Dataset Information

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.

ABSTRACT: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.

SUBMITTER: Olson HE

PROVIDER: S-EPMC7120929 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.

Olson Heather E HE Demarest Scott T ST Pestana-Knight Elia M EM Swanson Lindsay C LC Iqbal Sumaiya S Lal Dennis D Leonard Helen H Cross J Helen JH Devinsky Orrin O Benke Tim A TA

Pediatric neurology 20190223

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnost ...[more]

PMID: 30928302

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Project description:BackgroundCyclin-dependent kinase 12 (CDK12) loss occurs in 3-7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established.ObjectiveTo determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.Design, setting, and participantsA retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n?=?172) or circulating tumor DNA (n?=?145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).Outcome measurements and statistical analysisPatients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.Results and limitationsThe median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median?=?34.9 mo, p?=? 0.004) and development of castration-resistant disease (median = 32.7 mo, p?<? 0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, p?=? 0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data.ConclusionsOur data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers.Patient summaryIn this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ?8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.

Dataset Information

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.

Publications

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.

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