Congenital mirror movements: Phenotypes associated with DCC and RAD51 mutations
Introduction
Congenital mirror movements are involuntary mirror reversals of voluntary movements on the opposite body side, and typically occur in the distal upper limbs [1], [2], [3]. Non-syndromic CMM, which is the focus of this study, presents with no known comorbidities. A genetic basis for CMM is supported with familial [3], [4], [5], [6], [7], [8], [9] but also sporadic occurrences well described [1], [2]. The mechanism of inheritance in some families has been shown to be autosomal dominant, with locus heterogeneity becoming evident in more recent molecular studies. Sporadic cases could also reflect autosomal dominant inheritance, either with an affected parent being non-penetrant for the trait, or there having been a de novo mutation. Penetrance in autosomal dominant CMM is incomplete and possibly higher in males compared to females [10].
Mutations in three genes, DCC, RAD51, and DNAL4, have thus far been identified. The first gene identified to play a role is DCC. Studies on a five-generation Iranian family (initially described in [4]), a four-generation French-Canadian family [10], and a three-generation Italian family [7], all demonstrated a frameshift mutation predicting the production of a truncated and presumably non-functional DCC protein. Known interactions of DCC with Netrin-1, and the known role of Netrin-1 in axon guidance [11], [12] provide plausible grounds for its having a role in the causation of CMM [7], [10]. The second gene to be implicated was RAD51. Depienne et al. [7] identified a nonsense mutation in a four-generation French family, and a frameshift mutation in a German mother and son. Further examples of mutations in DCC and RAD51 were recently given in a study of 26 subjects [13]. The only known instance of proven autosomal recessive inheritance came from a Pakistani family, in which a homozygous splice site mutation was found in the DNAL4 gene [14]. How RAD51 and DNAL4 could lead to the generation of CMM is less apparent than might be supposed for DCC given their molecular roles, respectively, in DNA repair by homologous recombination, and maintenance of the dynein complex.
Diagnosis of CMM is typically based upon visual observation of mirroring, through descriptions of self-reports and reports of family members, or incidentally upon medical examination for unrelated conditions [10]. Early manifestations of CMM can be concealed due to the fact that mirroring may occur as a normal phenomenon during the first years of life, but thereafter resolves [15], [16]. Although CMM does not resolve or become more marked with age, affected individuals can learn to suppress some of the effects of the involuntary movements with concentrated attentional focus, leading to diagnostic difficulties [3].
Implicated neural processes are still under debate. Numerous studies using focal transcranial magnetic stimulation (TMS) have revealed bilateral motor evoked potentials in the muscles of the hands with stimulation to a single motor cortex in people with CMM. The proposal that there exist abnormal fast-conducting ipsilateral corticospinal projections from motor cortex hand areas to spinal cord loci is well supported [1], [17], [18]. Those investigations include participants who are known heterozygotes for DCC or RAD51 mutations [6], [9]. Recording of scalp potentials during movement preparation, and interference with the cortical motor output by focal TMS, have further revealed bilateral activation of the motor cortex during intended unilateral movements [1], [6], [19], [20], [21] including in one participant later confirmed as having a DCC mutation [6]. Current data strongly suggest that these different, anomalous processes, coexist in people with CMM, and that abnormal supplementary motor cortex activity and callosal interhemispheric inhibition mechanisms also play a role [9], [18]. It also remains possible that bilateral cortical activity during intended unilateral movements in people with CMM reflects, at least in part, involvement of compensatory mechanisms intended to reduce the effects of mirroring [9], [18]. How multiple affected neural pathways give rise to CMM, and/or act as compensatory mechanisms, remains to be determined.
Certain elements of the mirroring phenomenon require precise phenotyping to elucidate and assess generalizability across individuals with CMM. These include the prevalence of CMM in motor systems other than the fingers and hands, whether amplitude of mirroring is the same on both sides of the body, and whether subclinical elements of mirroring can be quantified. Whether mirroring can occur in different forms, for example, actual mirroring in which the involuntary hand produces a smooth and continuous mirroring of the precise movements of the voluntary hand, versus more fractionated mirroring which is saccadic, is also not known.
We have sought in this study: to distinguish different forms of mirroring, specifically, “actual” versus “fractionated” mirroring; to ascertain if such differences might relate to the particular causative gene; and to assess whether sophisticated laboratory testing might show subtle mirroring in clinically non-penetrant heterozygotes.
Section snippets
Participants
Fourteen individuals from five CMM families were recruited through previous research of EAF [3] and through social media. This includes Family A from the United States of America, B and D from Australia, C from England, and F from New Zealand; data are listed in Table 1, and pedigrees are shown in Fig. 1. Initial interviews with an index case in each family provided information on first observable evidence of mirroring and how diagnosed, medical history including developmental history, family
Qualitative assessments
All CMM participants were qualitatively assessed as having no associated comorbidities. Qualitative scores of mirroring obtained during our interview session were assigned and later checked against videotaped performance and logged (Table 1). These initial assessments suggested that the most marked mirroring occurred in family A, particularly III:4, IV:1, IV:2, and IV:3, in whom the non-volitional (involuntary) hand and fingers virtually mirrored the volitional hand precisely in all movements
Discussion
We identified mutations in two known genes in two of the five CMM families studied, the RAD51 and the DCC genes. No mutation in either of these genes was found in the remaining three families, nor in DNAL4, indicating, as others [13] also have concluded, that further CMM genes remain to be discovered.
We have confirmed a distinction between CMM in which the non-volitional hand follows smoothly and closely the movements of the volitional hand, which we have called “actual” mirroring; and CMM in
Conclusions
We describe a protocol for the laboratory analysis of mirror movements, enabling an assessment more sensitive and beyond the scope of visual observation, and allowing a dissection of different CMM phenotypes. Applying this technique to the study of individuals from five families with CMM has made it possible for us to investigate some subtle distinctions in the expression of gene-dependent phenotypes. Additional genes remain to be found, and genotype–phenotype correlations might prove
Acknowledgements
This study is funded by the Marsden Fund of the Royal Society of New Zealand. SPR is supported by Cure Kids. All authors declare no disclosures. The authors also thank the participants of this study for their generous contributions, and Tim Morgan, Paul Crane, Jeremy Anderson, and Richard Hamelink for their technical assistance.
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2017, Clinical NeurophysiologyCitation Excerpt :Congenital mirror movements (CMM), a disorder characterised by unintentional mirroring of motor systems on the contralateral side of voluntary movements, usually of the hands and wrists, is regarded as a rare condition of human movement (Schott and Wyke, 1981); its prevalence is unknown. CMM can be difficult to detect due to its isolated occurrence in the distal portions of the upper limbs in most individuals affected, and in particular, because there are no other known comorbidities (Franz, 2003; Franz et al., 2015). In recent years, the genetic basis of CMM has begun to be understood, with the discovery of three gene mutations found in separate multigenerational families, two of which have shown to be autosomal dominant: DCC (Depienne et al., 2012; Sharafaddinzadeh et al., 2008; Srour et al., 2009) and RAD51 (Depienne et al., 2012; Meneret et al., 2014; Gallea et al., 2013), and one autosomal recessive: DNAL4 (Ahmed et al., 2014).