Abstract
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.
Mirror movements are involuntary movements of a side of the body that imitate intentional movements on the opposite side. 1,2 Mild mirror movements are physiologic in young children up to 7 years of age. 1,2 Mirror movements that appear in infancy or early childhood and persist beyond 7 years of age are called congenital mirror movements. 1,2 Their characteristics are: predominant involvement of the distal upper limbs; a decreased amplitude compared to the corresponding voluntary movements; 2 and the intensity often increases with the complexity of the voluntary movement. 3 Congenital mirror movements usually persist throughout life, without deterioration or improvement. 2
Congenital mirror movements may present as an isolated phenomenon or in association with other neurologic and neuro-radiologic findings. Congenital mirror movements have been described in association with heterozygous variants in DCC, RAD51, and NTN1 1,4 -6 and homozygous variants in DNAL4. 7 Patients with DCC, RAD51, and NTN1 usually demonstrate normal brain MRIs, although partial or complete agenesis of the corpus callosum have been reported in patients with DCC mutations. 8,9 A combination of congenital mirror movements and developmental brain malformations has been occasionally described in association with: Joubert syndrome due to a AHI1 variant, 10 alpha-dystroglycanopathy due to a novel POMK variant, 11 and X-linked Kallmann syndrome due to a KAL1 variant. 12
We describe 9 individuals from 5 families with congenital mirror movements, depicting different brain malformations and a diverse genetic etiology.
Methods
Clinical Evaluation
All individuals enrolled in the study were evaluated at the Pediatric Neurology Unit and Pediatric Movement Disorders Service at Wolfson Medical Center, Holon, Israel. Participants were examined by pediatric neurologists (TLS, IZ, MH, AN) and a pediatric movement disorders specialist (LB).
In the adult participants, mirror movements were evaluated by employing the tasks devised by Woods and Teuber 13 and included 3 tasks performed separately by each hand: (1) rapid tapping of the index finger on the distal joint of the thumb; (2) rotation of the fist by alternating supination and pronation of the forearm; (3) sequential touching of each fingertip with the tip of the thumb. We used tasks 1 and 2 from the Woods and Teuber survey but swapped task 3 for a repetitive finger flexion and extension test since this was more easily performed by our young patients. Due to the limited cooperation of our young patients and a patient with intellectual difficulties, we assessed the mirror movements by observing them playing with small toys with 1 hand. Our tasks mimicked the tasks from Woods and Teuber survey and included (1) squeezing and releasing a rattle with a handle, which mimics the finger flexion and extension task; (2) rotation of a rattle with 1 hand, which mimics rotation of the fist by alternating supination and pronation of the forearm; (3) grasping beads and pins with a pincer-like movement, which mimics tapping the index finger on the distal joint of the thumb. We also decreased the duration of the tasks for young patients 15-20 seconds.
Since our adapted tests had not been formally validated, we also evaluated them during the routine neurological examinations of 22 other patients, aged 8 to 48 months, who were referred to our pediatric neurology clinic and had neither significant developmental delay nor brain malformation. Mirror movements were not observed in none of these children.
The severity of the mirror movements was graded on a 4-point scale, according to Woods and Teuber classification: 13 not present (–), suspected (+) (barely discernible), obvious (++) (clear and sustained), and equal (+++) (intensity similar to intentional movements). The right and left hands were assessed separately.
All individuals were videotaped during performance of the tasks.
All procedures were approved by the local ethics committee (IRB 0075-17-WOMC). The adult participants and the legal guardians of the children provided written consents.
Neuroimaging Studies
Fetal brain MRI (1.5 T GE Sigma Horizon, Echo speed, LX MRI scanner, Milwaukee, WI, USA) was performed after consultation at the Fetal Neurology Unit. Following a localizing gradient-echo sequence, ultra T2-weighted single shot fast spin echo MR images were collected in the axial, coronal, and sagittal planes according to fetal position (TR/TE, infinite/90; bandwidth, 32 KHz; field of view, 16 × 28 cm; matrix, 256 × 192; slice thickness, 3-5 mm; gap, 0-1 mm; and number of excitations, 0.5). A torso phased array coil was used. All mothers received oral diazepam (5-15 mg) prior to the MRI scan aimed to reduce total scan time, maternal anxiety, and fetal and maternal movements for exquisite imaging.
