Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABAAR) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671T>C (p.F224S) was discovered in the GABRB2 gene, which encodes the β2 subunit of GABAAR. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABAAR channel function, we conducted transient expression experiments using GABAAR subunits in HEK293T cells. The GABAARs containing mutant β2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABAAR containing the β2 (F224S) subunit was significantly smaller compared to the wild type GABAAR. We propose that GABRB2 variant F224S is pathogenic and GABAARs containing this β2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.

Background: The SMARCB1 gene encodes a subunit of the BRG1-Associated Factor (BAF) complex, and mutations in this gene have been linked to Coffin-Siris Syndrome (CSS) type 3. CSS is characterized by a range of developmental disabilities, facial dysmorphic features, and feeding difficulties. There\'s been noted genotype-phenotype correlation in CSS, with cases involving SMARCB1 mutations often exhibiting more severe language impairment and intellectual disability. Method: We conducted a review of reported CSS type 3 cases and presented the first instance of CSS associated with a SMARCB1 variant wherein the patient exhibited normal intelligence and only mild selective neuropsychological deficits. The patient underwent evaluation for feeding challenges, growth delay, and dysmorphic features during their second year of life. Subsequently, CSS diagnosis was confirmed due to a de novo heterozygous c.568C > T (p.Arg190Trp) variant in the SMARCB1 gene. Due to learning difficulties, the patient underwent a comprehensive neuropsychological assessment, which was related to the retrospective reconstruction of her medical and developmental history. Results: The patient demonstrated normal intelligence and adaptive functioning, with specific deficits in arithmetic and selective difficulties in verbal learning and long-term memory. Feeding difficulties and language delay observed in early childhood showed significant improvement over time. Discussion: We discuss this case in relation to previously reported CSS type 3 cases, emphasizing neuropsychological aspects. It\'s evident that neuropsychological features of CSS can vary among affected individuals, highlighting the importance of personalized support and interventions tailored to specific cognitive and emotional needs by healthcare professionals. Our case suggests avenues for future research to identify specific modifiers of phenotypic expression to explain variability in intellect among patients and pinpoint potential targets for gene therapy.

UNASSIGNED: Developmental Delay (DD) is highly common in American Indian and Alaska Native (AI/AN; Indigenous) toddlers and leads to high numbers of AI/AN children who eventually need special education services. AI/AN children are 2.89 times more likely to receive special education compared to other children in the U.S., yet developmental disorders are more frequently under diagnosed and untreated in AI/AN infants and toddlers. DD, which can be identified as early as toddlerhood, can lead to negative impacts on developmental trajectories, school readiness, and long-term health. Signs of DD can be identified early with proper developmental screening and remediated with high quality early intervention that includes effective parent training. There are many evidence-based language facilitation interventions often used in Early Intervention programs. However, in communities in rural parts of the Navajo Nation where there are limited services and resources, infants and toddlers with early signs of DD are often missed and do not get the culturally responsive support and evidence-based intervention they deserve.
UNASSIGNED: The community-based +Language is Medicine (+LiM) study team partnered with tribal home visitors, community members, and a Diné linguist/elder using a collaborative virtual workgroup approach in 2021 and 2022 to present the +LiM pilot study aims and to discuss strategies for enhancing a language intervention for toddlers experiencing DD in their tribal community. This paper will detail the stages of community engagement, intervention enhancement and preparation for field testing of the +LiM intervention to address elevated rates of DD in toddlers in the Northern Agency of the Navajo Nation.
UNASSIGNED: Two major outcomes from this collaborative workgroup included: (1) a team-initiated redefining of language nutrition to align with Indigenous values that center cultural connectedness and native language use and (2) a five-lesson caregiver-facilitated curriculum titled +Language is Medicine which includes caregiver lessons on language nutrition, language facilitation, shared book reading, pretend play, and incorporation of native language into home routines. These two workgroup outcomes were leveraged to develop a pilot pre-/post-intervention study to test the effectiveness of the +LiM intervention with caregiver-toddler dyads living on the Navajo Nation.
UNASSIGNED: Delivering tailored child interventions through tribal home visiting are cost-effective and innovative methods for reaching reservation-based families who benefit from culturally responsive parent coaching and instruction. The +LiM team has applied a precision tribal home visiting approach to enhance methods of early intervention for children with DD. Our enhancement process was grounded in Indigenous community-based participatory research that centered culture and language.

This case report presents the physiotherapy intervention of a one-year-old male child diagnosed with non-communicating hydrocephalus primary to developmental delay. Hydrocephalus is marked by an accumulation of cerebrospinal fluid and often leads to significant developmental delays and neurological impairments in affected infants. The physiotherapy intervention aimed to achieve head and trunk control, improve sensory awareness, and enhance overall body coordination and balance. Various techniques, including neurodevelopmental techniques, sensory stimulation, hippotherapy, and sensory integration therapy, were utilized to target specific developmental milestones and functional abilities. Outcome measures, including the Gross Motor Function Measure, Infant Neurological International Battery, Hammersmith Infant Neurological Examination, and New Ballard Score, were used to assess the patient\'s progress pre- and post-intervention. Significant improvements were observed across all outcome measures following four months of physiotherapy rehabilitation. The patient demonstrated substantial gains in gross motor function, neurological examination scores, and overall developmental milestones. These findings underscore the effectiveness of physiotherapy rehabilitation in addressing developmental delays associated with non-communicating hydrocephalus. This case underscores the significance of early physiotherapy intervention, which plays a vital role in enhancing outcomes and improving the quality of life for affected children.

Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.

