NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Congenital Mirror Movements

Synonym: Congenital Mirror Movement Disorder

, MD, , BS, , PhD, and , MD, PhD.

Author Information

Initial Posting: .

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

The disorder of congenital mirror movements (CMM) is characterized by early-onset, obvious mirror movements (involuntary movements of one side of the body that mirror intentional movements on the opposite side) in individuals with no other clinical signs or symptoms. Although mirror movements vary in severity, most affected individuals have strong and sustained mirror movements of a lesser amplitude than the corresponding voluntary movements. Mirror movements usually persist throughout life, without deterioration or improvement, and are not associated with subsequent onset of additional neurologic manifestations.

Diagnosis/testing.

The clinical diagnosis of the disorder of CMM can be confirmed by the identification of a heterozygous pathogenic variant in either DCC or RAD51; however, to date only 35% of affected individuals/families have been found to have a pathogenic variant in one of these two genes.

Management.

Treatment of manifestations: Adaptation of the school environment (e.g., allocation of extra time during examinations and limitation of the amount of handwriting) is recommended. Adolescents and young adults should be encouraged to consider a profession that does not require complex bimanual movements, repetitive or sustained hand movements, or extensive handwriting.

Agents/circumstances to avoid: Complex bimanual movements or sustained/repetitive hand activity in order to reduce pain or discomfort in the upper limbs.

Genetic counseling.

CMM is generally inherited in an autosomal dominant (AD) manner; however, a recent study suggests that in rare instances autosomal recessive (AR) inheritance is possible. For AD inheritance: Most individuals with CMM resulting from mutation of DCC or RAD51 have inherited the pathogenic variant from a parent who may be symptomatic or asymptomatic; the proportion of CMM caused by de novo pathogenic variants is unknown. If a parent of the proband is affected or has a DCC or RAD51 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Of note, the sibs of a proband who has clinically unaffected parents are still at increased risk for CMM because of the possibility of reduced penetrance in a parent. Each child of an individual with CMM resulting from mutation of DCC or RAD51 has a 50% chance of inheriting the variant; however, because of reduced penetrance, offspring who inherit a DCC or RAD51 pathogenic variant may not manifest CMM. If the DCC or RAD51 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible. Of note, requests for prenatal testing for conditions which (like CMM) do not affect intellect are not common.

Diagnosis

The diagnosis of the disorder of congenital mirror movements (CMM) is established by clinical findings and, in some instances, molecular genetic testing.

Clinical findings

  • Onset of mirror movements in infancy or early childhood. Mirror movements are defined as involuntary movements of one side of the body that mirror intentional movements on the opposite side.
  • Persistence of mirror movements throughout adulthood and absence of the following:
  • Predominant involvement of the upper limbs, with more severe distal involvement, especially in the muscles controlling the fingers and hands, which are always involved

Molecular genetic testing

The clinical diagnosis of CMM disorder can be confirmed by the identification of a heterozygous pathogenic variant in either DCC or RAD51; however, to date only 35% of affected individuals/families have been found to have a pathogenic variant in one of these two genes.

Molecular testing approaches can include single-gene testing and use of a multigene panel:

Table 1.

Molecular Genetic Testing Used in Congenital Mirror Movements

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
DCCSequence analysis 212/48 3
Gene-targeted deletion/duplication analysis 41/24 3
RAD51Sequence analysis 24/46 3
Gene-targeted deletion/duplication analysis 40/24 3
Unknown 5NA
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.
4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

Significant locus heterogeneity is hypothesized. Mutation of DNAL4 has been implicated, but not confirmed, as a cause of CMM [Ahmed et al 2014, Méneret et al 2014b].

Clinical Characteristics

Clinical Description

The disorder of congenital mirror movements (CMM) is characterized by early onset of obvious mirror movements that persist throughout adulthood in individuals with no other clinical disorders. In particular, the mirror movements are not associated with subsequent onset of additional neurologic manifestations. Mirror movements usually persist throughout life, without deterioration or improvement.