MRI imaging in children and adults was performed by a routine protocol as part of the clinical evaluation.
Genetic Studies
A molecular evaluation was obtained as clinically indicated, by performing whole exome sequencing in a single or trio format. DNA samples were enriched with Sureselect Human All Exome v.6 kit 60 Mb (Agilent, Santa Clara, CA, USA). The generated library was sequenced on an Illumina platform to obtain an average coverage depth of ∼100x. Reads were aligned with the human reference genome (assembly GRCh37/hg19); primary filtering out of low quality reads and probable artefacts, and subsequent annotation of variants, were applied. All diseases causing variants reported in the Human Gene Mutation Database, in ClinVar, or in CentoMD as well as all variants with minor allele frequency of less than 1% in gnomAD database were considered. Evaluation was focused on coding exons along with flanking ±20 intronic bases. All pertinent inheritance patterns were considered. In addition, provided family history and clinical information were used to evaluate eventually identified variants. All identified variants were evaluated with respect to their pathogenicity and causality. Additional afflicted family members were detected by targeted Sanger sequencing to the relevant mutation.
Case Histories
Family I
Case 1
A 2-year-old girl was referred to our clinic for follow-up because of partial agenesis of corpus callosum on fetal brain MRI (Table 1) (Figure 1a).
Clinical, Radiological, and Genetic Data of Individuals with Congenital Mirror Movements.
Brain imaging of family I (cases 1 and 2, DCC mutation). Midsagittal T2 imaging in 32-week-old fetuses: Arrows point over short CC in case 1 (1a) compared to control (1b). Midsagittal T1 imaging in 34-year-old (case 2). Solid arrows point to short and thick dysmorphic CC (1c, 1d).
She was born after an in-vitro fertilization pregnancy to a healthy father and a mother with congenital heart disease. The mother was referred to fetal brain MRI due to an abnormal corpus callosum appearance on a routine fetal sonography. Brain MRI at 32 weeks of gestation revealed a short and thick corpus callosum (Figure 1a). Similar MRI findings were revealed in the asymptomatic father, leading to the decision to continue pregnancy. Delivery and perinatal history were uneventful.
At 2 years of age, she had a mild motor delay, warranting physical and occupational therapy. Her cognitive and communication skills were normal and she attended successfully a regular kindergarten. She was normocephalic and had no dysmorphic features. Her neurological examination was unremarkable, except walking with assistance.
Mirror movements. While grasping small toys, pins and beads with a pincer movement she demonstrated an involuntary pincer grip in the opposite hand; the intensity of the mirroring was less severe (obvious) in the dominant hand and equal in the non-dominant hand (Table 2)
Severity of Mirror Movements.
Note: Severity of mirror movements: none (—), suspected (+), obvious (++), equal (+++).
* Dominant hand.
Case 2
A 34-year-old healthy college graduate male is the father of case 1. He was referred to brain MRI due to in utero brain malformation in his unborn daughter (case 1) (Table 1). Imaging revealed a short and thick corpus callosum, with no additional malformations (Figures 1c, 1d).
He was born after an uneventful pregnancy and delivery. Developmental milestones were achieved on time, but he stated that mirror movements caused him mild functional impairment with unimanual skills since childhood. He was normocephalic, had no dysmorphic features, and his neurological examination was unremarkable.
Mirror movements
He demonstrated obvious mirror movements in the finger tapping test and in the repetitive finger flexion and extension test. Mirror movements were bilateral with no difference in intensity between the dominant and non-dominant hand (Table 2).
Molecular Diagnosis
Whole exome sequencing performed on case 2 revealed a heterozygous c. 2T>C change in the ATG start codon of the DCC gene, presumed to affect the translation of the protein - p.Met1*. The same variant was confirmed on Sanger sequencing in case 1.
