Alternative titles; symbols
ORPHA: 238722;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q21.2 | Mirror movements 1 and/or agenesis of the corpus callosum | 157600 | Autosomal dominant | 3 | DCC | 120470 |
A number sign (#) is used with this entry because of evidence that mirror movements-1 (MRMV1) is caused by heterozygous loss-of-function mutation in the DCC gene (120470) on chromosome 18q21.
Mirror movements are contralateral involuntary movements that mirror voluntary ones. Whereas mirror movements are occasionally found in normal young children, persistence beyond the age of 10 years is abnormal. Congenital mirror movements tend to persist throughout adulthood and tend to occur more commonly in the upper extremities (summary by Sharafaddinzadeh et al., 2008 and Srour et al., 2010). Some patients with DCC mutations have agenesis of the corpus callosum (Marsh et al., 2017).
Genetic Heterogeneity of Mirror Movements
See also MRMV2 (614508), caused by mutation in the RAD51 gene (179617) on chromosome 15q15; MRMV3 (606059), caused by mutation in the DNAL4 gene (610565) on chromosome 22q13; and MRMV4 (618264), caused by mutation in the NTN1 gene (601614) on chromosome 17p13.
According to Rosemary Harvey (2008), the biographer of William Bateson (1861-1926), Bateson carried on a conversation with H. Drinkwater concerning this condition, which he referred to as bimanual synergia. The patient was a boy who seemed normal in all respects except for the movements of his 2 hands and the sensation in his arms. He could not flex or extend the fingers of one hand without making the same movements with the other hand. Drinkwater found that the condition was hereditary and was transmitted through the mother who herself was normal. The patient's maternal aunt could control the synergic movements but only by a strong effort. The boy's brother had shown the condition in childhood but grew out of it in his early teens and recovered completely. If the boy felt a painful stimulus on one side, he immediately felt it in the same part of the other hand or arm. Drinkwater was said to have sent information on this case to the Neurological Section of the International Medical Congress meeting in London in 1913. In later correspondence, Drinkwater concluded that his pedigree of bimanual synergia did not follow mendelian rules.
Sharafaddinzadeh et al. (2008) reported the 5-generation pedigree of a large Persian-speaking family from the Isfahan province of southeast Iran. There were 17 affected members of this family segregating this autosomal dominant trait with incomplete penetrance. There were far more males than females, with a 12 to 5 male-to-female ratio. All affected family members had otherwise completely normal neurologic and psychiatric examinations and brain and cervical MRI. Mirror movements were confirmed by electromyography.
Srour et al. (2009) reported a 4-generation pedigree segregating autosomal dominant congenital mirror movements not associated with other neurologic abnormalities. The family was a French Canadian family originating from the Lanaudiere region of Quebec. There was no known consanguinity. Transmission was autosomal dominant with high but incomplete penetrance. Penetrance was higher in males, with a male-to-female ratio of 9 to 2. Mirror movements were present in the hands, fingers, and forearms of all affected individuals: upon voluntary activation of one hand, the contralateral hand would mirror both simple and complex movements such as writing, typing, and tapping. Three individuals reported mirror movements in the toes and feet which were observable during foot tapping and movement of the toes. In most, mirror movements were noted at birth or infancy, and persisted unchanged throughout life. Half could partially suppress the movements. Despite often high amplitude of usually observable movements, patients functioned essentially normally. One patient worked successfully as an electrician performing high precision bimanual tasks, and another worked as a secretary and could type rapidly. Three reported mild clumsiness during childhood. Several reported social impairment, stating that they felt conspicuous or embarrassed by their muscle movements. Neurologic exam was otherwise normal in all. One had a normal MRI of the brain and cervical cord.
Depienne et al. (2011) reported a 3-generation Italian family in which 4 individuals had mirror movements of the arms and hands with onset in infancy or early childhood. Affected individuals had difficulty in fine bimanual movements, and 1 reported pain and muscle cramping during sustained manual activities. Only 1 patient reported some improvement during childhood; none required treatment.
Sagi-Dain et al. (2020) reported 4 symptomatic individuals, aged 3.5 to 32 years, from 2 generations of an Ethiopian Jewish family with mirror movements. All 4 had normal psychomotor development. Three of the 4 had brain imaging, which was normal. An additional 26-year-old family member carried the familial DCC mutation but was asymptomatic. Two pregnancies in this family were terminated due to prenatal detection of agenesis of the corpus callosum and dilated lateral ventricles; the only fetus tested carried the mutation.
