Defining the Genetic Landscape of Congenital Mirror Movements in 80 Affected Individuals.

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Congenital Mirror Movements Associated With Brain Malformations.

BACKGROUND: Congenital mirror movements are involuntary movements of a side of the body imitating intentional movements on the opposite side, appearing in early childhood and persisting beyond 7 years of age. Congenital mirror movements are usually idiopathic but have been reported in association with various brain malformations. METHODS: We describe clinical, genetic, and radiologic features in 9 individuals from 5 families manifesting congenital mirror movements. RESULTS: The brain malformations associated with congenital mirror movements were: dysplastic corpus callosum in father and daughter with a heterozygous p.Met1* mutation in DCC; hypoplastic corpus callosum, dysgyria, and malformed vermis in a mother and son with a heterozygous p.Thr312Met mutation in TUBB3; dysplastic corpus callosum, dysgyria, abnormal vermis, and asymmetric ventricles in a father and 2 daughters with a heterozygous p.Arg121Trp mutation in TUBB; hypoplastic corpus callosum, dysgyria, malformed basal ganglia and abnormal vermis in a patient with a heterozygous p.Glu155Asp mutation in TUBA1A; hydrocephalus, hypoplastic corpus callosum, polymicrogyria, and cerebellar cysts in a patient with a homozygous p.Pro312Leu mutation in POMGNT1. CONCLUSION: DCC, TUBB3, TUBB, TUBA1A, POMGNT1 cause abnormal axonal guidance via different mechanisms and result in congenital mirror movements associated with brain malformations.

Developmental Dynamic Dysphasia: Are Bilateral Brain Abnormalities a Signature of Inefficient Neural Plasticity?

The acquisition and evolution of speech production, discourse and communication can be negatively impacted by brain malformations. We describe, for the first time, a case of developmental dynamic dysphasia (DDD) in a right-handed adolescent boy (subject D) with cortical malformations involving language-eloquent regions (inferior frontal gyrus) in both the left and the right hemispheres. Language evaluation revealed a markedly reduced verbal output affecting phonemic and semantic fluency, phrase and sentence generation and verbal communication in everyday life. Auditory comprehension, repetition, naming, reading and spelling were relatively preserved, but executive function was impaired. Multimodal neuroimaging showed a malformed cerebral cortex with atypical configuration and placement of white matter tracts bilaterally and abnormal callosal fibers. Dichotic listening showed right hemisphere dominance for language, and functional magnetic resonance imaging (fMRI) additionally revealed dissociated hemispheric language representation with right frontal activation for phonology and bilateral dominance for semantic processing. Moreover, subject D also had congenital mirror movements (CMM), defined as involuntary movements of one side of the body that mirror intentional movements of the other side. Transcranial magnetic stimulation and fMRI during voluntary unimanual (left and right) hand movements showed bilateral motor cortex recruitment and tractography revealed a lack of decussation of bilateral corticospinal tracts. Genetic testing aimed to detect mutations that disrupt the development of commissural tracts correlating with CMM (e.g., Germline DCC mutations) was negative. Overall, our findings suggest that DDD in subject D resulted from the underdevelopment of the left inferior frontal gyrus with limited capacity for plastic reorganization by its homologous counterpart in the right hemisphere. Corpus callosum anomalies probably contributed to hinder interhemispheric connectivity necessary to compensate language and communication deficits after left frontal involvement.

Pre-movement planning processes in people with congenital mirror movements.

OBJECTIVE: Pre-movement processes were investigated in people with Congenital mirrormovement (CMM), a rare disorder in which bilateral movement (mirroring) occurs in the upper distal extremities (primarily the hands and fingers) during intended unilateral movements. Abnormal density of ipsilateral corticospinal projections is an established hallmark of CMM. This study tested whether the Lateralised Readiness Potential (LRP), which reflects movement planning and readiness, is also abnormal in people with CMM. METHODS: Twenty-eight neurologically-normal controls and 8 people with CMM were tested on a unimanual Go/No-go task while electroencephalography (EEG) was recorded to assess the LRP. RESULTS: No significant group differences were found in reaction time (RT). However, significantly smaller LRP amplitudes were found, on average, in the CMM group compared to Controls at central-motor (C3,C4) sites in stimulus-locked and response-locked epochs; similar group differences were also found at further frontal sites (F3,F4) during response-locked epochs. CONCLUSIONS: Abnormal brain activity in pre-movement processes associated with response planning and preparation is present in people with CMM. SIGNIFICANCE: Aberrant bilateral activity during pre-movement processes is clearly implicated; whether part of the etiology of CMM, or as a mechanism of neuro-compensation, is not yet known.

Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations.

Congenital mirror movements (CMM) is a disorder characterized by unintentional mirroring in homologous motor systems of voluntary movements on the opposite side, usually affecting the distal upper extremities. Genetic analyses have revealed involvement of three genes (DCC, RAD51, and DNAL4). We sought to distinguish whether different phenotypes of CMM exist, and if so, whether they might map to different causative genes. We studied 14 individuals across five families with dominantly-inherited CMM. We used accelerometer gloves to analyse the fine detail of index finger tapping movements, and applied standard genetic methodology to analyse DNA samples. Two forms of mirroring were distinguished: 'actual' in which the mirroring followed precisely the movements of the voluntary hand, and 'fractionated' in which the mirroring was saccadic. We found that actual mirroring was characteristic of individuals in a family with a RAD51 mutation, and fractionated more characteristic of a family with a DCC mutation. These findings are suggestive of specific genotype-phenotype correlations in CMM. Three heterozygous individuals (one RAD51; two DCC) showed no apparent mirroring on visual inspection, although mirroring was detectable with the accelerometer gloves. Thus, subclinical mirroring may be present even when undetectable on clinical observation.

Persistencia de movimientos en espejo congénitos en una hemiplejía por infarto cerebral / Persistance of congenital mirror movements in the hemiplejic side after ischemic stroke

The simultaneous and involuntary displacement of the opposite limb during a volitional movement is called mirror movements. They mimic the gesture, partly or wholly. They can be congenital, familiar or installed in various CNS pathologies. We present a 64 years old woman with familiar history of mirror movements that affect their hands, since childhood. At admission presented confused with left hemiplegia and homolateral sensory involvement. The brain CT defined a right ischemic stroke affecting the posterior limb of the internal capsule, lenticular nucleus, sub insular region and par ventricular white matter. The paretic left hand, unable to perform voluntary movements, presented mirror movements during volitional movements of the contra lateral hand. Neurophysiologic studies have suggested that mirror movements are due the activation of the direct corticospinal pathway or simultaneous discharge of both motor cortexes due inhibitory pathways failures. Cortical origin seems unlikely for the movements in this patient, due to the injury of the internal capsule. Our case could be interpreted by the simultaneously brain innervations on both anterior horns, together with a congenital deregulation of the Central Pattern Generator Networks.

Se denomina movimiento en espejo (ME) el desplazamiento involuntario, imitativo y simultáneo de la extremidad opuesta al de un movimiento volitivo. Los ME pueden tener un origen congénito y familiar o generarse por patologías diversas del sistema nervioso central. Se presenta una mujer de 64 años con el antecedente de ME desde la infancia de carácter familiar. Ingresa en estado confusional y presentando una hemiplejía y hemihipoestesia faciobraquicrural izquierda. La tomografía cerebral mostraba compromiso del brazo posterior de la cápsula interna, núcleo lenticular, región subinsular y de la sustancia blanca paraventricular. La mano izquierda pléjica que era incapaz de realizar movimientos voluntarios, se movía en espejo al mover la mano derecha. Esta curiosa manifestación hace necesario una más ajustada interpretación neurofisiológica de los movimientos en espejo. Se ha postulado una activación de la vía corticoespinal directa, o la descarga simultánea de ambas cortezas motoras por fallas en la natural inhibición transcortical. En este caso parece improbable un origen cortical contralateral de los movimientos, debido a la lesión de la cápsula. Tal vez podrían comprenderse los ME de esta paciente, si se demostrara una doble inervación de ambas astas anteriores, asociada a una falla en la inhibición normal por desregulación congénita de los Circuitos Generadores Centrales.