Autism Spectrum Disorder and Atypical Epilepsy Presentation in KCNQ3 Mutations: Expansion of Phenotypic Spectrum With...

Mutations in the KCNQ3 gene are primarily associated with benign familial neonatal epilepsy; however, recent studies have expanded its phenotypic spectrum to include developmental and epileptic encephalopathies (DEE) and neurodevelopmental disorders, including autism spectrum disorder (ASD). This report describes an atypical presentation of a patient with a de novo KCNQ3 mutation, manifesting as neonatal-onset epilepsy, ASD traits, and abnormal neuroimaging findings, contributing to the evolving understanding of KCNQ3-related disorders.

A 5-year-old boy presented with neonatal seizures that initially responded to antiepileptic therapy but subsequently relapsed with atypical, drug-resistant seizures. Neurodevelopmental assessment revealed moderate intellectual disability, ASD features, and speech delay. Brain MRI showed hippocampal asymmetry and diffuse enlargement of perivascular spaces, raising questions about potential structural correlates of genetic epilepsies. Whole-exome sequencing identified a de novo heterozygous KCNQ3 variant, absent in both parents.

This case highlights the expanding phenotypic variability of KCNQ3 mutations, supporting their role in epileptic encephalopathies and neurodevelopmental disorders. While previous reports primarily associate KCNQ3 mutations with early-onset epilepsy, this case suggests a broader neurodevelopmental impact, including ASD traits and neuroimaging abnormalities, emphasizing the importance of genetic screening in complex epilepsy syndromes. Additionally, the hippocampal asymmetry and prominent perivascular spaces warrant further investigation into their relevance in KCNQ3-related disorders.

This study expands the clinical and neuroimaging spectrum of KCNQ3-related epileptic encephalopathy, reinforcing its association with neurodevelopmental comorbidities. Early genetic diagnosis may guide treatment choices and provide valuable prognostic insights, advocating for a multidisciplinary approach in managing these patients.