A rare cause of epileptic encephalopathy: case report of a novel patient with PEHO-like phenotype and CCDC88A gene pathogenic variants.

BACKGROUND: The Coiled-Coil Domain-Containing Protein 88 A (CCDC88A) gene encodes the actin-binding protein Girdin, which plays important roles in maintaining the actin cytoskeleton and in cell migration and was recently associated with a specific form of epileptic encephalopathy. Biallelic protein-truncating variants of CCDC88A have been considered responsible for progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome. To date, only three consanguineous families with loss-of-function homozygous variants in the CCDC88A gene have been reported. The described patients share many clinical features, such as microcephaly, neonatal hypotonia, seizures, profound developmental delay, face and limb edema, and dysmorphic features, with a similar appearance of the eyes, nose, mouth, and fingers. CASE PRESENTATION: We report on a child from a nonconsanguineous family who presented with profound global developmental delay, severe epilepsy, and brain malformations, including subcortical band heterotopia. The patient harbored two heterozygous pathogenic variants in the trans configuration in the CCDC88A gene, which affected the coiled-coil and C-terminal domains. CONCLUSIONS: We detail the clinical and cerebral imaging data of our patient in the context of previously reported patients with disease-causing variants in the CCDC88A gene, emphasizing the common phenotypes, including cortical malformations, that warrant screening for sequence variants in this gene.

Case Report: Cerebral folate deficiency caused by FOLR1 variant.

Background: Cerebral folate transport deficiency (CFD) is a rare neurological disease characterized by a deficiency in 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid, with a normal peripheral total folate level. Late infantile-onset refractory seizures, ataxia, movement disorders, hypotonia, developmental delays, and developmental regression characterize CFD. Some patients present with visual and hearing impairments and autism-like manifestations. This study aimed to elucidate the clinical features, diagnostic approach, and therapeutic outcomes in siblings with CFD due to FOLR1 variants, highlighting the importance of early diagnosis and treatment. Case presentation: We reported the cases of two siblings with CFD caused by a new variant in FOLR1. They presented with intractable epilepsy, developmental regression, and ataxia, and the younger sibling developed autism. Whole-exon sequencing revealed a c.148G>A homozygous variant, resulting in a change in the amino acid sequence (p.Glu50Lys). Low 5-MTHF levels were detected in the cerebrospinal fluid. Conclusions: This report illustrates that CFD was caused by FOLR1 variants in two siblings. They had intractable epilepsy, developmental regression, and ataxia, and a diagnosis of CFD was confirmed by a c.148G>A (p.Glu50Lys) variant in FOLR1, a new pathogenic variant in FOLR1. Early diagnosis is essential and can improve outcomes in affected patients.

[Guide to neurological follow-up in premature newborns]. / Guía de seguimiento neurológico en recién nacidos prematuros.

One in ten babies are born preterm, as defined as being less than 37 weeks of gestational age. Premature births are associated with a high risk of poor neurodevelopmental outcomes, including hearing, visual, motor, and cognitive impairments. Currently, there is no specific standardization for neurological follow-up infants born premature. Most formal neonatal intensive care units, follow-up programs monitor children until early childhood. However, some deficits, such as mild cognitive impairment, may only become apparent in school years. This review outlines a neurological follow-up timeline, as well as the different standardized measures that can be used to monitor development to ensure that children born preterm receive timely and appropriate therapies and services.

Uno de cada diez bebés nacidos es prematuro, el cual se define como el nacido antes de las 37 semanas de edad gestacional. La prematuridad está asociada con un alto riesgo de trastornos del neurodesarrollo con limitaciones en la audición, visión, área cognitiva y motora. Actualmente, no existen programas estandarizados específicos para el seguimiento neurológico de los prematuros. La mayoría son desarrollados por las unidades de cuidados intensivos neonatales y dan seguimiento hasta la edad pre-escolar. Sin embargo, algunas deficiencias, como el deterioro cognitivo leve, son reconocidos tardíamente. Esta revisión describe un cronograma para el seguimiento neurológico y las herramientas estandarizadas que pueden utilizarse para vigilar el desarrollo y asegurar que los niños nacidos prematuros reciban terapias y otros servicios adecuados y oportunos.

Flame retardant tetrabromobisphenol A (TBBPA) disrupts histone acetylation during zebrafish maternal-to-zygotic transition.

