Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.<b>SIGNIFICANCE STATEMENT</b> CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures.
Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.<b>SIGNIFICANCE STATEMENT</b> CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures.
Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.<b>SIGNIFICANCE STATEMENT</b> CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures.
Notably, selected mutants of all categories (RS1-F108C, -R141H, and -R209H) failed to regulate retinal MAP kinase signaling and Na/K-ATPase localization in Rs1h<sup>-/Y</sup> retinal explants, and could not attenuate photoreceptor degeneration.
While most of the XLRS associated mutations strongly interfere with cellular secretion, this is not true for mutants RS1-F108C, -R141G, -R141H, -R182C, -H207Q and -R209H.
Notably, selected mutants of all categories (RS1-F108C, -R141H, and -R209H) failed to regulate retinal MAP kinase signaling and Na/K-ATPase localization in Rs1h<sup>-/Y</sup> retinal explants, and could not attenuate photoreceptor degeneration.
In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free.
In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free.
We investigated a group of 30 female patients with a clinically heterogeneous phenotype ranging from nonspecific intellectual disability to a severe neonatal encephalopathy and identified two heterozygous CDKL5 missense mutations, the previously reported p.Val999Met and the novel mutation p.Pro944Thr.
Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations.
In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk.
In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk.
In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk.
In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk.
A novel c.2854C>T (p.R952X) was identified in an ambulatory girl who had severe mental retardation, multiple types of seizures without Rett-like features.
Our data show that the R213W mutation in RS1 causes various severities of retinoschisis in a large Chinese family, providing further evidence for X-linked juvenile retinoschisis phenotypic variability.
Severe XLRS phenotypes are associated with the frameshift mutation 26 del T, splice donor site mutation (IVS1+2T to C), and Arg102Gln, Asp145His, Arg209His, and Arg213Gln mutations.
Severe XLRS phenotypes are associated with the frameshift mutation 26 del T, splice donor site mutation (IVS1+2T to C), and Arg102Gln, Asp145His, Arg209His, and Arg213Gln mutations.
Severe XLRS phenotypes are associated with the frameshift mutation 26 del T, splice donor site mutation (IVS1+2T to C), and Arg102Gln, Asp145His, Arg209His, and Arg213Gln mutations.