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  • br Genotype phenotype correlations Genotype phenotype correl

    2020-01-14


    Genotype-phenotype correlations Genotype-phenotype correlations are limited. Compared with individuals with truncating variants, those with pathogenic missense variants in the adenosine triphosphate binding site had a milder disorder, some with ability to walk unaided, better hand use, and less refractory epilepsy. One individual in the COE cohort with a missense variant, p.Tyr24Cys, in the adenosine triphosphate binding site has refractory epilepsy but is making more developmental progress than most individuals with CDD and lacks cortical visual impairment. Another study found that females with late truncating variants after amino Fungicidin 781 had better gross motor, hand function, and communication milestones than earlier truncating variants.34, 68 Seizure frequency was lower in individuals with truncating variants between amino acids 172 and 781 compared with those with no functional protein (incidence rate ratio 0.57; 95% confidence interval 0.35 to 0.93). The influence of somatic CDKL5 mosaicism on clinical phenotype is unknown.
    Clinical trials and treatments suggested from animal studies An open-label phase 2 clinical trial of cannabidiol in CDD and three other early life genetic epileptic encephalopathies suggested improvement in frequency of motor seizures >3 seconds in duration. The CDD group had a median reduction in motor seizures from median 66.4 per 28 days (interquartile range 25.9 to 212.0) to 35.8 (interquartile range 8.9 to 141.6) at 12 weeks, with stable frequency at 48 weeks. A phase 2 randomized, placebo-controlled crossover study of ataluren, a medication that targets pathogenic nonsense variants in other genetic diseases, is in process in CDD (NCT02758626), but results are not yet available. Another phase 2 trial is being initiated for TAK-935, a novel medication that modulates the N-methyl-D-aspartate receptor system (NCT03694275). Ganaxolone, a synthetic methyl derivative of allopregnanolone, is a neurosteroid for which there have been previous trials in the epilepsies including for infantile spasms, status epilepticus, and protocadherin 19-related epilepsy. A phase 2 open-label clinical study is completed, and a phase 3 randomized, placebo-controlled study is ongoing in CDD (NCT03572933). CDKL5 regulates the interaction of IQ motif containing GTPase activating protein 1 with microtubule plus end tracking protein cytoplasmic linker protein 170 (CLIP170), disrupting microtubule dynamics in CDD. Allopregnanolone restores microtubule association of CLIP170 in CDKL5-deficient neurons, rescuing morphologic defects. Molecular pathway abnormalities in CDD rodent models suggest additional possible therapies. Dysregulation in the GSK3-beta pathway in Cdkl5 knockout mouse model led to treatment with a GSK3-beta inhibitor, tideglusib. Treatment during the juvenile period improved hippocampal development and hippocampus-dependent behaviors, whereas treatment in adult mice was not beneficial. Reduced expression of the GluA2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor was identified in CDKL5 knockout mice. Treatment of the mice with the antidepressant tianeptine normalized the expression of membrane-inserted α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors containing GluA2. Treatment of rodents with IGF-1, which activates the AKT/mTOR pathway, rescued dendritic spine instability. Protein substitution therapy has been evaluated in animal models with promising results, although feasibility and timeframe to bring this approach to human trials are uncertain. Novel therapeutic approaches including genome editing, RNA-based therapeutics, and gene therapy are being strongly considered.
    Conclusions CDD is an epileptic encephalopathy, defined by the International League Against Epilepsy as a disorder in which “the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone and that these may worsen over time.” The transient regressions that occur in CDD are consistent with this definition although there is undoubtedly a developmental component as well. Future studies of the natural history of CDD will better define the role of seizures, interictal epileptiform activity, and antiseizure medications as factors that may adversely affect these children. We hope that increased preclinical studies to define the molecular consequences of impaired CDKL5 and advances in novel, targeted drug development and molecular biology and genetic approaches will radically transform the prognosis for children with CDD.