Cyclin-Dependent Kinase-Like 5 (<i>CDKL5</i>) Mutation Screening in Rett Syndrome and Related Disorders

White, R. W.; Ho, Gladys; Schmidt, Swetlana; Scheffer, Ingrid E.; Fischer, Alexandra E.; Yendle, Simone C.; Bienvenu, Thierry; Nectoux, Juliette; Ellaway, Carolyn; Darmanian, Artur; Tong, XingZhang; Cloosterman, Desiree; Bennetts, Bruce; Kalra, Veena; Fullston, Tod; Gécz, Jozef; Cox, Timothy C.; Christodoulou, John

doi:10.1375/twin.13.2.168

Cited by 34 publications

(30 citation statements)

References 47 publications

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“…Previous studies of the CDKL5 disorder have also reported dysmorphic features including: large deep-set eyes, strabismus, high forehead, full lips, wide mouth, widely spaced teeth and a high palate. 1,4,5,7,13,18,20,22,25,26,[28][29][30]35 Dysmorphic features have been described in other conditions presenting with early-onset encephalopathy, such as those with FOXG1 mutations and in Pitt-Hopkins syndrome (PHS). In those with FOXG1 mutations, subtle, non-specific dysmorphic features have been reported, along with severe microcephaly, which is typical of FOXG1 syndrome but not common in individuals with the CDKL5 disorder.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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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 ¼ 86) and females with MECP2 mutations (n ¼ 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.

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Section: Discussionmentioning

confidence: 99%

“…1,4,5,7,13,18,20,22,25,26,[28][29][30]35 The presence of typical facial or other features could provide additional assistance in the clinical identification of individuals with a CDKL5 mutation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…In contrast, truncations of the C-terminus seem to enhance its phosphorylation and cause its nuclear accumulation and activity [Rusconi et al, 2008]. Interestingly, recent data suggest that missense mutations negatively affecting the catalytic activity of CDKL5 could be associated with a more severe clinical picture than that caused by truncating mutations located in the last exons of CDKL5 that are predicted to truncate only amino acids of the CDKL5 COOH-terminus [Evans et al, 2005;Bahi-Buisson et al, 2008b;Russo et al, 2009;White et al, 2010].…”

Section: Functions Of the Cdkl5 Proteinmentioning

confidence: 99%

<i>CDKL5</i>-Related Disorders: From Clinical Description to Molecular Genetics

Bahi-Buisson¹,

Bienvenu

2011

Mol Syndromol

101

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Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. To date, with more than 80 reported cases, the phenotype of CDKL5-related encephalopathy is better defined. The main features consist of early-onset seizures starting before 5 months of age, severe mental retardation with absent speech and Rett-like features such as hand stereotypies and deceleration of head growth. On the other hand, neuro-vegetative signs and developmental regression are rare in CDKL5 mutation patients. The CDKL5 gene encodes a serine threonine kinase protein which is characterized by a catalytic domain and a long C-terminal extension involved in the regulation of the catalytic activity of CDKL5 and in the sub-nuclear localization of the protein. To our knowledge, more than 70 different point mutations have been described including missense mutations within the catalytic domain, nonsense mutations causing the premature termination of the protein distributed in the entire open reading frame, splice variants, and frameshift mutations. Additionally, CDKL5 mutations have recently been described in 7 males with a more severe epileptic encephalopathy and a worse outcome compared to female patients. Finally, about 23 male and female patients have been identified with gross rearrangements encompassing all or part of the CDKL5 gene, with a phenotype reminiscent of CDKL5-related encephalopathy combined with dysmorphic features. Even if recent data clearly indicate that CDKL5 plays an important role in brain function, the protein remains largely uncharacterized. Phenotype-genotype correlation is additionally hampered by the relatively small number of patients described.

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“…Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome, although the predominant phenotype is an epileptic encephalopathy. [3][4][5] The congenital variant is characterised by infantile hypotonia and developmental delay evident earlier than in classic Rett syndrome but causative mutations have previously rarely been identified in these patients. 6 Recent reports of microdeletions in the 14q12 region found in Rett syndrome patients have found a third gene, forkhead box protein G1 (FOXG1), to be highly associated with the congenital variant.…”

Section: Introductionmentioning

confidence: 99%

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

Ellaway

Bettella

et al. 2012

Eur J Hum Genet

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Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in B90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.

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Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

Cited by 34 publications

References 47 publications

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

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

<i>CDKL5</i>-Related Disorders: From Clinical Description to Molecular Genetics

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype

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