic characteristics. Our findings, for the first time, revealed that fever-related seizure reduction is a distinctive and prevalent genotype-phenotype for CDD, thereby providing evidence for further fundamental research into the underlying mechanisms and offering potential clinical implications for seizure control in CDD.
2026-04-04 | nELAVL phosphorylation by CDKL5 regulates RNA metabolism and condensates communication to promote experience-dependent maturation of the visual cortex
Summary Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), an X-linked neurodevelopmental condition. Through a phosphoproteomic screen, we identified the neuron-specific nELAVL family of RNA-binding proteins as direct activity-dependent substrates of CDKL5. In support of this regulatory axis, single-nuclei transcriptomics of Cdkl5 knockout (KO) cortices revealed an enriched reduction in activity-dependent mRNAs. Mechanistically, we show that nELAVL proteins undergo phase separation to form biomolecular condensates, the size of which is gated by CDKL5 phosphorylation. Loss of CDKL5 leads to enlarged nELAVL condensates, which exhibit reduced binding affinity for the target mRNA Fos , resulting in its accelerated degradation. This disruption extends to inter-condensate communication: phosphodeficient nELAVL show diminished interaction with P-bodies, which themselves become enlarged in CDD mutant iNeurons. Functionally, the absence of nELAVL phosphorylation recapitulates the deficits in experience-dependent visual function observed in Cdkl5 KO mice. Our findings establish a critical molecular mechanism by which CDKL5-mediated phosphorylation governs mRNA metabolism by tuning the properties of nELAVL condensates and their communication with other biomolecular condensates, ultimately promoting experience-dependent maturation of the visual cortex.
2026-03-28 | Endocannabinoid Enhancement via MAGL Inhibition in CDKL5 Deficiency: Selective Cellular Benefits and Domain-Specific Functional Effects in Adult Cdkl5 KO Mice.
CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early disruptions of synaptic maturation and network stability, leading to persistent motor, cognitive, and behavioral impairments. Given the role of the endocannabinoid system in synaptic development, neuroinflammation, and neuronal resilience, we investigated whether the sustained enhancement of endogenous 2-arachidonoylglycerol (2-AG) signaling via monoacylglycerol lipase (MAGL) inhibition could mitigate key pathological features in adult Cdkl5 knockout (KO) mice. Using an intermittent 6-week treatment, the MAGL inhibitor JZL184 robustly increased plasma 2-AG levels, reduced MAGL protein levels, and activated CB1-AKT signaling without evidence of receptor desensitization. Despite this clear pharmacodynamic efficacy, behavioral effects were domain-specific: neither dose ameliorated core behavioral deficits, although the higher dose selectively reduced stereotypic jumping and modestly improved cue-dependent associative memory. At the cellular level, JZL184 induced biologically meaningful effects, partially restoring dendritic spine maturation in the primary somatosensory cortex and increasing neuronal survival in the vulnerable CA1 hippocampal region. In contrast, microglial responses were dose-dependent and divergent, with the lower dose exerting anti-inflammatory effects, while the higher dose increased cortical microglial density and Allograft Inflammatory Factor-1 (AIF-1) expression, suggesting engagement of compensatory or off-target mechanisms. Overall, these findings show that MAGL inhibition activates neuroprotective pathways and ameliorates select structural deficits in adult Cdkl5 KO mice, but is insufficient to produce broad behavioral recovery, highlighting the domain-specific effects of selective 2-AG enhancement via MAGL inhibition and the need for developmentally informed or multimodal therapeutic strategies in CDD.
2026-03-16 | Rescuing functional defects in a zebrafish model of CDKL5 deficiency disorder: Contribution to the identification of new therapeutic compounds
ABSTRACT Mutations in the CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental encephalopathy characterized by a broad range of symptoms, including early-onset seizures, profound motor impairment and dysmorphic facial features. Current treatment options remain limited and largely focus on seizure management, which is often challenging to control, underscoring the critical need for new effective therapies. To identify potential novel candidate molecules for the treatment of CDD, we performed the first in vivo drug screening using a cdkl5 mutant zebrafish model. Recapitulating key features of the human disorder, cdkl5 -/- larvae exhibit reduced locomotor behavior, providing a robust readout to assess therapeutic efficacy. By screening 170 compounds from MAPK Inhibitor and Histone Modification Libraries, both implicated in CDKL5 dysfunction, we identified 18 and 12 small molecules that partially or fully restored locomotor activity, respectively. Among these, fisetin, divalproex, resveratrol, and VX-702 were further evaluated for their capacity to rescue cdkl5 -/- craniofacial defects and altered gene expression. Fisetin demonstrated the most consistent phenotypic improvement, including partial restoration of craniofacial abnormalities and normalization of gene expression levels. Future research aimed at elucidating the molecular mechanisms underlying the observed rescue effects will be critical to understand their mode of action. Overall, our study demonstrates the utility of this rapid and scalable zebrafish-based screening approach for therapeutic discovery in CDD and identifies promising therapeutic molecules that warrant further validation in complementary preclinical systems.