Although mirror movements vary in severity, most affected individuals have strong and sustained mirror movements of a lesser amplitude than the corresponding voluntary movements.

The severity of the mirror movements (MM) is defined according to the Woods and Teuber scale [Woods & Teuber 1978] as follows:

0.

No MM

1.

Barely discernible but repetitive MM

2.

Slight but sustained MM or stronger but briefer MM

3.

Strong and sustained repetitive MM

4.

MM equal to that observed in the intended hand

Affected individuals have moderate difficulties with activities of daily living, including inability to perform pure unimanual movements, difficulty with tasks requiring skilled bimanual coordination, and occasional pain in the upper limbs during sustained manual activities [Galléa et al 2011, Méneret et al 2015].

Genotype-Phenotype Correlations

There are no clear genotype-phenotype correlations, as individuals with pathogenic variants in DCC or RAD51 are clinically indistinguishable, and the severity of the phenotype does not correlate with the type of pathogenic variant. In particular, severity may be quite variable within the same family.

However, there appears to be a correlation between the type of pathogenic variant and whether it occurs in simplex cases (i.e., a single occurrence in a family) or familial cases: all eight pathogenic variants reported to date in families with CMM (6 with mutation of DCC and 2 with mutation of RAD51) introduced premature termination codons, whereas seven of the nine possibly pathogenic variants found in simplex cases (5 with mutation of DCC and 2 with mutation of RAD51) were missense variants [Méneret et al 2014a].

Penetrance

Penetrance does not appear to be sex-related or age-related, as mirror movements are present from early childhood in all symptomatic individuals.

Truncating variants. Penetrance associated with truncating variants in families with CMM with mutation of either DCC or RAD51 was estimated to be 50% [Srour et al 2010, Depienne et al 2012, Méneret et al 2014a].

Missense variants. Penetrance associated with missense variants in families with CMM with mutation of either DCC or RAD51 was significantly reduced: in four of the five simplex cases for which segregation data were available, the possibly pathogenic variant was transmitted by an asymptomatic parent [Méneret et al 2014a]. Thus, rather than representing monogenic pathogenic variants with reduced penetrance, missense variants may possibly be susceptibility factors for CMM or benign variants, in which case their transmission from an unaffected parent may not indicate reduced penetrance.

Nomenclature

The term "synkinesis" may be appropriate, although it is more often used to describe mirror movements acquired later in life, as a result of either neurodegenerative diseases or acute brain lesions [Cox et al 2012].

The term "bimanual synergia" is mentioned in OMIM as having been used by William Bateson (1861-1926) in a family with CMM of apparent autosomal dominant inheritance and incomplete penetrance (OMIM 157600).

Prevalence

Congenital mirror movements is a very rare disorder, with an estimated prevalence of less than 1:1,000,000 [Orphanet 238722; accessed 12-02-14], although the actual prevalence could be significantly higher due to underdiagnosis, especially in individuals with milder manifestations.

Differential Diagnosis

The differential diagnosis of congenital mirror movements (CMM) from mirror movements of other causes is mainly theoretical, as the findings in CMM are distinctive and easily recognized.

Physiologic mirror movements. The intensity of the mirror movements and their persistence after age seven years clearly differentiate pathologic from physiologic mirror movements. Mild physiologic mirror movements are frequent in normally developing young children. They usually disappear completely before age seven years and tend to recur gradually in old age [Bonnet et al 2010, Koerte et al 2010].