Family II
Case 3
A 4-year-old boy was referred to our clinic following the discovery of brain anomalies in his mother and 2 sibling fetuses (Table 1). He was born after an uneventful first pregnancy to 2 healthy unrelated parents. He was delivered by Caesarian section at 36 weeks of gestation, due to maternal pre-eclampsia, with an Apgar score of 9/10. Brain US demonstrated bilateral intraventricular hemorrhage grade 2 and asymmetric enlargement of the lateral ventricles, left more than right. His developmental milestones were mildly delayed: he started walking at the age of 18 months and spoke in short sentences at the age of 2.5 years. He was treated by speech and occupational therapy, but attended successfully a regular kindergarten. His mild developmental delay did not warrant brain imaging.
He was referred for neuroimaging at the age of 3.5 years following the discovery of brain anomalies in his mother and 2 in utero siblings. Brain MRI revealed a hypoplastic corpus callosum, folial disorganization of the vermis and right cerebellar hemisphere, mild asymmetric ventriculomegaly (Figures 2a, 2b, 2c), and right posterior frontal dysgyria.
Brain imaging of family II (cases 3 and 4, TUBB3 mutation). Brain MRI case 3 (age 3.5 years) (2a, 2b, 2c) and case 4 (age 36 years) (2d, 2e, 2f). Sagittal midline T1 imaging depicts hypoplastic corpus callosum with underdeveloped rostrum (2a, d) (arrow head). Axial T1 (2b) and T2 (2e) images reveal asymmetric enlargement of left lateral ventricle (2b, 2e) (solid arrow). Coronal T2 (2c) and axial T2 (2f) demonstrate disorganized vermian and adjacent cerebellar hemisphere folia (2c, 2f) (arrow) and asymmetric brainstem (2f).
Following these imaging findings, he was referred to our clinic. On examination at the age of 4 years, he had a borderline head circumference 49.5 cm (–2 SD) and no dysmorphic features. Neurological examination was unremarkable, except mild speech and language delay. He presented hyperactive but otherwise age appropriate behavior and normal communicative skills.
Mirror movements
During fist rotation test the patient showed obvious bilateral mirror movements. In the repetitive fingers flexion and extension test in each hand separately he demonstrated obvious mirror movements in his left (non-dominant) hand and suspected mirror movements in his right hand (Table 2).
Case 4
A healthy 36-year-old college student, mother of case 3, was referred to brain imaging and our clinic following the discovery of a hypoplastic corpus callosum and cerebellar dysplasia in her fetuses during her second and third gestations (Table 1). Her brain MRI revealed mildly short corpus callosum with small rostrum and thin mid-body, subtle anterior vermian foliar disorganization and mildly enlarged left lateral ventricle (Figures 2d, 2e, 2f).
She was born after a normal pregnancy and delivery. Her past medical history was remarkable for mild motor delay, which did not warrant treatment.
On physical examination she had low borderline head circumference (52 cm, –2 SD), but no dysmorphic features. On neurological examination she had mild tandem gait ataxia.
Mirror movements
The patient showed obvious bilateral mirror movements of fist rotation in both hands. During flexion and extension of fingers and rapid finger tapping she demonstrated obvious mirror movements in the right (non-dominant) hand and suspected mirror movements in her left hand (Table 2).
Molecular Diagnosis
WES trio analysis performed on the mother (case 4) and the 2 fetuses, demonstrated a heterozygous pathogenic variant in TUBB3: c.935C>T (NM_006086.3); pThr312Met in all 3 of them. Sanger sequencing confirmed the mutation in her son (case 3).
Family III
Case 5
A 9 months-old girl was referred for neurologic follow up following identification of a short and thin corpus callosum, asymmetric ventriculomegaly and suspected malformation of cortical development in utero (Table 1) (Figures 3a, 3b). She was the product of a spontaneous pregnancy to healthy unrelated parents. She was referred to fetal brain imaging at 32 weeks of gestation, due to fetal brain anomalies in a previous pregnancy which was terminated. Her father (case 6) subsequently underwent a brain MRI and following the discovery of similar findings the pregnancy was continued. She was born at term, with no perinatal complications.