2026-02-20 | Loss of cyclin-dependent kinase-like 5 results in susceptibility to audiogenic seizures in mice.
CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early-onset, treatment-resistant epilepsy. Mice lacking CDKL5 display several clinically relevant phenotypes, but spontaneous seizures are not consistently reported, and it is unknown if CDD model mice are susceptible to sensory stimulus-triggered seizures, a well-documented clinical feature of CDD. Here, we tested the hypothesis that CDKL5 deficiency confers susceptibility to audiogenic seizures (AGS). We exposed adult male Cdkl5 knockout, female heterozygous, and wildtype littermates (P80-217) to audiogenic challenges and, in a separate cohort, monitored for spontaneous seizures. Audiogenic stimulation triggered severe, lethal (80%) seizures in Cdkl5 knockout mice. In contrast, heterozygous mice were largely resistant to audiogenic stimulus (92% survival). These findings establish susceptibility to AGS as a highly penetrant phenotype in a CDD mouse model. Furthermore, spontaneous seizures were detected in a subset of Cdkl5 knockout mice during chronic video-EEG monitoring. AGS may provide a translationally relevant screen for investigating hyperexcitability and for evaluating potential therapeutics to prevent seizures in CDD. PLAIN LANGUAGE SUMMARY: CDKL5 deficiency disorder (CDD) is a severe genetic condition causing early-onset seizures. Mice with the same mutation are useful models but don't consistently have epilepsy. We tested if these mice in our lab are sensitive to sound-triggered seizures. We discovered that male CDD mice are highly vulnerable to sound, which triggered severe seizures in most of them. Female CDD mice and normal mice were resistant. This is the first report of sound-triggered seizures in a CDD model and provides a useful new method to study epilepsy in CDD and screen for antiseizure treatments.
gene therapies
2026-04-11 | Base editing restores CDKL5 expression and rescues neuronal deficits in a patient-derived model of CDKL5 deficiency disorder.
Cyclin-dependent kinase like 5 (CDKL5) deficiency disorder (CDD) is a rare monogenic neurodevelopmental disorder caused by pathogenic mutations in the CDKL5 gene, with approximately 50% of reported variants being point mutations. Base editing presents a promising therapeutic strategy to correct such mutations, restore endogenous CDKL5 expression, and pave the way for novel treatments for CDD. To assess the therapeutic potential of base editing for CDD, we applied adenine base editing (ABE) to correct a CDKL5-R550* (c.1648 C > T) mutation in induced pluripotent stem cells (iPSCs) derived from a CDD patient. Isogenic control, CDKL5-R550* mutant, and ABE-corrected iPSCs were differentiated into neurons and the restoration of CDKL5-related and functional recovery were assessed. In this study, we demonstrated that ABE successfully restored CDKL5 protein levels and CDKL5-dependent signalling pathways in edited iPSC-differentiated neurons to levels comparable to the isogenic control. Morphological deficits, and genes expression were normalized in the ABE-corrected neurons. This study provides evidence that ABE can precisely correct pathogenic mutation and functionally rescue some CDD-associated neuronal phenotypes in patient-derived cells, supporting its potential as a valuable gene therapy for CDD. Moreover, these findings underscore the broader applicability of base editing for treating other monogenic neurodevelopmental disorders caused by point mutations.
2026-03-09 | An Open‐Source Pipeline for Calcium Imaging and All‐Optical Physiology in Human Stem Cell‐Derived Neurons
High-throughput, single-cell resolution profiling of neuronal activity is critical for understanding brain function and modeling neurological disorders, yet existing approaches are often limited by scalability and manual workflows. Here, we present an open-source, scalable imaging and analysis platform that integrates optogenetic stimulation, calcium imaging, automated acquisition, single-cell and network analyses. The platform enables robust quantification of spontaneous and evoked neuronal activity across hundreds of human stem cell-derived neurons over multiple timepoints, supporting functional phenotyping at both cellular and network levels. We demonstrate the versatility of the platform across multiple disease-relevant contexts, including models of CDKL5 Deficiency, SSADH Deficiency, and tuberous sclerosis complex (TSC). Additionally, we generate CRISPR-Cas9 knock-in hiPSC lines expressing GCaMP6s and demonstrate partial reversal through pharmacological intervention in TSC. By linking single-cell dynamics to network-level measures, this platform provides a generalizable framework for scalable functional phenotyping and high-throughput screening in human neuronal models.
2026-02-01 | Developmental and Epileptic Encephalopathy due to Cyclin-Dependent Kinase-Like 5 Deficiency: A Single-Center Experience Across Sex Differences.