Clinical Variability
Meneret et al. (2014) reported a family with mirror movements associated with a heterozygous truncating mutation in the DCC gene (R275X; 120470.0006). In a reassessment of this family, Marsh et al. (2017) found that partial or complete agenesis of the corpus callosum (ACC) also segregated with the mutation. Two patients with mirror movements had partial agenesis of the corpus callosum, whereas a family member without mirror movements had complete agenesis of the corpus callosum. The family originated from North Africa. The findings indicated that both features are part of the phenotype associated with DCC mutations.
Marsh et al. (2017) reported 3 additional families, 2 from Australia and 1 from North Africa, in which a heterozygous DCC mutation segregated with mirror movements and/or partial or complete agenesis of the corpus callosum. Intellectual abilities of the patients ranged from normal to borderline impaired, and some had specific cognitive impairments, including language delay or visuospatial deficits. Diffusion MRI tractography studies showed that mirror movements were consistently associated with decreased crossing of descending corticospinal tract projections at the pyramidal decussation. ACC was associated with absence of the hippocampal commissure and cingulate gyri, as well as dysmorphic lateral ventricles. The individuals had a more favorable outcome compared to unfavorable developmental outcomes associated with syndromic forms of ACC. Marsh et al. (2017) concluded that prenatal detection of isolated ACC related to a pathogenic DCC mutation is indicative of a lower risk of a poor neurodevelopmental outcome, with implications for genetic counseling.
The transmission pattern of MRMV1 in the family reported by Srour et al. (2009) was consistent with autosomal dominant inheritance with incomplete penetrance.
In a review of individuals with mutations in the DCC gene in their study and in the literature, Marsh et al. (2017) found significant incomplete penetrance: the penetrance of mirror movements was estimated to be 42%, and the penetrance of ACC was estimated to be 26%. There was some evidence for a male bias in phenotypic manifestations, and in vitro studies suggested that androgens could influence DCC expression.
Srour et al. (2010) conducted a genomewide linkage analysis and identified a single significant locus on chromosome 18q21.2 in their 4-generation family with congenital mirror movements. Haplotype analysis indicated that all affected individuals share a common risk haplotype. The region spans 2.5 megabases and contains 3 known genes including the DCC (120470) gene.
Heterogeneity
Depienne et al. (2012) excluded mutations in the DCC gene and in the exons of the RAD51 gene in affected members of a British family with mirror movements, suggesting genetic heterogeneity.
Srour et al. (2010) sequenced the 29 coding exons of DCC in a French Canadian family with congenital mirror movements and identified a splice site mutation in the donor site of exon 6 (120470.0003). This exon skipping results in a frameshift and the introduction of a stop codon 15 amino acids further down the new reading frame. Srour et al. (2010) also sequenced the DCC gene in an Iranian family with congenital mirror movements, originally reported by Sharafaddinzadeh et al. (2008), and found a 1-bp insertion resulting in frameshift and truncation (120470.0004). Srour et al. (2010) proposed that DCC mutations in individuals with congenital mirror movements cause a reduction in gene dosage and less robust midline guidance, which may lead to a partial failure of axonal fiber crossing and development of an abnormal ipsilateral connection. They also concluded that DCC has a central role in the development of human nervous system lateralization.
Depienne et al. (2011) identified a truncating mutation in the DCC gene (120470.0005) in an Italian family with 4 affected members.
In individuals from 4 unrelated multigenerational families with congenital mirror movements and/or agenesis of the corpus callosum, Marsh et al. (2017) identified heterozygous mutations in the DCC gene (120470.0006-120470.0009). The mutations were found by a combination of methods, including linkage analysis, whole-exome sequencing, and direct sequencing. Two mutations were truncating mutations, predicted to result in haploinsufficiency, and 2 were missense mutations affecting the netrin-1 (NTN1; 601614) binding domain. Heterozygous missense DCC mutations were subsequently found in 5 of 70 probands with isolated ACC. Functional studies of the variants and studies of patient cells were not performed. Marsh et al. (2017) noted that developmental differences between the corpus callosum and the corticospinal tract may influence the phenotype. Corticospinal axons and callosal axons use slightly different signaling to approach and cross the midline, such that a DCC mutation may differentially affect commissural versus subcerebral axon trajectories, resulting in the variable features of mirror movements, ACC, or both.
In 5 members of an Ethiopian Jewish family with MRMV1, Sagi-Dain et al. (2020) identified heterozygosity for a frameshift mutation in the DCC gene (120470.0012). The mutation, which was found by whole-exome sequencing, was also identified in an asymptomatic female family member. A fetus with agenesis of the corpus callosum from a terminated pregnancy in this family was not tested for the mutation.