Syndromes with early-onset (congenital) mirror movements. Early-onset mirror movements are not always isolated; they may be a component of complex syndromes including X-linked Kallmann syndrome [Manara et al 2015], Klippel-Feil syndrome (OMIM 118100) [Tassabehji et al 2008], and congenital hemiplegia, the most common form of cerebral palsy [Norton et al 2008]. Early-onset mirror movements have also been occasionally reported in Joubert syndrome [Ferland et al 2004], Moebius syndrome (OMIM 157900) [Webb et al 2014], Seckel syndrome (OMIM PS210600) [Thapa & Mukherjee 2010], and Wildervanck syndrome (OMIM 314600) [Högen et al 2012], and are sometimes associated with agenesis of the corpus callosum [Lepage et al 2012]. Although the clinical characteristics of mirror movements have been less comprehensively investigated in these conditions, they resemble those of CMM. In practice, differential diagnosis of isolated CMM is rarely an issue, as the associated findings are generally more significant. When the diagnosis is in doubt, brain and cervical MRI may be considered in children or adolescents with mirror movements.

  • Kallmann syndrome (KS) is a genetically heterogeneous syndrome characterized by a combination of hyposmia and hypogonadotropic hypogonadism. Mirror movements in individuals with KS are almost always linked to mutation of KAL1, which accounts for only 5%-10% of cases. The prevalence of MM in KAL1 X-linked KS is 75% [Dodé & Hardelin 2010].
  • Klippel-Feil syndrome (KFS) is another genetically heterogeneous syndrome, characterized by the congenital fusion of cervical vertebrae. The typical phenotype includes a low posterior hairline, short neck, and reduced amplitude of neck movements. Mirror movements are also present in a minority of persons with KFS, in whom they are likely linked to cervicomedullary neuroschisis. To date, pathogenic variants in three genes have been implicated: GDF3 and GDF6 with autosomal dominant KFS, and MEOX1 with autosomal recessive KFS [Tassabehji et al 2008, Mohamed et al 2013].
  • Joubert syndrome corresponds to a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic "molar tooth sign" and variable accompanying neurologic symptoms, including CMM in some cases [Ferland et al 2004]. To date, pathogenic variants in 21 genes account for about 50% of individuals with Joubert syndrome. Although Joubert syndrome is predominantly inherited in an autosomal recessive manner, Joubert syndrome caused by mutation of OFD1 is inherited in an X-linked manner. Digenic inheritance has been reported.
  • Moebius syndrome minimum criteria are congenital, non-progressive facial weakness in association with limited abduction of one or both eyes. Mirror movements are only occasionally reported [Webb et al 2014]. The molecular basis of Moebius syndrome is unknown.
  • Seckel syndrome, a heterogeneous disorder with significant clinical and molecular overlap with primary microcephaly, is characterized by primary microcephaly and often prenatal-onset growth restriction, and intellectual disability. One individual with mirror movements has been reported [Thapa & Mukherjee 2010]. Seckel syndrome is inherited in an autosomal recessive manner.
  • Wildervanck syndrome consists of Klippel-Feil syndrome associated with congenital perceptive deafness and abducens palsy with narrowing of the palpebral fissure (Duane syndrome). One individual with mirror movements has been described [Högen et al 2012]. Affected individuals are almost exclusively female. The molecular basis of Wildervanck syndrome is unknown.

Acquired mirror movements. Age of onset differentiates acquired mirror movements (usually associated with neurodegenerative disorders in adults) from congenital mirror movements.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with congenital mirror movements (CMM), evaluations to document difficulties with activities of daily living are recommended.

Consultation with a clinical geneticist and/or genetic counselor may also be proposed.

Treatment of Manifestations

It is important to avoid stigmatizing children and adolescents with CMM and to assure that educational opportunities including university are not lost as a result of the mirror movements.

Physicians should explain the disorder to parents and teachers, making it clear that intellectual disability is not associated.

Adaptation of the school environment (e.g., allocation of extra time during examinations and limitation of the amount of handwriting) is recommended.

Adolescents and young adults should be encouraged to consider a profession that does not require complex bimanual movements, repetitive or sustained hand movements, or extensive handwriting.

