CDKL5 deficiency disorder in males: Five new variants and review of the literature

Varesio, Costanza; Freri, Elena; Darra, Francesca; Gana, Simone; Mei, Davide; Porta, Francesco; Fontana, Elena; Galati, Giulia; Solazzi, Roberta; Niceta, Marcello; Veggiotti, Pierangelo; Alfei, Enrico

doi:10.1016/j.ejpn.2021.04.007

Cited by 22 publications

(48 citation statements)

References 71 publications

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“…[2][3][4][5][6] Pathogenic variants of CDKL5 (de novo-or mosaicism-derived missense, nonsense, deletion, frameshift, and/or splicing mutations) 1,7-9 lead to the development of CDKL5 deficiency disorder (CDD), a rare, X-linked disorder with an incidence of approximately one in 40,000 live births and a female to male ratio of 4:1. 10,11 Although males are generally reported as experiencing more severe disease versus females, 12,13 results from a recent report suggest otherwise. 14 Additionally, cases of a milder phenotype have been reported in mosaic males.…”

Section: Introductionmentioning

confidence: 99%

“…14 Additionally, cases of a milder phenotype have been reported in mosaic males. 11 Severity in females is also variable, possibly due to X-chromosome inactivation. 7,15 CDD is a developmental and epileptic encephalopathy characterized by early-onset, refractory seizures and severe global developmental impairment; cortical visual impairment, sleep disturbances, and hypotonia are also common.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

Pestana-Knight

Amin

Bahi‐Buisson

et al. 2022

The Lancet Neurology

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

Pestana-Knight

Amin

Bahi‐Buisson

et al. 2022

The Lancet Neurology

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“…Thirty-five studies were excluded after reading the full texts. Ultimately, 12 studies (9 studies in English and 3 studies in Chinese) with 193 patients were included for literature analysis [8,19,[22][23][24][25][26][27][28][29][30][31].…”

Section: Search Resultsmentioning

confidence: 99%

Efficacy of ketogenic diet in CDKL5-related epilepsy: a single arm meta-analysis

Zhang

Chang

et al. 2022

Orphanet J Rare Dis

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Background Drug-resistant epilepsy is one of the most important features of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. The ketogenic diet (KD) may be effective for patients with CDKL5-related epilepsy, but there is little high-quality evidence to confirm the efficacy. This meta-analysis investigated the efficacy and safety of KD in CDKL5-related epilepsy. Methods The PubMed, Embase, Web of Science, Cochrane Library, WanFang, CNKI and VIP databases were searched for relevant studies published up to January 1, 2022. Two reviewers independently screened the literature according to inclusion and exclusion criteria and evaluated the bias risk of the included studies. Meta-analysis was performed using Review Manager 5.3 software. Results A total of 12 retrospective studies involving 193 patients met the inclusion criteria. Meta-analysis revealed that the definite responder rate to KD in the treatment of CDKL5-related epilepsy was 18.0% [95% CI (0.07, 0.67)], with no statistical heterogeneity among studies (I2 = 0%, P = 0.45). The clinical responder rate was 50.5% [95% CI (0.75, 1.39)], and there was no statistical heterogeneity among all studies (I2 = 46%, P = 0.05). Subgroup analysis showed that there was no significant difference in the clinical responder rate between the two groups with seizure onset age before and after 1 month (P = 0.14). Only one study mentioned adverse reactions, and the incidence of adverse reactions was 78.3% (18/23). Constipation and vomiting were the main manifestations, implying a high incidence of gastrointestinal adverse reactions. Conclusions The definite responder rate to KD in CDKL5-related epilepsy was 18%, and the gastrointestinal adverse reactions were probably common in these patients. All the studies included in the meta-analysis were retrospective, and most of them had small sample sizes. Additional high-quality studies are needed to confirm the efficacy and tolerance of KD in CDKL5-related epilepsy.

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“…In males, postzygotic mosaicism, which accounts for 16% of the cases, contributes to this variability. Based on these issues, genotype–phenotype correlations are still challenging [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

Musante

Costa

Zanus

et al. 2022

Genes

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Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.

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CDKL5 deficiency disorder in males: Five new variants and review of the literature

Cited by 22 publications

References 71 publications

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

Efficacy of ketogenic diet in CDKL5-related epilepsy: a single arm meta-analysis

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

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