Congenital Mirror Movements
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 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.
Diagnosis
The diagnosis of the disorder of congenital mirror movements (CMM) is established by clinical findings and, in some instances, molecular genetic testing.
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. Normal brain MRI or partial or complete agenesis of the corpus callosum
Family history. 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 variant in DCC, NTN1, or RAD51 by molecular genetic testing (see Table 1).
Note: Identification of a heterozygous DCC, NTN1, or RAD51 variant of uncertain significance does not establish or rule out a diagnosis of CMM.
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).
Option 1
When the phenotypic findings suggest the diagnosis of CMM, molecular genetic testing approaches include use of a multigene panel.
A multigene panel that includes DCC, NTN1, and RAD51 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of CMM has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be pursued.
Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Congenital Mirror Movements
| Gene 1 | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method | |
|---|---|---|
| Sequence analysis 3 | Gene-targeted deletion/duplication analysis 4 | |
| DCC | 24/25 5 | 1/25 6 |
| NTN1 | 3/3 7 | None reported 7 |
| RAD51 | 7/7 8 | None reported 8 |
| Unknown 9 | NA | |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
- 4.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 5.
Srour et al [2010], Depienne et al [2011], Djarmati-Westenberger et al [2011], Depienne et al [2012], Ahmed et al [2014], Méneret et al [2014a], Méneret et al [2014b], Franz et al [2015], Marsh et al [2017], Bierhals et al [2018], Sagi-Dain et al [2020]
- 6.
Méneret et al [2014a]
- 7.
Méneret et al [2017]
- 8.
Srour et al [2010], Depienne et al [2011], Djarmati-Westenberger et al [2011], Depienne et al [2012], Ahmed et al [2014], Méneret et al [2014a], Méneret et al [2014b], Franz et al [2015], Trouillard et al [2016], Demirayak et al [2018]
- 9.
Significant locus heterogeneity is hypothesized. Pathogenic variants in DNAL4 have been suggested, but not confirmed, as a cause of CMM [Ahmed et al 2014, Méneret et al 2014b].
Clinical Characteristics
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 less than 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.
Differential Diagnosis
The differential diagnosis of congenital mirror movements (CMM) from mirror movements of other causes is mainly theoretic, as the findings in CMM are distinctive, isolated, 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 (see Table 2) and congenital hemiplegia (the most common form of cerebral palsy) [Norton et al 2008]. 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 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.
Table 2.
Syndromes with Early-Onset Mirror Movements
| Disorder | Gene(s) | MOI | Mirror Movements | Other Features |
|---|---|---|---|---|
| ANOS1 Kallmann syndrome (KS) (See Isolated GnRH Deficiency.) | ANOS1 (KAL1) | XL |
| Hyposmia & hypogonadotropic hypogonadism |
| Joubert syndrome | ≥34 genes | AR XL 2 | CMM is observed in some affected persons. 3 | Hypoplasia of cerebellar vermis w/characteristic neuroradiologic molar tooth sign & variable accompanying neurologic symptoms |
| Klippel-Feil syndrome (KFS) (OMIM PS118100) 4 | GDF3 GDF6 MEOX1 MYO18B | AD AR | MM is present in minority of persons w/KFS (MM is likely linked to cervicomedullary neuroschisis). |
|
| Moebius syndrome (OMIM 157900) | Unknown | AD | MM is only occasionally reported. 5 | Minimum criteria are congenital, non-progressive facial weakness in assoc w/limited abduction of 1 or both eyes. |
| Nevoid basal cell carcinoma syndrome (Gorlin syndrome) | PTCH1 (PTCH2) 6 SUFU | AD | MM reported in 1 person 7 | Multiple basal cell carcinomas, jaw keratocysts, & skeletal malformations |
| Seckel syndrome (OMIM PS210600) | ATR CENPJ CEP152 CEP63 DNA2 NIN NSMCE2 RBBP8 TRAIP | AR | 1 reported person w/MM 8 | Primary microcephaly, intellectual disability, & often prenatal-onset growth restriction |
| Wildervanck syndrome (OMIM 314600) | Unknown | XL? | 1 reported person w/MM 9 |
|
AD = autosomal dominant; AR = autosomal recessive; CMM = congenital mirror movements; GnRH = gonadotropin-releasing hormone; MM = mirror movements; MOI = mode of inheritance; XL = X-linked
- 1.
Dodé & Hardelin [2010], Manara et al [2015]
- 2.
Digenic inheritance has been reported.
- 3.
Ferland et al [2004]
- 4.
Tassabehji et al [2008], Mohamed et al [2013]
- 5.
Webb et al [2014]
- 6.
Occasional variants in PTCH2 have been found in individuals with NBCCS but these may not be conclusive (see Nevoid Basal Cell Carcinoma Syndrome).
- 7.
Sag et al [2016]
- 8.
Thapa & Mukherjee [2010]
- 9.
Högen et al [2012]
- 10.
Duane syndrome = abducens palsy with narrowing of the palpebral fissure
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), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Mirror Movements
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Evals to document difficulties w/ADL | Consider referral to rehab specialist. |
| Consider head MRI imaging. | To assess for abnormalities of CC, esp in those w/pathogenic DCC variant | |
| Consider neuropsychological eval. 1 | In those w/abnormalities of CC | |
| Genetic counseling | By genetics professionals 1 | To inform affected persons & their families re nature, MOI, & implications of CMM to facilitate medical & personal decision making |
| Family support/ resources | Assess:
|
ADL = activities of daily living; CC = corpus callosum; CMM = congenital mirror movements; MOI = mode of inheritance
- 1.
Spencer-Smith et al [2020]
- 2.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Congenital Mirror Movements
| Manifestation/Concern | Treatment/Counseling | Considerations/Other |
|---|---|---|
| MM | Adaptation of school environment | Incl allocation of extra time during exams & limitation of amount of handwriting |
| Avoid stigmatizing children & adolescents. | To assure that educational opportunities incl university are not lost as result of MM | |
| Education of parents & teachers | Reassurance that intellectual disability is not typically associated | |
| Education of affected persons | Encourage a profession that does not require complex bimanual movements, repetitive or sustained hand movements, or extensive handwriting. | |
| Developmental delay / Neurocognitive deficits | Standard treatment | Consider referral to neurodevelopmental specialist. |
MM = mirror movements
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.