Brain imaging of family III (cases 5, 6, and 7, TUBB mutation). Sagittal midline T2 images in case 5 (32-week-old fetus) (3a), case 6 (37 years old) (3b) and case 7 (9 years old) (3c) depict dysplastic corpus callosum (white arrow). Coronal T2 in case 5 (3d), T1 in case 6 (3e) and T2 (3f) in case 7 shows asymmetric ventricles (arrowhead). Axial T1 in case 5 and T2 (3g) in case 7 (3h) reveals abnormal alignment of vermis foliation with adjacent cerebellar hemisphere folia (black arrow).
At 9 months of age her motor, verbal and social skills were appropriate for age. She was normocephalic and had no dysmorphic features. Her neurologic examination was normal, though on first impression she seemed to have overflow dystonia, which was later identified as mirror movements.
Mirror movements
Repetitive squeezing and releasing the toy was considered to be equivalent to the finger flexion and extension test. While grabbing a toy with 1 hand she presented a similar sequence of movements, finger opening and finger flexion, in the opposite hand. The fist rotation test was evaluated whilst holding and rotating a rattle. The mirror movements in the opposite hand were equal in intensity with the performing hand on both sides. The movements of the opposite hand mimicked dystonic posturing, but with careful observation were identified as mirror movements (Table 2) (suppl video 1).
Case 6
A 37-year-old college graduate male, was referred to our clinic, after brain imaging performed for prenatal counseling during pregnancy with his daughter (patient 5) (Table 1). Brain MRI revealed a short and thick corpus callosum, asymmetric ventriculomegaly, vermian folia disorganization and dysgyria (Figures 3d, 3e, 3f).
He was born after a normal pregnancy and delivery. He had normal developmental milestones and was college educated. He was asymptomatic until the age of 37 years, when he sustained a focal motor seizure with preserved awareness. EEG revealed right centro-parietal spikes. Seizures were controlled with carbamazepine.
On examination he was normocephalic and had no dysmorphic features. On neurologic examination he demonstrated mild difficulty with tandem gait, left end point nystagmus and retraction of left eye upon left gaze.
Mirror movements
The individual exhibited suspected mirror movements in his non-dominant hand during finger tapping but obvious ones in the finger flexion extension test (Table 2).
Case 7
A 9-year-old girl, was referred to brain imaging due to brain abnormalities in her sister (case 5) and father (case 6) (Table 1). Her brain MRI at this age revealed a short corpus callosum, mild asymmetric ventriculomegaly, disorganized vermian and cerebellar hemisphere foliation, asymmetric brainstem (Figures 3g, 3h, 3i).
She was born after a normal pregnancy and delivery. Developmental milestones were achieved on time. She attended a regular school but had mild learning difficulties.
On examination she had no dysmorphic features, borderline head circumference 48.5 cm (–2 SD). On neurological examination she had alternating esotropia, and mild terminal kinetic tremor on the finger chase test.
Mirror movements
In the finger tapping test she showed obvious bilateral mirror movements. She had suspected mirroring in the non-dominant hand in the fist rotation test (Table 2).
Molecular Diagnosis
Whole exome sequencing revealed a heterozygous pathogenic variant, c.361C>T, p.Arg121Trp in TUBB (NM_178014.4) in the younger sibling (case 5) and the father (case 6). Sanger sequencing revealed the same variant in the older sibling (case 7).
Family IV
Case 8
A 9-year-old boy was referred due to intellectual disability and complex brain malformations, discovered on imaging performed at 8.5 years of age (Table 1). Brain MRI depicted a hypoplastic corpus callosum, asymmetric ventriculomegaly, hypoplastic vermis with abnormal foliation, small asymmetric brainstem (Figures 4a, 4b, 4c, 4d), dysmorphic basal ganglia with effacement of the anterior limb of the internal capsule (Figure 4c) generalized dysgyria interspersed with polymicrogyria (Figure 4b).
Brain imaging in family IV (case 8, TUBA1A1 mutation). Brain MRI imaging at 8.5 years of age: Midline sagittal T2 imaging (4a) depicts a hypoplastic corpus callosum (arrowhead) with hypoplastic vermis (black arrow) and hypoplastic brainstem (white solid arrow). Axial T1 images (4b, 4c, 4d) show asymmetrical mildly enlarged lateral ventricles (white arrow), dysplastic basal ganglia, with effacement of the anterior limb of the internal capsula (black arrow), generalized dysgyria with isles of polymicrogyria (black arrowhead), small asymmetric brainstem (white arrowhead), and hypoplastic vermis with abnormal foliation (white solid arrow).
