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 who typically have 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 usually associated with subsequent onset of additional neurologic manifestations. However, a subset of affected individuals with a heterozygous pathogenic variant in DCC may have CMM with abnormalities of the corpus callosum and concomitant cognitive and/or neuropsychiatric issues.

Diagnosis/testing.

The diagnosis of CMM is established in a proband with suggestive clinical findings and occasionally by identification of a heterozygous pathogenic variant in DCC, NTN1, or RAD51.

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. Stigmatizing children and adolescents should be avoided to assure that educational opportunities are not lost as a result of mirror movements. 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. Standard therapy for any neurocognitive issues is recommended.

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. (Autosomal recessive inheritance has been suggested in one family.) For AD inheritance: most individuals with CMM resulting from a pathogenic variant in DCC, NTN1, or RAD51 inherited the pathogenic variant from a parent who may be symptomatic or asymptomatic. If a parent of the proband is affected and/or has a DCC, NTN1, 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 significant possibility of reduced penetrance in a heterozygous parent. Each child of an individual with AD CMM has a 50% chance of inheriting the causative variant; however, because of reduced penetrance, offspring who inherit the pathogenic variant may not manifest CMM. Once the CMM-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CMM should be suspected in individuals with the following clinical features, imaging findings, and family history.

Clinical features

• Onset of mirror movements (defined as involuntary movements of one side of the body that mirror intentional movements on the opposite side) in infancy or early childhood
• Predominant involvement of the upper limbs, with more severe distal involvement, especially in the muscles controlling the fingers and hands, which are always involved
• Persistence of mirror movements throughout adulthood and absence of the following:
  • Evidence of other clinical findings that would suggest an underlying syndrome [Bonnet et al 2010] (See Differential Diagnosis.)
  • Subsequent development of additional neurologic findings

Imaging findings include normal brain MRI or partial or complete agenesis of the corpus callosum.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CMM is established in a proband with suggestive clinical findings and occasionally by identification of a heterozygous pathogenic (or likely pathogenic) variant in DCC, NTN1, or RAD51 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous DCC, NTN1, or RAD51 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CMM has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Physiologic mild mirror movements may be seen in young children, but their persistence after age seven years is pathologic [Galléa et al 2011]. The disorder of congenital mirror movements (CMM) is characterized by early-onset obvious mirror movements that persist throughout adulthood in individuals who typically have no other clinical disorders. In particular, the mirror movements are not usually associated with subsequent onset of additional neurologic manifestations. However, a subset of individuals with a heterozygous DCC pathogenic variant may have concomitant cognitive and/or neuropsychiatric issues, particularly if abnormalities of the corpus callosum are present (see Phenotype Correlations by Gene and Genetically Related Disorders). Mirror movements usually persist throughout life, without deterioration or improvement.

Mirror movements (MM) predominantly involve the upper limbs, with more severe distal involvement. The muscles that control the fingers and hands are always involved. Muscles involving the toes may be slightly involved, without interfering with ambulation.

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 is defined according to the Woods and Teuber scale [Woods & Teuber 1978] as follows:

1.

No MM

2.

Barely discernible but repetitive MM

3.

Slight but sustained MM or stronger but briefer MM

4.

Strong and sustained repetitive MM

5.

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].

Sensory issues. There are no sensory issues in CMM, but clinical examination in rare affected individuals may show sensory coupling, which is the perception of a sensation in the limb contralateral to the one being stimulated [Spencer-Smith et al 2020].

Neuroimaging. Brain MRI is normal in most cases but may show partial or complete agenesis of the corpus callosum (ACC) in some individuals with a heterozygous pathogenic DCC variant (see Phenotype-Correlations by Gene).

Phenotype Correlations by Gene

DCC. Individuals with a heterozygous DCC pathogenic variant may have CMM with or without partial or complete agenesis of the corpus callosum. These individuals may also have specific neuropsychological deficits associated with variable cognitive outcomes [Marsh et al 2017, Brown & Paul 2019, Spencer-Smith et al 2020]. The possible occurrence of slight neuropsychological deficits has also been suggested in individuals with a heterozygous DCC pathogenic variant without ACC [Spencer-Smith et al 2020].

NTN1 and RAD51. So far, there have been no reports of individuals with a heterozygous pathogenic variant in NTN1 or RAD51 who have corpus callosum abnormalities.

Genotype-Phenotype Correlations

There are no clear and validated genotype-phenotype correlations for NTN1 or RAD51.

