-
Frontiers in Neuroscience 2023Primary microcephaly (MCPH), is a neurological disorder characterized by small brain size that results in numerous developmental problems, including intellectual... (Review)
Review
Primary microcephaly (MCPH), is a neurological disorder characterized by small brain size that results in numerous developmental problems, including intellectual disability, motor and speech delays, and seizures. Hitherto, over 30 MCPH causing genes () have been identified. Among these , , which encodes abnormal spindle-like microcephaly-associated protein (ASPM), is the most frequently mutated gene. ASPM regulates mitotic events, cell proliferation, replication stress response, DNA repair, and tumorigenesis. Moreover, using a data mining approach, we have confirmed that high levels of expression of ASPM correlate with poor prognosis in several types of tumors. Here, we summarize the neurological and non-neurological functions of ASPM and provide insight into its implications for the diagnosis and treatment of MCPH and cancer.
PubMed: 37599996
DOI: 10.3389/fnins.2023.1242448 -
Human Molecular Genetics Sep 2023N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates...
N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates other proteins. It is characterized by severe global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of transaminases, (hypo)alacrima and progressive, diffuse, length-dependent sensorimotor polyneuropathy. A prospective natural history study (NHS) was conducted to elucidate clinical features and disease course. Twenty-nine participants were enrolled (15 onsite, 14 remotely) and followed for up to 32 months, representing ~29% of the ~100 patients identified worldwide. Participants exhibited profound developmental delays, with almost all developmental quotients below 20 on the Mullen Scales of Early Learning, well below the normative score of 100. Increased difficulties with sitting and standing suggested decline in motor function over time. Most patients presented with (hypo)alacrima and reduced sweat response. Pediatric quality of life was poor except for emotional function. Language/communication and motor skill problems including hand use were reported by caregivers as the most bothersome symptoms. Levels of the substrate biomarker, GlcNAc-Asn (aspartylglucosamine; GNA), were consistently elevated in all participants over time, independent of age. Liver enzymes were elevated for some participants but improved especially in younger patients and did not reach levels indicating severe liver disease. Three participants died during the study period. Data from this NHS informs selection of endpoints and assessments for future clinical trials for NGLY1 deficiency interventions. Potential endpoints include GNA biomarker levels, neurocognitive assessments, autonomic and motor function (particularly hand use), (hypo)alacrima and quality of life.
Topics: Humans; Child; Prospective Studies; Quality of Life; Congenital Disorders of Glycosylation; Biomarkers
PubMed: 37379343
DOI: 10.1093/hmg/ddad106 -
Journal of Neurology Dec 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor and... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor and non-motor symptoms. Recent evidence suggests that ALS is indeed a multisystem disorder, associated with cognitive impairment, dysautonomia, pain and fatigue, excess of secretions, and sensory symptoms. To evaluate whether sensory neuropathy could broaden its spectrum, we systematically reviewed its presence and characteristics in ALS, extracting data on epidemiological, clinical, neurophysiological, neuropathological, and genetic features. Sensory neuropathy can be found in up to 20% of ALS patients, affecting both large and small fibers, although there is a great heterogeneity related to different techniques used for its detection (electromyography vs skin biopsy vs nerve biopsy). Moreover, the association between CIDP-like neuropathy and ALS needs to be better explored, although it could be interpreted as part of the neuroinflammatory process in the latter disease. Sensory neuropathy in ALS may be associated with a spinal onset and might be more frequent in SOD1 patients. Moreover, it seems mutually exclusive with cognitive impairment. No associations with sex and other genetic mutation were observed. All these data in the literature reveal the importance of actively looking for sensory neuropathy in ALS patients, and suggest including sensory neuropathy among ALS non-motor features, as it may explain sensory symptoms frequently reported throughout the course of the disease. Its early identification could help avoid diagnostic delays and improve patients' treatment and quality of life.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Quality of Life; Motor Neurons; Electromyography
PubMed: 37610446
DOI: 10.1007/s00415-023-11954-1 -
International Journal of Molecular... Dec 2023Neuromuscular disorders (NMDs) encompass a large heterogeneous group of hereditary and acquired diseases primarily affecting motor neurons, peripheral nerves, and the... (Review)
Review
Neuromuscular disorders (NMDs) encompass a large heterogeneous group of hereditary and acquired diseases primarily affecting motor neurons, peripheral nerves, and the skeletal muscle system. The symptoms of NMDs may vary depending on the specific condition, but some of the most common ones include muscle weakness, pain, paresthesias, and hyporeflexia, as well as difficulties with swallowing and breathing. NMDs are currently untreatable. Therapeutic options include symptomatic and experimental medications aimed at delaying and alleviating symptoms, in some cases supplemented by surgical and physical interventions. To address this unmet medical need, ongoing research is being conducted on new treatments, including studies on medical cannabis, endocannabinoids, and related molecules with cannabimimetic properties. In this context, a significant amount of knowledge about the safety and effectiveness of cannabinoids in NMDs has been obtained from studies involving patients with multiple sclerosis experiencing pain and spasticity. In recent decades, numerous other preclinical and clinical studies have been conducted to determine the potential benefits of cannabinoids in NMDs. This review article aims to summarize and provide an unbiased point of view on the current knowledge about the use of cannabinoids, endocannabinoids, and synthetic analogs in NMDs, drawing from an array of compelling studies.
