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

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.

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed. Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. Interpretation: As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales.

BACKGROUND: Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by regression of language and motor skills, cognitive impairment, and frequent seizures. Although the diagnostic criteria focus on communication, motor impairments, and hand stereotypies, behavioral abnormalities are a prevalent and disabling component of the RTT phenotype. Among these problematic behaviors, anxiety is a prominent symptom. While the introduction of the Rett Syndrome Behavioral Questionnaire (RSBQ) represented a major advancement in the field, no systematic characterization of anxious behavior using the RSBQ or other standardized measures has been reported. METHODS: This study examined the profiles of anxious behavior in a sample of 74 girls with RTT, with a focus on identifying the instrument with the best psychometric properties in this population. The parent-rated RSBQ, Anxiety, Depression, and Mood Scale (ADAMS), and Aberrant Behavior Checklist-Community (ABC-C), two instruments previously employed in children with neurodevelopmental disorders, were analyzed in terms of score profiles, relationship with age and clinical severity, reliability, concurrent validity, and functional implications. The latter were determined by regression analyses with the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) and the Child Health Questionnaire (CHQ), a quality of life measure validated in RTT. RESULTS: We found that scores on anxiety subscales were intermediate in range with respect to other behavioral constructs measured by the RSBQ, ADAMS, and ABC-C. Age did not affect scores, and severity of general anxiety was inversely correlated with clinical severity. We demonstrated that the internal consistency of the anxiety-related subscales were among the highest. Test-retest and intra-rater reliability was superior for the ADAMS subscales. Convergent and discriminant validity were measured by inter-scale correlations, which showed the best profile for the social anxiety subscales. Of these, only the ADAMS Social Avoidance showed correlation with quality of life. CONCLUSIONS: We conclude that anxiety-like behavior is a prominent component of RTT's behavioral phenotype, which affects predominantly children with less severe neurologic impairment and has functional consequences. Based on available data on standardized instruments, the ADAMS and in particular its Social Avoidance subscale has the best psychometric properties and functional correlates that make it suitable for clinical and research applications.