Treating Congenital Mirror Movements with Botulinum Toxin.
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ABSTRACT:
SUBMITTER: Allegra C
PROVIDER: S-EPMC6353364 | biostudies-literature | 2017 Nov-Dec
REPOSITORIES: biostudies-literature
Publications
Treating Congenital Mirror Movements with Botulinum Toxin.
Allegra Cosimo C Girlanda Paolo P Morgante Francesca F
Movement disorders clinical practice 20170925 6
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Project description:Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans.
| S-EPMC3276668 | biostudies-literature
Project description:Mirror movements (MMs) occur on the contralateral side of a limb being used intentionally. Because few families with congenital MMs and no other neurological signs have been reported, the underlying mechanisms of MMs are still not entirely clear. We report on the clinical, genetic, neurophysiological and neuroimaging findings of 10 of 26 living members of a novel four-generation family with congenital MMs. DCC and RAD51 were sequenced in affected members of the family. Five of the ten subjects with MMs underwent neurophysiological and neuroimaging evaluations. The neurophysiological evaluation consisted of electromyographic (EMG) mirror recordings, investigations of corticospinal excitability, and analysis of interhemispheric inhibition using transcranial magnetic stimulation techniques. The neuroimaging evaluation included functional MRI during finger movements. Eight (all females) of the ten members examined presented MMs of varying degrees at the clinical assessment. Transmission of MMs appears to have occurred according to an autosomal-dominant fashion with variable expression. No mutation in DCC or RAD51 was identified. EMG mirror activity was higher in MM subjects than in healthy controls. Short-latency interhemispheric inhibition was reduced in MM subjects. Ipsilateral motor-evoked potentials were detectable in the most severe case. The neuroimaging evaluation did not disclose any significant abnormalities in MM subjects. The variability of the clinical features of this family, and the lack of known genetic abnormalities, suggests that MMs are heterogeneous disorders. The pathophysiological mechanisms of MMs include abnormalities of transcallosal inhibition and corticospinal decussation.
| S-EPMC6353446 | biostudies-literature
Project description:Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.
| S-EPMC5663368 | biostudies-literature
Project description:Cell outgrowth and migration in the developing nervous system result from guidance cues, whose molecular bases and clinical correlates are only partly known. We describe a patient with brain stem malformation, paroxysmal left sided lacrimation when eating ("crocodile tears") and mirror movements in addition to Wildervanck's cervico-oculo-acusticus (COA) syndrome, which encompasses Klippel-Feil anomaly, congenital hearing loss and Duane's syndrome. The unique symptom constellation has not been reported in that combination before and can be discussed in the context of congenital disordered axonal migration based on dysfunction of signalling pathways. However, mutations in some recently discovered genes, associated with single findings also present in our patient, were not found. Therefore, we suppose that the disturbance of an as yet unknown regulatory factor may explain the congenital malformation syndrome of our patient. In general, only a few human disorders have yet been found to result from defects in axon guidance. Nevertheless, disorders of axon guidance can certainly be regarded as a new category of neurodevelopmental disorders.
| S-EPMC3517171 | biostudies-literature
Project description:OBJECTIVE: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51. METHODS: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. RESULTS: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC, one DCC mutation leading to a frameshift, 5 missense variants in DCC, and 2 missense variants in RAD51. All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls (p < 0.001 for both RAD51 and DCC). CONCLUSION: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered.
| S-EPMC4105259 | biostudies-literature
Project description:Mirror movements are simultaneous, involuntary, identical movements occurring during contralateral voluntary movements. These movements are considered as soft neurologic signs seen uncommonly in clinical practice. The mirror movements are described in various neurological disorders which include parkinsonism, cranio veretebral junction anamolies, and hemiplegic cerebral palsy. These movements are intriguing and can pose significant disability. However, no such observation regarding mirror movements in progressive hemifacial atrophy have been reported previously. We are reporting a teenage girl suffering from progressive hemifacial atrophy and epilepsy with demonstrable mirror movements in hand.