Topics: Humans; Endocannabinoids; Cannabinoids; Neuromuscular Diseases; Multiple Sclerosis; Pain
PubMed: 38203407
DOI: 10.3390/ijms25010238 -
BioRxiv : the Preprint Server For... Oct 2023Methylphenidate (MPH, brand: Ritalin) is a common stimulant used both medically and non-medically. Though typically prescribed for its cognitive effects, MPH also...
Methylphenidate (MPH, brand: Ritalin) is a common stimulant used both medically and non-medically. Though typically prescribed for its cognitive effects, MPH also affects movement. While it is known that MPH noncompetitively blocks the reuptake of catecholamines through inhibition of dopamine and norepinephrine transporters, a critical step in exploring how it affects behavior is to understand how MPH directly affects neural activity. This would establish an electrophysiological mechanism of action for MPH. Since we now have biologically-grounded network-level hypotheses regarding how populations of motor cortical neurons plan and execute movements, there is a unique opportunity to make testable predictions regarding how systemic MPH administration - a pharmacological perturbation - might affect neural activity in motor cortex. To that end, we administered clinically-relevant doses of MPH to Rhesus monkeys as they performed an instructed-delay reaching task. Concomitantly, we measured neural activity from dorsal premotor and primary motor cortex. Consistent with our predictions, we found dose-dependent and significant effects on reaction time, trial-by-trial variability, and movement speed. We confirmed our hypotheses that changes in reaction time and variability were accompanied by previously established population-level changes in motor cortical preparatory activity and the condition-independent signal that precedes movements. We expected changes in speed to be a result of changes in the amplitude of motor cortical dynamics and/or a translation of those dynamics in activity space. Instead, our data are consistent with a mechanism whereby the neuromodulatory effect of MPH is to increase the gain and/or the signal-to-noise of motor cortical dynamics during reaching. Continued work in this domain to better understand the brain-wide electrophysiological mechanism of action of MPH and other psychoactive drugs could facilitate more targeted treatments for a host of cognitive-motor disorders.
PubMed: 37905157
DOI: 10.1101/2023.10.15.562405 -
Current Biology : CB Sep 2023Motor planning facilitates rapid and precise execution of volitional movements. Although motor planning has been classically studied in humans and monkeys, the mouse has...
Motor planning facilitates rapid and precise execution of volitional movements. Although motor planning has been classically studied in humans and monkeys, the mouse has become an increasingly popular model system to study neural mechanisms of motor planning. It remains yet untested whether mice and primates share common behavioral features of motor planning. We combined videography and a delayed response task paradigm in an autonomous behavioral system to measure motor planning in non-body-restrained mice. Motor planning resulted in both reaction time (RT) savings and increased movement accuracy, replicating classic effects in primates. We found that motor planning was reflected in task-relevant body features. Both the specific actions prepared and the degree of motor readiness could be read out online during motor planning. The online readout further revealed behavioral evidence of simultaneous preparation for multiple actions under uncertain conditions. These results validate the mouse as a model to study motor planning, demonstrate body feature movements as a powerful real-time readout of motor readiness, and offer behavioral evidence that motor planning can be a parallel process that permits rapid selection of multiple prepared actions.
Topics: Humans; Animals; Mice; Psychomotor Performance; Reaction Time; Movement; Volition; Uncertainty
PubMed: 37582373
DOI: 10.1016/j.cub.2023.07.029