CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients

Archer, Hayley; Evans, Julie; Edwards, Stuart W; Colley, James; Newbury‐Ecob, Ruth; O'Callaghan, Finbar; Huyton, M; O’Regan, Mary; Tolmie, John; Sampson, Julian R.; Clarke, Angus; Osborne, J. P.

doi:10.1136/jmg.2006.041467

Cited by 177 publications

(186 citation statements)

References 22 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…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%

See 1 more Smart Citation

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…[2][3][4][5][6][7][8] The gene is composed of 20 encoding exons, and so far 450 mutations in patients with CDKL5-related encephalopathy have been reported, affecting quasi-exclusively girls. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Patients with CDKL5 mutations typically present severe intellectual disability and early seizures, microcephaly in B1/3 of cases, as well as RTT-like features such as severe hypotonia, hand stereotypies and sleep disturbances. 22 Several patients having symptoms reminiscent of a CDKL5-related disease profile have had no mutation identified, in spite of the large screening strategy that is available, suggesting that other unexplored regions and/or genetic loci are involved in the disease.…”

Section: Introductionmentioning

confidence: 99%

An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain

et al. 2010

View full text Add to dashboard Cite

We report the identification of a novel exon, which is referred to as exon 16b, within the cyclin-dependent kinase (CDK)-like 5 (CDKL5) gene that is implicated in the X-linked infantile spasm syndrome and the early-onset seizure variant of Rett syndrome. Interestingly, it is highly conserved in species through evolution, suggesting a potential functional role, but does not display any homology with other referenced sequences. Most importantly, the transcript including this exon is specifically expressed in brain. We suggest that CDKL5 exon 16b should now be considered in the genetic screening of patients presenting with a CDKL5-related disease profile.

show abstract

“…RTT (MIM 312750), an X-linked dominant male lethal neurodevelopmental disorder caused by a mutation in the MECP2 gene and characterized by a wide spectrum of clinical manifestations, was also found to be associated with West syndrome (4). Mutation analysis suggests the existence of additional loci possibly involved in both ISS and RTT (3,(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Disruption of the IQSEC2 transcript in a female with X;autosome translocation t(X;20)(p11.2;q11.2) and a phenotype resembling X-linked infantile spasms (ISSX) syndrome

Morleo

Iaconis²,

Chitayat³

et al. 2008

Mol Med Report

View full text Add to dashboard Cite

Abstract. We report on a female patient with severe infantile spasms, profound global developmental arrest, hypsarrhythmia and severe mental retardation, associated with a de novo apparently balanced X;autosome translocation. Her neurological phenotype resembles that of X-linked infantile spasms (ISSX). Molecular study showed that the translocation disrupts a transcript involved in GTPases signalling, IQSEC2, mapped to the Xp11.22 region. Several genes involved in intracellular signalling pathways via Ras-homologous small GTPase have been implicated in X-linked neurological disorders. Expression studies revealed that the murine homolog of this transcript, Iqsec2, is highly expressed in the nervous system from the early stages of development. These data suggest that IQSEC2 could be considered a candidate gene for X-linked neurological disorders.

show abstract

CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients

Cited by 177 publications

References 22 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

An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain

Disruption of the IQSEC2 transcript in a female with X;autosome translocation t(X;20)(p11.2;q11.2) and a phenotype resembling X-linked infantile spasms (ISSX) syndrome

Contact Info

Product

Resources

About