Agents/Circumstances to Avoid

Complex bimanual movements or sustained/repetitive hand activity should be limited in order to reduce the occurrence of pain or discomfort in the upper limbs.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Noninvasive modulation of brain interhemispheric communication may be a possibility in the future [Galléa et al 2014].

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The disorder of congenital mirror movements (CMM) is generally inherited in an autosomal dominant manner. A recent study suggests that in rare instances CMM can be inherited in an autosomal recessive manner [Ahmed et al 2014].

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

  • If a parent of the proband is affected or has a DCC or RAD51 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for CMM because of the possibility of reduced penetrance in a parent.
  • If the DCC or RAD51 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Each child of an individual with CMM caused by a pathogenic variant in DCC or RAD51 has a 50% chance of inheriting the variant.
  • Because of reduced penetrance, offspring who inherit a DCC or RAD51 pathogenic variant may not manifest CMM.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected or has the DCC or RAD51 pathogenic variant identified in the proband, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with autosomal dominant CMM has the pathogenic variant identified in the proband, the variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored. Absence of clinical evidence of CMM in parents does not imply that the pathogenic variant occurred de novo, as penetrance is incomplete.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring) to young adults who are affected or at risk of having the DCC or RAD51 pathogenic variant.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the DCC or RAD51 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CMM are possible.

Requests for prenatal testing for conditions which (like CMM) do not affect intellect are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Congenital Mirror Movements have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Congenital Mirror Movements: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Congenital Mirror Movements (View All in OMIM)

120470DCC NETRIN 1 RECEPTOR; DCC
157600MIRROR MOVEMENTS 1; MRMV1
179617RAD51, S. CEREVISIAE, HOMOLOG OF; RAD51
614508MIRROR MOVEMENTS 2; MRMV2

DCC

Gene structure. DCC comprises 29 exons. Several transcript variants have been reported, the longest one (NM_005215.3) encompassing 10210 bp. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, six DCC variants have been reported in families with congenital mirror movements (CMM). All were nonsense or frameshift variants introducing or predicting premature termination codons [Srour et al 2010, Depienne et al 2011, Méneret et al 2014a]. One frameshift variant has also been found in a simplex case [Méneret et al 2014a]. These variants are most certainly pathogenic, as they probably result in degradation of the mutated mRNA with no protein translated from the mutated allele and subsequent haploinsufficiency [Srour et al 2010, Méneret et al 2014a].

One exon deletion of DCC, probably pathogenic, was found in an additional simplex case [Méneret et al 2014a].

Variants of uncertain significance. Rare missense variants of DCC, found to date exclusively in simplex cases (i.e., a single occurrence in a family), may have different consequences at the molecular level, and cannot be deemed as more than possibly or probably pathogenic (although their frequency is significantly higher in individuals with CMM than in the general population). All five missense variants listed in Table 2 alter highly conserved amino acids and are predicted to be damaging by prediction algorithms (Sift and/or Polyphen2); four of the five are referenced in the Single Nucleotide Polymorphism Database (dbSNP) [Méneret et al 2014a].

Table 2.

DCC Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Uncertain significance (may be associated w/higher risk for CMM)c.527A>G 1p.Asn176SerNM_005215​.3
NP_005206​.2
c.1409G>A 1p.Gly470Asp
c.2000 G>A 1p.Arg667His
c.2105A>G 1p.Asn702Ser
c.2407G>A 1p.Gly803Arg
Pathogenicc.377C>A 1p.Ser126Ter
c.571dupG 2p.V191GfsTer35
c.823C>T 1p.Arg275Ter
c.1140+1G>A 2p.V329GfsTer15
c.1336_1337insAGCC 1p.Arg446GlnfsTer27
c.2871_2875dup 1p.Pro960GlyfsTer8
c.3835_3836del 3p.Leu1279ProfsTer24
c.698-?_985+?del 1p.Asp233_Leu328del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.
3.