Cincotta et al. (2003) used single- and paired-pulse transcranial magnetic stimulation to examine 2 Italian patients with congenital mirror movements. Both had dissociation of task-related intracortical inhibitory modulation, supported the existence of a separate ipsilateral fast-conducting corticospinal projection. The findings indicated that the motor cortex was abnormally connected to both side of the spinal cord via separate crossed and uncrossed fast-conducting corticospinal projections. One of the individuals showed marked reduction of mirror movements after training, suggesting that unwanted mirror activity can be suppressed by learning.
Kanga mice, as described by Finger et al. (2002), have a deletion of DCC exon 29 and exhibit mirror-type movements that result in a distinctive hopping gait. The mutant also shows defects in the crossing of corticospinal tracts and persistence of ipsilateral corticospinal tracts in hindbrain and spinal cord.
Cincotta, M., Borgheresi, A., Balzini, L., Vannucchi, L., Zeloni, G., Ragazzoni, A., Benvenuti, F., Zaccara, G., Arnetoli, G., Ziemann, U. Separate ipsilateral and contralateral corticospinal projections in congenital mirror movements: neurophysiological evidence and significance for motor rehabilitation. Mov. Disord. 18: 1294-1300, 2003. [PubMed: 14639670] [Full Text: https://doi.org/10.1002/mds.10545]
Depienne, C., Bouteiller, D., Meneret, A., Billot, S., Groppa, S., Klebe, S., Charbonnier-Beaupel, F., Corvol, J.-C., Saraiva, J.-P., Brueggemann, N., Bhatia, K., Cincotta, M., and 13 others. RAD51 haploinsufficiency causes congenital mirror movements in humans. Am. J. Hum. Genet. 90: 301-307, 2012. [PubMed: 22305526] [Full Text: https://doi.org/10.1016/j.ajhg.2011.12.002]
Depienne, C., Cincotta, M., Billot, S., Bouteiller, D., Groppa, S., Brochard, V., Flamand, C., Hubsch, C., Meunier, S., Giovannelli, F., Klebe, S., Corvol, J. C., Vidailhet, M., Brice, A., Roze, E. A novel DCC mutation and genetic heterogeneity in congenital mirror movements. Neurology 76: 260-264, 2011. [PubMed: 21242494] [Full Text: https://doi.org/10.1212/WNL.0b013e318207b1e0]
Finger, J. H., Bronson, R. T., Harris, B., Johnson, K., Przyborski, S. A., Ackerman, S. L. The Netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons. J. Neurosci. 22: 10346-10356, 2002. [PubMed: 12451134] [Full Text: https://doi.org/10.1523/JNEUROSCI.22-23-10346.2002]
Harvey, R. Personal Communication. Cambridge, England 2008.
Marsh, A. P. L., Heron, D., Edwards, T. J., Quartier, A., Galea, C., Nava, C., Rastetter, A., Moutard, M.-L., Anderson, V., Bitoun, P., Bunt, J., Faudet, A., and 41 others. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Nature Genet. 49: 511-514, 2017. [PubMed: 28250454] [Full Text: https://doi.org/10.1038/ng.3794]
Meneret, A., Depienne, C., Riant, F., Trouillard, O., Bouteiller, D., Cincotta, M., Bitoun, P., Wickert, J., Lagroua, I., Westenberger, A., Borgheresi, A., Doummar, D., and 18 others. Congenital mirror movements: mutational analysis of RAD51 and DCC in 26 cases. Neurology 82: 1999-2002, 2014. [PubMed: 24808016] [Full Text: https://doi.org/10.1212/WNL.0000000000000477]
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Sagi-Dain, L., Kurolap, A., Ilivitzki, A., Mory, A., Paperna, T., Regeneron Genetics Center, Kedar, R., Gonzaga-Jauregui, C., Peleg, A., Feldman, H. B. A novel heterozygous loss-of-function DCC netrin 1 receptor variant in prenatal agenesis of corpus callosum and review of the literature. Am. J. Med. Genet. 182A: 205-212, 2020. [PubMed: 31697046] [Full Text: https://doi.org/10.1002/ajmg.a.61404]
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Srour, M., Philibert, M., Dion, M.-H., Duquette, A., Richer, F., Rouleau, G. A., Chouinard, S. Familial congenital mirror movements: report of a large 4-generation family. Neurology 73: 729-731, 2009. [PubMed: 19720981] [Full Text: https://doi.org/10.1212/WNL.0b013e3181b59bda]
Srour, M., Riviere, J.-B., Pham, J. M. T., Dube, M.-P., Girard, S., Morin, S., Dion, P. A., Asselin, G., Rochefort, D., Hince, P., Diab, S., Sharafaddinzadeh, N., Chouinard, S., Theoret, H., Charron, F., Rouleau, G. A. Mutations in DCC cause congenital mirror movements. Science 328: 592 only, 2010. [PubMed: 20431009] [Full Text: https://doi.org/10.1126/science.1186463]