Congenital mirror movement disorder

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Congenital mirror movement disorder
Autosomal dominant - en.svg
This condition is inherited via autosomal dominant manner

Congenital mirror movement disorder(CMM disorder) is a rare genetic neurological disorder which is characterized by mirrored movement, sometimes referred to as associated or synkinetic movement, most often in the upper extremity of the body. [1] [2] These movements are voluntary intentional movements on one, ipsilateral, side of the body that are mirrored simultaneously by involuntary movements on the contralateral side. [3]

Contents

The reproduction of involuntary movement usually happens along the head-tail axis, having a left-right symmetry. [1] For example, if someone were to voluntarily make a fist with their left hand, their right hand would do the same. In most cases, the accompanying contralateral involuntary movements are much weaker than the ipsilateral voluntary ones, although the extent and magnitude of the mirrored movement vary across patients. [4] This disorder has not yet been found to be associated with any other neurologic disease or cognitive disability, and currently, no cures nor means to improve signs or symptoms have been found. [2] [5]

The congenital mirror movements begin in infancy and persist throughout the patient's life, often with very little improvement, or deterioration. [3] Consequently, patients with this movement disorder have serious difficulty carrying out tasks that require manual dexterity or precision, such as playing a two handed musical instrument or typing on a keyboard, for their whole lives. [4] [6] Patients also often experience discomfort or pain in the upper limbs due to prolonged use of the same muscles. Therefore, quality of life can be severely hampered. [3]

CMM disorder's prevalence in the world is thought to be less than 1 in 1 million people. [1] [5] Because of its rarity, researchers suggest that some mildly affected individuals may never be diagnosed. [2] [6] It is important not to confuse congenital mirror movement disorders, a rare genetically based neurologic disease, with acquired mirror movement disorders that present themselves during one's lifetime due to other reasons (stroke for example). [2]

Presentation

Causes

The specific molecular mechanism that underpins this movement disorder is not well known. [2] However, most researchers suggest that it follows an autosomal dominant genetic inheritance pattern in which mutations in certain genes give rise to structural abnormalities in nervous system networks responsible for voluntary skeletal muscle movement, which, in turn, result in the functional movement abnormalities seen in patients. [1] [2] [7] [8] [9] Despite being autosomal dominant, it is important to note that the disease has variable expressivity. [3] That is, patients who have inherited a mutated dominant allele, along with their genetically affected parent, can be symptomatic or asymptomatic for CMM disorder. [4] The genes that currently have evidence to be associated with CMM disorder include DCC (deleted in colorectal carcinoma), DNAL4 (dynein axonemal light chain 4), and RAD51 (recombination protein A). [6] [10]

DCC encodes a receptor for NTN1 (netrin-1), a protein thought to be responsible for axon guidance and neuronal cell migration during development. [11] [12] A mutation of this gene (including nonsense, splice site mutation, insertions, frameshift) has been identified as a possible cause for CMM disorder. [2] [13] [14] Experiments in mice also support the claim that CMM disorder is associated with genetic mutations in DCC. [9] Kanga mice, lacking the P3 intracellular domain of the DCC receptor, show a hopping gait, moving their hind legs in a strictly paired fashion, as do kangaroos. [3] [15]

DNAL4 encodes a component of dynein motor complex in commissural neurons of the corpus callosum. [1] [6] [3] In contrast to DCC, DNAL4 is thought to have a recessive inheritance pattern for the CMM disorder. [8] In CMM disorder patients, researchers found splice site mutations on DNAL4, which caused skipping of exon 3, and thereby omission of 28 amino acids from DNAL4 protein. [8] This mutant DNAL4 protein, in turn, could lead to faulty cross-hemisphere wiring, resulting in CMM. [8] [16]

RAD51 maintains genome integrity by repairing DNA double-strand breaks through homologous recombination. [7] RAD51 heterozygous mutations, specifically premature termination codons, have been found in many CMM disorder patients through genome-wide linkage analysis and exome sequencing. [1] [2] [4] [6] In a mouse model, researchers also found RAD51 products in corticospinal tract axons at the pyramidal decussation. [7] They therefore suggest that RAD51 might be a gene that, when haploinsufficient, causes CMM disorder in humans. [7]

