Adult Phenotypes in Angelman- and Rett-Like Syndromes

Willemsen, Marjolein H.; Rensen, J.H.M.; Valk, H.M.J. van Schrojenstein-Lantman de; Hamel, B.C.J.; Kleefstra, Tjitske

doi:10.1159/000335661

Cited by 27 publications

(25 citation statements)

References 103 publications

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“…Cdkl5 -/y mice display hyperactivity, motor defects, reduced anxiety, decreased sociability, and impaired learning and memory. These phenotypes have been described in other ASD and RTT mouse models (2, 16, 17, 19, 26) and may mimic the absence of hand skills, intellectual disability, hyperactivity, and poor response to social interactions that have been described in CDKL5 patients (12,41). While video-EEG monitoring revealed an absence of spontaneous seizures in Cdkl5 -/y mice, ERP analysis showed attenuated and delayed ERP polarity peaks suggestive of impaired neuronal connectivity, which is consistent with findings in ASD and RTT patients (30,31) and animal models (19,28,29).…”

Section: Discussionmentioning

confidence: 76%

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Wang

Allen²,

Goffin³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

186

247

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Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKTmammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.C yclin-dependent kinase-like 5 (CDKL5) is an X-linked gene associated with early infantile epileptic encephalopathy 2 (EIEE2) (1), atypical Rett syndrome (RTT) (2), and autism spectrum disorders (ASDs) (3, 4). Patients with CDKL5 mutations display a heterogenous array of clinical phenotypes, the most prominent of which include early-onset seizures, intellectual disability, and autistic features (5).CDKL5 is a serine/threonine (S/T) kinase that is highly expressed in the brain (6). In vitro studies have demonstrated that CDKL5 may mediate the phosphorylation of methyl-CpG binding protein 2 (MeCP2) (7), DNA methyltransferase 1 (DNMT1) (8), and netrin-G1 ligand (NGL-1) (9). RNAi-mediated knockdown studies show that CDKL5 can regulate neuronal outgrowth and synapse stability (9, 10). Despite these proposed functions, the exact role of CDKL5 in the phosphorylation of MeCP2 (7, 11) and in dendritic outgrowth (9, 10) remains unclear, and thus requires further investigation. The limited understanding of CDKL5 function and its associated signal transduction pathways has hindered the development of therapeutics for CDKL5-related disorders. Current treatments focus on managing symptoms and reducing seizure frequency, but have limited effectiveness (12).To investigate the function of CDKL5 in a disease model and identify potential avenues of therapeutic intervention, we developed a Cdkl5 knockout mouse. We found that mice lacking CDKL5 show autistic-like behavioral abnormalities, deficits in neural circuit communication, and alterations in multiple signal transduction pathways. We establish a causal link between Cdkl5 loss-of-function and disease-related phenotypes and identify the AKT-mammalian target of rapamycin (mTOR) pathway as a unique candidate for targeted therapeutic intervention of CDKL5-related disorders. ResultsGeneration of Cdkl5 Knockout Mice. To investigate the pathophysiology underlying CDKL5-related disorders, we generated ...

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Section: Discussionmentioning

confidence: 76%

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Wang

Allen²,

Goffin³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

186

247

View full text Add to dashboard Cite

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“…The two first studies reported the same family with two affected brothers with PMS (Verhoeven et al, 2012;Willemsen et al, 2012). Until the age of 17, the development of the younger brother was marked by the severity of the ID and hyperactivity together with temper tantrums and absence of language.…”

Section: Shank and Bipolar Disordermentioning

confidence: 97%

The emerging role of SHANK genes in neuropsychiatric disorders

Guilmatre

Huguet

Delorme

et al. 2013

Developmental Neurobiology

230

174

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The genetic heterogeneity of neuropsychiatric disorders is high, but some pathways emerged, notably synaptic functioning. A large number of mutations have been described in genes such as neuroligins, neurexins, and SHANK that play a role in the formation and the maintenance of synapses. This review focuses on the disorders associated with mutations in SHANK3 and the other members of its family, SHANK1 and SHANK2. SHANKs are scaffolding proteins of the postsynaptic density of glutamatergic synapses. SHANK3 has been described in the Phelan-McDermid syndrome (PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to moderate to severe intellectual disability (ID) and poor language. The evolution of patients with PMS includes symptoms of bipolar disorder and regression. SHANK2 has been identified in patients with ASD with mild to severe ID. SHANK1 has been associated with high-functioning autism in male patients, while carrier females only display anxiety and shyness. Finally, based on neuropathological findings in animal models and patients, a possible role of SHANK in Alzheimer's disease is discussed. Altogether, this review describes the clinical trajectories associated with different mutations of the SHANK genes and provides information to further investigate the role of the SHANK genes in neuropsychiatric disorders.

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“…Apart from these 3 genes, there are at least 28 OMIM morbid genes (https://www.omim.org/) described in literature in which variants may cause gene disorders/syndromes with overlapping Rett-like phenotypes ( Table 2). 9,10,14,[36][37][38] Some of these genes are associated with well-known syndromes such as Pitt-Hopkins syndrome (TCF4, Among the patients, without deficiencies in 1 of these 3 genes (n = 35), pathogenic sequence variants were identified in SCN2A…”

Section: Many Genes Many Disordersmentioning

confidence: 99%

“…,61 Kleefstra syndrome is caused by 9q34.3 microdeletions including EHMT1 or sequence variants of this gene. 60 EHMT1 variants have not yet been reported in patients with a Rett-like phenotype, but have great phenotypic overlap and has been linked to the Rett-like spectrum 36. …”

mentioning

confidence: 99%

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

et al. 2018

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The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders with data from a Danish cohort of 35 patients with Rett-like phenotypes emphasizing the diagnostic overlap with Pitt-Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett-like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome-related genes described to date, and hence serves as a guide for diagnosing patients with Rett-like phenotypes.

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Adult Phenotypes in Angelman- and Rett-Like Syndromes

Cited by 27 publications

References 103 publications

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

The emerging role of SHANK genes in neuropsychiatric disorders

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

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