Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia.

Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly conserved Pro-Val-Pro motif within the pore of the Kv1.1 channel in a girl affected by early onset epilepsy, ataxia and developmental delay. Other mutations causing severe epilepsy are located in Kv1.1 pore domain. The patient was initially treated with a combination of antiepileptic drugs with limited benefit. Finally, seizures and ataxia control were achieved with lacosamide and acetazolamide. The aim of this study was to functionally characterize Kv1.1 mutant channel to provide a genotype-phenotype correlation and discuss therapeutic options for KCNA1-related epilepsy. To this aim, we transfected HEK 293 cells with Kv1.1 or P403A cDNAs and recorded potassium currents through whole-cell patch-clamp. P403A channels showed smaller potassium currents, voltage-dependent activation shifted by +30 mV towards positive potentials and slower kinetics of activation compared with Kv1.1 wild-type. Heteromeric Kv1.1+P403A channels, resembling the condition of the heterozygous patient, confirmed a loss-of-function biophysical phenotype. Overall, the functional characterization of P403A channels correlates with the clinical symptoms of the patient and supports the observation that mutations associated with severe epileptic phenotype cluster in a highly conserved stretch of residues in Kv1.1 pore domain. This study also strengthens the beneficial effect of acetazolamide and sodium channel blockers in KCNA1 channelopathies.

Psychiatric morbidity with focus on obsessive-compulsive disorder in an Israeli cohort of adolescents with mild to moderate mental retardation.

The study evaluated the prevalence of DSM-IV-TR-defined psychiatric disorders in adolescents with mental retardation, with a focus on obsessive-compulsive disorder (OCD), for which data at present are sparse. Eighty-seven adolescents with mild to moderate mental retardation attending the Israeli special-education system were screened for psychiatric disorders in general and obsessive-compulsive symptoms in particular. Sixty-one percent had at least one psychiatric disorder. Of the 13 participants receiving antipsychotic medication, none had an underlying psychotic disorder and most had anxiety or depressive disorders. OCD was detected in 11% of participants and was characterized by high rates of psychiatric comorbidities. The severity of autistic symptoms predicted 39% of the variance in the severity of OCD symptoms. Adolescents with mild to moderate mental retardation have high rates of psychiatric morbidities that are often inappropriately treated. OCD is prevalent in this population and is strongly associated with autistic symptoms. Further studies are required in adolescents with mental retardation to better delineate psychiatric morbidities and their appropriate treatment in this at-risk population.