The cyclin-dependent kinase-like 5 deficiency disorder (CDD) is an ultrarare X-linked disorder causing early-onset epileptic encephalopathy and severe developmental deficits. Few studies exist on its electroclinical features, outcomes, sex differences, and neuroimaging, particularly from India. This study aims to describe the electroclinical syndrome, developmental profile, radiological findings, and outcomes in patients with CDD and to compare these factors between males and females. This is a hospital-based observational study of patients diagnosed with CDD identified from a prospectively maintained registry of children with developmental and epileptic encephalopathy. Data on demographics, seizure types, epilepsy syndromes, antiseizure medications, electroencephalography findings, developmental assessments, genetic characteristics, brain magnetic resonance imaging, and outcomes were collected. We included 12 patients with pathogenic (9) and likely pathogenic (3) variants in cyclin-dependent kinase-like 5 (CDKL5), among whom seven were female. The mean age at onset of seizures was 5.95 ± 5.56 months and was higher for males than females (8.6 ± 7.23 vs 3.19 ± 2.47). The most common seizure types at onset were tonic seizures in 6 (50%) children and epileptic spasms in 4 (33.3%). Lennox-Gastaut syndrome and West syndrome were the most frequent epilepsy syndromes. The median number of seizures per person was 2.9, and the median number of antiseizure medications used was 6 during their lifetime. Magnetic resonance imaging revealed cerebral volume loss in 7 children and white matter lesions in 6. Severe developmental deficits, a Rett-like phenotype, and cortical visual impairment were observed in three-fourths of the children, and regression of milestones occurred in two-thirds. Repetitive motor behavior (P 0.0455) and regression (P 0.0101) were more common in females. CDD causes refractory epilepsy and severe developmental deficits irrespective of the sex of the patient, variant type, and treatment.
2026-01-14 | Baseline characteristics and feasibility of clinical outcome measures in CDKL5 deficiency disorder: The CANDID observational study.
CDKL5 deficiency disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy caused by loss-of-function variants in the CDKL5 gene. Preclinical experiments using enzyme replacement or gene therapies show promise and could be transformative therapies. This precompetitive consortium sought to harmonize nonseizure clinical endpoint selection for efficacy trials. Clinical Assessment of Neurodevelopmental Measures in CDD (CANDID) is an ongoing study evaluating the feasibility and suitability of neurocognitive tests and functioning scales in CDD patients. CANDID is a 3-year, longitudinal, noninterventional global study involving children and adults with CDD. On-site and remote visits include clinical, behavioral, developmental, and quality of life assessments. We enrolled 112 patients (111 included in analyses); mean age = 8.3 years (range <1-28); 93% female; 10 participants were ≥18 years old. In the first 28 days, 82% had >16 seizures; six were seizure-free. Median seizure onset was at 1.5 months (range = 0-66). Patients used an average of 2.6 antiseizure medications at baseline. The most frequent comorbidities included gastrointestinal hypomotility, muscle tone abnormalities, and sleep disorders. Gross Motor Function Measure-88 (GMFM-88) scores indicated a floor effect in crawling, standing, and walking across all ages. Vineland-3 and Bayley-4 scores could be derived in most, with receptive language, interpersonal relationships, and fine and gross motor scores increasing with age. Bruni sleep questionnaire identified sleep initiation, sleep-awake transition, and excessive somnolence as the most disrupted components across all age groups. The mean Quality of Life Inventory-Disability total scores ranged from 53% to 64%, the independence domain being the most impacted. The scales in the CANDID study capture disease-related deficits and phenotype variability in CDD. Floor effects in subdomains aligned with disease severity. The GMFM-88 lacks granularity, and its operational limitations make it unsuitable for CDD trials. Baseline analyses demonstrate the feasibility and potential value of most selected scales, supporting their use in optimizing trial design and endpoint selection for future CDD clinical trials.
2026-01-01 | P221: Loss of the single fly ortholog of the human CDKL1-5, Cdkl, causes seizures, neuronal degeneration, mitochondrial defects, and sleep disturbances
The CDKL (cyclin-dependent kinase-like) genes consisting of CDKL1-5 encode a conserved family of protein kinases. The genes are expressed in a variety of tissues, including the nervous system. We have recently identified de novo variants in CDKL1 and CDKL2 in seven individuals. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. In addition, pathogenic variants in CDKL5 have already been linked to CDKL5 deficiency disorder (CDD) which is a distinct epileptic encephalopathy.
oligonucleotides
2024-04-01 | Gut microbiota profile in CDKL5 deficiency disorder patients.
CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. Patients with CDD frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in individuals with CDD (n = 17) and their healthy relatives (n = 17). Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. In particular, at genus level, CDD microbial communities were characterized by an increase in the relative abundance of Clostridium_AQ, Eggerthella, Streptococcus, and Erysipelatoclostridium, and by a decrease in Eubacterium, Dorea, Odoribacter, Intestinomonas, and Gemmiger, pointing toward a dysbiotic profile. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features and ambulation capacity. Enrichment in Lachnoclostridium and Enterobacteriaceae was observed in the microbiota of patients with more severe GI symptoms, while Clostridiaceae, Peptostreptococcaceae, Coriobacteriaceae, Erysipelotrichaceae, Christensenellaceae, and Ruminococcaceae were enriched in patients experiencing daily epileptic seizures. Our findings suggest a potential connection between CDD, microbiota and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in subjects with CDD. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of patients with CDD.
proteins
2026-09-24 | Microtubule-associated protein 1S phosphorylation regulates dynein-driven transport in the brain and synaptogenesis in neurons.
Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine kinase enriched in the mammalian brain whose loss of function causes a severe developmental and epileptic encephalopathy named CDKL5 Deficiency Disorder. We previously showed that CDKL5 phosphorylates the microtubule-associated protein MAP1S, but how this regulates microtubule-dependent functions is not well understood. To address this question, we generated MAP1S phosphomutant mice in which the CDKL5 phosphorylation sites S786 and S812 were mutated to alanine (MAP1S S786/812A; MAP1S SA). Using a microtubule cosedimentation assay, we found that dynein binding to microtubules was reduced in MAP1S SA and CDKL5 knockout (KO) brain lysates, and time-lapse imaging showed impaired dynein motility in dendrites from both genotypes. MAP1S SA mice also exhibited reduced AMPA receptor transport, dendritic spine density, and excitatory synapses, accompanied by anxiety-like behavior and motor, social, and memory deficits relevant to CDD. Mechanistically, MAP1S SA and CDKL5 KO neurons showed increased microtubule stability and reduced tubulin tyrosination, consistent with excessive MAP1S-mediated stabilization. Restoring tubulin tyrosination by expressing tubulin-tyrosine ligase rescued dynein transport defects. Together, these findings identify MAP1S phosphorylation as a critical regulator of microtubule dynamics and dynein-dependent transport.
2026-05-26 | From Sea to Therapy: Development and Analytical Control of Recombinant Human CDKL5 Production in the Marine Bacterium Pseudoalteromonas haloplanktis TAC125.
Marine bacteria are increasingly explored as alternative microbial platforms for the production of high-value biopharmaceuticals. In this study, we investigate the Antarctic marine bacterium Pseudoalteromonas haloplanktis TAC125 (PhTAC125), an unconventional host capable of yielding soluble and biologically active human cyclin-dependent kinase-like 5 (hCDKL5). This serine/threonine kinase plays a crucial role in neuronal development, and its deficiency causes CDKL5 Deficiency Disorder, a severe and currently untreatable neurodevelopmental disease. Recombinant production of hCDKL5 is a prerequisite for the development of enzyme replacement therapy; however, current manufacturing processes remain insufficient for industrial translation, particularly in terms of product quality and functional consistency. To address these limitations, we developed dedicated analytical strategies: protein accumulation was quantified using a customised sandwich Enzyme-Linked Immunosorbent Assay (ELISA) designed to selectively detect full-length hCDKL5, while protein functionality was assessed by mass spectrometry-based quantification of autophosphorylation, a critical determinant of kinase activation. These complementary tools were applied to characterise hCDKL5 production under different growth conditions. Overall, this work establishes an integrated analytical framework aligned with a Quality by Design approach, enabling the simultaneous assessment of yield, structural integrity, and functional activation, and providing a robust basis for rational process optimisation towards scalable hCDKL5 manufacturing.
2025-07-18 | A Cross-Correction Gene Therapy Approach for CDKL5 Deficiency Disorder Improves the Pathological Phenotype of CDD Patient-Derived Cortical Organoids
Efficient delivery of biological material to the central nervous system (CNS) remains a key limitation of conventional gene therapies. Recently, we developed a novel strategy based on a secretable and cell-penetrating TATk-CDKL5 fused protein which enhances the brain biodistribution and the therapeutic efficiency of the gene therapy approach in a mouse model of CDKL5 Deficiency Disorder (CDD). Here, to compare the efficacy of the TATk-CDKL5 gene therapy with a conventional approach in correcting the CDD pathological phenotype, we employed cortical organoids generated from CDD patient-derived iPSCs as a human model of CDD. We found greater therapeutic efficacy of the recombinant TATk-CDKL5 protein compared to the CDKL5 protein alone in improving or ameliorating defects caused by the absence of CDKL5, such as abnormal hyperexcitability evaluated with microelectrode arrays (MEA). Interestingly, CDD cortical organoids exhibited reduced cell proliferation and increased neuronal cell death compared to control cortical organoids; defects that were only restored by the expression of the recombinant TATk-CDKL5 protein. These findings suggest the superior efficiency of a gene therapy based on a cross-correction approach for treating CDD.
