Selective chromatid segregation mechanism invoked for the human congenital mirror hand movement disorder development by RAD51 mutations: a hypothesis.

The vertebrate body plan externally is largely symmetrical across the midline but internal organs develop asymmetrically. The biological basis of asymmetric organ development has been investigated extensively for years, although the proposed mechanisms remain controversial. By comparison, the biological origin of external organs symmetry has not been extensively investigated. Bimanual hand control is one such external organs symmetry allowing independent motor control movements of both hands to a person. This gap in our knowledge is illustrated by the recent reports of heterozygous rad51 mutations causing mysterious symptoms of congenital mirror hand movement disorder (MM) in humans with 50% penetrance by an unknown mechanism. The analysis of mutations that vary symmetry or asymmetry could be exploited to decipher the mechanisms of laterality development. Here I present a hypothesis for explaining 50% penetrance of the rad51 mutation. The MM's origin is explained with the Somatic Strand-specific Imprinting and selective sister chromatid Segregation (SSIS) hypothesis proposed originally as the mechanism of asymmetric cell division to promote visceral organs body plan laterality development in vertebrates. By hypothesis, random sister chromatid segregation in mitosis occurs for a specific chromosome due to rad51/RAD51 constitution causing MM disorder development in 50% of subjects.

RAD51 deficiency disrupts the corticospinal lateralization of motor control.

Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movement disorder is a rare condition characterized by mirror movements that persist throughout adulthood in subjects with no other clinical abnormalities. The affected individuals have mirror movements predominating in the muscles that control the fingers and are unable to perform purely unimanual movements. Congenital mirror movement disorder thus provides a unique paradigm for studying the lateralization of motor control. We conducted a multimodal, controlled study of patients with congenital mirror movements associated with RAD51 haploinsufficiency (n = 7, mean age 33.3 ± 16.8 years) by comparison with age- and gender-matched healthy volunteers (n = 14, mean age 33.9 ± 16.1 years). We showed that patients with congenital mirror movements induced by RAD51 deficiency had: (i) an abnormal decussation of the corticospinal tract; (ii) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (iii) an abnormal involvement of the supplementary motor area during both unimanual and bimanual movements. The lateralization of motor control thus requires a fine interplay between interhemispheric communication and corticospinal wiring. This fine interplay determines: (i) the delivery of appropriate motor plans from the supplementary motor area to the primary motor cortex; (ii) the lateralized activation of the primary motor cortex; and (iii) the unilateral transmission of the motor command to the limb involved in the intended movement. Our results also unveil an unexpected function of RAD51 in corticospinal development of the motor system.

Bilateral subthalamic nucleus deep brain stimulation for dopa-responsive dystonia in a 6-year-old child.

Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive metabolic disease that results in the decreased production of catecholamines. Standard treatment relies on combinations of levodopa and carbidopa, anticholinergic agents, serotonergic agonists, and monamine oxidase B inhibitors. Unfortunately, severely affected children often require escalating doses of medication and suffer from dyskinesias as well as significant on/off symptomatology. The authors present a case of medically intractable dopa-responsive dystonia in a 6-year-old boy whose condition significantly improved with bilateral subthalamic nucleus deep brain stimulation. This case is unique in its novel approach to tyrosine hydroxylase deficiency and the young age of the patient.

Mutations in DCC cause congenital mirror movements.

Mirror movements are involuntary contralateral movements that mirror voluntary ones and are often associated with defects in midline crossing of the developing central nervous system. We studied two large families, one French Canadian and one Iranian, in which isolated congenital mirror movements were inherited as an autosomal dominant trait. We found that affected individuals carried protein-truncating mutations in DCC (deleted in colorectal carcinoma), a gene on chromosome 18q21.2 that encodes a receptor for netrin-1, a diffusible protein that helps guide axon growth across the midline. Functional analysis of the mutant DCC protein from the French Canadian family revealed a defect in netrin-1 binding. Thus, DCC has an important role in lateralization of the human nervous system.

Congenital unilateral adduction associated with jaw movement: a rare variant of trigemino-oculomotor synkinesis.

A 21-year-old man had abnormal adducting movements of his left eye on mastication. This suggested an anomalous innervation of the medial rectus muscle from the motor branch of the trigeminal nerve that innervated the external pterygoid muscle.

"On the other hand": a case of hereditary, congenital mirror movement.

We describe a 20-year-old male Singaporean army recruit with hereditary, congenital mirror movements who presented with difficulties in military training because releasing the grip of one hand resulted in a similar release by the other hand. His father has mirror movements with a significant decrease in symptoms with time, a phenomenon that has not been previously described. Both father and son have no associated neurological abnormalities. Bilateral cortical representation for hand muscles and the presence of active ipsilateral corticospinal projections have been postulated as the mechanisms responsible for this condition.

Involuntary rhythmic leg movements time-locked with the respiratory cycle.

Involuntary rhythmic leg movements in childhood is an uncommon condition, the generators of which remain unknown. We report on a male 3 years of age with distinct features providing important clues concerning the location of one of these generators. At the age of 7 months, the previously healthy young male started with low frequency, rhythmic, and continuous (both during wakefulness and sleep) flexion/extension movements of the lower limbs. Movements interfered significantly with gait acquisition, and, despite normal cognitive development, he was able to walk only at age 2 years, 4 months. The neurologic examination revealed the absence of automatic stepping in the neonatal period, but was otherwise normal. A polygraphic electroencephalogram/electromyogram (EEG/EMG) recording, at the age of 2 years, 9 months, revealed rhythmic and synchronous legs with EMG activity at 0.5 Hz. A more complete polygraphic recording at the age of 3 years, 10 months, showed a lower frequency (0.35 Hz) for the movements, which were time-locked with the respiratory cycle. Magnetic resonance imaging (MRI) of the brain revealed an increased T(2) signal in the upper medulla-lower pons regions. The generator of the rhythmic legs movements is postulated to be the respiratory center, connecting with the reticulospinal projecting neurons through an aberrant pathway.