Congenital Mirror Movements in a New Italian Family Alfonso Fasano, MD, PhD, 1 Matteo Bologna, MD, PhD, 2 Ennio Iezzi, MD, PhD, 2 Luigi Pavone, ME, 3,4 Myriam Srour, MD, 5,6 Francesca Di Biasio, MD, 2 Giovanni Grillea, MD, 2 Guy A. Rouleau, MD, PhD, 7 Annie Levert, MD, 7 Fabio Sebastiano, PhD, 2 Claudio Colonnese, MD, 2,8 Alfredo Berardelli, MD 2,8, * Abstract: Mirror movements (MMs) occur on the contralateral side of a limb being used intentionally. Because few families with congenital MMs and no other neurological signs have been reported, the underlying mechanisms of MMs are still not entirely clear. We report on the clinical, genetic, neurophysiological and neuroimaging findings of 10 of 26 living members of a novel four-generation family with congenital MMs. DCC and RAD51 were sequenced in affected members of the family. Five of the ten subjects with MMs underwent neurophysiological and neuroimaging evaluations. The neurophysiological evaluation consisted of electromyographic (EMG) mirror recordings, investigations of corticospinal excitability, and analysis of interhemispheric inhibition using transcranial magnetic stimulation techniques. The neuroimaging evaluation included functional MRI during finger movements. Eight (all females) of the ten members examined presented MMs of varying degrees at the clinical assessment. Transmission of MMs appears to have occurred according to an autosomal-dominant fashion with variable expression. No mutation in DCC or RAD51 was identified. EMG mirror activity was higher in MM subjects than in healthy controls. Short-latency interhemispheric inhibition was reduced in MM subjects. Ipsilateral motor-evoked potentials were detectable in the most severe case. The neuroimaging evaluation did not disclose any significant abnormalities in MM subjects. The variability of the clinical features of this family, and the lack of known genetic abnormalities, suggests that MMs are heterogeneous disorders. The pathophysiological mechanisms of MMs include abnormalities of transcallosal inhibition and corticospinal decussation. Mirror movements (MMs) are involuntary movements on one side of the body that accompany and mirror intentional move- ments on the opposite side, mainly involving the distal upper limbs. 1 MMs are present in patients with a variety of movement disorders, such as dystonia, 2 Parkinson’s disease, 3 and essential tre- mor, 4 as well as in congenital nervous system disorders, including Klippel-Feil, 5 Kallmann syndrome, 6 and congenital hemiplegia. 7 MMs may also be present in healthy subjects and, on rare occasions, even in several members of the same family with no other neurological signs (“congenital MMs”). 8–11 Mutations in the DCC gene were found to be the cause of congenital MMs in three unrelated families. 12,13 The likelihood of genetic heterogeneity is supported by the observation that no mutations in the DCC gene were found either in sporadic cases with con- genital MMs 11 or in a French and German family. 13 More recently, one of these families and another family from Germany were found to carry heterozygous mutations introducing prema- ture termination codons in the RAD51 gene. 14,15 RAD51 has been suggested to be involved in the decussation process of the corticospinal pathways 14 as well as in the development of normal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements. 15 Neurophysiological studies in subjects with congenital MMs point to a failure in corticospinal crossing and the development 1 Movement Disorders Center, TWH, UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada; 2 Neuromed Institute, IRCCS, Pozzilli (IS), Italy; 3 Innomed srl, Pozzilli (IS), Italy; 4“ Neurone” Foundation for Research in Neuropsychobiology and Clinical Neurosciences, Rome, Italy; 5 Sainte Justine Hospital Research Center, Montr eal, Qu ebec, Canada; 6 Montr eal Children’s Hospital, Department of Neurology and Neurosurgery, McGill University, Montr eal, Qu ebec, Canada; 7 Montr eal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montr eal, Qu ebec, Canada; 8 Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy * Correspondence to: Dr. Alfredo Berardelli, Department of Neurology and Psychiatry, “Sapienza” University of Rome, Vialedell’Universit  a 30, 00185 Rome, Italy; E-mail: alfredo.berardelli@uniroma1.it Keywords: corticospinal excitability, electromyography, functional magnetic resonance imaging, interhemispheric inhibition, mirror movements, neurophysiology, transcranial magnetic stimulation. Relevant disclosures and conflicts of interest are listed at the end of this article. Received 15 February 2014; revised 5 May 2014; accepted 17 May 2014. Published online 28 July 2014 in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/mdc3.12066 © 2014 International Parkinson and Movement Disorder Society 180 doi:10.1002/mdc3.12066 RESEARCH ARTICLE CLINICAL PRACTICE