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

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.

SUBMITTER: Fehr S

PROVIDER: S-EPMC3573195 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Fehr Stephanie S Wilson Meredith M Downs Jenny J Williams Simon S Murgia Alessandra A Sartori Stefano S Vecchi Marilena M Ho Gladys G Polli Roberta R Psoni Stavroula S Bao Xinhua X de Klerk Nick N Leonard Helen H Christodoulou John J

European journal of human genetics : EJHG 20120808 3

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 CD ...[more]

PMID: 22872100

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Project description:The aim of the present study was to elucidate the genetic features of early-onset colorectal cancer (CRC), particularly the genetic mutations that may be regarded as prognostic and/or predictive markers in CRC and other malignancies. In total, 40 patients with non-polyposis CRC aged 35 or younger were selected. The formalin-fixed, paraffin-embedded tumors acquired were subjected to mismatch repair (MMR) protein immunochemical staining and gene analysis with next-generation sequencing (44 exons, 17 genes; Ion Torrent Sequencing Platform). A total of 11 (27.5%) tumors presented with MMR protein deficiency (dMMR) and 26 (65%) tumors harbored one or more genetic mutations, including K-RAS proto-oncogene (35%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA; 20%), B-Raf proto-oncogene (5%), erb-b2 receptor tyrosine kinase 2 (5%), discoidin domain receptor tyrosine kinase 2 (5%), N-RAS proto-oncogene (2.5%), KIT proto-oncogene (2.5%), TSC complex subunit 1 (2.5%), DNA methyltransferase 3 alpha (2.5%) and ABL proto-oncogene 1 (2.5%). Of the dMMR tumors, 81.8% (9/11) of cases presented with mutations in the tested genes, while only 58.6% (17/29) of the MMR-proficient (pMMR) tumors presented with these (P=0.158). PI3KCA was frequently mutated in dMMR tumors compared to pMMR tumors (P=0.025). In a subgroup with a family history of CRC, the dMMR status (P<0.001) and PIK3CA genetic mutation status (P=0.01) were more frequently observed compared to the other two groups (with a family history of other cancer types or no malignancy). Almost all patients who had relatives with CRC presented with both dMMR and other genetic mutations, while this was not observed in the patients who had relatives with other types of carcinoma. Certain genetic mutations that are rarely reported in CRC were only identified in those patients with a family history of carcinoma. In conclusion, non-polyposis CRC in young adults presents as a distinct entity with a unique set of genetic features. However, investigation of more cases in further studies is required to verify the present results.

Dataset Information

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

Publications

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

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