| S-EPMC4445209 | biostudies-literature
Project description:The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).
| S-EPMC5722687 | biostudies-literature
Project description:BackgroundFunctional tremors can be diagnosed based on clinical and physiologic criteria such as entrainment, suggestibility, distractibility, variable nature with the associated clinical history of psychosomatic co-morbidities. The current case report highlights the underrecognized utility of neurophysiology in the correct diagnosis of tremors, providing useful clinical and neurophysiologic insights into clinical and physiological assessment of tremors.Case reportA 62-year-old woman with a past medical history of polio was referred by a movement disorders neurologist for evaluation of tremor with concerns of a likely functional etiology. On first assessment there were findings notable for a possible organic etiology, but upon subsequent evaluation the tremor was noted to be variable and entrainable, suggestive of a functional etiology. Neurophysiological tremor study could identify an underlying organic tremor (likely of multi-factorial etiology). Tremor entrainment with contralateral hand tapping could be mirror movements or functional movements, as the underlying organic tremor was not entrained. The amplitude of mirrored movement was commensurate with the tapping amplitude.DiscussionFunctional tremors may mask an underlying organic tremor. Additionally, motor overflow which may happen especially with large amplitude movements may masquerade as mirror movements, which can be difficult to differentiate from an entrained functional tremor. Objective physiology and refinement of the current clinical and physiologic tremor evaluation techniques may help identify an underlying organic etiology.
| S-EPMC6134172 | biostudies-literature
Project description:BackgroundAutosomal dominant congenital mirror movements (CMM) is a neurodevelopmental disorder characterized by early onset involuntary movements of one side of the body that mirror intentional movements on the contralateral side; these persist throughout life in the absence of other neurological symptoms. The main culprit genes responsible for this condition are RAD51 and DCC. This condition has only been reported in a few families, and the molecular mechanisms linking RAD51 mutations and mirror movements (MM) are poorly understood.MethodsWe collected demographic, clinical, and genetic data of a new family with CMM due to a truncating mutation of RAD51. We reviewed the literature to identify all reported patients with CMM due to RAD51 mutations.ResultsWe identified a heterozygous nonsense mutation c.760C>T (p.Arg254*) in eight subjects: four with obvious and disabling MM, and four with a mild phenotype. Including our new family, we identified 32 patients from 6 families with CMM linked to RAD51 variants.DiscussionOur findings further support the involvement of RAD51 in CMM pathogenesis. Possible molecular mechanisms involved in CMM pathogenesis are discussed.
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Project description:The use of botulinum toxin A (BTX-A) has revolutionized the treatment of neurogenic lower urinary tract dysfunction (NLUTD) over the past three decades. Initially, it was used as a sphincteric injection for detrusor sphincter dyssynergia but now is used mostly as intradetrusor injection to treat neurogenic detrusor overactivity (NDO). Its use is supported by high-level-of-evidence studies and it has become the gold-standard treatment for patients with NDO refractory to anticholinergics. Several novelties have emerged in the use of BTX-A in neurourology over the past few years. Although onabotulinumtoxinA (BOTOX®, Allergan, Inc., Irvine, CA) remains the only BTX-A for which use is supported by large, multicenter, randomized, controlled trials (RCT), and is therefore the only one to be licensed in the United States and Europe, a second BTX-A, abobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Basking Ridge, NJ), is also supported by high-level-of-evidence studies. Other innovations in the use of BTX-A in neurourology during the past few years include the BTX switch (from abobotulinumtoxinA to onabotulinumtoxinA or the opposite) as a rescue option for primary or secondary failures of intradetrusor BTX-A injection and refinements in intradetrusor injection techniques (number of injection sites, injection into the trigone). There is also a growing interest in long-term failure of BTX-A for NDO and their management, and a possible new indication for urethral sphincter injections.
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