Abstracts

Rationale:
Patients with developmental and epileptic encephalopathies (DEEs) exhibit a wide range of health complications, including gastrointestinal symptoms (GI-SX). To determine the prevalence of GI-SX among DEE channelopathy patients and identify commonalities between patients exhibiting GI-SX, we analyzed functional, diagnostic, and treatment information provided by parents of SCN1A-, KCNB1-, and KCNQ2-linked DEE patients as part of a natural history survey.
Method:
Several parent-formed epilepsy organizations disseminated information about the survey to their members. DEE patient information was collected in CLIRINX©. Analysis focused on the prevalence, frequency, and severity of GI-SX (specifically reports of constipation or dysmotility in the past month) between patient groups and the associations of GI-SX with functional mobility (wheelchair dependence), chewing and swallowing difficulties, ketogenic diet, autism diagnosis, and medications.
Results:
Parents of patients with DEEs (N=168, 55% female, median age=6.25 years, IQR=3.3 to 10.3 years) linked to variants in SCN1A (n=59), KCNB1 (n=31), and KCNQ2 (n=78) completed information about GI-SX. GI-SX were reported for 44% SCN1A-DEE patients, 35% KCN1B-DEE patients, and 71% KCNQ2-DEE patients (p< 0.001); The majority (73%) of patients experiencing GI-SX reported either daily or weekly symptoms, and a subset of these patients exhibited frequent or serious discomfort (32%) and appetite disturbances (14%) as a result. After adjustment for DEE type, current use of ketogenic diet (6% reported on diet vs 94% not on diet) was associated with GI-SX (p< 0.05). Factors not clearly associated with GI-SX after adjustment for DEE type were patient age (p=0.09), functional mobility (p=0.47), chewing and swallowing difficulties (p=0.52), and autism (p=0.20). Overall, no individual seizure medication appeared to be associated with GI-SX.
Conclusion:
GI-SX are prevalent and often severe in DEE patients and are not fully explained by factors often implicated in GI dysfunction (functional mobility, diet, medications).  Voltage-gated sodium (Nav) and potassium (Kv) channels are expressed in the human GI tract and are involved in GI cell excitability and proper GI function. By focusing on DEE patients with variants in genes encoding Nav and Kv channels, this study highlights the need to better understand the role of aberrant function of voltage-gated ion channels that may directly contribute to the observed GI pathology. An improved understanding of the mechanism(s) underlying the GI symptoms commonly observed in DEE patients could lead to novel treatments that address this disruptive comorbidity and improve quality of life for patients and caregivers. Future research should focus on the biological role of these channels in the GI system to better understand how genetic variants may directly influence GI dysfunction in DEE patients.
Funding:
:Stanley Manne Children’s Research Institute and Ann & Robert H. Lurie Children’s Hospital of Chicago Precision Medicine Strategic Research Initiative and Pediatric Epilepsy Research Consortium, Dallas, TX to ATB and NIH R37-NS076752 to LLI