Mirror Movements 4

A number sign (#) is used with this entry because of evidence that mirror movements-4 (MRMV4) is caused by heterozygous mutation in the NTN1 gene (601614) on chromosome 17p13.

Description

Congenital mirror movements-4 is an autosomal dominant condition characterized by involuntary movements on either side of the body that accompany and mirror intentional movements on the opposite side. Mirror movements usually involve the upper limb and hands, resulting in difficulty performing pure unimanual movements. The pathophysiology is probably related to developmental abnormalities of fiber decussation in the corticospinal tract (summary by Meneret et al., 2017).

For a discussion of genetic heterogeneity of mirror movements, see MRMV1 (157600).

Clinical Features

Meneret et al. (2017) reported 2 families from France and the U.K. with congenital mirror movements and a patient from Canada with sporadic occurrence of the condition. The patients were unable to perform unimanual movements and had difficulty with skills requiring dissociated movements of the 2 hands. Mirror movements mainly affected the upper extremities, but some patients also had involvement of the feet. Two patients in 1 family had childhood-onset constipation-dominant irritable bowel syndrome and 2 patients had peripheral vasoconstriction when exposed to cold. Brain imaging, performed in 1 patient, was normal, with no hypoplasia of the corpus callosum. Diffusion tensor imaging, performed on 1 patient, showed a higher proportion of uncrossed fibers in the corticospinal tract compared to controls, indicating that fewer axons had crossed the midline and more were on the ipsilateral side. Electrophysiologic studies, performed in 2 patients, showed that unilateral stimulation of the primary motor cortex frequently elicited bilateral motor-evoked potentials in patients compared to controls. The findings indicated that the patients had an increased proportion of ipsilateral corticospinal tract projections.

Inheritance

The transmission pattern of MRMV4 in the families reported by Meneret et al. (2017) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In members of 2 unrelated families and in an unrelated patient with MRMV4, Meneret et al. (2017) identified heterozygous mutations in the NTN1 gene (601614.0001-601614.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the condition in the 2 families; the patient in the third family had sporadic occurrence and the mutation occurred de novo. All mutations occurred in the NTR domain and were predicted to affect protein structure and/or stability. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant proteins were almost exclusively found in the intracellular compartments and could not be detected in the supernatant. Since netrin-1 is a diffusible extracellular cue, the pathophysiology probably involved a loss of function. The patients were ascertained from a cohort of 47 index cases with congenital mirror movements in whom mutations in other MRMV-associated genes were excluded.

Animal Model

Serafini et al. (1996) found that homozygous Ntn1-null mice were born but apparently did not suckle and died within a few days. Netrin-1-deficient mice exhibited defects in spinal commissural axon projections that were considered consistent with netrin-1 guiding these axons. Defects in several forebrain commissures were also observed, suggesting additional guidance roles for netrin-1.