3,3',5.5'-Tetrabromobisphenol A (TBBPA) is a widely used brominated flame-retardant. The objective of this study is to use zebrafish as a model and determine the effects of TBBPA exposure on early embryogenesis. We initiated TBBPA exposures at 0.75 h post fertilization (hpf) and showed that TBBPA induced developmental delays during maternal-to-zygotic transition (MZT) and zygotic genome activation (ZGA). To examine the genetic basis of TBBPA-induced delays, we conducted mRNA-sequencing on embryos exposed to 0 or 40 µM TBBPA from 0.75 hpf to 2, 3.5 or 4.5 hpf. Read count data showed that while TBBPA exposures had no overall impacts on maternal or maternal-zygotic genes, collective read counts for zygotically activated genes were lower in TBBPA treatment at 4.5 hpf compared to time-matched controls, suggesting that TBBPA delays ZGA. Gene ontology assessments for both time- and stage-matched differentially expressed genes revealed TBBPA-induced inhibition of chromatin assembly- a process regulated by histone modifications. Immunostaining and in vitro experiments showed inhibition of histone H3 lysine 27 acetylation (H3K27Ac) as well as its catalyzing enzyme, p300. Finally, co-exposure with a p300 activator showed partial mitigation of effects, demonstrating that inhibition of histone acetylation drives TBBPA-induced developmental delays.

Ultrasonographic Measurement of Anterior Fontanelle Size in Infants with Deformational Plagiocephaly.

Background/Objectives: We aimed to investigate the relationship between deformational plagiocephaly (DP) severity and anterior fontanelle size and to explore the connection between fontanelle size and developmental delay. Methods: We enrolled 189 (122 boys and 67 girls; mean corrected age, 119.79 days) of the 256 infants who visited our clinic for plagiocephaly between March 2022 and June 2023. This study analyzed the correlation between cranial vault asymmetry (CVA) and anterior fontanelle size as measured using skull anteroposterior (AP) radiography and ultrasonography. The severity of DP was graded from minimal to severe based on the Argenta classification. Infants were grouped according to CVA severity as follows: Group 1 (CVA ≤ 5 mm), Group 2 (5 mm < CVA < 10 mm), and Group 3 (CVA ≥ 10 mm). Additionally, 40 infants underwent the Denver Developmental Screening Test II (DDST-II) for neurodevelopmental delays and were divided into groups based on the presence or absence of developmental delays for fontanelle size comparison. Results: Age showed a significant negative correlation with fontanelle size (correlation coefficient -0.234, p < 0.05), indicating that fontanelle size decreases as infants age. No significant differences in fontanelle size were observed among the three CVA groups (p = 0.074) or between the developmentally delayed and non-delayed groups (p = 0.09). This study found no correlation between CVA and fontanelle size or between fontanelle size and developmental delay. Conclusions: The findings show that, while anterior fontanelle size decreased with age, there was no significant correlation between the fontanelle size and the severity of deformational plagiocephaly or developmental delays.

Novel homozygous missense variants in MED27 associated with neurodevelopmental disorder: Clinical and pathogenetic research.

Background: Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (NEDSCAC), induced by MED27 gene, is an autosomal recessive rare disorder characterized by widespread developmental delay with varying degrees of intellectual impairment. Other symptoms include limb spasticity, cataracts, and cerebellar hypoplasia. So far there have been limited reports on NEDSCAC. Methods: In this study, we conducted genetic testing on a child presenting with developmental delay as the primary clinical feature. The genetic test results indicated the presence of novel homozygous missense variants c.74G > A, p.(Arg25His) in the MED27 gene. In vitro functional validation experiments, including plasmid construction and cell transfection, Western blotting, and molecular dynamics structural modeling, were performed on the MED27 Arg25His variant. Results: The results demonstrated a significant reduction in protein expression of MED27 Arg25His and indicated may weaken the interaction force between the MED27 subunit and MED14 subunit. Conclusions: This study expands our understanding of MED27 gene variants and their associated clinical phenotypes. Additionally, it contributes to the investigation of the potential pathogenesis of NEDSCAC caused by MED27 gene variants.

Do maternal and paternal education protect against developmental delays?

