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

Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
European journal of human genetics: EJHG (Impact Factor: 4.23). 08/2012; DOI: 10.1038/ejhg.2012.156
Source: PubMed

ABSTRACT 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.European Journal of Human Genetics advance online publication, 8 August 2012; doi:10.1038/ejhg.2012.156.


Available from: Stephanie Fehr, May 12, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Individuals with the CDKL5 disorder have been described as having severely impaired development. A few individuals have been reported having attained more milestones including walking and running. Our aim was to investigate variation in attainment of developmental milestones and associations with underlying genotype. Data was sourced from the International CDKL5 Disorder Database, and individuals were included if they had a pathogenic or probably pathogenic CDKL5 mutation and information on early development. Kaplan-Meier time-to-event analyses investigated the occurrence of developmental milestones. Mutations were grouped by their structural/functional consequence, and Cox regression was used to investigate the relationship between genotype and milestone attainment. The study included 109 females and 18 males. By 5 years of age, only 75% of the females had attained independent sitting and 25% independent walking whilst a quarter of the males could sit independently by 1 year 3 months. Only one boy could walk independently. No clear relationship between mutation group and milestone attainment was present, although females with a late truncating mutation attained the most milestones. Attainment of developmental milestones is severely impaired in the CDKL5 disorder, with the majority who did attain skills attaining them at a late age. It appears as though males are more severely impaired than the females. Larger studies are needed to further investigate the role of genotype on clinical variability.
    Journal of Neurodevelopmental Disorders 01/2015; 7(1):2. DOI:10.1186/1866-1955-7-2 · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mind bomb 1 (Mib1) ubiquitin ligase is essential for controlling metazoan development by Notch signaling and possibly the Wnt pathway. It is also expressed in postmitotic neurons, regulating neuronal morphogenesis and synaptic activity, but by mechanisms that are largely unknown. We sought to comprehensively characterize the Mib1 interactome and study its potential function in neuron development utilizing a novel sequential elution strategy for Mib1 affinity purification, in which Mib1 binding proteins were eluted under different stringency and then quantified by the isobaric labeling method. The strategy recovered the Mib1 interactome with both deep coverage and the ability to distinguish high affinity partners from low affinity partners. A total of 817 proteins were identified during the Mib1 affinity purification, including 56 high affinity partners and 335 low affinity partners, while the remaining 426 proteins are likely co-purified contaminants or extremely weak binding proteins. The analysis essentially detected all previously known Mib1-interacting proteins, and revealed a large number of novel components involved in Notch and Wnt pathways, endocytosis and vesicle transport, the ubiquitin-proteasome system, cellular morphogenesis, and synaptic activities. Immunofluorescence studies further showed colocalization of Mib1 with five selected proteins: the Usp9x (FAM) deubiquitinating enzyme, alpha-, beta-, and delta-catenins, and CDKL5. Mutations of CDKL5 are associated with early infantile epileptic encephalopathy-2, a severe form of mental retardation. We found that the expression of Mib1 downregulated the protein level of CDKL5, and antagonized CDKL5 function during the formation of dendritic spines. Thus, the sequential elution strategy enables biochemical characterization of protein interactomes; and Mib1 analysis provides a comprehensive interactome for investigating its role in signaling networks and neuronal development. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Molecular &amp Cellular Proteomics 04/2015; DOI:10.1074/mcp.M114.045898 · 7.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetic mechanisms explain the pathophysiology of many forms of epilepsy and other paroxysmal disorders, such as alternating hemiplegia of childhood, familial hemiplegic migraine, and paroxysmal dyskinesias. Epilepsy is a key feature of well-defined genetic syndromes including tuberous sclerosis complex, Rett syndrome, Angelman syndrome, and others. There is an increasing number of single-gene causes or susceptibility factors associated with several epilepsy syndromes, including the early-onset epileptic encephalopathies, benign neonatal/infantile seizures, progressive myoclonus epilepsies, genetic generalized and benign focal epilepsies, epileptic aphasias, and familial focal epilepsies. Molecular mechanisms are diverse, and a single gene can be associated with a broad range of phenotypes. Additional features, such as dysmorphisms, head size, movement disorders, and family history may provide clues to a genetic diagnosis. Genetic testing can impact medical care and counseling. We discuss genetic mechanisms of epilepsy and other paroxysmal disorders, tools and indications for genetic testing, known genotype-phenotype associations, the importance of genetic counseling, and a look toward the future of epilepsy genetics.
    Seminars in Neurology 07/2014; 34(3):266-79. DOI:10.1055/s-0034-1386765 · 1.78 Impact Factor