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Clinical Neurophysiology Practice 2024Accurate and rapid diagnosis of amyotrophic lateral sclerosis (ALS) is essential in order to provide accurate information for patient and family, to avoid time-consuming... (Review)
Review
Accurate and rapid diagnosis of amyotrophic lateral sclerosis (ALS) is essential in order to provide accurate information for patient and family, to avoid time-consuming investigations and to permit an appropriate management plan. ALS is variable regarding presentation, disease progression, genetic profile and patient reaction to the diagnosis. It is obviously important to exclude treatable conditions but, in most patients, for experienced neurologists the diagnosis is clear-cut, depending on the presence of progressive upper and lower motor neuron signs. Patients with signs of restricted lower motor neuron (LMN) or upper motor neuron (UMN) dysfunction may present diagnostic difficulty, but electromyography (EMG) is often a determinant diagnostic test since it may exclude other disorders. Transcranial magnetic stimulation may aid detection of UMN dysfunction, and brain and spinal cord MRI, ultrasound and blood neurofilament measurements, have begun to have clinical impact, although none are themselves diagnostic tests. Several sets of diagnostic criteria have been proposed in the past; all rely on clinical LMN and UMN signs in different anatomic territories, EMG changes, exclusion of other disorders, and disease progression, in particular evidence of spreading to other anatomic territories. Fasciculations are a characteristic clinical feature and increased importance is now attached to fasciculation potentials detected by EMG, when associated with classical signs of denervation and reinnervation. The Gold Coast diagnostic criteria rely on the presence of UMN and LMN signs in one (or more) anatomic territory, or LMN signs in two (or more) anatomic territories, recognizing the fundamental clinical requirements of disease progression and exclusion of other diseases. Recent studies confirm a high sensitivity without loss of specificity using these Gold Coast criteria. In considering the diagnosis of ALS a critical question for future understanding is whether ALS should be considered a syndrome or a specific clinico-pathologic entity; this can only be addressed in the light of more complete knowledge.
PubMed: 38249779
DOI: 10.1016/j.cnp.2023.12.003 -
Neural Regeneration Research Jun 2022The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly. These... (Review)
Review
The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly. These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions. Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders. Supporting this notion, efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation, maturation, synaptogenesis and synaptic function. Fasciculation and elongation protein zeta-1, a Kinesin-1 adapter, has emerged as a key central player involved in many of these processes. Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment. Furthermore, it acts downstream of guidance cue pathways to regulate axo-dendritic development. Significantly, perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system. Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders. Moreover, altered phosphorylation of the protein contributes to neurodegenerative disorders. Together, these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.
PubMed: 34782550
DOI: 10.4103/1673-5374.327327 -
Brain : a Journal of Neurology Apr 2022Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural...
Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural development, including cilia organization, neuron migration and axon navigation. Here, we address its role in axon regeneration. We show that Celsr2 is highly expressed in both mouse and human spinal motor neurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones, with increased expression of end-binding protein 3 and higher potassium-induced calcium influx. Mice with Celsr2 conditional knockout in spinal motor neurons do not exhibit any behavioural deficits; however, after branchial plexus injury, axon regeneration and functional forelimb locomotor recovery are significantly improved. Similarly, knockdown of CELSR2 using shRNA interference in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motor neurons, Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun. In conclusion, Celsr2 negatively regulates motor axon regeneration and is a potential target to improve neural repair.
Topics: Animals; Axon Fasciculation; Axons; Cadherins; Humans; Mice; Motor Neurons; Nerve Regeneration; Spinal Cord; Spinal Cord Injuries
PubMed: 34983065
DOI: 10.1093/brain/awab317 -
World Journal of Biological Chemistry Feb 2019Fasciculation and elongation zeta/zygin (FEZ) proteins are a family of hub proteins and share many characteristics like high connectivity in interaction networks, they... (Review)
Review
Fasciculation and elongation zeta/zygin (FEZ) proteins are a family of hub proteins and share many characteristics like high connectivity in interaction networks, they are involved in several cellular processes, evolve slowly and in general have intrinsically disordered regions. In 1985, gene was firstly described and involved in axonal growth in , and in 1997 Bloom and Horvitz enrolled also the human homologues genes, and , in this process. While nematodes possess one gene (), mammalians have one more copy ( and ). Several animal models have been used to study FEZ family functions like: , and human cells. Complementation assays were performed and demonstrated the function conservation between paralogues. Human FEZ1 protein is more studied followed by UNC-76 and FEZ2 proteins, respectively. While FEZ1 and UNC-76 shared interaction partners, FEZ2 evolved and increased the number of protein-protein interactions (PPI) with cytoplasmatic partners. FEZ proteins are implicated in intracellular transport, acting as bivalent cargo transport adaptors in kinesin-mediated movement. Especially in light of this cellular function, this family of proteins has been involved in several processes like neuronal development, neurological disorders, viral infection and autophagy. However, nuclear functions of FEZ proteins have been explored as well, due to high content of PPI with nuclear proteins, correlating FEZ1 expression to and gene regulation and retinoic acid signaling. These recent findings open new avenue to study FEZ proteins functions and its involvement in already described processes. This review intends to reunite aspects of evolution, structure, interaction partners and function of FEZ proteins and correlate them to physiological and pathological processes.