2024-08-29 | CDKL5's role in microtubule-based transport and cognitive function
Abstract Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine kinase highly enriched in mammalian neurons. CDKL5 is located on the X-chromosome and its loss-of-function leads to a severe neurodevelopmental disorder called CDKL5 deficiency disorder (CDD). CDKL5 phosphorylates microtubule-associated protein MAP1S and regulates its binding to microtubules. How MAP1S phosphorylation affects microtubule function is not well understood. To address this question, we generated MAP1S phosphomutant mice, in which the CDKL5 phosphorylation sites S786 and S812 are mutated to Alanine (MAP1S S786/812A or MAP1S SA). Using a microtubule co-sedimentation assay, we showed that dynein binding to microtubules is severely reduced in CDKL5 knockout (KO) and MAP1S SA brains. Time-lapse imaging in primary neurons showed impaired dynein motility in both Cdkl5 KO and MAP1S SA. Dynein-driven cargo transport was affected in mutant neuron dendrites, including the delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We next studied tubulin tyrosination in Cdkl5 KO and MAP1S SA neurons and found that both mutants had a reduced tubulin tyrosination when compared to WT neurons. Since dynein-dynactin has a higher affinity for tyrosinated microtubules, we hypothesized that reduced tyrosination in MAP1S phosphomutant mice could be the mechanistic cause of impaired dynein motility. In support of this, we show that upon expression of tubulin tyrosine kinase TTL, we rescued dynein motility defects in MAP1S phosphomutant neurons. Hippocampal neurons derived from MAP1S SA mice revealed a significant reduction in spine density and synapses, and altered spine morphology. Finally, behavioral phenotyping of MAP1S phosphomutant mice showed increased anxiety, impaired motor performance, social and memory deficits, mirroring to some extent the clinical manifestations present in CDD patients. Our results reveal MAP1S phosphorylation to be an important contributor to dynein-mediated transport and synapse formation. Graphical abstract
2024-02-08 | Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder
Abstract Background Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer’s disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expressions, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD. Methods We used SH- CDKL5 -KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects. Results We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl 5 KO mice, resulting in limited behavioral benefit. Conclusions At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.
small molecules
2026-08-26 | Nationwide Survey of Association Between Fever and Epileptic Seizure in CDKL5 Deficiency Disorder Revealed Therapeutic Implications.
CDKL5 deficiency disorder (CDD) is a rare, severe developmental and epileptic encephalopathy. There is a pressing need to develop effective and sustainable therapeutic strategies. We aimed to investigate the causal association between febrile episodes and epileptic seizures for therapeutic implications in CDD patients. The study was a nationwide, cross-sectional survey on CDD patients in China (ClinicalTrials.gov, NCT06663163). Detailed phenotypic and genotypic data were collected through an online questionnaire with uploaded original medical records, genetic testing results, and peri-fever seizure diaries. The primary outcome was changes in epileptic seizure frequency during and post-fever phases compared to a 1-month pre-fever phase based on seizure diaries. Between October 2024 and December 2024, we received 131 questionnaires. Forty-seven questionnaires were removed after excluding duplicates and missing data. Ultimately, 84 eligible participants with complete uploads were included, from 26 of 34 (76.5%) province-level regions in China. Among these, 47 (56.0%) patients had significant decreased seizure frequency only during febrile episodes, and 27 (32.1%) patients with daily seizures achieved at least a seizure-free day. Notably, 20 patients (23.8%) exhibited post-fever seizure reduction: 12 (25.5%) for 3 days to 1 week, and 6 (12.8%) for more than 2 weeks (maximum > 40 days). The effect was independent of patients' clinical and genetic characteristics. Our findings, for the first time, revealed that fever-related seizure reduction is a distinctive and prevalent genotype-phenotype for CDD, thereby providing evidence for further fundamental research into the underlying mechanisms and offering potential clinical implications for seizure control in CDD.
2026-04-04 | nELAVL phosphorylation by CDKL5 regulates RNA metabolism and condensates communication to promote experience-dependent maturation of the visual cortex
Summary Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), an X-linked neurodevelopmental condition. Through a phosphoproteomic screen, we identified the neuron-specific nELAVL family of RNA-binding proteins as direct activity-dependent substrates of CDKL5. In support of this regulatory axis, single-nuclei transcriptomics of Cdkl5 knockout (KO) cortices revealed an enriched reduction in activity-dependent mRNAs. Mechanistically, we show that nELAVL proteins undergo phase separation to form biomolecular condensates, the size of which is gated by CDKL5 phosphorylation. Loss of CDKL5 leads to enlarged nELAVL condensates, which exhibit reduced binding affinity for the target mRNA Fos , resulting in its accelerated degradation. This disruption extends to inter-condensate communication: phosphodeficient nELAVL show diminished interaction with P-bodies, which themselves become enlarged in CDD mutant iNeurons. Functionally, the absence of nELAVL phosphorylation recapitulates the deficits in experience-dependent visual function observed in Cdkl5 KO mice. Our findings establish a critical molecular mechanism by which CDKL5-mediated phosphorylation governs mRNA metabolism by tuning the properties of nELAVL condensates and their communication with other biomolecular condensates, ultimately promoting experience-dependent maturation of the visual cortex.
