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CDKL5 deficiency disorder (CDD) results in early-onset epilepsy and lifelong cognitive and motor impairments. With no validated measure for communication in CDD, this study evaluated the psychometric properties of the Communication and Symbolic Behavior Scales-Developmental Profile Infant Toddler Checklist (CSBS–DP ITC). Caregivers (n = 150; affected individuals aged 1–29 years) completed the CSBS-DP ITC. Distribution of scores indicated a floor effect. There was poor divergent validity for the three-factor model but goodness of fit and convergent validity data were satisfactory for the one-factor model. Individuals with poorer overall functional abilities scored lower on the CSBS-DP ITC. Test–retest reliability was excellent. The floor effect could explain the very high reliability, suggesting problems as a sensitive outcome measure in clinical trials for CDD.

CDKL5 deficiency disorder (CDD) was first identified as a cause of human disease in 2004. Although initially considered a variant of Rett syndrome, CDD is now recognised as an independent disorder and classified as a developmental epileptic encephalopathy. It is characterised by early-onset (generally within the first 2 months of life) seizures that are usually refractory to polypharmacy. Development is severely impaired in patients with CDD, with only a quarter of girls and a smaller proportion of boys achieving independent walking; however, there is clinical variability, which is probably genetically determined. Gastrointestinal, sleep, and musculoskeletal problems are common in CDD, as in other developmental epileptic encephalopathies, but the prevalence of cerebral visual impairment appears higher in CDD. Clinicians diagnosing infants with CDD need to be familiar with the complexities of this disorder to provide appropriate counselling to the patients' families. Despite some benefit from ketogenic diets and vagal nerve stimulation, there has been little evidence that conventional antiseizure medications or their combinations are helpful in CDD, but further treatment trials are finally underway.

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 ( CDKL5 ) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood–brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.

Background Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy. Design This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6–12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy. Methods Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity. Results Twenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019–11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine. Conclusions Short-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT. Trial registration Registered at clinicaltrials.gov NCT03633058.

Introduction The clinical, research and advocacy communities for Rett syndrome are striving to achieve clinical trial readiness, including having fit-for-purpose clinical outcome assessments. This study aimed to (1) describe psychometric properties of clinical outcome assessment for Rett syndrome and (2) identify what is needed to ensure that fit-for-purpose clinical outcome assessments are available for clinical trials. Methods Clinical outcome assessments for the top 10 priority domains identified in the Voice of the Patient Report for Rett syndrome were compiled and available psychometric data were extracted. The clinical outcome assessments measured clinical severity, functional abilities, comorbidities and quality of life, and electrophysiological biomarkers. An international and multidisciplinary panel of 29 experts with clinical, research, psychometric, biostatistical, industry and lived experience was identified through International Rett Syndrome Foundation networks, to discuss validation of the clinical outcome assessments, gaps and next steps, during a workshop and in a follow-up questionnaire. The identified gaps and limitations were coded using inductive content analysis. Results Variable validation profiles across 26 clinical outcome assessments of clinical severity, functional abilities, and comorbidities were discussed. Reliability, validity, and responsiveness profiles were mostly incomplete; there were limited content validation data, particularly parent-informed relevance, comprehensiveness and comprehensibility of items; and no data on meaningful change or cross-cultural validity. The panel identified needs for standardised administration protocols and systematic validation programmes. Conclusion A pipeline of collaborative clinical outcome assessment development and validation research in Rett syndrome can now be designed, aiming to have fit-for-purpose measures that can evaluate meaningful change, to serve future clinical trials and clinical practice.

Background CDKL5 Deficiency Disorder (CDD) is a rare neurodevelopmental disorder characterised by early onset seizures combined with complex healthcare needs and developmental impairment that influence functional domains including communication. Communication is a high priority domain for families but currently used measures demonstrate floor effects. Emerging disease-modifying trials necessitate the precise and granular measurement of communication to determine drug efficacy. This study evaluated a new measure of communication for CDD called the Communication Inventory Disability – Observer Reported (CID-OR). Methods CID-OR was developed using a communication framework for CDD created from qualitative data and informed through evaluation of current measures and consultation with clinical experts. Scores for items describing communicative purpose were derived from ratings of consistency and the mode of delivery. An online survey was administered to parents of people with CDD ( n  = 184) recruited from the International CDKL5 Clinical Research Network. Most caregivers (96%) completed the Communication and Symbolic Behavior Scales - Developmental Profile Infant Toddler Checklist (CSBS–DP ITC). A confirmatory factor analysis was conducted. Test-retest reliability and comparison of known groups were assessed using intraclass correlation coefficients and linear regression, respectively. Results The median age of people with CDD was 9.8 (1–43) years. A single factor model was evaluated. For 34 items, item loadings were satisfactory. For the scale, internal consistency and goodness-of-fit statistics were satisfactory, except for the Root Mean Square Error of Approximation statistic. The distribution of CID-OR scores was less right skewed than for CSBS-DP ITC scores although there was a high correlation between CID-OR and CSBS scores ( r  = 0.89). Test-retest reliability was high (ICC 0.966). Conclusion Preliminary analysis suggests that CID-OR is a reliable and valid measure of communication in CDD. This new tool has strong potential to measure responsiveness to interventions in CDD and may extend to similar developmental and epileptic encephalopathy conditions.