Normal gene product. DCC encodes a transmembrane receptor for netrin-1, a protein that helps guide axons of the developing nervous system across the midline of the body. DCC associates with protein synthesis machinery and regulates translation [Tcherkezian et al 2010]. The DCC protein is composed of 1447 amino acids and comprises four extracellular immunoglobulin-like C2 domains, six extracellular fibronectin type III-like domains, a transmembrane domain, and a cytoplasmic domain. The fourth and fifth fibronectin type III-like domains likely bind to netrin-1 (encoded by NTN1).

Abnormal gene product. DCC pathogenic variants probably result in haploinsufficiency, which may lead to disruption of axonal guidance with abnormal decussation of the corticospinal tracts and persistence of an abnormal ipsilateral corticospinal tract [Srour et al 2010, Depienne et al 2011]. Some putative pathogenic missense variants of DCC are located within or in the vicinity of the netrin-binding domain and may thereby alter the function of the protein [Méneret et al 2014a].

It has been suggested that DCC pathogenic variants induce a defect in netrin-1 binding and subsequent alteration of midline guidance, leading to the persistence of an ipsilateral CST [Srour et al 2010].

Dcc knockout mice die in the neonatal period and have severe defects of commissure development in the brain and spinal cord. Mice with deletion of exon 29 of Dcc ("Kanga" mice) exhibit mirror-type movements resulting in a hopping gait and show defects in the crossing of the CST with persistence of an ipsilateral component [Finger et al 2002].

Cancer and benign tumors. Sporadic tumors (including colorectal cancers) occurring as single tumors in the absence of CMM frequently harbor somatic pathogenic variants in DCC that are not present in the germline [Rasool et al 2014].

RAD51

Gene structure. RAD51 comprises ten exons. Several transcript variants have been reported, the longest one encompassing 2299 bp (NM_002875.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, two RAD51 pathogenic variants have been reported in families with CMM; both predict the introduction of a premature termination codon (Table 3).

Variants of uncertain significance. Rare missense variants of RAD51, found to date exclusively in simplex cases (i.e., a single occurrence in a family), may have different consequences at the molecular level and cannot be deemed as more than possibly or probably pathogenic (although their frequency is significantly higher in individuals with CMM than in the general population). Both missense variants listed in Table 3 alter conserved amino acids, are predicted to be damaging by at least one prediction algorithm, and are not reported in the Single Nucleotide Polymorphism Database (dbSNP) [Méneret et al 2014a].

Table 3.

RAD51 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Uncertain significance (may be associated w/higher risk for CMM)c.140A>G 1p.His47ArgNM_002875​.4
NP_002866​.2
c.406A>T 1p.Ile136Phe
Pathogenicc.760C>T 2p.Arg254Ter
c.855dup 2p.Pro286ThrfsTer37

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

Normal gene product. RAD51 is mostly known for its role in DNA repair through homologous recombination [Park et al 2008], but its recent implication in CMM has revealed its role in the development of the motor system [Galléa et al 2013]. The RAD51 protein comprises 339 amino acids and has a helix-hairpin-helix domain and an ATPase domain.

Abnormal gene product. RAD51 pathogenic variants induce haploinsufficiency resulting from the degradation of the mutated messenger RNA by nonsense-mediated RNA decay [Depienne et al 2012].

The precise mechanisms linking RAD51 deficiency to mirror movements remain unclear. Individuals with congenital mirror movements induced by RAD51 deficiency display: (a) an abnormal decussation of the corticospinal tracts; (b) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (c) abnormal involvement of the supplementary motor area during both unimanual and bimanual repetitive movements [Galléa et al 2013].

Mouse models suggest insufficient RAD51-related DNA repair during early corticogenesis might lead to excessive apoptosis and altered central nervous system development, as observed in mice lacking BRCA1 or XRCC2, also involved in HR-mediated DNA repair [Deans et al 2000, Pao et al 2014].