BACKGROUND: Parental education is linked to child development and wellbeing, but unique and combined contributions of maternal and paternal education have rarely been studied. AIMS: This study assessed the individual and joint associations of maternal and paternal education on children's odds of a probable developmental delay. METHODS AND PROCEDURES: Mothers (N = 3566) from the Upstate KIDS cohort study reported on theirs and the father's highest level of education and completed the Ages and Stages Questionnaires up to 7 times when the child was 4- to 36-months-old. A nonparametric constrained inference technique assessed the association between education and probable developmental delays. OUTCOMES AND RESULTS: Higher levels of maternal and paternal education were protective against child probable developmental delays in years 2 (18, 24 months; p-trends<.001) and 3 (30, 36 months; p-trends<.001), but not year 1 (4, 8, 12 months; p-trend=.486-.832). Trends held adjusting for parental age and race. When adjusting for the other parent's education, only maternal education had unique associations with delays. Among parents with the same or similar education levels, when both parents had one level higher education it was also protective. CONCLUSIONS AND IMPLICATIONS: Both maternal and paternal education may protect against children's developmental delays in toddlerhood, but maternal education may be particularly important.

Effectiveness of training on primary care nurses' knowledge and screening practice in identification of children at risk for developmental delay: An Indian perspective.

Background: In India, overall, 1.5-19.8% of the children were found to be developmentally delayed. The evaluation of development in young children and health professionals' early referrals for diagnostic assessment will accelerate appropriate early intervention as early as possible. Nurses can screen the children and help the parents by providing the necessary information and support. Aim: To train the primary care nurses on developmental screening and early identification of developmental delay (DD) in children and find the effectiveness of the same. Objectives of the study: To evaluate the effectiveness of the training program on the knowledge and screening practice of the nurses towards the identification of children at risk for DD and to find out the relationship between nurses' knowledge and screening practice. Methods and Materials: A quasi-experimental, one-group pretest, post-test design was adopted among 69 nurses, who were providing child care services and working in the selected government hospitals in Bengaluru, South India. Nurses' knowledge and screening practice in identifying children at risk for DD were assessed before and after the training. SPSS package 21.00 version was used to analyse the descriptive and inferential statistics. Results: The training program was effective in the enhancement of primary care nurses' knowledge and screening practice in the identification of DDs in under-five children. Conclusion: The findings of this study concluded that developmental screening can be performed by nurses with suitable training programs. The training program played a significant role in the enhancement of nurses' knowledge and screening practice in the identification of DDs in under-five children.

Simultaneous closure of a perilymphatic fistula and placement of cochlear implant in a case of complex inner ear malformation.

Key Clinical Message: In young infants, under the age of one-year, cochlear malformation with profound hearing loss complicated by a perilymphatic fistula (PLF), presents a serious clinical challenge, warranting immediate audiological and surgical intervention. Timely PLF detection and closure, along with an early CI can significantly improve the prognosis of such patients and helps them in achieving their maximum hearing and developmental potential, in the long term. Abstract: Inner ear malformation (IEM) with incomplete partition and cystic cochlea is mostly accompanied by profound hearing loss. It gets further complicated with other malformations such as a perilymphatic fistula (PLF). This case concerns an 8-month-old child cochlear malformation and profound hearing loss. Surgical intervention identified a PLF at the stapedial footplate, which was successfully closed. The surgery also included the placement of a cochlear implant (CI) in the right ear, via the round window. The left ear was equipped with hearing aids, with persistent hearing thresholds at 70-80 db. At the age of 6 years, the child showed a good hearing outcome with the CI, with only moderate speech delay. Cochlear malformation accompanied by a perilymphatic leakage warrants immediate surgical closure of the PLF, to minimize the risk of bacterial meningitis. Wherever possible, the feasibility of a CI should be explored in such cases and a CI should be placed for treatment of hearing loss. Audiological and speech outcomes may vary with the use of the CI, especially in cases of IEM. However, an early CI coupled with timely PLF detection and closure can help children with profound hearing loss, in achieving their maximum hearing and developmental potential, in the long run.

Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype.

BACKGROUND: Chromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty. RESULTS: We identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene. CONCLUSION: This report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.

Case report: Second report of neuromuscular syndrome caused by biallelic variants in ASCC3.

