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Ugeskrift For Laeger Dec 2021Untreated spinal muscular atrophy (SMA) causes progressive motor impairment in affected children. Clinical trials of newly developed disease-modifying drugs have shown... (Review)
Review
Untreated spinal muscular atrophy (SMA) causes progressive motor impairment in affected children. Clinical trials of newly developed disease-modifying drugs have shown the greatest effect in young and in pre-symptomatic children as summarised in this review. An application for neonatal screening in Denmark is currently under consideration. Diagnosis and treatment of children with SMA is often delayed, and until a national screening becomes available, the only way to reduce diagnostic delay is to increase the awareness of medical staff and to make information on early signs of SMA available for concerned families.
Topics: Child; Delayed Diagnosis; Early Diagnosis; Humans; Infant, Newborn; Muscular Atrophy, Spinal; Neonatal Screening
PubMed: 34981731
DOI: No ID Found -
ELife Aug 2021Human standing balance relies on self-motion estimates that are used by the nervous system to detect unexpected movements and enable corrective responses and adaptations...
Human standing balance relies on self-motion estimates that are used by the nervous system to detect unexpected movements and enable corrective responses and adaptations in control. These estimates must accommodate for inherent delays in sensory and motor pathways. Here, we used a robotic system to simulate human standing about the ankles in the anteroposterior direction and impose sensorimotor delays into the control of balance. Imposed delays destabilized standing, but through training, participants adapted and re-learned to balance with the delays. Before training, imposed delays attenuated vestibular contributions to balance and triggered perceptions of unexpected standing motion, suggesting increased uncertainty in the internal self-motion estimates. After training, vestibular contributions partially returned to baseline levels and larger delays were needed to evoke perceptions of unexpected standing motion. Through learning, the nervous system accommodates balance sensorimotor delays by causally linking whole-body sensory feedback (initially interpreted as imposed motion) to self-generated balance motor commands.
Topics: Adult; Computer Simulation; Feedback, Sensory; Female; Humans; Learning; Male; Motion; Postural Balance; Posture; Robotics; Vestibule, Labyrinth; Young Adult
PubMed: 34374648
DOI: 10.7554/eLife.65085 -
Autism Research : Official Journal of... May 2022Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and...
Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions.
Topics: Angelman Syndrome; Animals; Autism Spectrum Disorder; Disease Models, Animal; Gait; Humans; Mice; Movement Disorders; Muscle Hypotonia; Outcome Assessment, Health Care
PubMed: 35274462
DOI: 10.1002/aur.2697 -
Molecular Medicine Reports Oct 2017Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which involves the progressive degeneration of motor neurons. ALS has long been considered a... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which involves the progressive degeneration of motor neurons. ALS has long been considered a disease of the grey matter; however, pathological alterations of the white matter (WM), including axonal loss, axonal demyelination and oligodendrocyte death, have been reported in patients with ALS. The present review examined motor neuron death as the primary cause of ALS and evaluated the associated WM damage that is guided by neuronal‑glial interactions. Previous studies have suggested that WM damage may occur prior to the death of motor neurons, and thus may be considered an early indicator for the diagnosis and prognosis of ALS. However, the exact molecular mechanisms underlying early‑onset WM damage in ALS have yet to be elucidated. The present review explored the detailed anatomy of WM and identified several pathological mechanisms that may be implicated in WM damage in ALS. In addition, it associated the pathophysiological alterations of WM, which may contribute to motor neuron death in ALS, with similar mechanisms of WM damage that are involved in multiple sclerosis (MS). Furthermore, the early detection of WM damage in ALS, using neuroimaging techniques, may lead to earlier therapeutic intervention, using immunomodulatory treatment strategies similar to those used in relapsing‑remitting MS, aimed at delaying WM damage in ALS. Early therapeutic approaches may have the potential to delay motor neuron damage and thus prolong the survival of patients with ALS. The therapeutic interventions that are currently available for ALS are only marginally effective. However, early intervention with immunomodulatory drugs may slow the progression of WM damage in the early stages of ALS, thus delaying motor neuron death and increasing the life expectancy of patients with ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Progression; Humans; Models, Biological; White Matter
PubMed: 28791401
DOI: 10.3892/mmr.2017.7186 -
Annals of the Royal College of Surgeons... May 2023This is a retrospective study of 100 consecutive patients with iatrogenic nerve injuries, as seen in a tertiary referral centre over a six-year period. (Review)
Review
INTRODUCTION
This is a retrospective study of 100 consecutive patients with iatrogenic nerve injuries, as seen in a tertiary referral centre over a six-year period.
MATERIALS AND METHODS
Patients who presented with new-onset nerve palsy involving a motor or mixed motor/sensory nerve following an operation were studied.
RESULTS
There were 44 male and 56 female patients with a mean age of 53 years (range 5-87 years). The median duration from the index procedures to referral was six months (range 0 days to 12 years). Approximately one third of referrals were made over 12 months since the index procedures. Twenty patients recovered spontaneously and were managed expectantly. Eighty patients underwent secondary interventions.
DISCUSSION
There remains a significant delay in referring postoperative nerve palsy to a nerve specialist. The majority of these cases will warrant secondary reconstructive surgery and delay in treatment may have a negative effect on the ultimate outcomes.
Topics: Humans; Male; Female; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Retrospective Studies; Paralysis; Peripheral Nerve Injuries; Referral and Consultation; Iatrogenic Disease
PubMed: 35175099
DOI: 10.1308/rcsann.2021.0300 -
Children (Basel, Switzerland) Apr 2022Infants with critical congenital heart defects (CCHDs) are at increased risk for neurodevelopmental delays. The early identification of motor delays is clinically...
Infants with critical congenital heart defects (CCHDs) are at increased risk for neurodevelopmental delays. The early identification of motor delays is clinically relevant to prevent or reduce long-term consequences. The current study aims to describe the motor-developmental pathways of infants with a CCHD. Motor development was assessed in 215 infants and toddlers using the Dutch version of the Bayley-III. At 3 months ( = 165), 9 months ( = 188), and 18 months ( = 171) the motor composite scores were 97, 98, and 104, respectively. A motor composite score of ≤-2 SD was only seen in 2.4%, 0%, and 2.3%, respectively, with gross motor deficits being observed more often than fine motor deficits (12% vs. 0% at 18 months). Over 90% of infants who scored average at 9 months still did so at 18 months. The majority of infants with below-average gross motor scores (≤-1) at 9 months still had a below-average or delayed motor score (≤-2 SD) at 18 months. Abnormal gross motor scores (≤-2 SD) increased with age. Infants with single-ventricle physiology performed significantly ( ≤ 0.05) worse on both fine and gross motor skills at 9 and 18 months compared to infants with other CCHDs.
PubMed: 35455614
DOI: 10.3390/children9040570 -
International Journal of Molecular... Mar 2023DJ-1 is a redox sensitive protein with a wide range of functions related to oxidative stress protection. Mutations in the gene, which codes for DJ-1 are associated with...
DJ-1 is a redox sensitive protein with a wide range of functions related to oxidative stress protection. Mutations in the gene, which codes for DJ-1 are associated with early onset familial Parkinson's disease and increased astrocytic DJ-1 levels are found in pathologic tissues from idiopathic Parkinson's disease. We have previously established a DJ-1 knockout zebrafish line that developed normally, but with aging the DJ-1 null fish had a lowered level of tyrosine hydroxylase, respiratory mitochondrial failure and a lower body mass. Here we have examined the DJ-1 knockout from the early adult stage and show that loss of DJ-1 results in a progressive, age-dependent increase in both motoric and non-motoric symptoms associated to Parkinson's disease. These changes coincide with changes in mitochondrial and mitochondrial associated proteins. Recent studies have suggested that a decline in NAD+ can contribute to Parkinson's disease and that supplementation of NAD+ precursors may delay disease progression. We found that the brain NAD+/NADH ratio decreased in aging zebrafish but did not correlate with DJ-1 induced altered behavior. Differences were first observed at the late adult stage in which NAD+ and NADPH levels were decreased in DJ-1 knockouts. Considering the experimental power of zebrafish and the development of Parkinson's disease-related symptoms in the DJ-1 null fish, this model can serve as a useful tool both to understand the progression of the disease and the effect of suggested treatments.
Topics: Animals; Parkinson Disease; Zebrafish; NAD; Brain; Protein Deglycase DJ-1
PubMed: 37047429
DOI: 10.3390/ijms24076456 -
Developmental Medicine and Child... Oct 2020To investigate the differences in attainment of developmental milestones between young males with Duchenne muscular dystrophy (DMD) and young males from the general...
AIM
To investigate the differences in attainment of developmental milestones between young males with Duchenne muscular dystrophy (DMD) and young males from the general population.
METHOD
As part of the case-control 4D-DMD study (Detection by Developmental Delay in Dutch boys with Duchenne Muscular Dystrophy), data on developmental milestones for 76 young males with DMD and 12 414 young males from a control group were extracted from the health care records of youth health care services. The characteristics of DMD were acquired from questionnaires completed by parents. Logistic regression analyses were performed with milestone attainment (yes/no) as the dependent variable and DMD (yes/no) as the independent variable, with and without adjustment for age at visit.
RESULTS
The mean number of available milestones was 43 (standard deviation [SD]=13, range: 1-59) in the DMD group and 40 (SD=15, range: 1-60) in the control group. The presence of developmental delay was evident at 2 to 3 months of age, with a higher proportion of young males with DMD failing to attain milestones of gross/fine motor activity, adaptive behaviour, personal/social behaviour, and communication (range age-adjusted odds ratios [ORs]=2.3-4.0, p<0.01). Between 12 and 36 months of age, differences in the attainment of developmental milestones concerning gross motor activity increased with age (range age-adjusted ORs=10.3-532, p<0.001). We also found differences in developmental milestones concerning fine motor activity, adaptive behaviour, personal/social behaviour, and communication between 12 and 48 months of age (range age-adjusted ORs=2.5-9.7, p<0.01).
INTERPRETATION
We found delays in the attainment of motor and non-motor milestones in young males with DMD compared to the control group. Such delays were already evident a few months after birth. Developmental milestones that show a delay in attainment have the potential to aid the earlier diagnosis of DMD.
Topics: Case-Control Studies; Child Development; Child, Preschool; Humans; Infant; Male; Motor Activity; Muscular Dystrophy, Duchenne
PubMed: 32692451
DOI: 10.1111/dmcn.14623 -
Global Pediatric Health 2021A mere 33% of all children meet the recommended minimum physical activity guidelines for adequate health maintenance. Available literature however suggests children are... (Review)
Review
A mere 33% of all children meet the recommended minimum physical activity guidelines for adequate health maintenance. Available literature however suggests children are more likely to be active when they are competent with their own motor ability. This review aimed to evaluate how several regimented motor skills training courses and interventions improve motor skill competence among children compared with age matched control peers. Electronic databases were searched and included Medline Complete and Psych INFO (both hosted by EBSCO Host). The search syntax examined titles and abstracts. The study aimed to create novelty by examining participants with and without developmental delays simultaneously from studies around the globe. Included interventions were aimed at the most crucial developmental years for children (between 3 and 11 years). Results were found in favor of the motor skill intervention groups (from pre-to post-test). Included interventions involved weekly motor skills exposure of 60 to 120 minutes for periods of between 2 and 6 months. Over 50% of included interventions involved alterations to current school curriculums. The included studies were of moderate to high quality. The findings suggest that for those with and without developmental delays, several interventions can be effectively applied in once weekly 60-minute sessions (over eight or more weeks) to improve children's motor skill abilities. Applying appropriate difficulty to interventions seems equally influential. Implications are discussed.
PubMed: 34841010
DOI: 10.1177/2333794X211057707 -
Cold Spring Harbor Molecular Case... Jun 2023PPP2 syndrome type R5D, or Jordan's syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants in , a β-subunit of the Protein Phosphatase 2A...
PPP2 syndrome type R5D, or Jordan's syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants in , a β-subunit of the Protein Phosphatase 2A (PP2A). The condition is characterized by global developmental delays, seizures, macrocephaly, ophthalmological abnormalities, hypotonia, attention disorder, social and sensory challenges often associated with autism, disordered sleep, and feeding difficulties. Among affected individuals, there is a broad spectrum of severity, and each person only has a subset of all associated symptoms. Some, but not all, of the clinical variability is due to differences in the genotype. These suggested clinical care guidelines for the evaluation and treatment of individuals with PPP2 syndrome type R5D are based on data from 100 individuals reported in the literature and from an ongoing natural history study. As more data are available, particularly for adults and regarding treatment response, we anticipate that revisions to these guidelines will be made.
Topics: Adult; Humans; Intellectual Disability; Jordan; Neurodevelopmental Disorders; Autistic Disorder; Syndrome; Reference Standards; Protein Phosphatase 2
PubMed: 37339871
DOI: 10.1101/mcs.a006285