He was born after an uneventful pregnancy and delivery to healthy unrelated parents. Global developmental delay was evident from infancy, and started walking independently for short distances at 5 years of age, and talking in short sentences at 6 years. Currently, he can currently read a few words and his communication skills are appropriate. He was evaluated in the Child Developmental Center and found to function within moderate intellectual disability range, but formal Mental Development Index is lacking. He is attending special schooling for moderate intellectual disability.
On examination he is normocephalic and has no dysmorphic features. On neurological he walks for short distances with an ataxic gait and has severe motor dyspraxia. He has distal bilateral dystonia in the lower limbs and a positive Babinski sign.
Mirror movements
The patient revealed mirror movements with a lower amplitude than the intentional movements during repetitive rapid fingers flexion and extension, pincer grip and wrist rotation. The movements were more prominent in the non-dominant hand (obvious) than the dominant hand (suspected) (Table 2).
Molecular Diagnosis
Whole exome sequencing revealed a de novo missense mutation p.Glu155Asp in the TUBA1A gene.
Family V
Case 9
A 38-month-old girl was evaluated for global developmental delay and multiple brain MRI abnormalities: bilateral frontoparietal polymicrogyria, thin corpus callosum, multiple cerebellar cysts and brainstem hypoplasia, in addition to communicating hydrocephalus with a supra-sellar cyst and diffuse hyperintense signal in the white matter on T2-weighted images (Table 1) (Figure 5).
Brain imaging of family II (case 9, POMGNT1 mutation). Brain MRI case 9 (age 2 years): Sagittal midline T1 imaging (5a) shows diffusely thin corpus callosum (solid arrow), hypoplastic brain stem (arrowhead), and vermis (arrow) and enlarged lateral and IVth ventricle and enlarged cysterna magna (arrow). Axial T2 imaging (5b) depicts enlarged lateral ventricles, bilateral frontal polymicrogyria (arrow), and diffuse non confluent hyperintense white matter signal (solid arrow). Coronal T1 imaging (5c) demonstrates asymmetrical enlarged lateral ventricles and multiple cerebellar cysts (arrow). Axial T2 imaging (5d) shows multiple cerebellar cysts (arrow), hypoplastic pons (arrowhead), and abnormal hyperintense signal in temporal white matter (solid arrow).
She was the product of an uneventful pregnancy and delivery, born to healthy remotely consanguineous parents. At 6 months of age, following an increase in head circumference an obstructive hydrocephalus was diagnosed and a ventriculo-peritoneal shunt was inserted. Later brain MRI performed at 24 months of age confirmed complex brain anomalies (Figure 5).
Developmental delay was present from birth and was marked: she started walking at the age of 3 years and did not develop expressive speech skills. Bayley Mental Development Index was 50, within moderate intellectual disability range. She was enrolled in a special education kindergarten for moderate intellectual disability.
On examination she was normocephalic, with no dysmorphic features. On neurologic examination, she had ataxia with wide based gait and frequent falls, but no signs of spasticity or myopathy. On first glance she seemed to have overflow dystonia in the inactive hand, but careful examination revealed mirror movements instead.
Mirror movements
While squeezing and releasing a rattle with a handle or performing rotating movements of the wrists whilst handling the toy, she demonstrated contralateral movements with similar intensity of flexion, relaxation of the hand and rotation of the wrist. The mirror movements in the inactive hand mimicked dystonia, but the clear similarity of the pattern to the active side enabled diagnosis of mirror movements (Table 2, suppl video 2).
Molecular Diagnosis
WES trio analysis revealed a homozygous suspected as pathogenic variant c.935C>T, p. Pro312Leu p. Pro312Leu in the POMGNT1 (NM_001243766.1) gene, inherited from each heterozygous parent.