Introduction: Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) has been implicated in the pathogenesis of neurodevelopmental disorders and neuromuscular diseases (MIM: 620700). This paper analyzes the clinical manifestations of three patients with developmental delay caused by ASCC3 genetic variation. Additionally, we discuss the previously reported clinical features of these patients along with our own findings, thereby enhancing our understanding of these genetic disorders and providing valuable insights into diagnosis, treatment, and potential interventions for affected individuals. Methods: In this study, we utilized trio-whole-exome sequencing (Trio-WES) and trio-copy number variations sequencing (Trio-CNV-seq) to analyze three unique families diagnosed with developmental delay caused by variation in ASCC3. Additionally, we retrospectively examined eleven previously reported ASCC3 genetic variations exhibiting similar clinical features. Results: Proband I (family 1) and Proband III (family 3) exhibited global developmental delays, characterized by intellectual disability, motor impairment, language retardation, lower muscle strength, and reduced muscle tone in their extremities. Proband II (family 2) presented poor response and dysphagia during feeding within 7 days after birth, clinical examination displayed short limbs, long trunk proportions, and clenched fists frequently observed alongside high muscle tone in his limbs -all indicative signs of developmental delay. Trio-WES revealed compound heterozygous variants in ASCC3 inherited from their parents. Proband I carried c. [489 dup]; [1897C>T], proband II carried c. [2314C>T]; [5002T>A], and proband III carried c. [5113G>T]; [718delG] variations, respectively. Conclusion: This study present the first report of Chinese children carrying compound heterozygous genetic variants in ASCC3 with LOF variants, elucidating the relationship between these variants and various aspects of intellectual disability. This novel finding expands the existing spectrum of ASCC3 variations.

Pediatrician Knowledge of Early Intervention Process as Contributor to Disparities in Management of Development Delay.

INTRODUCTION: Lack of knowledge of Early Intervention (EI) is a barrier to developmental delay (DD) management. We aimed to examine the feasibility of measuring pediatricians' knowledge of EI, determine the distribution of EI knowledge, and determine factors associated with increased EI knowledge. METHODS: We conducted an exploratory cross-sectional study with a convenience sample from a local American Academy of Pediatrics chapter to administer a survey with 10 multiple-choice questions regarding the EI referral process, evaluation process, eligibility criteria and fee structure. Our outcome variable was a composite score of these 10 multiple-choice questions, Total Knowledge Score (TKS). Our predictor variables included physician characteristics (i.e., years of experience, percentage of patients seen with private insurance, receipt of EI training in the last 5 years) and practice characteristics (i.e., medical home status). RESULTS: Our sample consisted of a total of 194 pediatric residents/attendings. Multivariable regression demonstrated seeing ≥ 50% patients who were privately insured, increased experience, and receiving training in the last 5 years were associated with higher TKS. DISCUSSION: We were able to quantitatively evaluate physician's knowledge of EI and demonstrated that seeing a majority of privately insured patients, having more experience, and having received formal EI training in the last 5 years were associated with higher EI knowledge. This disproportionate distribution of EI knowledge has the potential to contribute to disparities in the management of DD. This may indicate that medical institutions, where physicians see a small percent of privately insured patients, need to hire more experienced physicians, and provide routine EI training.

Presumed Perinatal Ischemic Left Middle Cerebral Artery Stroke With Cerebral Palsy, Developmental Delay, and Epilepsy: A Case Report.

The perinatal period is a high risk for ischemic events to occur leading to lifelong morbidity. Various patterns of ischemic injury to the fetal and neonatal brain have been studied depending on gestational age as well as the degree of hypoxia/ischemia. We present a case of presumed perinatal ischemic left middle cerebral artery stroke diagnosed by magnetic resonance imaging (MRI) in a child with global developmental delay, cerebral palsy, and epilepsy. Interestingly, the typical features of middle cerebral artery stroke are often not present in perinatal strokes, and hence these are not imaged perinatally. Since studies and research into neuroplasticity and neuromodulation are current topics of interest and several research studies are being conducted, we wish to add this case to the available scientific literature.

A Scoping Review of Intervention Implementation for Self-Care Skills among Children with Developmental Delay.

