Rationale:
To describe NEXMIF as a novel genetic etiology of continuous spike-wave during slow-wave sleep (CSWS) and the clinical implications of this association
Methods:
Case presentation:
At age 10, an otherwise healthy girl started exhibiting worsening academic performance and inattention at school. By age 11, she developed seizures with a mixed semiology characterized by atypical absence and generalized tonic-clonic components. Contrasted MRI of the brain was normal. Initial routine EEG showed right-sided frontal-central spikes; brivaracetam and oxcarbazepine were then started. Seizures became less frequent, but seizure freedom was never achieved, despite addition of zonisamide and maximum doses of all 3 medications by age 13.
At age 13, the patient was admitted for status epilepticus and underwent long-term EEG monitoring. During both asleep and awake states, there were abundant, nearly continuous medium-high amplitude generalized spike and wave discharges occurring at 1-2 Hz; spike-wave index averaged 85% during non-REM sleep (Fig 1). Brivaracetam was stopped, and valproate and clobazam were added, significantly decreasing her spike-wave index (Fig 2). INVITAE genetic epilepsy panel revealed a deletion within NEXMIF that resulted in a frameshift mutation (c.2638del p.M880Wfs*29); this variant does not appear in CLINVAR.
Results:
We present the first case implicating NEXMIF, known as ‘neurite extension and migration factor’, as a genetic etiology of CSWS. While NEXMIF mutations are known to cause intellectual disability and epilepsy, associated EEG patterns have been reported as spikes, poly-spikes, and waves – but not CSWS. When undergoing genetic epilepsy workup, an identified NEXMIF mutation should prompt careful evaluation for CSWS, the presence of which strongly influences prognosis and antiseizure regimen. Specifically, patients with CSWS are at higher risk of medically refractory seizures and tend to benefit from early initiation of benzodiazepines – as was the case with our patient.
Importantly, this case demonstrates that absence of CSWS on routine EEG does not preclude the possibility of CSWS on long-term EEG. Clinicians should have a low threshold for epilepsy monitoring unit admission in patients with known NEXMIF-related epilepsy, particularly if they exhibit medically refractory seizures, new status epilepticus, or cognitive deterioration like our patient. These high-risk clinical features may hint at a more aggressive underlying EEG pattern.
Finally, our case displays novelty from a neurogenetic perspective. The patient’s NEXMIF deletion does not appear in the gene's CLINVAR entry, which lists over 300 pathogenic variants. Also, CSWS is traditionally associated with channelopathies in GRIN2A, SCN2A, KCNA2, and KCNB1. The addition of NEXMIF to the list of CSWS-associated genes suggests that this EEG pattern can also result from aberrant neuronal wiring and interconnectivity.
Conclusions:
Patients with NEXMIF-related epilepsy must be evaluated for underlying CSWS, particularly in cases of medically refractory seizures, status epilepticus, or cognitive deterioration. Long-term EEG monitoring should be considered since routine EEG can be of low yield to detect CSWS.
Funding: None