Despite identification of three prospective genes, no genotype–phenotype correlations have yet been found. [1] [2] That is, the severity of clinical signs and symptoms does not correlate with the type of genetic variant. [3] [17] Mutations in the above genes account for a total of about 35 percent of cases. [1] Mutations in other genes that have not been identified likely account for the other cases of this disorder. [1]

Pathophysiology

There are three main pathophysiological hypotheses for congenital mirror movement disorder that exist.

Interhemispheric connections

First, some researchers believe that this neurological disorder is due to abnormal communication between cerebral hemispheres. [6] They explain the mechanism of the physiological miscommunication with on development. [18]

Amongst many neuronal changes in the brain during normal human brain development, researchers claim that the corpus callosum shows a gradual increase number of myelinated axons. [18] This suggests that up until a certain age, the corpus callosum is heavily unmyelinated. This would explain why children during normal development can be seen with CMM disorder up to the age of 7 years, likely due to lack of corpus callosum development. [6] [19] The normal disappearance of clinically significant mirror movements after this age is associated with anatomical and functional maturation of interhemispheric connections through the corpus callosum between motor cortices. [20] Researchers hypothesize that this axonal density in the corpus callosum is responsible for the interhemispheric communication that is ultimately responsible for the suppression of mirror movements during voluntary movements in healthy adults. [21] Therefore, disruptions in corpus callosum circuits could lead to CMM. [2]

Motor cortex

Another pathophysiological explanation that researchers suggest for CMM disorder is that there is a miscommunication during motor movement execution. [6] This claim is supported by evidence of structural abnormalities in the primary motor cortex (M1) in CMM patients. [1] [2] [4] [3] These structural abnormalities in the motor cortex might explain why the hands, requiring great motor dexterity and therefore have a large cortical representation, are often the target of and have more severe mirror movement in CMM disorder. [1]

Corticospinal tract

A third pathophysiological explanation proposed by researchers has to do with the corticospinal tract (CST). [1] [5] [16] [22] Healthy newborns in fact have ipsilateral CST projections up until the age of around 7. [23] During normal adult development, these axonal projects disappear. This might provide an alternate explanation for the presence of mild mirror movements in normally developing young children that typically disappear before the age of 7. [24]

Some researchers propose that DCC mutations cause a reduction in gene expression and less robust midline guidance, which may lead to a partial failure of axonal fiber crossing and encourage development of an abnormal ipsilateral connection. [7] This is confirmed by other researchers who demonstrate that patients with DDC mutants show an increased proportion of ipsilateral axonal projections, and show that even a very small number of aberrant ipsilateral descending axons is sufficient to induce incorrect movement patterns. [11] [14] [25]

These findings are corroborated by evidence from mice models, Kanga mice with a deletion of DCC, whose CST has been shown not to be altered, but rather partially rerouted ipsilaterally. [16]

Diagnosis

Currently, clinical diagnosis of CMM disorder has been based on clinical findings or molecular genetic testing. [2]

Clinical Findings (Signs and Symptoms) [1] [2] [10] [26] [14] :

Molecular genetic testing [1] :

Treatment

CMM has clear severe impacts on a patient's ability to carry out daily manual tasks. [27] [17] It is recommended that children be placed under more forgiving school environments, allowing more time for written evaluations and limiting handwritten assignments, to ease the burden of the movement disability. [1] [3] Furthermore, because of patients' inability to perform pure unilateral movements and their difficulty with tasks requiring skilled bimanual coordination, young and new members to the workforce are encouraged to consider professions that do not require complex bimanual movements, repetitive or sustained hand movements, or extensive handwriting, to reduce overuse, pain, and discomfort in upper limbs. [2] [5]

