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Nature Apr 2021Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life...
Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound motor and cognitive decline. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.
Topics: Animals; Biomedical Enhancement; Disease Models, Animal; Electrophysiology; Female; Male; Mice; Morris Water Maze Test; Neurons; Prodromal Symptoms; Psychomotor Performance; Rett Syndrome; Rotarod Performance Test; Spatial Learning; Time Factors
PubMed: 33762729
DOI: 10.1038/s41586-021-03369-7 -
Experimental and Therapeutic Medicine Oct 2021In patients with Parkinson's disease (PD), gastrointestinal dysfunction occurs from the early stages of the disease and even in the pre-motor phase. This condition can... (Review)
Review
In patients with Parkinson's disease (PD), gastrointestinal dysfunction occurs from the early stages of the disease and even in the pre-motor phase. This condition can include the entire digestive tract, with symptoms ranging from delays in gastric emptying to dysphagia, constipation and even malnutrition. Excess saliva accumulates in the mouth due to the low frequency of swallowing. Dysphagia develops in about 50% of patients and may be a reflection of both central nervous system and enteric nervous system disorder. Gastroparesis can cause a variety of symptoms, including nausea, and also may be responsible for some of the motor fluctuations observed with levodopa therapy. Intestinal dysfunction in PD may be the result of both delayed colon transit and impaired anorectal muscle coordination. In addition, recent studies have demonstrated the role of infection in the pathogenesis of diseases but also the occurrence of motor fluctuations by affecting the absorption of anti-parkinsonian medication. In this review, the main gastrointestinal dysfunctions associated with PD are presented.
PubMed: 34447476
DOI: 10.3892/etm.2021.10517 -
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 -
IScience May 2022Reward timing, that is, the delay after which reward is delivered following an action is known to strongly influence reinforcement learning. Here, we asked if reward...
Reward timing, that is, the delay after which reward is delivered following an action is known to strongly influence reinforcement learning. Here, we asked if reward timing could also modulate how people learn and consolidate new motor skills. In 60 healthy participants, we found that delaying reward delivery by a few seconds influenced motor learning. Indeed, training with a short reward delay (1 s) induced continuous improvements in performance, whereas a long reward delay (6 s) led to initially high learning rates that were followed by an early plateau in the learning curve and a lower performance at the end of training. Participants who learned the skill with a long reward delay also exhibited reduced overnight memory consolidation. Overall, our data show that reward timing affects the dynamics and consolidation of motor learning, a finding that could be exploited in future rehabilitation programs.
PubMed: 35573187
DOI: 10.1016/j.isci.2022.104290 -
Cold Spring Harbor Molecular Case... Feb 2022Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in (MIM #608451), characterized by global...
Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis.
Topics: Brain Diseases, Metabolic, Inborn; Humans; Mitochondrial Proteins; Nucleocytoplasmic Transport Proteins; Purpura; Sepsis
PubMed: 35165146
DOI: 10.1101/mcs.a006193 -
BMC Medicine Aug 2023Moderate and late preterm (MLPT) birth accounts for the vast majority of preterm births, which is a global public health problem. The association between MLPT and...
BACKGROUND
Moderate and late preterm (MLPT) birth accounts for the vast majority of preterm births, which is a global public health problem. The association between MLPT and neurobehavioral developmental delays in children and the underlying biological mechanisms need to be further revealed. The "placenta-brain axis" (PBA) provides a new perspective for gene regulation and risk prediction of neurodevelopmental delays in MLPT children.
METHODS
The authors performed multivariate logistic regression models between MLPT and children's neurodevelopmental outcomes, using data from 129 MLPT infants and 3136 full-term controls from the Ma'anshan Birth Cohort (MABC). Furthermore, the authors identified the abnormally regulated PBA-related genes in MLPT placenta by bioinformatics analysis of RNA-seq data and RT-qPCR verification on independent samples. Finally, the authors established the prediction model of neurodevelopmental delay in children with MLPT using multiple machine learning models.
RESULTS
The authors found an increased risk of neurodevelopmental delay in children with MLPT at 6 months, 18 months, and 48 months, especially in boys. Further verification showed that APOE and CST3 genes were significantly correlated with the developmental levels of gross-motor domain, fine-motor domain, and personal social domain in 6-month-old male MLPT children.
CONCLUSIONS
These findings suggested that there was a sex-specific association between MLPT and neurodevelopmental delays. Moreover, APOE and CST3 were identified as placental biomarkers. The results provided guidance for the etiology investigation, risk prediction, and early intervention of neurodevelopmental delays in children with MLPT.
Topics: Pregnancy; Infant; Infant, Newborn; Humans; Child; Female; Male; Premature Birth; Placenta; Brain; Computational Biology; Apolipoproteins E
PubMed: 37633927
DOI: 10.1186/s12916-023-03023-1 -
Journal of Paediatrics and Child Health Apr 2020Gross motor skills are important for children's health and development. Delays in these skills are a concern for healthy developmental trajectories and therefore early...
