A novel p.Arg970X mutation in the last exon of the CDKL5 gene resulting in late-onset seizure disorder

Psoni, Stavroula; Willems, Patrick J.; Kanavakis, Emmanuel; Mavrou, Ariadne; Frissyra, H; Traeger-Synodinos, Joanne; Sofokleous, Christalena; Makrythanassis, Periklis; Kitsiou-Tzeli, Sophia

doi:10.1016/j.ejpn.2009.03.006

Cited by 26 publications

(26 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, our data and the findings of others (BahiBuisson et al, 2008;Elia et al, 2008), strongly suggest that CDKL5 screening of MECP2 mutation-negative RTT patients is more likely to yield pathogenic mutations if they have early onset seizures, particularly an epileptic encephalopathy, and this notion is supported by the recent publications of Mei and colleagues (Mei et al, 2009) and Nemos and colleagues (Nemos et al, 2009). It remains to be seen whether individuals with milder phenotypes (Psoni et al, 2009) will be consistently found to have CDKL5 mutations.…”

Section: Discussionsupporting

confidence: 84%

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

White

Schmidt

et al. 2010

Twin Res Hum Genet

View full text Add to dashboard Cite

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

show abstract

Section: Discussionsupporting

confidence: 84%

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

White

Schmidt

et al. 2010

Twin Res Hum Genet

View full text Add to dashboard Cite

show abstract

“…11 On the basis of this line of evidence, a nonsense mutation p.Arg970X (c.2908C4T) was reported in 2009 in a girl, suggestive of 'atypical' Rett syndrome (severe intellectual disability, microcephaly, poor eye fixation, stereotypies, not able to walk, breathing irregularities, mild seizures at 17 months of age) but without regression, and was suggested to be pathogenic. 2 Although the p.Arg970X was not found in the mother of the proband, DNA analysis in her father and a further functional study were not performed. Two years later, another nonsense mutation p.Arg952X (c.2854C4T) located in exon 20 was identified in a 15-year-old girl with generalized tonic clonic seizure Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, milder phenotypes have been associated with sequence variations in the C-terminus of the CDKL5 gene, described by the authors as potential mutations. [2][3][4] These potential mutations were identified in patients carrying mutations inherited from either the mother or the father, and/or in patients with mental retardation of different degrees without regression or further symptoms. 4 On the other hand, three independent groups have recently identified novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the C-terminus of CDKL5: proceed with caution

et al. 2013

View full text Add to dashboard Cite

Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been described in girls with Rett-like features and earlyonset epileptic encephalopathy including infantile spasms. Milder phenotypes have been associated with sequence variations in the 3 0 -end of the CDKL5 gene. Identification of novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region strongly questions the eventual pathogenicity of sequence variations located in the 3 0 -end of the gene. We investigated a group of 30 female patients with a clinically heterogeneous phenotype ranging from nonspecific intellectual disability to a severe neonatal encephalopathy and identified two heterozygous CDKL5 missense mutations, the previously reported p.Val999Met and the novel mutation p.Pro944Thr. However, these mutations have also been detected in their healthy father. Considering our results and all data from the literature, we suggest that genetic variations beyond the codon 938 in human CDKL5 115 protein may have minor or no significance. It is probable that screening of exons 19-21 of the CDKL5 gene is not useful in practical molecular diagnosis of atypical Rett syndrome.

show abstract

“…Infantile spasms and refractory myoclonic epilepsy are frequent during the course of epilepsy but not always present in CDKL5 mutation patients ( tables 1 and 2 ) [Tao et al, 2004;Weaving et al, 2004;Evans et al, 2005;Mari et al, 2005;Scala et al, 2005;Archer et al, 2006;Buoni et al, 2006;Nectoux et al, 2006;Grosso et al, 2007;Bahi-Buisson et al, 2008b;Pintaudi et al, 2008;Nemos et al, 2009;Russo et al, 2009;Sprovieri et al, 2009;Bahi-Buisson et al, 2010;Mei et al, 2010;Psoni et al, 2010;Arts, 2011;Castren et al, 2011;Melani et al, 2011;Rademacher et al, 2011]. Patients who presented with a disrupted CDKL5 gene due to unbalanced translocations were excluded.…”

Section: Common and Rare Featuresmentioning

confidence: 99%

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

Bahi-Buisson¹,

Bienvenu

2011

Mol Syndromol

101

View full text Add to dashboard Cite

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.

show abstract

A novel p.Arg970X mutation in the last exon of the CDKL5 gene resulting in late-onset seizure disorder

Cited by 26 publications

References 16 publications

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

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

Mutations in the C-terminus of CDKL5: proceed with caution

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

Contact Info

Product

Resources

About