Because of its pronounced and obviously noticeable signs and symptoms, CMM patients can suffer social stigma; however, physicians need to make it clear to parents, family, and friends that the disorder bears no relation to intellectual abilities. [5] [28] However, the rarity of this neurologic disease, found in one in a million people, makes its societal and cultural significance quite limited. [6]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Reference, Genetics Home. "congenital mirror movement disorder". Genetics Home Reference. Retrieved 2017-12-06.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Méneret, Aurélie; Trouillard, Oriane; Depienne, Christel; Roze, Emmanuel (1993). "Congenital Mirror Movements". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora J.H.; Mefford, Heather C.; Stephens, Karen; Amemiya, Anne; Ledbetter, Nikki (eds.). GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID   25763452.
  3. 1 2 3 4 5 6 7 8 9 Galléa, Cécile; Popa, Traian; Billot, Ségolène; Méneret, Aurélie; Depienne, Christel; Roze, Emmanuel (November 2011). "Congenital mirror movements: a clue to understanding bimanual motor control". Journal of Neurology. 258 (11): 1911–1919. doi:10.1007/s00415-011-6107-9. ISSN   1432-1459. PMID   21633904. S2CID   22968346.
  4. 1 2 3 4 5 Schott, G D; Wyke, M A (July 1981). "Congenital mirror movements". Journal of Neurology, Neurosurgery, and Psychiatry. 44 (7): 586–599. doi:10.1136/jnnp.44.7.586. ISSN   0022-3050. PMC   491063 . PMID   7288446.
  5. 1 2 3 4 5 "Congenital mirror movement disorder | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2022-08-17. Retrieved 2017-12-06.
  6. 1 2 3 4 5 6 7 8 9 Méneret, Aurélie; Depienne, Christel; Riant, Florence; Trouillard, Oriane; Bouteiller, Delphine; Cincotta, Massimo; Bitoun, Pierre; Wickert, Julia; Lagroua, Isabelle (2014-06-03). "Congenital mirror movements". Neurology. 82 (22): 1999–2002. doi:10.1212/WNL.0000000000000477. ISSN   0028-3878. PMC   4105259 . PMID   24808016.
  7. 1 2 3 4 5 Depienne, Christel; Bouteiller, Delphine; Méneret, Aurélie; Billot, Ségolène; Groppa, Sergiu; Klebe, Stephan; Charbonnier-Beaupel, Fanny; Corvol, Jean-Christophe; Saraiva, Jean-Paul (2012-02-10). "RAD51 haploinsufficiency causes congenital mirror movements in humans". American Journal of Human Genetics. 90 (2): 301–307. doi:10.1016/j.ajhg.2011.12.002. ISSN   1537-6605. PMC   3276668 . PMID   22305526.
  8. 1 2 3 4 Ahmed, Iltaf; Mittal, Kirti; Sheikh, Taimoor I.; Vasli, Nasim; Rafiq, Muhammad Arshad; Mikhailov, Anna; Ohadi, Mehrnaz; Mahmood, Huda; Rouleau, Guy A. (November 2014). "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". Human Genetics. 133 (11): 1419–1429. doi:10.1007/s00439-014-1475-8. ISSN   1432-1203. PMID   25098561. S2CID   15670061.
  9. 1 2 Méneret, Aurélie; Franz, Elizabeth A.; Trouillard, Oriane; Oliver, Thomas C.; Zagar, Yvrick; Robertson, Stephen P.; Welniarz, Quentin; Gardner, R. J. MacKinlay; Gallea, Cécile (2017-11-01). "Mutations in the netrin-1 gene cause congenital mirror movements". The Journal of Clinical Investigation. 127 (11): 3923–3936. doi:10.1172/JCI95442. ISSN   1558-8238. PMC   5663368 . PMID   28945198.