Discussion
We describe a series of 9 patients with 5 distinct neurogenetic syndromes related to DCC, TUBB, TUBB3, TUBA1A, and POMGNT1. These genes cause different genetic disorders by diverse pathophysiological mechanisms (eg, tubulinopathies, dystroglycanopathies), but all of them have a unique mutual disturbance of axonal guidance, ultimately resulting in congenital mirror movements and brain malformations.
Patients from our cohort can be divided in 2 groups. Patients 1 to 7 belong to 3 families with autosomal dominant inherited mutations in DCC, TUBB3 and TUBB. Despite significant brain anomalies, these individuals have a good developmental and cognitive prognosis, with normal or subtle neurological signs. In contrast, patients with de novo inherited TUBA1a (8) and recessive POMGNT1 (9), had significant intellectual disability and grossly abnormal neurological examination. The presence of mirror movements in parents may be a clue to the diagnosis and positive outcome in children with congenital mirror movements.
Six out of 9 individuals from our cohort are children, aged 9 months to 10 years. In a recent article by Spencer-Smith et al, 14 children with DCC mutations aged 8-12 years were included, but to the best of our knowledge, our study represents the largest group of young patients with congenital mirror movements associated with brain malformations.
Mirror movements are defined as physiological in children younger than 7 years of age. However, we included 4 younger children in this study. Three of them (patients 1, 3, and 5) harbored an autosomal dominant inherited DCC, TUBB or TUBB3 variant, and their affected parents (2, 4, 6) as well as older sibling (7) demonstrated similar congenital mirror movements. Since congenital mirror movements is a prominent and diagnostic feature in parents and older siblings, mirror movements should be considered pathological and not physiological in offspring. The patient 9, with autosomal recessive disease due to POMGNT1 variant, demonstrated mirror movements, that emulated the exact sequence of the active hand, were equally severe in intensity and prevented unimanual activity; therefore it cannot be physiological mirror movements.
Of note, 2 young patients, 3 and 9, were initially misdiagnosed with overflow dystonia. Careful observation showed a similar sequence of movements, which enabled us to correctly identify mirror movements and to prevent inappropriate evaluation and treatment.
In adults, assessment of mirror movements includes repetitive tasks as fist rotation, finger flexion-extension and finger tapping, as described by Woods and Teuber. 13 Herein we propose an adaptation of these tasks for young children or intellectually disabled individuals, by using toys to emulate similar movements. These modified tests are based on our clinical experience with young children, but have not yet been validated. Further studies will be required in order to corroborate the validity of these tests.
All patients from our cohort had brain malformations. Malformations of cortical development were seen in 6-polymicrogyria or dysgyria; cerebellar foliation abnormalities in 6; brainstem asymmetry in 3 and corpus callosum dysgeneis in all 9. There was no correlation between the severity of the mirror movements and the complexity of the cortical malformation or intellectual disability, contrary to a previous work by Spencer-Smith et al. 14 However, we found a direct correlation with intellectual and neurological handicap in the patients harboring POMGNT1 and TUBA1A variants. Individuals with TUBB3 and TUBB mutations had milder cortical involvement (dysgyria), and their development was either normal or mildly delayed. These children attended regular classes and their parents had academic education. Some of them had subtle cerebellar signs or eye movements impairment.
In humans, unimanual movements occur when the primary motor cortex (M1) transmits a motor command to the contralateral hand through a crossed corticospinal tract, while secondary motor areas (M2) are involved in motor planning. 15,16 The supplementary motor area modulates interhemispheric interactions during movement preparation. 17 There are a few putative mechanisms of congenital mirror movements: (1) the presence of an ipsilateral direct corticospinal pathway due to abnormal decussation of the corticospinal tracts in the medulla results in a unilateral command transmission to both hands; (2) an abnormal interhemispheric inhibition results in co-activation of both primary motor areas (M1) whilst attempting unimanual maneuvers; (3) an inappropriate delivery of motor plans from the supplementary motor area to the primary motor cortex leads to bilateral cortical activation of primary motor areas during deliberate unimanual movements. 5,15 -25
Mirror movements require a particular mixture of contralateral and ipsilateral connectivity. For instance, patients with uncrossed ascending sensory and descending motor pathways due to biallelic ROBO3 mutations (a gene responsible for development of midline commissures) do not demonstrate mirror movements. 26
Diffusion tensor imaging studies in patients with TUBB3 demonstrated mis-orientation and disorganization of pyramidal fibers, abnormal transverse pontine fibers and fusion of corticospinal tracts. 27 -29 These findings may explain the mechanism of congenital mirror movements in tubulinopathies. There are no functional studies in patients with POMGNT1 mutations. However, an fMRI study in a patient with congenital mirror movements and POMK mutations (another dystroglycanopathy gene), demonstrated bilateral activation of sensorimotor and supplementary motor areas during unilateral hand tasks and a lack of decussation of bilateral corticospinal tracts at the medulla oblongata. 11 Unfortunately, the MRI studies done in our patients lacked diffusion tensor imaging, nor was it possible to perform fMRI, hence we could not corroborate these theories. The lack of tractography and functional neuroimaging is a major limitation of our study.
