The Nexmif syndrome
The Neurite EXtension and Migration Factor gene (NEXMIF – formerly known as KIAA2022, KIDLIA, XPN OR MRX-98) discovered in 2004 and clinically described between 2013 and 2016, is localized on the X chromosome at Xq13.2, with
little known biological function and encodes a deduced protein of 1516 amino acids.
The Nexmif knockdown leads to a marked impairment in neurite outgrowth, with a particular impact on dendrites and axons lenght.
The underlying mechanism is the probable loss of function ranging from a total loss in hemizygotic males to a partial loss, with variable protein expression decrease in females due to X chromosome (XCI) inactivation.
The protein product of this gene is thought to play an important role in early brain development, neuronal morphogenesis, migration and synapse formation.
Nexmif mRNA expression has been shown to begin as early as the fetal period, increase during development and continue to a lower level in adulthood, showing particularly strong expression in the cortex, hippocampus, cerebellum and olfactory bulb.
Symptoms of this mutation mainly concern intellectual disability and developmental delay starting from walking and talking.
In females, a severe drug-resistant epilepsy is often present. Behavioral disorders at various levels are reported very commonly, including hyperactivity and autism spectrum. Other comorbidities also occur such as infantile hypotonia, ataxia, gastroesophageal reflux, drooling, spasticity, lack of sphincter control, microcephaly and strabismus.
Mutations in the Nexmif gene should be suspected in all cases of X-linked intellectual disability in males or even in cases of refractory epilepsy in females.