  10. 1 2 Franz, Elizabeth A.; Chiaroni-Clarke, Rachel; Woodrow, Stephanie; Glendining, Kelly A.; Jasoni, Christine L.; Robertson, Stephen P.; Gardner, R. J. McKinlay; Markie, David (2015-04-15). "Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations". Journal of the Neurological Sciences. 351 (1–2): 140–145. doi:10.1016/j.jns.2015.03.006. ISSN   1878-5883. PMID   25813273. S2CID   140204598.
  11. 1 2 Depienne, C.; Cincotta, M.; Billot, S.; Bouteiller, D.; Groppa, S.; Brochard, V.; Flamand, C.; Hubsch, C.; Meunier, S. (2011-01-18). "A novel DCC mutation and genetic heterogeneity in congenital mirror movements". Neurology. 76 (3): 260–264. doi:10.1212/WNL.0b013e318207b1e0. ISSN   1526-632X. PMID   21242494. S2CID   9038530.
  12. ↑ Djarmati-Westenberger, A.; Brüggemann, N.; Espay, A. J.; Bhatia, K. P.; Klein, C. (2011-10-18). "A novel DCC mutation and genetic heterogeneity in congenital mirror movements". Neurology. 77 (16): 1580. doi:10.1212/WNL.0b013e318230b140. ISSN   1526-632X. PMID   22006891. S2CID   207120206.
  13. ↑ Kanouchi, T.; Yokota, T.; Isa, F.; Ishii, K.; Senda, M. (June 1997). "Role of the ipsilateral motor cortex in mirror movements". Journal of Neurology, Neurosurgery, and Psychiatry. 62 (6): 629–632. doi:10.1136/jnnp.62.6.629. ISSN   0022-3050. PMC   1074150 . PMID   9219752.
  14. 1 2 3 Srour, Myriam; Rivière, Jean-Baptiste; Pham, Jessica M. T.; Dubé, Marie-Pierre; Girard, Simon; Morin, Steves; Dion, Patrick A.; Asselin, Géraldine; Rochefort, Daniel (2010-04-30). "Mutations in DCC cause congenital mirror movements". Science. 328 (5978): 592. Bibcode:2010Sci...328..592S. doi:10.1126/science.1186463. ISSN   1095-9203. PMID   20431009. S2CID   206525182.
  15. ↑ "029220 - CBy.Cg-Dcc<kanga>/GrsrJ". www.jax.org. Retrieved 2017-12-06.
  16. 1 2 3 Welniarz, Quentin; Morel, Marie-Pierre; Pourchet, Oriane; Gallea, Cécile; Lamy, Jean-Charles; Cincotta, Massimo; Doulazmi, Mohamed; Belle, Morgane; Méneret, Aurélie (2017-03-24). "Non cell-autonomous role of DCC in the guidance of the corticospinal tract at the midline". Scientific Reports. 7 (1): 410. Bibcode:2017NatSR...7..410W. doi:10.1038/s41598-017-00514-z. ISSN   2045-2322. PMC   5428661 . PMID   28341853.
  17. 1 2 Galléa, Cécile; Popa, Traian; Billot, Ségolène; Méneret, Aurélie; Depienne, Christel; Roze, Emmanuel (2011-11-01). "Congenital mirror movements: a clue to understanding bimanual motor control". Journal of Neurology. 258 (11): 1911–1919. doi:10.1007/s00415-011-6107-9. ISSN   0340-5354. PMID   21633904. S2CID   22968346.
  18. 1 2 Giedd, J. N.; Blumenthal, J.; Jeffries, N. O.; Castellanos, F. X.; Liu, H.; Zijdenbos, A.; Paus, T.; Evans, A. C.; Rapoport, J. L. (October 1999). "Brain development during childhood and adolescence: a longitudinal MRI study". Nature Neuroscience. 2 (10): 861–863. doi:10.1038/13158. ISSN   1097-6256. PMID   10491603. S2CID   204989935.
  19. ↑ Garvey, M. A.; Ziemann, U.; Bartko, J. J.; Denckla, M. B.; Barker, C. A.; Wassermann, E. M. (September 2003). "Cortical correlates of neuromotor development in healthy children". Clinical Neurophysiology. 114 (9): 1662–1670. doi:10.1016/s1388-2457(03)00130-5. ISSN   1388-2457. PMID   12948795. S2CID   34087160.