AIM
Gross motor skills are important for children's health and development. Delays in these skills are a concern for healthy developmental trajectories and therefore early identification of delay is important. This study screened for gross motor delay in children from low-income communities and investigated potential risk factors associated with gross motor delay.
METHODS
This cross-sectional study involved 701 pre-schoolers (M = 54.1 ± 8.6 months, 52.8% boys) from childcare services in low-income and remote communities in Australia. Gross motor delay was assessed using the Ages and Stages Questionnaire - third edition. Potential risk factors included: sex, age, birthweight, prematurity status, weight status, childcare service, postcode, parent's education, parent's marital status, parent's employment and family income.
RESULTS
Results showed 4.4% of the children were delayed in gross motor skills and 8.8% were at risk of delay. Logistic regression showed being a boy (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.12-2.84), underweight (OR 2.72, 95% CI 1.18-6.30) or overweight (OR 1.83, 95% CI 1.00-3.33), and parental unemployment (OR 1.79, 95% CI 1.01-3.16) were factors associated with a higher odds of children being delayed or at risk of gross motor delay. A higher family income (OR 0.35, 95% CI 0.13-0.93) was associated with lower odds of delay.
CONCLUSION
This unique study demonstrated children in low-income communities, especially boys, underweight and overweight children, have higher odds of being at risk of gross motor delay. Therefore, early screening is vital in this population in order to identify delays and potentially intervene with appropriate motor skill interventions.
Topics: Australia; Child; Child, Preschool; Cross-Sectional Studies; Developmental Disabilities; Humans; Infant; Infant, Newborn; Male; Motor Skills; Prevalence; Risk Factors
PubMed: 31705779
DOI: 10.1111/jpc.14684 -
Translational Pediatrics Feb 2020Developmental diagnosis is based on an understanding of basic concepts of typical and atypical developmental progression. Child development is influenced by multiple... (Review)
Review
Developmental diagnosis is based on an understanding of basic concepts of typical and atypical developmental progression. Child development is influenced by multiple factors, including the development of the nervous system and other organ systems, and the child's physical and social environment. Different factors interplay with each other in influencing the overall development of the child. Development and behavior of the child are intricately associated. Typical child development follows certain basic principles. Some of the more commonly reported developmental concerns include global developmental delay, intellectual disability, cerebral palsy, delayed speech and language, attention deficits, autism, and specific learning disabilities. The clinical presentation of atypical development varies, depending up on the age of the child; with motor delay in early infancy, and learning difficulties in school age child. Regular surveillance and periodic screening help identify specific areas of developmental and behavioral concerns and suggest a need for further appropriate psychological, medical and laboratory evaluation. The principles of management of a child with developmental concerns include early intervention and response to treatment approach, remediation, accommodation, and specific behavioral and pharmacological interventions when indicated.
PubMed: 32206580
DOI: 10.21037/tp.2019.11.04 -
International Journal of Epidemiology Oct 2022Impaired neurodevelopment is reported among children conceived by assisted reproductive technologies (ART). However, this might be explained by conditions underlying...
BACKGROUND
Impaired neurodevelopment is reported among children conceived by assisted reproductive technologies (ART). However, this might be explained by conditions underlying parental subfecundity, rather than the ART procedure.
METHODS
We examined associations of parental time-to-pregnancy (TTP) and conception by ART with neurodevelopmental traits up to 8 years of age, including motor and language skills, social delays and difficulties, and inattention-hyperactivity, among 92 142 singletons participating in the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers reported TTP and neurodevelopmental traits through questionnaires. Mean differences in standardized neurodevelopmental traits were estimated using linear regression, adjusting for maternal age, parity, educational level, body mass index and smoking, and paternal age.
RESULTS
A longer TTP was associated with decreased language skills and motor skills at 6, 18 and 36 months (P-values for trend ≤0.01), prosocial skills delay at 36 months (P-values for trend ≤0.001) and increased scores for inattention-hyperactivity traits at all ages up to 8 years (P-values for trend from 0.06 to 0.01). Effect sizes were small, ranging between 0.03 and 0.05 difference in the standardized neurodevelopmental scores. Estimates for ART were imprecise, but there were no differences between children conceived by ART and naturally conceived children of subfecund parents (TTP ≥12 months).
CONCLUSIONS
Longer parental TTP is modestly but robustly associated with offspring neurodevelopmental delays and difficulties, with no added impact of ART. Future studies should investigate the underlying causes of-or aspects related to-parental subfecundity which might explain the association with offspring neurodevelopmental delays and difficulties.
Topics: Child; Cohort Studies; Female; Fertility; Humans; Mothers; Pregnancy; Reproductive Techniques, Assisted
PubMed: 35536321
DOI: 10.1093/ije/dyac094