Developmental delay and intellectual disability
Affected males typically have developmental delay that is noticed in the first year of life. Developmental regression is seen in up to 70%, sometimes correlating with seizure onset/recurrence. Most affected males have severe to profound intellectual disability (ID) at later age (~70%), though less severely affected males have been reported also. The developmental trajectory and cognitive outcome in female patients with NEXMIF-E is more variable. Developmental delay can be noted later in affected females and impairments concerning motor and language development can be less severe. Developmental regression is seen in about one third of affected females. Affected females are more likely to have mild-moderate ID (~ 65%) than severe-profound ID. Importantly, healthy female carriers have been reported as well.
Epilepsy
About 80% of individuals with NEXMIF-E have epilepsy, which is slightly more frequent in females compared to males, and typically of the generalized type. Seizure onset age does not significantly differ between males and females, with reported onset ages ranging from 1 month to 17 years. Absences including absence with eyelid myoclonia, myoclonic seizures, myoclonic-atonic and generalised tonic-clonic are most frequently seen, although other seizures type have also been described, including tonic seizures, epileptic spasms, and focal seizures. Non-convulsive status epilepticus is a known complication, seen in about 1 in 5 patients with epilepsy. Both electrical and clinical photosensitivity have been reported. The predominant EEG finding are generalised spike-and wave discharges. Of interested, paroxysmal fast activity and eye-closure sensitivity have been repeatedly reported.
Epilepsy syndromes associated with NEXMIF-E are Absence epilepsy with Eyelid Myoclonia and Myoclonic-atonic epilepsy, with several patients showing a Developmental and Epileptic Encephalopathy with overlapping features of the two.
Seizures in NEXMIF-E are often difficult to treat with > 80% having drug-resistant seizures.
Autistic features and behavioural problems
Autism spectrum disorder or autistic features are present in 50-75 % of patients. About 70% patients have behavioural problems including hyperactivity, attention deficit disorder, aggressive behaviour, or stereotypies.
Dysmorphic features
Dysmorphic features are observed in about 50 % of patients with NEXMIF-E but are often subtle and nonspecific.
Brain imaging
Brain-imaging in NEXMIF-E is typically normal, although some non-recurrent abnormalities have been described such as regional or more general brain atrophy.
Other neurological and non-neurological clinical features
Neurological examination is normal in about half of patients. Abnormal findings include hypotonia (~40%), ataxia or coordination problems (~15%) or spasticity (~10%). Microcephaly (< 2 SD mean) is observed in ~ 15 %.
Gastro-intestinal problems are relatively frequent with infantile gastroesophageal reflux occurring in about 1 in 5 individuals. Pre-or postnatal growth retardation is more frequently seen in males (~40%) than females. In adult patients overweight or obesity is present in about half of the patients, and more frequent in females. Other recurrent clinical features are strabismus, and dysfunction of the hypothalamic–pituitary axis.
NEXMIF