Introduction

Mirror movements (MM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the contralateral side.1 They can be a manifestation of various congenital or acquired neurological disorders.2,3 Autosomal dominant congenital mirror movements (CMM) are characterized by early onset MM that persist throughout life in the absence of other neurological symptoms.1 Since CMM predominantly affects the hands, difficulty carrying out activities of daily living is limited to tasks that require independent movements of the two hands, but patients can also experience chronic upper limb pain.4,5 The pathophysiology is related to abnormal development of the motor network and likely involves corticospinal tract abnormalities leading to bilateral downstream transmission of the motor command and altered interhemispheric communication resulting in bilateral activation of primary motor areas.6–10

The main culprit genes responsible for this condition are RAD51 and DCC.11–14 Only a few families and sporadic cases have been linked to RAD51 mutations. Here, we report a new family with autosomal dominant CMM with a RAD51 mutation and review the literature for previously reported patients. We also discuss the possible pathogenic molecular mechanism in CMM-RAD51 patients.

Methods

Results

Study of the New RAD51-MM family

The characteristics of the patients are shown in Table 1. By direct sequencing of the RAD51 coding sequence (NM_002875.4), we identified a heterozygous nonsense mutation c.760C>T (p.Arg254*) in the eight subjects (Figure 1). Among them, four had obvious MM in their hands that disturbed their activities of daily living (subjects #1, #2, #3, #4). The remaining four mutation carriers had no complaints despite having mild MM when attempting to perform strictly unilateral movements (subjects #5, #6, #7; #8) (Video 1). No other non-neurological phenotype cosegregated with the RAD51 variants.

Table 1

Patient Characteristics

Patient-Sex/Age	MM Severity1/Location	Asymmetry	Associated Disorders	Functional Disability
1-M/59	3/UL	No	No	Difficulties in fine bimanual activities
2-F/5	3/UL	No	No	Difficulties in fine bimanual activities
3-F/3	3/UL; 1/LL	No	No	Difficulties in fine bimanual activities
4-F/22	3/UL; 1/LL	No	No	Difficulties in fine bimanual activities
5-F/70	1/UL	R>L	Chronic fatigue	None
6-M/45	1/UL	R>L	No	None
7-M/44	1/UL	L>R	No	Chronic UL pain
8-M/43	1/UL	R>L	No	None

Abbreviations: F, Female; L, Left; LL, Lower Limbs; M, Male; MM, Mirror Movements; R, Right; UL, Upper Limbs.

¹According to the Woods and Teuber MM severity scale: (0: No MM; 1: Barely discernible but repetitive MM; 2: Either 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).

Figure 1 

Identification of the R254* Mutation in the Norwegian Family. (A) Segregation of the mutation. Black symbols represent individuals with strong congenital mirror movements, and gray symbols represent individuals with mild congenital mirror movements. Circles indicate females; squares, males; symbols with a diagonal line, deceased; m: mutated allele, +: wild-type allele. (B) Sequence profile of the mutation in the heterozygous state in a congenital mirror movement patient compared with an unaffected subject. The red arrow points to sequence changes; electrophoregrams were obtained with SeqScape software (v2.6, Applied Biosystems).

Video 1 

Illustrative video of severe and mild mirror movements. Two patients (subjects #2 and #3) with severe mirror movements (severity score = 3), and then a patient (subject #7) with mild mirror movements (severity score = 1). The red arrow indicates the side of the voluntary movement.

Discussion

We report a new CMM family with a RAD51 truncating mutation, providing further support for the involvement of RAD51 in CMM pathogenesis. A review of all published cases of RAD51-linked CMM raises the possibility of a molecular pathogenesis other than mere haploinsufficiency.

In this paper, we report the first CMM family from Norway comprising eight affected members: four with strong MM, and four with a mild phenotype. All affected patients have a heterozygous nonsense mutation of RAD51, previously demonstrated to cause CMM in a large, unrelated French family.12 The exact age of onset is difficult to ascertain in CMM patients, including in the family described here. In our clinical experience, the age of onset corresponds to the period of manual skill development in toddlers, regardless of the culprit gene (DCC or RAD51). Males with a DCC mutation may be more prone to develop MM,11,13,14 whereas the sex ratio seems to be well balanced (18 males/14 females) in patients with CMM due to RAD51 mutations. In the Norwegian family described here, there was considerable intrafamilial variability in MM severity, and the available data were too scarce to properly discuss the penetrance. Typically, penetrance is incomplete, and phenotypic severity varies widely within families with CMM (including RAD51-CMM families),11–14 from asymptomatic carriers to subjects with strong, sustained MM. The incomplete penetrance and phenotypic variability of CMM due to RAD51 mutations may be related neither to age nor sex, but it could be linked to greater expression of RAD51 from the remaining normal allele or to other genetic, epigenetic, or environmental modifiers. In mildly affected subjects, it can be difficult to distinguish among mild genetically determined “pathologic” MM, physiologic MM, and secondary MM. Indeed, subtle mirroring can be seen in otherwise healthy subjects, particularly in young children or elderly subjects.17 Mild MM can similarly be observed in patients with various central nervous system (CNS) disorders, including poststroke hemiplegia,18 amyotrophic lateral sclerosis,19 multiple sclerosis,20 Parkinson’s disease,21–23 essential tremor,24,25 Huntington’s disease,26 and corticobasal degeneration.27 In this setting, the MM are acquired and therefore presumably absent before CNS disorder onset.

Since the RAD51 protein is well known for its important role in DNA repair through homologous recombination,28 its role in a developmental CNS disorder such as CMM was totally unexpected. The first RAD51 mutations discovered in CMM patients were nonsense or frameshift mutations.12 In particular, we described a French family carrying the same mutation as the Norwegian family (reported here), and the phenotypes are very similar.12 CMM patients in the French family exhibited a downregulation of RAD51 mRNA, corresponding to the degradation of the mutated mRNA by nonsense-mediated decay. Western blot analyses failed to detect any truncated protein in lymphoblastic cells of affected family members. Taking genotypic and phenotypic similarities into account, haploinsufficiency is likely the pathogenic mechanism accounting for CMM in both families. In keeping with this, Exome Aggregation Consortium (ExAC) data show that RAD51 is highly intolerant to loss of function (probability of loss of function intolerance  =  0.99). Therefore, the prevailing hypothesis has been one of a haploinsufficiency leading to CMM in RAD51 patients. The recent finding that a missense pathogenic RAD51 mutation was responsible for CMM in a large family16 raises the possibility of pathophysiologic mechanisms other than mere haploinsufficiency. Interestingly, a dominant-negative effect of RAD51 mutations was recently proposed for patients affected with Fanconi’s anemia, another disorder linked to RAD51 mutations.29,30 To date, there is no report of a patient with both CMM and Fanconi’s anemia. Similarly, none of the RAD51 pathogenic variants have been described in both disorders. This suggests that CMM and Fanconi’s anemia are allelic disorders due to mutations with mechanistically distinct functional effects on RAD51 activity. Further functional studies are needed to investigate the genotype/phenotype correlation in patients with RAD51 mutations in depth and clarify the impact of nongenetic factors on the phenotype and penetrance.