That RAD51 is expressed in the cytoplasm of cortical cells during mouse brain development, suggests a role of RAD51 different from its role in homologous recombination occurring within the nucleus. In particular, RAD51 is probably expressed in a subpopulation of corticospinal axons at the level of the pyramidal decussation. As shown for DCC, RAD51 could therefore play a direct or indirect role in axonal guidance [Depienne et al 2012].

Another hypothesis concerns a putative role of RAD51 in selective chromatid segregation. Due to RAD51 deficiency, random chromatid segregation would occur for a specific chromosome during mitosis, inducing asymmetric cell division responsible for the CMM phenotype in 50% of individuals with the pathogenic variant, and normal symmetric cell division in the remaining 50%. According to the author, this hypothesis would explain the 50% penetrance of RAD51 pathogenic variants [Klar 2014]. However, that hypothesis does not explain the presence of RAD51 in the cytoplasm of cortical cells during mouse brain development, and is not supported by any experimental evidence.

Cancer and benign tumors. RAD51 is essential for maintaining genomic integrity through its role in homologous recombination. Defective homologous recombination is predicted to contribute to genomic instability and tumor development. Therefore, pathogenic variants in RAD51 have long been predicted to increase the risk of developing cancers [Klein 2008]. However, a single germline missense variant of doubtful pathogenicity was reported in only two individuals with breast cancer, indicating that RAD51 is not a major cancer predisposition gene [Kato et al 2000].

