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Gene Nov 2023The TBL1XR1 gene encodes the protein transducin-beta-like 1 receptor1, widely distributed in the pituitary, hypothalamus, white and brown adipose tissue, muscle, and... (Review)
Review
BACKGROUND
The TBL1XR1 gene encodes the protein transducin-beta-like 1 receptor1, widely distributed in the pituitary, hypothalamus, white and brown adipose tissue, muscle, and liver. Current evidence suggests that heterozygous TBL1XR1 pathogenic variants can lead to a wide spectrum of phenotypes. This study aims to reveal the clinical phenotype and genetic profiles of de novo TBL1XR1 variations and summarize the relevant clinical and genetic features.
METHODS
We analyzed four new cases harboring de novo TBL1XR1 variants and reviewed all reported cases.
RESULTS
All probands suffered from global developmental delay. Moreover, patient 1 exhibited susceptibility to startle, patient 2 had hypovitaminosis D, short stature and hyponatremia, and patients 3 and 4 both presented with ASD (Autism spectrum disorder) and short stature. They all had a de novo TBL1XR1 variant (NM_024665.7), c.1184A > G (p.Tyr395Cys), c.1108G > A (p.Asp370Asn), c.1047 + 1G > C, and c.1097C > T (p.Ser366Phe) respectively. In addition, pooled analysis of 51 cases showed that they had speech impairment (38/39), intellectual developmental disorder (28/28), global developmental delay (42/42), and hypotonia (24/27), and some of them had epilepsy (10/22), ASD (13/25), and developmental regression (4/13).
CONCLUSIONS
We report four new patients with de novo TBL1XR1 variants and provide a comprehensive overview of 47 previously reported individuals with TBL1XR1 variants, enriching the genotypic and phenotypic spectrum of TBL1XR1-related disease. This report further validates the pathogenicity de novo TBL1XR1 variants.
Topics: Humans; Autism Spectrum Disorder; Genotype; Phenotype; Heterozygote; Adipose Tissue, Brown; Repressor Proteins; Receptors, Cytoplasmic and Nuclear
PubMed: 37683765
DOI: 10.1016/j.gene.2023.147777 -
Therapeutic Advances in Neurological... 2023Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental... (Review)
Review
Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox-Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.
PubMed: 37655228
DOI: 10.1177/17562864231191000 -
Frontiers in Genetics 2024The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities... (Review)
Review
The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities for research and treatment development, and a few genetic disorders (e.g., spinal muscular atrophy) have recently been treated with gene-based therapies. is found on the X chromosome and regulates the transcription of thousands of genes. Loss of gene product leads to Rett Syndrome, a disease found primarily in females, and is characterized by developmental regression, motor dysfunction, midline hand stereotypies, autonomic nervous system dysfunction, epilepsy, scoliosis, and autistic-like behavior. Duplication of causes MECP2 Duplication Syndrome (MDS). MDS is found mostly in males and presents with developmental delay, hypotonia, autistic features, refractory epilepsy, and recurrent respiratory infections. While these two disorders share several characteristics, their differences (e.g., affected sex, age of onset, genotype/phenotype correlations) are important to distinguish in the light of gene-based therapy because they require opposite solutions. This review explores the clinical features of both disorders and highlights these important clinical differences.
PubMed: 38410154
DOI: 10.3389/fgene.2024.1332469 -
JAMA Network Open Oct 2023Although the effects of lead (Pb) exposure on neurocognition in children have been confirmed, the individual associations of prenatal Pb exposure and its interaction...
IMPORTANCE
Although the effects of lead (Pb) exposure on neurocognition in children have been confirmed, the individual associations of prenatal Pb exposure and its interaction with genetic factors on cognitive developmental delay (CDD) in children remain unclear.
OBJECTIVE
To investigate the association of prenatal Pb exposure and its interaction with genetic factors with CDD risk.
DESIGN, SETTING, AND PARTICIPANTS
Women in Wuhan, China, who had an expected delivery date between March 2014 and December 2017, were recruited for this prospective cohort study. Children were assessed for cognitive development at approximately 2 years of age (March 2016 to December 2019). Maternal venous blood, cord blood, and venous blood from children were collected in a longitudinal follow-up. Data analysis was performed from March 2022 to February 2023.
EXPOSURE
Prenatal Pb exposure, and genetic risk for cognitive ability evaluated by polygenic risk score constructed with 58 genetic variations.
