To present a pediatric patient with RYR1 and GNAS variants and episodic hypotonia of unknown etiology responsive to calcium-channel blocker pharmacotherapy.

We present the case of a 19-month-old right-handed female with a complex medical history, including CFTR-related metabolic syndrome, feeding difficulties status post G-tube and Nissen fundoplication, a monoallelic likely pathogenic variant in RYR1, and a pathogenic variant in GNAS. She presented with recurrent episodes of hypotonia and weakness, first noted at one month of age. Initially, episodes were characterized by flaccidity with preserved awareness and visual tracking. Over time, the episodes progressed in severity, resulting in unresponsiveness and impaired tracking.

Episodes are intermittent, sometimes unilateral—more commonly affecting the left side—or generalized, lasting from 30 seconds to an hour. They are exacerbated by acute illness, discomfort or physical exertion. Vital signs remain stable during events, and there are no associated electrolyte abnormalities. Between episodes, the patient is developmentally appropriate with mild hypotonia.

Electrodiagnostic testing revealed decreased amplitude and slowed conduction in the motor median nerve. Muscle biopsy demonstrated nonspecific ultrastructural abnormalities, including Z-band streaming, sarcomeric disorganization, and mild mitochondrial pleomorphism.

Given her RYR1 variant, a diagnosis of periodic paralysis was initially suspected, and she was treated with Albuterol and Acetozolamide without clinical improvement. Inpatient evaluation with prolonged EEG did not show ictal correlates associated with the events. Due to the unilateral nature of her episodes, treatment with Verapamil—reportedly used in a case of Alternating Hemiplegia of Childhood (AHC)—was initiated. Following this intervention, she demonstrated marked clinical improvement, without further prolonged episodes reported.