DCC

• Pathogenic variants in the NTN1 binding interface may predispose to abnormalities in the development of the corpus callosum with or without CMM [Spencer-Smith et al 2020] (see Genetically Related Disorders).
• Males with truncating DCC pathogenic variants are more likely to present with CMM, while females with truncating DCC pathogenic variants are more likely to present with isolated ACC (see Genetically Related Disorders) [Marsh et al 2017].

Penetrance

Penetrance is incomplete regardless of whether the causative pathogenic variant is in DCC, NTN1, or RAD51. Penetrance for the CMM phenotype was estimated to be 42% in those with a heterozygous pathogenic DCC variant – the most frequent cause of CMM [Marsh et al 2017].

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 <1:1,000,000 (Orphanet 238722; accessed 9-21-20), although the actual prevalence could be significantly higher due to underdiagnosis, especially in individuals with milder manifestations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with congenital mirror movements (CMM), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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

Botulinum toxin injections have been successfully tried in one affected individual [Allegra et al 2017] but are not usually proposed, as the risk of inducing a motor deficit generally exceeds the possible benefit.

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

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

The disorder of congenital mirror movements (CMM) is generally inherited in an autosomal dominant manner.

Possible autosomal recessive inheritance of CMM was reported in one family [Ahmed et al 2014]; further studies are needed to confirm this finding.

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

• Most individuals with CMM resulting from a pathogenic variant in DCC, NTN1, or RAD51 inherited this variant from a parent, who may be symptomatic or asymptomatic [Méneret et al 2014a, Méneret et al 2017].
• A proband with CMM may have the disorder as the result of a de novo pathogenic variant [Méneret et al 2014a]. The proportion of CMM caused by a de novo pathogenic variant is unknown.
• If the causative pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant identified in the proband is not identified in either parent, several possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
• The family history of some individuals diagnosed with CMM may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, when the molecular basis of CMM is known, molecular genetic testing is the most accurate means of determining the genetic status of at-risk individuals.

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 and/or has a DCC, NTN1, or RAD51 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Sibs who inherit a pathogenic variant may or may not manifest CMM (see Penetrance).
• If the proband has a known DCC, NTN1, or RAD51 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents of the proband are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CMM because of the significant possibility of reduced penetrance in a parent and the theoretic possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual with CMM caused by a pathogenic variant in DCC, NTN1, or RAD51 has a 50% chance of inheriting the variant.
• Because of reduced penetrance in CMM, offspring who inherit a DCC, NTN1, or RAD51 pathogenic variant may or 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 and/or has the DCC, NTN1, or RAD51 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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, NTN1, or RAD51 pathogenic variant.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the CMM-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CMM are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Two of the genes (DCC and NTN1) associated with CMM encode proteins that have a role in axonal guidance, whereas the role of RAD51 remains unclear.

DCC encodes DCC, a transmembrane receptor for netrin-1, a protein that helps guide axons of the developing nervous system across the midline of the body [Tcherkezian et al 2010]. Loss of DCC 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].

NTN1 encodes the DCC ligand, netrin-1. Netrins play a role in neuronal guidance.

RAD51 encodes RAD51, a protein with an established role in DNA repair. RAD51 contains a helix-hairpin-helix domain and an ATPase domain [Park et al 2008]. Association with CMM has revealed an unsuspected role of RAD51 in central nervous system development [Galléa et al 2013]. The precise mechanisms linking RAD51 deficiency to mirror movements remain unclear. Regulation of netrin-1 signaling by RAD51 has been hypothesized [Glendining et al 2017].

Mechanism of disease causation. Loss of function is hypothesized to be the main mechanism for all three known genes, although the impact of missense variants remains to be studied.

Cancer and Benign Tumors

Genes associated with CMM have also been associated with tumors or genomic integrity in individuals who do not have CMM.

• DCC. Sporadic tumors (including colorectal and esophageal cancers) frequently harbor somatic variants in DCC that are not present in the germline [Rasool et al 2014].
• NTN1. Sporadic tumors may harbor variants in NTN1 that are not present in the germline [Hao et al 2020].
• RAD51. RAD51 is essential for maintaining genomic integrity through its role in homologous recombination; therefore, 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, suggesting that RAD51 is not a major cancer predisposition gene in this tissue [Kato et al 2000]. In addition, sporadic tumors may harbor rare variants in RAD51 that are not present in the germline [Marshall et al 2019].

Revision History

• 24 September 2020 (ma) Comprehensive update posted live
• 12 March 2015 (me) Review posted live
• 5 November 2014 (am) Original submission

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