MAIN OUTCOMES AND MEASURES
Cognitive developmental delay of children aged approximately 2 years was assessed using the Chinese revision of the Bayley Scale of Infant Development. A series of multivariable logistic regressions was estimated to determine associations between prenatal Pb exposure and CDD among children with various genetic backgrounds, adjusting for confounding variables.
RESULTS
This analysis included 2361 eligible mother-child pairs (1240 boys [52.5%] and 1121 girls [47.5%]; mean [SD] ages of mothers and children, 28.9 [3.6] years and 24.8 [1.0] months, respectively), with 292 children (12.4%) having CDD. Higher maternal Pb levels were significantly associated with increased risk of CDD (highest vs lowest tertile: odds ratio, 1.55; 95% CI, 1.13-2.13), adjusting for demographic confounders. The association of CDD with maternal Pb levels was more evident among children with higher genetic risk (highest vs lowest tertile: odds ratio, 2.59; 95% CI, 1.48-4.55), adjusting for demographic confounders.
CONCLUSIONS AND RELEVANCE
In this cohort study, prenatal Pb exposure was associated with an increased risk of CDD in children, especially in those with a high genetic risk. These findings suggest that prenatal Pb exposure and genetic background may jointly contribute to an increased risk of CDD for children and indicate the possibility for an integrated strategy to assess CDD risk and improve children's cognitive ability.
Topics: Male; Infant; Pregnancy; Humans; Female; Child, Preschool; Prenatal Exposure Delayed Effects; Lead; Cohort Studies; Prospective Studies; Cognition
PubMed: 37870833
DOI: 10.1001/jamanetworkopen.2023.39108 -
American Journal of Obstetrics and... Sep 2023Preeclampsia, a hypertensive pregnancy disorder, is a leading cause of maternal and fetal morbidity and mortality, with remote cardio- and cerebrovascular implications....
BACKGROUND
Preeclampsia, a hypertensive pregnancy disorder, is a leading cause of maternal and fetal morbidity and mortality, with remote cardio- and cerebrovascular implications. After preeclampsia, women may report serious disabling cognitive complaints, especially involving executive function, but the extent and time course of these complaints are unknown.
OBJECTIVE
This study aimed to determine the impact of preeclampsia on perceived maternal cognitive functioning decades after pregnancy.
STUDY DESIGN
This study is part of a cross-sectional case-control study named Queen of Hearts (ClinicalTrials.gov Identifier: NCT02347540), a collaboration study of 5 tertiary referral centers within the Netherlands investigating long-term effects of preeclampsia. Eligible participants were female patients aged ≥18 years after preeclampsia and after normotensive pregnancy between 6 months and 30 years after their first (complicated) pregnancy. Preeclampsia was defined as new-onset hypertension after 20 weeks of gestation along with proteinuria, fetal growth restriction, or other maternal organ dysfunction. Women with a history of hypertension, autoimmune disease, or kidney disease before their first pregnancy were excluded. Attenuation of higher-order cognitive functions, that is, executive function, was measured with the Behavior Rating Inventory of Executive Function for Adults. Crude and covariate-adjusted absolute and relative risks of clinical attenuation over time after (complicated) pregnancy were determined with moderated logistic and log-binomial regression.
RESULTS
This study included 1036 women with a history of preeclampsia and 527 women with normotensive pregnancies. Regarding overall executive function, 23.2% (95% confidence interval, 19.0-28.1) of women experienced clinically relevant attenuation after preeclampsia, as opposed to 2.2% (95% confidence interval, 0.8-6.0) of controls immediately after childbirth (adjusted relative risk, 9.20 [95% confidence interval, 3.33-25.38]). Group differences diminished yet remained statistically significant (P < .05) at least 19 years postpartum. Regardless of history of preeclampsia, women with lower educational attainment, mood or anxiety disorders, or obesity were especially at risk. Neither severity of preeclampsia, multiple gestation, method of delivery, preterm birth, nor perinatal death was related to overall executive function.
CONCLUSION
After preeclampsia, women were 9 times more likely to experience clinical attenuation of higher-order cognitive functions as opposed to after normotensive pregnancy. Despite overall steady improvement, elevated risks persisted over decades after childbirth.