  20. ↑ Leinsinger, G L; Heiss, D T; Jassoy, A G; Pfluger, T; Hahn, K; Danek, A (1997-05-01). "Persistent mirror movements: functional MR imaging of the hand motor cortex". Radiology. 203 (2): 545–552. doi:10.1148/radiology.203.2.9114119. ISSN   0033-8419. PMID   9114119.
  21. ↑ Wahl, Mathias; Lauterbach-Soon, Birgit; Hattingen, Elke; Jung, Patrick; Singer, Oliver; Volz, Steffen; Klein, Johannes C.; Steinmetz, Helmuth; Ziemann, Ulf (2007-11-07). "Human motor corpus callosum: topography, somatotopy, and link between microstructure and function". The Journal of Neuroscience. 27 (45): 12132–12138. doi: 10.1523/JNEUROSCI.2320-07.2007 . ISSN   1529-2401. PMC   6673264 . PMID   17989279.
  22. ↑ Ueki, Y.; Mima, T.; Oga, T.; Ikeda, A.; Hitomi, T.; Fukuyama, H.; Nagamine, T.; Shibasaki, H. (February 2005). "Dominance of ipsilateral corticospinal pathway in congenital mirror movements". Journal of Neurology, Neurosurgery, and Psychiatry. 76 (2): 276–279. doi:10.1136/jnnp.2004.040949. ISSN   0022-3050. PMC   1739493 . PMID   15654052.
  23. ↑ Koerte, Inga; Eftimov, Lara; Laubender, Ruediger Paul; Esslinger, Olaf; Schroeder, Andreas Sebastian; Ertl-Wagner, Birgit; Wahllaender-Danek, Ute; Heinen, Florian; Danek, Adrian (December 2010). "Mirror movements in healthy humans across the lifespan: effects of development and ageing". Developmental Medicine and Child Neurology. 52 (12): 1106–1112. doi: 10.1111/j.1469-8749.2010.03766.x . ISSN   1469-8749. PMID   21039436. S2CID   23856550.
  24. ↑ Mayston, M. J.; Harrison, L. M.; Stephens, J. A. (May 1999). "A neurophysiological study of mirror movements in adults and children". Annals of Neurology. 45 (5): 583–594. doi:10.1002/1531-8249(199905)45:5<583::aid-ana6>3.0.co;2-w. ISSN   0364-5134. PMID   10319880. S2CID   13576328.
  25. ↑ Jain, Roshan A.; Bell, Hannah; Lim, Amy; Chien, Chi-Bin; Granato, Michael (2014-02-19). "Mirror movement-like defects in startle behavior of zebrafish dcc mutants are caused by aberrant midline guidance of identified descending hindbrain neurons". The Journal of Neuroscience. 34 (8): 2898–2909. doi:10.1523/JNEUROSCI.2420-13.2014. ISSN   1529-2401. PMC   3931503 . PMID   24553931.
  26. ↑ Meneret, Aurelie; Trouillard, Oriane; Brochard, Vanessa; Roze, Emmanuel (August 2015). "Congenital mirror movements caused by a mutation in the DCC gene". Developmental Medicine and Child Neurology. 57 (8): 776. doi: 10.1111/dmcn.12810 . ISSN   1469-8749. PMID   26011025.
  27. ↑ Cincotta, M.; Borgheresi, A.; Boffi, P.; Vigliano, P.; Ragazzoni, A.; Zaccara, G.; Ziemann, U. (2002-04-23). "Bilateral motor cortex output with intended unimanual contraction in congenital mirror movements". Neurology. 58 (8): 1290–1293. doi:10.1212/WNL.58.8.1290. ISSN   0028-3878. PMID   11971104. S2CID   33506544.
  28. ↑ Rasmussen, Peder (1993-08-01). "Persistent Mirror Movements: A Clinical Study of 17 Children, Adolescents and Young Adults". Developmental Medicine & Child Neurology. 35 (8): 699–707. doi:10.1111/j.1469-8749.1993.tb11715.x. ISSN   1469-8749. PMID   8335159. S2CID   11868085.
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