References

Literature Cited

  • Ahmed I, Mittal K, Sheikh TI, Vasli N, Rafiq MA, Mikhailov A, Ohadi M, Mahmood H, Rouleau GA, Bhatti A, Ayub M, Srour M, John P, Vincent JB. Identification of a homozygous splice site mutation in the dynein axonemal light chain 4 gene on 22q13.1 in a large consanguineous family from Pakistan with congenital mirror movement disorder. Hum Genet. 2014;133:1419–29. [PubMed: 25098561]
  • Bonnet C, Roubertie A, Doummar D, Bahi-Buisson N, Cochen de Cock V, Roze E. Developmental and benign movement disorders in childhood. Mov Disord. 2010;25:1317–34. [PubMed: 20564735]
  • Cox BC, Cincotta M, Espay AJ. Mirror movements in movement disorders: a review. Tremor Other Hyperkinet Mov (N Y). 2012;2. pii: tre-02-59-398-1.
  • Deans B, Griffin CS, Maconochie M, Thacker J. Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. EMBO J. 2000;19:6675–85. [PMC free article: PMC305908] [PubMed: 11118202]
  • Depienne C, Cincotta M, Billot S, Bouteiller D, Groppa S, Brochard V, Flamand C, Hubsch C, Meunier S, Giovannelli F, Klebe S, Corvol JC, Vidailhet M, Brice A, Roze E. A novel DCC mutation and genetic heterogeneity in congenital mirror movements. Neurology. 2011;76:260–4. [PubMed: 21242494]
  • Depienne C, Bouteiller D, Méneret A, Billot S, Groppa S, Klebe S, Charbonnier-Beaupel F, Corvol JC, Saraiva JP, Brueggemann N, Bhatia K, Cincotta M, Brochard V, Flamand-Roze C, Carpentier W, Meunier S, Marie Y, Gaussen M, Stevanin G, Wehrle R, Vidailhet M, Klein C, Dusart I, Brice A, Roze E. RAD51 haploinsufficiency causes congenital mirror movements in humans. Am J Hum Genet. 2012;90:301–7. [PMC free article: PMC3276668] [PubMed: 22305526]
  • Djarmati-Westenberger A, Brüggemann N, Espay AJ, Bhatia KP, Klein C. A novel DCC mutation and genetic heterogeneity in congenital mirror movements. Neurology. 2011;77:1580. [PubMed: 22006891]
  • Dodé C, Hardelin JP. Clinical genetics of Kallmann syndrome. Ann Endocrinol (Paris). 2010;71:149–57. [PubMed: 20362962]
  • Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet. 2004;36:1008–13. [PubMed: 15322546]
  • Finger JH, Bronson RT, Harris B, Johnson K, Przyborski SA, Ackerman SL. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons. J Neurosci. 2002;22:10346–56. [PubMed: 12451134]
  • Galléa C, Popa T, Billot S, Méneret A, Depienne C, Roze E. Congenital mirror movements: a clue to understanding bimanual motor control. J Neurol. 2011;258:1911–9. [PubMed: 21633904]
  • Galléa C, Popa T, Hubsch C, Valabregue R, Brochard V, Kundu P, Schmitt B, Bardinet E, Bertasi E, Flamand-Roze C, Alexandre N, Delmaire C, Méneret A, Depienne C, Poupon C, Hertz-Pannier L, Cincotta M, Vidailhet M, Lehericy S, Meunier S, Roze E. RAD51 deficiency disrupts the corticospinal lateralization of motor control. Brain. 2013;136:3333–46. [PubMed: 24056534]
  • Galléa C, Popa T, Meunier S, Roze E. Reply: Congenital mirror movements: lack of decussation of pyramids Mirror movement: from physiopathology to treatment perspectives. Brain. 2014;137:e293. [PMC free article: PMC4610187] [PubMed: 24727566]
  • Högen T, Chan WM, Riedel E, Brüning R, Chang HH, Engle EC, Danek A. Wildervanck's syndrome and mirror movements: a congenital disorder of axon migration? J Neurol. 2012;259:761–3. [PMC free article: PMC3517171] [PubMed: 21947222]
  • Kato M, Yano K, Matsuo F, Saito H, Katagiri T, Kurumizaka H, Yoshimoto M, Kasumi F, Akiyama F, Sakamoto G, Nagawa H, Nakamura Y, Miki Y. Identification of Rad51 alteration in patients with bilateral breast cancer. J Hum Genet. 2000;45:133–7. [PubMed: 10807537]
  • Klar AJ. Selective chromatid segregation mechanism invoked for the human congenital mirror hand movement disorder development by RAD51 mutations: a hypothesis. Int J Biol Sci. 2014;10:1018–23. [PMC free article: PMC4159693] [PubMed: 25210500]
  • Klein HL. The consequences of Rad51 overexpression for normal and tumor cells. DNA Repair (Amst). 2008;7:686–93. [PMC free article: PMC2430071] [PubMed: 18243065]
  • Koerte I, Eftimov L, Laubender RP, Esslinger O, Schroeder AS, Ertl-Wagner B, Wahllaender-Danek U, Heinen F, Danek A. Mirror movements in healthy humans across the lifespan: effects of development and ageing. Dev Med Child Neurol. 2010;52:1106–12. [PubMed: 21039436]
