Search

Objective: To quantify pain response in girls affected by Rett syndrome (RTT) using electrodermal activity (EDA), a measure of skin conductance, reflecting sympathetic activity known to be modulated by physical and environmental stress., Methods: EDA increase, heart rate (HR) increase and Face Legs Activity Cry Consolability (FLACC) values calculated during venipuncture (invasive) and vital signs collection (non-invasive) events were compared with values calculated during a prior baseline and a RTT clinical severity score (CSS)., Results: EDA and HR increase were significantly higher than baseline during venipuncture only and not significantly correlated with FLACC or CSS. EDA increase was the most sensitive measure of pain response., Conclusions: These preliminary findings revealed that motor impairment might bias non-verbal pain scales, underscore the importance of using autonomic measures when assessing pain and warrant further investigation into the utility of using EDA to objectively quantify RTT pain response to inform future RTT pain management.

Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks., (© 2015 Wiley Periodicals, Inc.)

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Purpose of Review: Rare genetic diseases that affect behavior and cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of animal models, which can lead to development of hypotheses and treatments testable in human beings. Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are both Mendelian disorders that present with autism, epilepsy, and intellectual disability, in which animal model work has been directly translated into clinical treatment trials currently underway. Here, we review the recent advances in our understanding of RTT and TSC pathogenesis and signaling pathways that may be targeted for novel treatments., Recent Findings: Animal models generated by engineering mutant forms of the mouse homologs of human genes involved in RTT and TSC have allowed dissection of the molecular pathology. They have further acted as in-vivo assays of potential therapeutic strategies that have translated to human clinical trials., Summary: Single-gene disorders associated with neurodevelopmental disorders provide powerful model systems to study the roles of individual molecules and associated signaling pathways in the genesis of autism, epilepsy, cognitive impairment, and neuropsychiatric symptoms. These diseases are leading to disease-modifying human therapies that may eventually translate to wider therapeutic strategies for autism.

Analysis of 819 participants enrolled in the Rett syndrome (RTT) Natural History Study validates recently revised diagnostic criteria. 765 females fulfilled 2002 consensus criteria for classic (653/85.4%) or variant (112/14.6%) RTT. All participants classified as classic RTT fulfilled each revised main criterion; supportive criteria were not uniformly present. All variant RTT participants met at least 3 of 6 main criteria in the 2002, 2 of 4 main criteria in the current format, and 5 of 11 supportive criteria in both. This analysis underscores the critical role of main criteria for classic RTT; variant RTT requires both main and supportive criteria.

Background: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness.Methods: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input.Results: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included.Conclusions: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders. [ABSTRACT FROM AUTHOR]