Topics: Adult; Female; Humans; Infant, Newborn; Male; Pregnancy; Case-Control Studies; Cognition; Cross-Sectional Studies; Hypertension; Pre-Eclampsia; Premature Birth; Adolescent
PubMed: 36863645
DOI: 10.1016/j.ajog.2023.02.020 -
JAMA Network Open Dec 2023Sleep disturbances and mental health problems are highly comorbid and bidirectionally correlated across childhood. The association between the natural history of sleep...
IMPORTANCE
Sleep disturbances and mental health problems are highly comorbid and bidirectionally correlated across childhood. The association between the natural history of sleep disturbances and the transition of mental health problems has not been quantified.
OBJECTIVE
To examine the association between the natural history of sleep disturbances and resolved and incident emotional and behavioral difficulties (EBDs).
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used data from the Shanghai Children's Health, Education and Lifestyle Evaluation-Preschool (SCHEDULE-P), a prospective and population-based longitudinal cohort study of children enrolled in preschools in Shanghai, China, from November 10 to 24, 2016. A total of 20 324 children aged 3 to 4 years were recruited from the junior class of 191 kindergartens, of whom 17 233 (84.8%) participated in the 2-year follow-up. A multilevel regression model was used to evaluate the association between the development of sleep disturbances and the occurrence of resolved and incident EBDs. The data analysis spanned from August 4, 2021, to October 31, 2023.
EXPOSURES
Sleep disturbances were assessed using the Children's Sleep Habit Questionnaire; EBDs were assessed using the Strengths and Difficulties Questionnaire.
MAIN OUTCOMES AND MEASURES
Occurrence of incident and resolved EBDs at the 2-year follow-up.
RESULTS
The cohort included 17 182 participants, with a mean (SD) age of 3.73 (0.29) years at enrollment; 52.0% were boys. The prevalence of EBDs at school entry and graduation years was 27.8% and 18.7%, respectively, while the prevalence of sleep disturbances was 41.3% and 31.5%, respectively. Among those with EBDs at the entry year, 35.0% maintained stability in the graduation year, while sleep disturbances were stable in 50.0% of those with sleep disturbances. After controlling for confounding factors, the odds ratio (OR) for resolved EBDs was lower in the incident sleep disturbance (ISD) group (OR, 0.50 [95% CI, 0.41-0.62]; P < .001) and stable sleep disturbance (SSD) group (OR, 0.47 [95% CI, 0.40-0.56]; P < .001) compared with the group with no sleep disturbances. The ORs for incident EBDs among the ISD group (OR, 2.58 [95% CI, 2.22-3.01]; P < .001) and SSD group (OR, 2.29, [95% CI, 1.98-2.64]; P < .001) were higher than among the group with no sleep disturbances.
CONCLUSIONS AND RELEVANCE
In this prospective cohort study, the natural history of sleep disturbances among preschool-aged children was associated with both resolved and incident EBDs. Routine screening and precise intervention for sleep disturbances may benefit the psychosocial well-being of this population.
Topics: Child; Male; Humans; Child, Preschool; Female; Cohort Studies; Prospective Studies; Longitudinal Studies; China; Sleep Wake Disorders; Sleep
PubMed: 38095895
DOI: 10.1001/jamanetworkopen.2023.47623 -
Revista Paulista de Pediatria : Orgao... 2023To estimate the prevalence of developmental defects in dental enamel and its possible association with prenatal, neonatal and postnatal conditions in six-year-old...
OBJECTIVE
To estimate the prevalence of developmental defects in dental enamel and its possible association with prenatal, neonatal and postnatal conditions in six-year-old schoolchildren in a southern Brazilian municipality.
METHODS
A cross-sectional study was conducted involving 655 six-year-old schoolchildren. Sociodemographic and health data were collected through interviews with mothers and children's oral examinations at schools. Multivariate analyses were performed using Poisson regression with robust estimator.
RESULTS
The prevalence of developmental defects of enamel was 44.0%. Demarcated opacities were the most prevalent, followed by diffuse opacities. Late pregnancy, maternal schooling less than eight years, female gender and child's white skin color were independently associated with the prevalence of demarcated opacities.
CONCLUSIONS
The prevalence of developmental defects in dental enamel was 44.0%. Late pregnancy, maternal schooling less than eight years, female gender and child's white skin color were associated with the prevalences.
Topics: Child; Infant, Newborn; Humans; Female; Pregnancy; Cross-Sectional Studies; Brazil; Educational Status; Mothers; Vitamins; Dental Enamel
PubMed: 37646751
DOI: 10.1590/1984-0462/2024/42/2022226