  • Lepage JF, Beaulé V, Srour M, Rouleau G, Pascual-Leone A, Lassonde M, Théoret H. Neurophysiological investigation of congenital mirror movements in a patient with agenesis of the corpus callosum. Brain Stimul. 2012;5:137–40. [PubMed: 22037131]
  • Manara R, Salvalaggio A, Citton V, Palumbo V, D'Errico A, Elefante A, Briani C, Cantone E, Ottaviano G, Pellecchia MT, Greggio NA, Weis L, D'Agosto G, Rossato M, De Carlo E, Napoli E, Coppola G, Di Salle F, Brunetti A, Bonanni G, Sinisi AA, Favaro A. Brain anatomical substrates of mirror movements in Kallmann syndrome. Neuroimage. 2015;104:52–8. [PubMed: 25300200]
  • Méneret A, Depienne C, Riant F, Trouillard O, Bouteiller D, Cincotta M, Bitoun P, Wickert J, Lagroua I, Westenberger A, Borgheresi A, Doummar D, Romano M, Rossi S, Defebvre L, De Meirleir L, Espay AJ, Fiori S, Klebe S, Quélin C, Rudnik-Schöneborn S, Plessis G, Dale RC, Sklower Brooks S, Dziezyc K, Pollak P, Golmard JL, Vidailhet M, Brice A, Roze E. Congenital mirror movements: mutational analysis of RAD51 and DCC in 26 cases. Neurology. 2014a;82:1999–2002. [PMC free article: PMC4105259] [PubMed: 24808016]
  • Méneret A, Trouillard O, Vidailhet M, Depienne C, Roze E. Congenital mirror movements: no mutation in DNAL4 in 17 index cases. J Neurol. 2014b;261:2030–1. [PubMed: 25236653]
  • Méneret A, Welniarz Q, Trouillard O, Roze E. Congenital mirror movements: From piano player to opera singer. Neurology. 2015;84:860. [PubMed: 25713113]
  • Mohamed JY, Faqeih E, Alsiddiky A, Alshammari MJ, Ibrahim NA, Alkuraya FS. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly. Am J Hum Genet. 2013;92:157–61. [PMC free article: PMC3542464] [PubMed: 23290072]
  • Norton JA, Thompson AK, Chan KM, Wilman A, Stein RB. Persistent mirror movements for over sixty years: the underlying mechanisms in a cerebral palsy patient. Clin Neurophysiol. 2008;119:80–7. [PubMed: 18042427]
  • Pao GM, Zhu Q, Perez-Garcia CG, Chou SJ, Suh H, Gage FH, O'Leary DD, Verma IM. Role of BRCA1 in brain development. Proc Natl Acad Sci U S A. 2014;111:E1240–8. [PMC free article: PMC3977248] [PubMed: 24639535]
  • Park JY, Yoo HW, Kim BR, Park R, Choi SY, Kim Y. Identification of a novel human Rad51 variant that promotes DNA strand exchange. Nucleic Acids Res. 2008;36:3226–34. [PMC free article: PMC2425499] [PubMed: 18417535]
  • Rasool S, Rasool V, Naqvi T, Ganai BA, Shah BA. Genetic unraveling of colorectal cancer. Tumour Biol. 2014;35:5067–82. [PubMed: 24573608]
  • Srour M, Rivière JB, Pham JM, Dubé MP, Girard S, Morin S, Dion PA, Asselin G, Rochefort D, Hince P, Diab S, Sharafaddinzadeh N, Chouinard S, Théoret H, Charron F, Rouleau GA. Mutations in DCC cause congenital mirror movements. Science. 2010;328:592. [PubMed: 20431009]
  • Tassabehji M, Fang ZM, Hilton EN, McGaughran J, Zhao Z, de Bock CE, Howard E, Malass M, Donnai D, Diwan A, Manson FD, Murrell D, Clarke RA. Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat. 2008;29:1017–27. [PubMed: 18425797]
  • Tcherkezian J, Brittis PA, Thomas F, Roux PP, Flanagan JG. Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell. 2010;141:632–44. [PMC free article: PMC2881594] [PubMed: 20434207]
  • Thapa R, Mukherjee K. Seckel syndrome with asymptomatic tonsillar herniation and congenital mirror movements. J Child Neurol. 2010;25:231–3. [PubMed: 19372093]
  • Webb BD, Frempong T, Naidich TP, Gaspar H, Jabs EW, Rucker JC. Mirror movements identified in patients with moebius syndrome. Tremor Other Hyperkinet Mov (N Y). 2014;4:256. [PMC free article: PMC4107286] [PubMed: 25120946]
  • Woods BT, Teuber HL. Mirror movements after childhood hemiparesis. Neurology. 1978;28:1152–7. [PubMed: 568735]

Suggested Reading

  • Peng J, Charron F. Lateralization of motor control in the human nervous system: genetics of mirror movements. Curr Opin Neurobiol. 2013;23:109–18. [PubMed: 22989473]

Chapter Notes

Revision History

  • 12 March 2015 (me) Review posted live
  • 5 November 2014 (am) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK279760PMID: 25763452

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...