2026-03-28 | Endocannabinoid Enhancement via MAGL Inhibition in CDKL5 Deficiency: Selective Cellular Benefits and Domain-Specific Functional Effects in Adult Cdkl5 KO Mice.
CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early disruptions of synaptic maturation and network stability, leading to persistent motor, cognitive, and behavioral impairments. Given the role of the endocannabinoid system in synaptic development, neuroinflammation, and neuronal resilience, we investigated whether the sustained enhancement of endogenous 2-arachidonoylglycerol (2-AG) signaling via monoacylglycerol lipase (MAGL) inhibition could mitigate key pathological features in adult Cdkl5 knockout (KO) mice. Using an intermittent 6-week treatment, the MAGL inhibitor JZL184 robustly increased plasma 2-AG levels, reduced MAGL protein levels, and activated CB1-AKT signaling without evidence of receptor desensitization. Despite this clear pharmacodynamic efficacy, behavioral effects were domain-specific: neither dose ameliorated core behavioral deficits, although the higher dose selectively reduced stereotypic jumping and modestly improved cue-dependent associative memory. At the cellular level, JZL184 induced biologically meaningful effects, partially restoring dendritic spine maturation in the primary somatosensory cortex and increasing neuronal survival in the vulnerable CA1 hippocampal region. In contrast, microglial responses were dose-dependent and divergent, with the lower dose exerting anti-inflammatory effects, while the higher dose increased cortical microglial density and Allograft Inflammatory Factor-1 (AIF-1) expression, suggesting engagement of compensatory or off-target mechanisms. Overall, these findings show that MAGL inhibition activates neuroprotective pathways and ameliorates select structural deficits in adult Cdkl5 KO mice, but is insufficient to produce broad behavioral recovery, highlighting the domain-specific effects of selective 2-AG enhancement via MAGL inhibition and the need for developmentally informed or multimodal therapeutic strategies in CDD.
2026-03-16 | Rescuing functional defects in a zebrafish model of CDKL5 deficiency disorder: Contribution to the identification of new therapeutic compounds
ABSTRACT Mutations in the CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental encephalopathy characterized by a broad range of symptoms, including early-onset seizures, profound motor impairment and dysmorphic facial features. Current treatment options remain limited and largely focus on seizure management, which is often challenging to control, underscoring the critical need for new effective therapies. To identify potential novel candidate molecules for the treatment of CDD, we performed the first in vivo drug screening using a cdkl5 mutant zebrafish model. Recapitulating key features of the human disorder, cdkl5 -/- larvae exhibit reduced locomotor behavior, providing a robust readout to assess therapeutic efficacy. By screening 170 compounds from MAPK Inhibitor and Histone Modification Libraries, both implicated in CDKL5 dysfunction, we identified 18 and 12 small molecules that partially or fully restored locomotor activity, respectively. Among these, fisetin, divalproex, resveratrol, and VX-702 were further evaluated for their capacity to rescue cdkl5 -/- craniofacial defects and altered gene expression. Fisetin demonstrated the most consistent phenotypic improvement, including partial restoration of craniofacial abnormalities and normalization of gene expression levels. Future research aimed at elucidating the molecular mechanisms underlying the observed rescue effects will be critical to understand their mode of action. Overall, our study demonstrates the utility of this rapid and scalable zebrafish-based screening approach for therapeutic discovery in CDD and identifies promising therapeutic molecules that warrant further validation in complementary preclinical systems.
2026-02-20 | Loss of cyclin-dependent kinase-like 5 results in susceptibility to audiogenic seizures in mice.
CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early-onset, treatment-resistant epilepsy. Mice lacking CDKL5 display several clinically relevant phenotypes, but spontaneous seizures are not consistently reported, and it is unknown if CDD model mice are susceptible to sensory stimulus-triggered seizures, a well-documented clinical feature of CDD. Here, we tested the hypothesis that CDKL5 deficiency confers susceptibility to audiogenic seizures (AGS). We exposed adult male Cdkl5 knockout, female heterozygous, and wildtype littermates (P80-217) to audiogenic challenges and, in a separate cohort, monitored for spontaneous seizures. Audiogenic stimulation triggered severe, lethal (80%) seizures in Cdkl5 knockout mice. In contrast, heterozygous mice were largely resistant to audiogenic stimulus (92% survival). These findings establish susceptibility to AGS as a highly penetrant phenotype in a CDD mouse model. Furthermore, spontaneous seizures were detected in a subset of Cdkl5 knockout mice during chronic video-EEG monitoring. AGS may provide a translationally relevant screen for investigating hyperexcitability and for evaluating potential therapeutics to prevent seizures in CDD. PLAIN LANGUAGE SUMMARY: CDKL5 deficiency disorder (CDD) is a severe genetic condition causing early-onset seizures. Mice with the same mutation are useful models but don't consistently have epilepsy. We tested if these mice in our lab are sensitive to sound-triggered seizures. We discovered that male CDD mice are highly vulnerable to sound, which triggered severe seizures in most of them. Female CDD mice and normal mice were resistant. This is the first report of sound-triggered seizures in a CDD model and provides a useful new method to study epilepsy in CDD and screen for antiseizure treatments.