Difficulties with self-care skills are frequently observed in children with developmental delays. Given the scarcity of robust evidence backing self-care interventions for this group, this scoping review is designed to aggregate existing literature on the implementation of such interventions. Therefore, this scoping review aims to collate literature on the nature of self-care intervention implementation to increase understanding of the current practice and inform future research directions. This scoping review endeavoured to explore the body of literature concerning the existence of self-care interventions and their implementation strategies in children who have developmental delays. Relevant studies were identified by searching through the following databases: Web of Science (W0S), Scopus, ASEAN Citation Index (ACI), CINAHL EBSCO and PubMed. Six types of interventions using various approaches were identified. Occupational therapists mainly manage intervention providers with multidisciplinary co-facilitator and parents' involvement. Whilst session information varied, some evidence suggests that at least 30 min per session, minimum once per week up to twice per week, ranging from 10 to 23 sessions, may be sufficient. Intervention plans should be tailored to each child's unique needs, taking into account the variety of available interventions. Collaboration among occupational therapists, parents, educators and health professionals in home programmes enhances self-care intervention outcomes. These results are set to inform future research and practice, paving the way for enhanced support and improved outcomes for children with developmental delays.

A novel STAG1 variant associated with congenital clubfoot and microphthalmia: A case report.

The cohesin protein complex plays a vital role in various cellular processes such as sister chromatid cohesion, chromosome condensation, DNA repair, and transcriptional regulation. It is constituted by SMC1, SMC3, RAD21, STAG1/STAG2 subunits, and several regulatory proteins. Pathogenic variants in these components cause cohesinopathies, with common clinical features including facial dysmorphism, delayed growth, developmental delay, and limb anomalies. Pathogenic variants in the STAG1 contribute to an emerging syndromic developmental disorder with only 21 reported cases in the literature. We describe a 3-year-old girl presenting with congenital bilateral clubfoot and unilateral microphthalmia-clinical manifestations not previously reported in the literature. Whole exome sequencing revealed a novel de novo nonsense variant (c.1183C>T, p.(Arg395*)) in the STAG1, expanding the clinical and molecular spectrum of STAG1-related cohesinopathy. This patient's unique phenotype highlights the clinical diversity within cohesinopathies, emphasizing their relevance in cases of developmental delay and dysmorphic features. Further studies, including genotype-phenotype correlation analyses and functional investigations, are essential for enhancing our understanding of STAG1-related cohesinopathy.

A Novel m.1636A > G Variant in Mitochondrial TV Gene Might Cause New Phenotype of Mitochondrial Disease in a 2-Year Old Chinese Boy.

Pathogenic variants of mitochondrial DNA (mtDNA) are associated with a large number of heterogeneous diseases involving multiple systems with which patients may present with a wide range of clinical phenotypes. Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that was performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis. In this study, we describe a 2-year-old Chinese boy with global developmental delay, Charcot-Marie-Tooth (CMT) disease, progressive myoclonic epilepsy, paroxysmal arrhythmia, and brain atrophy with elevated blood lactate levels. The clinical manifestations of the patient were improved after metabolic therapy, but the development regressed after infection. The molecular finding of whole-exome sequencing is unremarkable, but the mtDNA genome sequencing of the proband and his monther revealed a de novo novel heteroplasmic variant, m.1636A > G, located next to the highly conserved anticodon loop of tRNA Val (MT-TV) gene. Moreover, the higher levels of mutational load in urinary epithelial cells (19.05%) and oral mucosa cells (20.8%) were detected than that in blood (17.4%). Combined with the phenotypic and molecular genetics analysis of this family, this novel variation was currently considered to be a likely pathogenic variant. Our results added evidence that the de novo m.1636A > G variation in the highly conserved sequence of MT-TV appears to suggest a childhood-onset mitochondrial phenotype of a 2-year-old patient, thus broaden the genotypic interpretation of mitochondrial DNA-related disease.

Proximal 4p Deletion Syndrome in an Infant With Multiple Systemic Anomalies.

BACKGROUND: Contiguous gene deletion in the short arm of chromosome 4 is linked to various neurodevelopmental disorders. METHODS: In this study, we conducted peripheral blood chromosome G-banding karyotyping and whole-exome sequencing (WES) on a proband presenting with anal atresia, global developmental delay, lymphocytosis, and other multisystem anomalies. Additionally, chromosome G-banding karyotyping was also carried out on the proband's parents and brother. RESULTS: The 7-month-old proband was found to have a 26.738 Mb 4p15.33-p14 deletion as identified by chromosome G-banding karyotyping and WES. CONCLUSION: We identified a patient with proximal 4p deletion syndrome by karyotype and WES analysis, which might explain some of his phenotypes. Our research enhances clinicians' knowledge of this rare condition, and offers valuable genetic counseling to the affected family. Further research is necessary to identify the causative gene or critical region associated with proximal 4p deletion syndrome.

Exome sequence analysis identifies a homozygous, pathogenic, frameshift variant in the MAN2B1 gene underlying clinical variant of α-mannosidosis.

Background: α-mannosidosis (MAN) is a rare genetic condition that segregates in an autosomal recessive manner. Lack of lysosomal alpha-mannosidase is the underlying cause of the disease. Symptoms of the disease gradually worsen with the age. Newborns are usually asymptomatic, however, some cases are reported with either congenital ankle equinus or hydrocephalus during the first year. Primary symptoms are characterized by immune deficiency, hearing loss, skeletal abnormalities, progressive mental, motor and speech functions' impairment followed by facial asymmetry. Methods: We studied two Saudi families (A and B) with bilateral moderate hearing loss (family A) and clubfoot with glaucoma (family B). Clinical diagnosis was not reached based on phenotype of patients. Therefore, hypothesis-free whole exome sequencing (WES) was performed on DNA samples from affected individuals of both the families, followed by Sanger sequencing and segregation analysis to validate the segregation of the identified variant. Furthermore, 3D protein modelling was performed to determine the in silico effects of the identified variant on the protein structure and function. Results: Re-examination of clinical features revealed that the patients in family A have speech delay and hearing impairment along with craniostenosis, whereas the patients from family B have only clubfoot and glaucoma. WES identified a well known pathogenic homozygous frameshift variant (NM_000528.4: c.2402dupG; p.S802fs*129) in MAN2B1 in both the families. Sanger sequencing confirmed the segregation of the variant with the disease phenotype in both the families. 3D structural modeling of the MAN2B1 protein revealed significant changes in the tertiary structure of the mutant protein, which would affect enzyme function. This report presents a new case where partial and novel α-mannosidosis phenotypes are associated with a MAN2B1 gene pathogenic variant. Conclusion: Patients in both the families have manifested peculiar set of clinical symptoms associated with α-mannosidosis. Family A manifested partial clinical symptoms missing several characteristic features like intellectual disability, dysmorphic features, neurological and abdominal manifestations, whereas family B has no reported clinical symptoms related to α-mannosidosis except the novel symptoms including club foot and glaucoma which has never been reported earlier The current findings support the evidence that biallelic variants of MAN2B1 are associated with new clinical variants of α-mannosidosis.

Design and validation of AQUA CHILD-Pre-aquatic questionnaire assessing child development.

PURPOSE: We developed a proxy questionnaire for parents of children with Developmental Delay (DD) to provide comprehensive information for instructors about the child's functioning before participating in aquatic activities. This dedicated information will enable a high-quality treatment plan to promote the child's functioning in everyday life. METHODS: Based on the International Classification of Functioning, Disability, and Health (ICF) Coreset development and linking rules method, a set of questions was constructed in a preliminary process. A draft version was sent to instructors and parents in Israel. Seventy-five questionnaires from instructors and 25 from parents returned to the statistical analysis procedure. Reliability and face validity were analyzed by experts. RESULTS AND CONCLUSIONS: The questionnaire showed high validity and reliability for its purposes and allowed self-completion by the parents.

Relationship between fundamental motor skills and physical fitness in children with global developmental delay.

Importance: Understanding the significance of motor skills in promoting physical fitness (PF) can offer valuable insights for devising comprehensive intervention and clinical rehabilitation programs for children with global developmental delay (GDD). However, it remains unclear whether fundamental motor skills (FMS) can improve the PF of children with GDD. Objective: To investigate the correlation between FMS and PF in children with GDD. Methods: A total of 180 children with GDD and 180 typically developing (TD) children aged 3-5 years were selected. All participants completed the Gesell Developmental Schedule, FMS, and PF tests at Beijing Children's Hospital between September 2022 and August 2023. Partial correlation and regression analyses were performed to examine the relationship between FMS and PF. Results: Children with GDD had significantly lower FMS and PF scores compared to TD children (P < 0.05). No significant differences were found between males and females with GDD in FMS and PF score (P > 0.05). A more severe developmental delay was associated with lower FMS and PF scores. The correlation coefficients between individual FMS items and individual PF items, as well as the total PF score, ranged from 0.20 to 0.56. Regression analysis indicated that manual dexterity (ß = 0.241, P = 0.029) and body balance (ß = 0.399, P = 0.001) significantly predicted the total PF score. Interpretation: In children with GDD, both FMS and PF are underdeveloped. Focusing on motor skills development is vital for promoting their PF.