Background: CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy (DEE) associated with multiple impairments and comorbidities. Outcome measures for disease‐modifying clinical trials for DEEs should measurably capture a spectrum of caregiver priorities and be externally validated. Methods: The International CDKL5 Clinical Research Network was the data source for this observational study. A Structural Equation Model was constructed with latent, exogenous variables related to observed clinical features to calculate a global severity score from the following assessments: the CDKL5 Clinical Severity Assessment‐Clinician and ‐Caregiver, Communication and Symbolic Behavior Scales Developmental Profile Infant Toddler Checklist and the Sleep Disturbance Scale for Children. Quantitative EEG power was measured as a biomarker. The Quality of Life Inventory—Disability measured quality of life. Results: Acceptable fit statistics for models were obtained using data from 206 subjects (median [range] age 6.8 [3 months to 40] years). Motor and communication measures were the most important weighted contributors to the global severity score which correlated well with the biomarker and quality of life to support external validation. Conclusions: The resultant global severity score provided evidence that the assessments formed a coherent set of measures that reliably and meaningfully captured the diversity of severity in CDD. The models illustrated how the symptoms form a measurable network of relationships which may be suitable as an outcome measure for CDD and DEEs more broadly in clinical trials. A validated global measure of severity for CDKL5 deficiency disorder was obtained from structural equation modeling that enables clinical trial readiness.

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits ( GRIN1 ) and two GluN2 subunits ( GRIN2A - GRIN2D ). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a +/− and Grin2a −/− mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b ). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a +/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a +/− mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a −/− mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients. Null  GRIN2A human patients display a largely transient seizure burden that resolves with age, which may be attributable to a transient delay in the developmental maturation of parvalbumin-positive interneurons in CA1 as is observed in Grin2a +/− and Grin2a - /- mice.

Background Mutations in the X-linked gene cyclin-dependent kinase-like 5 ( CDKL5 ) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5 −/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5 −/y rats. Methods To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 −/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca 2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 −/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Background Rett syndrome (RTT) is a rare neurodevelopmental disorder associated with pathogenic MECP2 variants. Because the MECP2 gene is subject to X‐chromosome inactivation (XCI), factors including MECP2 genotypic variation, tissue differences in XCI, and skewing of XCI all likely contribute to the clinical severity of individuals with RTT. Methods We analyzed the XCI patterns from blood samples of 320 individuals and their mothers. It includes individuals with RTT (n = 287) and other syndromes sharing overlapping phenotypes with RTT (such as CDKL5 Deficiency Disorder [CDD, n = 16]). XCI status in each proband/mother duo and the parental origin of the preferentially inactivated X chromosome were analyzed. Results The average XCI ratio in probands was slightly increased compared to their unaffected mothers (73% vs. 69%, p = .0006). Among the duos with informative XCI data, the majority of individuals with classic RTT had their paternal allele preferentially inactivated (n = 180/220, 82%). In sharp contrast, individuals with CDD had their maternal allele preferentially inactivated (n = 10/12, 83%). Our data indicate a weak positive correlation between XCI skewing ratio and clinical severity scale (CSS) scores in classic RTT patients with maternal allele preferentially inactivated XCI (rs = 0.35, n = 40), but not in those with paternal allele preferentially inactivated XCI (rs = −0.06, n = 180). The most frequent MECP2 pathogenic variants were enriched in individuals with highly/moderately skewed XCI patterns, suggesting an association with higher levels of XCI skewing. Conclusion These results extend our understanding of the pathogenesis of RTT and other syndromes with overlapping clinical features by providing insight into the both XCI and the preferential XCI of parental alleles. X chromosome inactivation (XCI) analysis of 320 proband‐mother duos showed that majority of individuals with classic Rett syndrome had their paternal allele preferentially inactivated, while, in sharp contrast, majority of individuals with CDKL5 Deficiency Disorder had their maternal allele preferentially inactivated. Our data also indicated that in individuals with classic Rett syndrome, there is a weak positive correlation between XCI skewing ratio and clinical severity of individuals with maternal allele preferentially inactivated, but not in those with paternal allele preferentially inactivated.