gene therapies
2026-04-11 | Base editing restores CDKL5 expression and rescues neuronal deficits in a patient-derived model of CDKL5 deficiency disorder.
Cyclin-dependent kinase like 5 (CDKL5) deficiency disorder (CDD) is a rare monogenic neurodevelopmental disorder caused by pathogenic mutations in the CDKL5 gene, with approximately 50% of reported variants being point mutations. Base editing presents a promising therapeutic strategy to correct such mutations, restore endogenous CDKL5 expression, and pave the way for novel treatments for CDD. To assess the therapeutic potential of base editing for CDD, we applied adenine base editing (ABE) to correct a CDKL5-R550* (c.1648 C > T) mutation in induced pluripotent stem cells (iPSCs) derived from a CDD patient. Isogenic control, CDKL5-R550* mutant, and ABE-corrected iPSCs were differentiated into neurons and the restoration of CDKL5-related and functional recovery were assessed. In this study, we demonstrated that ABE successfully restored CDKL5 protein levels and CDKL5-dependent signalling pathways in edited iPSC-differentiated neurons to levels comparable to the isogenic control. Morphological deficits, and genes expression were normalized in the ABE-corrected neurons. This study provides evidence that ABE can precisely correct pathogenic mutation and functionally rescue some CDD-associated neuronal phenotypes in patient-derived cells, supporting its potential as a valuable gene therapy for CDD. Moreover, these findings underscore the broader applicability of base editing for treating other monogenic neurodevelopmental disorders caused by point mutations.
2026-03-09 | An Open‐Source Pipeline for Calcium Imaging and All‐Optical Physiology in Human Stem Cell‐Derived Neurons
High-throughput, single-cell resolution profiling of neuronal activity is critical for understanding brain function and modeling neurological disorders, yet existing approaches are often limited by scalability and manual workflows. Here, we present an open-source, scalable imaging and analysis platform that integrates optogenetic stimulation, calcium imaging, automated acquisition, single-cell and network analyses. The platform enables robust quantification of spontaneous and evoked neuronal activity across hundreds of human stem cell-derived neurons over multiple timepoints, supporting functional phenotyping at both cellular and network levels. We demonstrate the versatility of the platform across multiple disease-relevant contexts, including models of CDKL5 Deficiency, SSADH Deficiency, and tuberous sclerosis complex (TSC). Additionally, we generate CRISPR-Cas9 knock-in hiPSC lines expressing GCaMP6s and demonstrate partial reversal through pharmacological intervention in TSC. By linking single-cell dynamics to network-level measures, this platform provides a generalizable framework for scalable functional phenotyping and high-throughput screening in human neuronal models.
2026-02-01 | Developmental and Epileptic Encephalopathy due to Cyclin-Dependent Kinase-Like 5 Deficiency: A Single-Center Experience Across Sex Differences.
The cyclin-dependent kinase-like 5 deficiency disorder (CDD) is an ultrarare X-linked disorder causing early-onset epileptic encephalopathy and severe developmental deficits. Few studies exist on its electroclinical features, outcomes, sex differences, and neuroimaging, particularly from India. This study aims to describe the electroclinical syndrome, developmental profile, radiological findings, and outcomes in patients with CDD and to compare these factors between males and females. This is a hospital-based observational study of patients diagnosed with CDD identified from a prospectively maintained registry of children with developmental and epileptic encephalopathy. Data on demographics, seizure types, epilepsy syndromes, antiseizure medications, electroencephalography findings, developmental assessments, genetic characteristics, brain magnetic resonance imaging, and outcomes were collected. We included 12 patients with pathogenic (9) and likely pathogenic (3) variants in cyclin-dependent kinase-like 5 (CDKL5), among whom seven were female. The mean age at onset of seizures was 5.95 ± 5.56 months and was higher for males than females (8.6 ± 7.23 vs 3.19 ± 2.47). The most common seizure types at onset were tonic seizures in 6 (50%) children and epileptic spasms in 4 (33.3%). Lennox-Gastaut syndrome and West syndrome were the most frequent epilepsy syndromes. The median number of seizures per person was 2.9, and the median number of antiseizure medications used was 6 during their lifetime. Magnetic resonance imaging revealed cerebral volume loss in 7 children and white matter lesions in 6. Severe developmental deficits, a Rett-like phenotype, and cortical visual impairment were observed in three-fourths of the children, and regression of milestones occurred in two-thirds. Repetitive motor behavior (P 0.0455) and regression (P 0.0101) were more common in females. CDD causes refractory epilepsy and severe developmental deficits irrespective of the sex of the patient, variant type, and treatment.