The formation of the CNS commissures and tracts is a complex process. DCC, TUBB, TUBB3, TUBA1A, and POMGNT1 cause abnormal axonal guidance via different mechanisms involving ligands, such as Netrin, Slit families, and their receptors, 8 ultimately resulting in congenital mirror movements and brain malformations. Netrins are a family of extracellular proteins that direct cell and axon migration during embryogenesis. 30 Netrin-1 binds to several transmembrane receptors including deleted in colorectal cancer. 30 Loss of either netrin -1 or deleted in colorectal cancer function results in failure of axons to cross from 1 side of the developing CNS to the other, resulting in an abnormal formation of the corpus callosum, and hippocampal and anterior commissures. 30 March et al described 26 patients with DCC mutations, with or without agenesis of corpus callosum who had congenital mirror movements. 9 The clinical presentation was similar to our patients with DCC pathogenic variants.
In this study, we describe 3 families with suspected pathogenic variants in 3 different tubulin genes. Qu et al demonstrated that TUBB3 is required for netrin-1-induced neurite outgrowth. 31 Huang et al showed that knockdown of TUBB3 blocks netrin-1-induced axon outgrowth, branching and attraction in vitro, and also inhibits spinal cord CA projection and pathfinding in vivo. 32 The authors concluded that TUBB3 mutations may disrupt the coupling of netrin/deleted in colorectal cancer signaling with microtubule dynamics, resulting in specific defects of netrin-mediated axon projection and pathfinding in the developing nervous system. 33 Pathophysiology of congenital mirror movements in TUBB and TUBA1A are less well understood but both are genes that are responsible for axonal guidance which is the leading pathogenic mechanism of congenital mirror movements.
POMGNT1 (protein O-mannose b-1,2-N-acetylglucosaminyltransferase 1) participates in dystroglycan glycosylation. 34 Glycosylated dystroglycan controls axon guidance through 2 distinct mechanisms. Dystroglycans are responsible for localization of axonal guidance Slit protein within the basement membrane and floor plate. In addition, glycosylated dystroglycans are involved in formation of the basement membrane required for growth and guidance of axons, including the aberrant Slit–ROBO signaling. 35
In conclusion, DCC, TUBB, TUBB3, TUBA1A, and POMGNT1 cause abnormal axonal guidance via different mechanisms resulting in congenital mirror movements and brain malformations. Mirror movements can be underdiagnosed on routine neurological examination, especially in young children. Congenital mirror movements associated with abnormalities of major brain commissures, especially the corpus callosum, may be a clue to diagnosis of specific genetic etiologies and when seen in a parent can help in prenatal counselling of a fetus with brain anomalies.
Footnotes
Author Contributions
AN: clinical data collection, writing-original draft preparation, reviewing and editing; KY, TG-H and DL: investigation; ZL: clinical data collection, writing-original draft preparation; IZ and MH: clinical data collection; TL-S: conceptualization, clinical data collection, writing – reviewing and editing; LB: conceptualization, clinical data collection, writing –original draft preparation, reviewing and editing.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Supplemental Material
Supplemental material for this article is available online.
Ethical Approval
All procedures were approved by the local ethics committee (IRB 0075-17-WOMC). The adult participants and the legal guardians of the children provided written consents.
References
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
