Developmental delay and intellectual disability (ID)
All affected individuals with NEXMIF-E show developmental delay that is already noticed in the first year of life in most. This leads to ID at older age, ranging from mild ID to severe-profound ID. Loss of previously acquired skills (“developmental regression”) is seen in ~30% of individuals, and can correlate with onset of seizures or seizure relapse. In general, males tend to be at the more severe end of the spectrum and in females the developmental and cognitive outcome is more variable. Healthy females who carry a disease causing NEXMIF-variant 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. Seizure onset age ranges from 1 month to 17 years old. Seizures are typically of the generalised type including, but not limited to, absences (with eyelid myoclonia), myoclonic or tonic-clonic seizures.
Seizures in NEXMIF-E are often difficult to treat with > 80% having drug-resistant epilepsy.
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 (purposeless repetitive sounds and movements).
Dysmorphic features
Dysmorphic features (abnormal facial features or body characteristics) 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.
Other neurological and non-neurological clinical features
Neurological examination is normal in about half of patients. Abnormal findings include loss or increase of body tone, coordination problems or a small head .
Gastro-intestinal problems are relatively frequent with infantile gastroesophageal reflux (where acid from the stomach leaks up into the oesophagus) occurring in about 1 in 5 individuals. Growth retardation is more frequently seen in males (~40%) than females. In adults 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