2026-01-14 | Baseline characteristics and feasibility of clinical outcome measures in CDKL5 deficiency disorder: The CANDID observational study.
CDKL5 deficiency disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy caused by loss-of-function variants in the CDKL5 gene. Preclinical experiments using enzyme replacement or gene therapies show promise and could be transformative therapies. This precompetitive consortium sought to harmonize nonseizure clinical endpoint selection for efficacy trials. Clinical Assessment of Neurodevelopmental Measures in CDD (CANDID) is an ongoing study evaluating the feasibility and suitability of neurocognitive tests and functioning scales in CDD patients. CANDID is a 3-year, longitudinal, noninterventional global study involving children and adults with CDD. On-site and remote visits include clinical, behavioral, developmental, and quality of life assessments. We enrolled 112 patients (111 included in analyses); mean age = 8.3 years (range <1-28); 93% female; 10 participants were ≥18 years old. In the first 28 days, 82% had >16 seizures; six were seizure-free. Median seizure onset was at 1.5 months (range = 0-66). Patients used an average of 2.6 antiseizure medications at baseline. The most frequent comorbidities included gastrointestinal hypomotility, muscle tone abnormalities, and sleep disorders. Gross Motor Function Measure-88 (GMFM-88) scores indicated a floor effect in crawling, standing, and walking across all ages. Vineland-3 and Bayley-4 scores could be derived in most, with receptive language, interpersonal relationships, and fine and gross motor scores increasing with age. Bruni sleep questionnaire identified sleep initiation, sleep-awake transition, and excessive somnolence as the most disrupted components across all age groups. The mean Quality of Life Inventory-Disability total scores ranged from 53% to 64%, the independence domain being the most impacted. The scales in the CANDID study capture disease-related deficits and phenotype variability in CDD. Floor effects in subdomains aligned with disease severity. The GMFM-88 lacks granularity, and its operational limitations make it unsuitable for CDD trials. Baseline analyses demonstrate the feasibility and potential value of most selected scales, supporting their use in optimizing trial design and endpoint selection for future CDD clinical trials.
2026-01-01 | P221: Loss of the single fly ortholog of the human CDKL1-5, Cdkl, causes seizures, neuronal degeneration, mitochondrial defects, and sleep disturbances
The CDKL (cyclin-dependent kinase-like) genes consisting of CDKL1-5 encode a conserved family of protein kinases. The genes are expressed in a variety of tissues, including the nervous system. We have recently identified de novo variants in CDKL1 and CDKL2 in seven individuals. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. In addition, pathogenic variants in CDKL5 have already been linked to CDKL5 deficiency disorder (CDD) which is a distinct epileptic encephalopathy.
oligonucleotides
2024-04-01 | Gut microbiota profile in CDKL5 deficiency disorder patients.
CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. Patients with CDD frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in individuals with CDD (n = 17) and their healthy relatives (n = 17). Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. In particular, at genus level, CDD microbial communities were characterized by an increase in the relative abundance of Clostridium_AQ, Eggerthella, Streptococcus, and Erysipelatoclostridium, and by a decrease in Eubacterium, Dorea, Odoribacter, Intestinomonas, and Gemmiger, pointing toward a dysbiotic profile. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features and ambulation capacity. Enrichment in Lachnoclostridium and Enterobacteriaceae was observed in the microbiota of patients with more severe GI symptoms, while Clostridiaceae, Peptostreptococcaceae, Coriobacteriaceae, Erysipelotrichaceae, Christensenellaceae, and Ruminococcaceae were enriched in patients experiencing daily epileptic seizures. Our findings suggest a potential connection between CDD, microbiota and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in subjects with CDD. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of patients with CDD.
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Drug Discovery Landscape
6 orphan drug designations for CDKL5-deficiency disorder, including 2 approved therapies.
6 orphan drug designations for CDKL5-deficiency disorder, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
allopurinol | small molecules | FDA | — | Jainu Jogani |
Fenfluramine hydrochloride | small molecules | EMA | UCB Pharma | |
fenfluramine hydrochloride | small molecules | FDA | UCB, Inc. | |
Ganaxolone [ZTALMY] | small molecules | EMA | Approved | Immedica Pharma AB |
Balipodect | small molecules | FDA | — | Takeda Development Center Americas, Inc. |
ganaxolone [Ztalmy] | small molecules | FDA | Approved | Immedica Pharma AB |
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