Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H

Abstract

Objective: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome.

Methods: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course.

Results: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism.

Significance: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches.

Keywords: Epileptic encephalopathy; Infantile spasms; KCNQ2; Myoclonus; Neonatal seizures.

Figure 1. Evolution of EEG during Early Infancy (Patient A)

A. EEG (7µV/mm) at two days of age showing a burst-suppression pattern. B. EEG (7µV/mm) at 47 days of age showing a pattern of multi-focal epileptiform discharges with random areas of attenuation while on ezogabine (level 1600ng/mL). C. EEG (7µV/mm), just prior to discharge from the neonatal intensive care unit at 106 days of age showing a pattern of multifocal epileptiform discharges on vigabatrin 50mg/kg/day.

Figure 2. Brain MRI at Three months of age in Infant with KCNQ2 R201C Variant

A. Axial T2 weighted image shows diffuse reduced brain volume with ex vacuo enlargement of the lateral ventricles, also notice subependymal heterotopias in the right ventricular atrium (white arrow). B. Sagittal T1 weighted image shows diffuse thinning of the corpus callosum (white arrow) that reflects bilateral volume loss in the cortex. C. Axial T1 weighted inversion recovery image shows no myelination in the anterior limb of internal capsule (should be present at three months of age), suggesting hypomyelination (patient A).

Figure 3. Respiratory and SpO₂ Recording in Infant with KCNQ2 R201C Variant

Respiratory and pulse oximetry recording at three months of age showing excessive sighing and unusual periodic breathing associated with intermittent hypoxia (patient A).