Movement disorder and neuronal migration disorder due to ARFGEF2 mutation

Abstract

We report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the phenotype. The brain MRI shows bilateral hyperintensity of the putamen, BPNH, and generalized atrophy. Loss of ARFGEF2 function affects vesicle trafficking, proliferation/apoptosis, and neurotransmitter receptor function. This can explain BPNH and microcephaly. We hypothesize that the movement disorder and the preferential damage to the basal ganglia, specifically to the putamen, may be caused by an increased sensitivity to degeneration, a dynamic dysfunction due to neurotransmitter receptor mislocalization or a combination of both.

Fig. 1

Brain MRI made at the age of 13 months (images A, B, and C) and at the age of 4 years and 10 months (images D, E, and F). A and D T1-weighted images showing bilateral periventricular nodular heterotopia with the intensity of gray matter (black arrow in image D). B and E T2-weighted images showing hyperintensity of the putamen and atrophy of the putamen and globus pallidus (white arrow in image E). C and F Flair images, coronal view, showing bilateral hyperintensity of the putamen, more clearly visible on image F made at a later age (white arrow), and mild atrophy of the hippocampi

Fig. 2

The sequences of the relevant areas of the ARFGEF2 gene are depicted showing the maternal origin of c.2031_2038dup and the paternal origin of c.3798_3802del