Epileptic Spasms in Congenital Disorders of Glycosylation

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, characterized by impaired glycosylation. Multisystemic involvement is common and neurological impairment is notably severe and disabling, concerning the central and peripheral nervous system. Epilepsy is frequent, but detailed electroclinical description is rare. We describe, retrospectively, the electroclinical features in five children with CDG and epileptic spasms. Epileptic spasms were observed in patients with ALG1-, ALG6, ALG11-CDG and CDG-Ix, and occurred at an early age, before 6 months in all cases, except one who had spasms that started at 18 months. In this patient, spasms had an unusual aspect; they did not occur in clusters and were immediately preceded by a myoclonus. All but one child also presented rare myoclonias. On EEG, background activity was poorly organized with abundant posterior spike and fast rhythm activity, but without hypsarrhythmia. At the last evaluation (age range: 6-12 years), two patients still presented epileptic spasms and subcortical myoclonias, one showed rare generalized tonic-clonic seizures, and two were seizure-free. CDG disorders can be associated with epileptic spasms showing particular features, such as absence of hypsarrhythmia, posterior EEG anomalies, and an unusual combination of epileptic spasms with myoclonus. These features, associated with pre-existing developmental delay and subcortical myoclonias, may shift toward CDG screening. [Published with video sequence and supplemental EEG plates on www.epilepticdisorders.com].info:eu-repo/semantics/publishedVersio

Integrating Technical Standards into ET Curricula to Meet ABET Standards and Industry Needs

With technical standards affecting nearly every aspect of our daily lives, from computers to the components and materials used in car engines, it is critical that undergraduate students are educated on the importance of standards and provided with opportunities to locate and apply relevant technical standards to real world situations. In addition, with ABET accreditation requiring students to have a “basic understanding and familiarity with,” and experience “using” codes and standards, faculty need to consider how such material can be naturally integrated into the curriculum. At Purdue University, education about codes and standards has been integrated into the mechanical engineering technology (MET) curriculum for decades with significant success. This paper discusses how standards are incorporated into mechanical design and quality control courses, as well as strategies for integrating standards into more courses in an MET curriculum. In addition, a discussion of standards resources that are freely available is included. Finally, a call to action for industry is presented, explaining the need and potential areas where industry can increase involvement in teaching students about technical standards

Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome

Background: Initially described as an early onset seizure variant of Rett syndrome, the CDKL5 disorder is now considered as an independent entity. However, little is currently known about the full spectrum of comorbidities that affect these patients and available literature is limited to small case series. This study aimed to use a large international sample to examine the prevalence in this disorder of comorbidities of epilepsy, gastrointestinal problems including feeding difficulties, sleep and respiratory problems and scoliosis and their relationships with age and genotype. Prevalence and onset were also compared with those occurring in Rett syndrome. Methods: Data for the CDKL5 disorder and Rett syndrome were sourced from the International CDKL5 Disorder Database (ICDD), InterRett and the Australian Rett syndrome Database (ARSD). Logistic regression (multivariate and univariate) was used to analyse the relationships between age group, mutation type and the prevalence of various comorbidities. Binary longitudinal data from the ARSD and the equivalent cross-sectional data from ICDD were examined using generalized linear models with generalized estimating equations. The Kaplan-Meier method was used to estimate the failure function for the two disorders and the log-rank test was used to compare the two functions. Results: The likelihood of experiencing epilepsy, GI problems, respiratory problems, and scoliosis in the CDKL5 disorder increased with age and males were more vulnerable to respiratory and sleep problems than females. We did not identify any statistically significant relationships between mutation group and prevalence of comorbidities. Epilepsy, GI problems and sleep abnormalities were more common in the CDKL5 disorder than in Rett syndrome whilst scoliosis and respiratory problems were less prevalent. Conclusion: This study captured a much clearer picture of the CDKL5 disorder than previously possible using the largest sample available to date. There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant

Building Bridges Between the Clinic and the Laboratory: A Meeting Review – Brain Malformations: A Roadmap for Future Research

In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific findings, to establish collaborations, and to discuss future directions for better diagnosis, etiology modeling and treatment of brain malformations. One hundred fifty scientists from twenty-two countries took part in this meeting. Thirty-eight talks were presented and as many as twenty-five posters were displayed. This review is aimed at presenting some of the highlights that the audience was exposed to during the three-day meeting

Characterisation of CDKL5 Transcript Isoforms in Human and Mouse

Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3’-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue- and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders

Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly

The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered gamma-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD

International consensus recommendations on the diagnostic work-up for malformations of cortical development

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk

A Kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

© 2020, The Author(s). Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI