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Brain : a Journal of Neurology Mar 2024Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in...
Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.
PubMed: 38456468
DOI: 10.1093/brain/awae056 -
Pediatric Research Sep 2023Studies in newborns with mild neonatal encephalopathy (mNE) demonstrated normal outcomes, but recent literature suggests otherwise.
BACKGROUND
Studies in newborns with mild neonatal encephalopathy (mNE) demonstrated normal outcomes, but recent literature suggests otherwise.
METHODS
This retrospective cohort study examined inborn infants between 2014 and 2017. Biochemical and clinical characteristics determined the presence of NE and an encephalopathy score categorized infants as Definite or Possible mNE. An Unexposed control group consisted of newborns not meeting the inclusion criteria. Long-term outcomes assessed included cerebral palsy, seizures, developmental disorder, and motor and speech delay. The association of mNE with seizure disorder by 3 years of age was assessed with logistic regression and developmental disorders with Cox proportional hazards models.
RESULTS
Of the 156,501 births, we identified 130 with Definite mNE and 445 with Possible mNE (0.8 and 2.8 per 1000 births, respectively). Both groups had significantly higher rates of any developmental disorder and motor and speech delay when compared to the Unexposed (p < 0.05, except for p = 0.07 for motor delay in the Possible NE group). The Definite mNE group had higher rates of developmental disorder and motor and speech delay when compared to the Unexposed with hazard ratios (95% CI) 2.0 (1.2-3.2), 3.7 (1.5-8.8), and 2.1 (1.3-3.5), respectively.
CONCLUSIONS
An estimate of short- and long-term consequences of mNE suggests that there may be a higher risk of adverse outcome.
IMPACT
Infants with mild NE are at significant risk for adverse short- and long-term outcomes. The risk of having an abnormal long-term outcome at 3 years of age were doubled in the mild NE group compared to the Unexposed group. Randomized clinical trials are needed as neuroprotective strategies may mitigate these.
Topics: Infant, Newborn; Infant; Humans; Infant, Premature; Retrospective Studies; Brain Diseases; Cerebral Palsy; Infant, Newborn, Diseases; Language Development Disorders
PubMed: 35999380
DOI: 10.1038/s41390-022-02249-8 -
Journal of Neuroimmune Pharmacology :... Sep 2023Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising...
Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation.
PubMed: 37326908
DOI: 10.1007/s11481-023-10068-9 -
European Journal of Pediatrics Mar 2024Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by... (Review)
Review
Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by varying degrees of early psychomotor developmental deficits, primarily in cognition, language, and motor development. This review summarizes the early mental cognitive development, language development, and motor development in patients with PWS, compares the correlation of genotype with phenotype, and provides an update regarding the effects and concerns related to potential main side effects of treatment with recombinant human growth hormone on early psycho-cognitive and motor function development along with the linear growth and body composition of children with PWS.Conclusion: Early psychomotor development is strongly correlated with the prognosis of patients with PWS; moreover, current studies support that the initiation of interventions at an early age can exert significant beneficial effects on enhancing the cognitive and linguistic development of patients with PWS and allow them to "catch up" with motor development. What is Known: • Prader-Willi syndrome is a rare genetic disorder characterized by multisystem damage, and children with Prader-Willi syndrome are typically characterized by early developmental delays, specifically in the areas of cognitive and motor development. • Recombinant human growth hormone therapy is the only medical treatment approved for Prader-Willi syndrome. What is New: • Extensive presentation of psycho-cognitive and motor development features and genotype-phenotype correlation in children with Prader-Willi syndrome. • The effects of growth hormone on early psychomotor development in children with Prader-Willi syndrome were thoroughly reviewed, including their short- and long-term outcomes and any associated adverse effects.
Topics: Child; Humans; Human Growth Hormone; Growth Hormone; Prader-Willi Syndrome; Cognition; Growth and Development
PubMed: 37987848
DOI: 10.1007/s00431-023-05327-z -
Frontiers in Neurorobotics 2023Robot learning based on implicitly extracted error detections (e.g., EEG-based error detections) has been well-investigated in human-robot interaction (HRI). In...
Robot learning based on implicitly extracted error detections (e.g., EEG-based error detections) has been well-investigated in human-robot interaction (HRI). In particular, the use of error-related potential (ErrP) evoked when recognizing errors is advantageous for robot learning when evaluation criteria cannot be explicitly defined, e.g., due to the complex behavior of robots. In most studies, erroneous behavior of robots were recognized visually. In some studies, visuo-tactile stimuli were used to evoke ErrPs or a tactile cue was used to indicate upcoming errors. To our knowledge, there are no studies in which ErrPs are evoked when recognizing errors only via the tactile channel. Hence, we investigated ErrPs evoked by tactile recognition of errors during HRI. In our scenario, subjects recognized errors caused by incorrect behavior of an orthosis during the execution of arm movements tactilely. EEG data from eight subjects was recorded. Subjects were asked to give a motor response to ensure error detection. Latency between the occurrence of errors and the response to errors was expected to be short. We assumed that the motor related brain activity is timely correlated with the ErrP and might be used from the classifier. To better interpret and test our results, we therefore tested ErrP detections in two additional scenarios, i.e., without motor response and with delayed motor response. In addition, we transferred three scenarios (motor response, no motor response, delayed motor response). Response times to error was short. However, high ErrP-classification performance was found for all subjects in case of motor response and no motor response condition. Further, ErrP classification performance was reduced for the transfer between motor response and delayed motor response, but not for the transfer between motor response and no motor response. We have shown that tactilely induced errors can be detected with high accuracy from brain activity. Our preliminary results suggest that also in tactile ErrPs the brain response is clear enough such that motor response is not relevant for classification. However, in future work, we will more systematically investigate tactile-based ErrP classification.
PubMed: 38162893
DOI: 10.3389/fnbot.2023.1297990 -
The American Journal of Occupational... Nov 2023Motor ability plays an important role in overall developmental profiles. Preschool children with autism spectrum disorder (ASD) are at risk of motor skills deficits and... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Motor ability plays an important role in overall developmental profiles. Preschool children with autism spectrum disorder (ASD) are at risk of motor skills deficits and delays. However, evidence of the efficacy of different motor interventions for the identification of optimal treatment types is lacking, especially for preschool children with ASD.
OBJECTIVE
To examine the efficacy of the Motor Skill Occupational Therapy Intervention ON ASD (MOTION-ASD) and Cognitive Orientation Exercise (CO-EXC) programs to improve motor skills performance, self-care performance, and adaptive behaviors among preschool children with ASD.
DESIGN
Randomized controlled trial, two-group, triple-blinded, repeated-measures design Setting: University laboratory.
PARTICIPANTS
Thirteen preschool children with ASD (M age = 4.91 yr).
OUTCOMES AND MEASURES
The Bruininks-Oseretsky Test of Motor Proficiency-Second Edition, Brief Form, Assessment of Motor and Process Skills, and Vineland Adaptive Behavior Scales-Third Edition.
RESULTS
Children in the MOTION-ASD group showed significantly greater improvements in manual coordination and overall gross and fine manual skills than those in the CO-EXC group immediately after the intervention. Significant improvements in fine manual control, body coordination, overall motor skills, and self-care performance were made throughout both interventions and were retained at the posttest and the 4-wk follow-up.
CONCLUSIONS AND RELEVANCE
These findings provide supporting evidence that motor skills interventions involving fundamental skills and cognitive training may be a viable therapeutic option for treating children with ASD. The results also suggest that practitioners may consider providing structured and strategic motor skills interventions for preschool children with ASD. What This Article Adds: This study's rigorous tests of motor skills interventions support ways to manage motor difficulties in children with autism spectrum disorder (ASD). An intervention based on motor learning theory could benefit preschool children with ASD, especially in terms of manual coordination ability and overall gross and fine motor skills.
Topics: Humans; Child, Preschool; Autism Spectrum Disorder; Pilot Projects; Motor Skills; Exercise; Physical Functional Performance
PubMed: 37992052
DOI: 10.5014/ajot.2023.050283 -
Frontiers in Bioscience (Landmark... Dec 2023Amyotrophic lateral sclerosis (ALS) is a systemic disease with multiple pathological effects, including neuroinflammation, oxidative stress, autophagy, mitochondrial...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a systemic disease with multiple pathological effects, including neuroinflammation, oxidative stress, autophagy, mitochondrial dysfunction, and endoplasmic reticulum stress. Despite many studies seeking to identify and develop effective therapies, effective ALS treatment has yet to be approved. Hence, patients with ALS ultimately experience muscle atrophy and loss of motor neurons. Herbal medicines have been used to treat numerous diseases by modulating multiple biological processes and exerting pharmacological effects, including anti-inflammatory and antioxidant properties. In particular, Koehne (CS) exhibits anti-hyperuricemic and nephroprotective effects and is used to treat anaphylaxis, viral infections, and neurodegenerative diseases, such as Alzheimer's disease. This study monitored the effects of CS supplementation on muscle function and motor neurons in hSOD1G93A mice, an established ALS animal model.
METHODS
Body weight measurements and behavioral tests were performed; additionally, western blotting and immunohistochemistry analyses were conducted using the mice gastrocnemius, tibialis anterior, and spinal cord.
RESULTS
CS augmented anti-inflammatory and antioxidant effects in the muscle and spinal cord of hSOD1G93A mice. Furthermore, CS improved motor function and regulated autophagy in the muscles of the hSOD1G93A mice.
CONCLUSIONS
CS might represent a promising supplement for improving motor function and delaying ALS progression. However, its development for clinical use warrants further investigation.
Topics: Humans; Mice; Animals; Amyotrophic Lateral Sclerosis; Mice, Transgenic; Disease Models, Animal; Spinal Cord; Rosaceae; Antioxidants; Plant Extracts
PubMed: 38179776
DOI: 10.31083/j.fbl2812326 -
Advances in Rehabilitation Science and... 2023Motor skills and movement-related functioning significantly shape how children experience and interact with the world around them. Among infants and young children,... (Review)
Review
Motor skills and movement-related functioning significantly shape how children experience and interact with the world around them. Among infants and young children, developmental motor disorders contribute to delays with motor, cognitive, and psychosocial development. Early and accurate identification of these disorders is necessary to facilitate timely access to therapeutic interventions that minimize the long-term effects of disability on everyday activities and participation. In the United States, motor assessments commonly used among children 0 to 3 years focus on completion of specific motor skills at a single point in time, which provides only a part of the greater picture that is a child's motor and movement-related functioning. Video-capture methods, like the General Movements Assessment (GMA) and the Infant Motor Profile (IMP), offer greater accuracy and predictive power to (1) identify motor deficits in young children and (2) facilitate early access to supportive, therapeutic intervention.
PubMed: 37928362
DOI: 10.1177/27536351231207740 -
Frontiers in Immunology 2023Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease characterized by the loss of motor neurons. Dysregulated peripheral immunity has... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease characterized by the loss of motor neurons. Dysregulated peripheral immunity has been identified as a hallmark of ALS. Neutrophils, as the front-line responders of innate immunity, contribute to host defense through pathogen clearance. However, they can concurrently play a detrimental role in chronic inflammation. With the unveiling of novel functions of neutrophils in neurodegenerative diseases, it becomes essential to review our current understanding of neutrophils and to recognize the gap in our knowledge about their role in ALS. Thus, a detailed comprehension of the biological processes underlying neutrophil-induced pathogenesis in ALS may assist in identifying potential cell-based therapeutic strategies to delay disease progression.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neutrophils; Neurodegenerative Diseases; Motor Neurons; Immunity, Innate
PubMed: 37662922
DOI: 10.3389/fimmu.2023.1246768 -
Indian Journal of Otolaryngology and... Dec 2023The Cri-du-chat Syndrome (CdCs) is a rare genetic syndrome first described by Jerome Lejeune in 1963, characterized mainly by the high pitched cat like cry. The...
The Cri-du-chat Syndrome (CdCs) is a rare genetic syndrome first described by Jerome Lejeune in 1963, characterized mainly by the high pitched cat like cry. The prevalence of CdCs was varied in between 1:15,000 to 1:50,000 in live birth and more common in female gender with a ratio of 4:3 [1, 2] .The condition may be accompanied by developmental and cognitive delays, poor spatial awareness, impaired ambulation, and poor sensori-motor skills. Other associated problems described include cardiovascular, renal, gastrointestinal, neurological abnormalities, preauricular tags, syndactyly, hypospadias, and cryptorchidism.1 Recent literatures show that autistic behaviours are common in various genetic disorders [3].Fatigue level of children with cri du chat syndrome was associated with the expression of autistic features [4]. Cri-du-chat syndrome is a rare genetic disorder resulting in various physical and psychological abnormalities due the deletion of chromosome 5P-. We encountered a case of cri-du-chat syndrome having external auditory canal atresia, hearing loss with speech delay. A multidisciplinary approach is required for diagnosis and management of such patients. Otological management is early identification of hearing loss and speech rehabilitation. Awareness about antenatal screening for congenital anomalies and genetic counselling is necessary among the general population.
PubMed: 37974816
DOI: 10.1007/s12070-023-04039-y