PubMed: 30815230
DOI: 10.4331/wjbc.v10.i2.28 -
International Journal of Molecular... Jul 2020The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While... (Review)
Review
The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon-environment and axon-target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon-axon interactions during the different steps of neural circuit formation.
Topics: Animals; Axons; Fasciculation; Growth Cones; Neural Conduction; Signal Transduction
PubMed: 32708320
DOI: 10.3390/ijms21145170 -
BMC Neurology Nov 2021Fasciculation is an important sign for the diagnosis of amyotrophic lateral sclerosis (ALS). Our study aimed to analyze the difference in fasciculation detected with...
BACKGROUND
Fasciculation is an important sign for the diagnosis of amyotrophic lateral sclerosis (ALS). Our study aimed to analyze the difference in fasciculation detected with muscle ultrasonography (MUS) between ALS patients and non-ALS patients with symptoms resembling ALS.
METHODS
Eighty-eight ALS patients and fifty-four non-ALS (eight multifocal motor neuropathy, 32 chronic inflammatory demyelinating polyneuropathy/Charcot-Marie-Tooth, and 14 cervical spondylopathy or lumbar spondylopathy) patients were recruited. MUS was performed on 19 muscle groups in cervical, lumbosacral, bulbar, and thoracic regions for each patient. The intensity of fasciculation was divided into five grades based on firing frequency and number in the involved muscle groups.
RESULTS
The overall detection rates were 72.8% in ALS and 18% in non-ALS patients. The fasciculation grades (median [IQR]) were 2 (0-3) in ALS and 0 (0-0) in non-ALS patients (P < 0.001). Fasciculations were observed in four regions for ALS patients and primarily distributed in proximal limbs. Fasciculations in non-ALS patients were primarily low-grade and mostly distributed in distal limbs.
DISCUSSION
The fasciculation grade was higher in ALS than non-ALS patients. The distribution pattern of fasciculation was different between ALS and non-ALS patients.
CONCLUSIONS
The fasciculation grade and distribution pattern detected with MUS could help distinguish ALS from non-ALS patients.
Topics: Amyotrophic Lateral Sclerosis; Electromyography; Fasciculation; Humans; Muscle, Skeletal; Polyneuropathies; Ultrasonography
PubMed: 34758775
DOI: 10.1186/s12883-021-02473-5 -
Molecules and Cells Aug 2021Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although... (Review)
Review
Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although substantial progress has been made over the last three decades in identifying numerous axon guidance molecules and their functional roles, little is known about how these guidance molecules collaborate to steer growth cones to their correct targets. Recent studies in point to the importance of the combinatorial action of guidance molecules, and further show that selective fasciculation and defasciculation at specific choice points serve as a fundamental strategy for motor axon guidance. Here, I discuss how attractive and repulsive guidance cues cooperate to ensure the recognition of specific choice points that are inextricably linked to selective fasciculation and defasciculation, and correct pathfinding decision-making.
Topics: Animals; Axon Fasciculation; Axon Guidance; Drosophila melanogaster; Motor Neurons; Muscles; Neuromuscular Junction
PubMed: 34385406
DOI: 10.14348/molcells.2021.0129 -
Clinical Neurophysiology : Official... Aug 2021Possessing a discrete functional repertoire, the anterior horn cell can be in one of two electrophysiological states: on or off. Usually under tight regulatory control... (Review)
Review
Possessing a discrete functional repertoire, the anterior horn cell can be in one of two electrophysiological states: on or off. Usually under tight regulatory control by the central nervous system, a hierarchical network of these specialist neurons ensures muscular strength is coordinated, gradated and adaptable. However, spontaneous activation of these cells and their axons can result in abnormal muscular twitching. The muscular twitch is the common building block of several distinct clinical patterns, namely fasciculation, myokymia and neuromyotonia. When attempting to distinguish these entities electromyographically, their unique temporal and morphological profiles must be appreciated. Detection and quantification of burst duration, firing frequency, multiplet patterns and amplitude are informative. A common feature is their persistence during sleep. In this review, we explain the accepted terminology used to describe the spontaneous phenomena of motor hyperexcitability, highlighting potential pitfalls amidst a bemusing and complex collection of overlapping terms. We outline the relevance of these findings within the context of disease, principally amyotrophic lateral sclerosis, Isaacs syndrome and Morvan syndrome. In addition, we highlight the use of high-density surface electromyography, suggesting that more widespread use of this non-invasive technique is likely to provide an enhanced understanding of these motor hyperexcitability syndromes.
Topics: Amyotrophic Lateral Sclerosis; Electromyography; Fasciculation; Humans; Isaacs Syndrome; Motor Neurons; Myokymia; Peripheral Nervous System Diseases
PubMed: 34130251
DOI: 10.1016/j.clinph.2021.03.053