KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism.

Researchers studied 15 children with specific changes in the KCNQ2 gene. All children had developmental delays and language difficulties, with two-thirds showing autism features. Unlike other KCNQ2 gene changes that cause seizures in newborns, these variants didn't cause early seizures but some children developed epilepsy later. The study found a medication called amitriptyline might help treat these children by targeting the specific brain channel problem.

This study examined 15 patients with KCNQ2 R144 gene variants (R144W, R144Q, R144G) and their clinical features. All patients had developmental delays with prominent language impairment, and 67% showed autistic features. Unlike typical KCNQ2 variants that cause neonatal seizures, these specific variants did not cause seizures in newborns but led to epilepsy in 40% of patients during infancy to childhood. Laboratory studies revealed these variants cause gain-of-function effects in potassium channels.

The medication amitriptyline showed potential as a targeted treatment by blocking the affected channels. The absence of neonatal seizures distinguishes these gain-of-function variants from loss-of-function KCNQ2 variants.

KCNQ2 R144 variants should be considered in children with developmental delays, language impairment, and autism features without neonatal seizures. Genetic testing can inform prognosis and treatment planning. Amitriptyline may represent a future targeted therapy but requires clinical trials to establish safety and efficacy.

Small sample size of 15 patients limits generalizability. Amitriptyline effects only tested in laboratory conditions, not in patients. Study design not clearly specified. Long-term outcomes and treatment effectiveness not assessed.

Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. Patients were identified using the RIKEE database and through clinical collaborators.

Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment.

R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects.

Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment.

Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.