UNASSIGNED: The role of caregivers in grooming the neuro-developmental outcome of high-risk newborns and developmental challenges in children needs to be explored.
UNASSIGNED: To find the knowledge and perception among parents regarding the neuro-developmental outcome of high-risk newborns, methods adopted to address these problems, and to identify areas on which awareness generation needs to focus.
UNASSIGNED: A questionnaire-based awareness survey was conducted to understand the knowledge, attitude, and practices of families of children with developmental challenges.
UNASSIGNED: The study revealed that more than 70 percent of families lack information about child development, developmental challenges, and means to deal with them. They are unaware of the available health care services and other resources. One in three families has misconceptions on developmental disabilities; consider them as curse or jinx and consequently neglected. Female children with developmental problems are further ostracized due to gender inequity in families. About 10 percent of families have shown great openness toward acquiring new skills and knowledge for handling their children with developmental delays.
UNASSIGNED: This study is based on the précis research findings of our grass-root level fieldwork conducted in remote rural Bengal areas. The observation will be of interest and learning materials for general primary care practitioners, family physicians, and stakeholders to initiate appropriate intervention strategies for properly rehabilitating children with developmental delay at grass-root levels of primary health care.

While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution. Optical genome mapping (OGM) enabled a more precise depiction of the breakpoint regions involved in the reciprocal translocation. While the breakpoint region on chromosome 6 did not encompass any known gene, OGM revealed the disruption of the RASGRF2 (Ras protein-specific guanine nucleotide releasing factor 2) gene on chromosome 5, implicating RASGRF2 as a potential candidate gene contributing to the observed developmental delay in the patient. Variations in RASGRF2 have so far not been reported in developmental delay, but research on the RASGRF2 gene underscores its significance in various aspects of neurodevelopment, including synaptic plasticity, signaling pathways, and behavioral responses. This study highlights the utility of OGM in identifying breakpoint regions, providing possible insights into the understanding of neurodevelopmental disorders. It also helps affected individuals in gaining more knowledge about potential causes of their conditions.

UNASSIGNED: X-linked adrenoleukodystrophy (ALD) is a rare genetic disorder caused by a pathogenic variant of the ABCD1 gene, leading to impaired peroxisomal function and the accumulation of very long-chain fatty acids (VLCFAs). ALD presents a wide range of neurological and adrenal symptoms, ranging from childhood cerebral adrenoleukodystrophy to adrenomyeloneuropathy and adrenal insufficiency. Newborn screening (NBS) for ALD is available in some regions but remains lacking in others, such as India.
UNASSIGNED: We present a case of a 10-year-old boy with ALD who presented with seizures, progressive weakness, visual impairment, and adrenal insufficiency. Despite symptomatic management and dietary adjustments, the disease progressed rapidly, leading to respiratory failure and eventual demise. The diagnosis was confirmed through molecular analysis and elevated VLCFA levels. Neuroimaging revealed characteristic white matter changes consistent with ALD.
UNASSIGNED: ALD is a devastating disease with no cure, emphasizing the importance of early detection through newborn screening and genetic testing. Management strategies include adrenal hormone therapy, gene therapy, and allogenic stem cell transplantation, as well as investigational treatments such as VLCFA normalization. Our case advocates the need for worldwide NBS and pediatric neurologic follow-up to enable early intervention and improve patient outcomes. Additionally, the association between ALD, recurrent febrile seizures, and unexplained developmental delay warrants further investigation to better understand disease progression and potential therapeutic targets.

OBJECTIVE: Accurate assessment of cognitive development of young children is a vital component of developmental evaluations. Direct assessment of developmental skills is not always feasible, but there is limited information on the agreement between direct assessment and caregiver-reported cognitive skills. There is limited information regarding the accuracy of the parent-reported Developmental Profile 4 (DP-4) in comparison to the widely-used developmental measure, the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4). The purpose of the current study was to evaluate whether a standardized parent interview can effectively identify children at risk for cognitive developmental delays.
METHODS: We compared the agreement between the Bayley-4 Cognitive and the Developmental Profile 4 (DP-4) in young children being evaluated in-person for early developmental delays. 182 children (134 with an autism diagnosis), ages 6-42 months, completed both assessments.
RESULTS: Results showed that Bayley-4 Cognitive scores had a moderately strong correlation with DP4-Cognitive scores (r = 0.70, p < 0.001). A cutoff of 70 or 69 on the DP-4 Cognitive was determined as ideal for identifying developmental delay based on diagnosis of global developmental delay or the Bayley-4 Cognitive.
CONCLUSIONS: Our analyses revealed good agreement between DP-4 and Bayley-4 Cognitive scores, even after controlling for confounding variables such as degree of ASD characteristics, age, and sex. These results suggest that caregiver-report measures can be a valid and useful tool in the assessment of young children, particularly when direct developmental assessment is not feasible.

UNASSIGNED: Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome (OMIM #616266) is an autosomal dominant hereditary disease that can lead to the congenital contracture of the limbs and face, hypotonia, and developmental delay. In addition, it may result in growth retardation and present various clinical symptoms, such as brain atrophy, a small pituitary gland, musculoskeletal abnormalities, abnormal breathing, abdominal hernia, and abnormal facial features. Herein, we describe a novel de novo missense genetic variant in the sodium leak channel, non-selective (NALCN) gene that is associated with CLIFAHDD syndrome.
UNASSIGNED: This study describes a patient with varus deformities in both feet, deviation of the ulnar side of the fingers, and severe hypotonia. This patient was subsequently confirmed to have CLIFAHDD syndrome through genetic testing, which also revealed a novel missense de novo genetic variant in the NALCN gene (c.3553G > A, p.Ala1185Thr).
UNASSIGNED: Our findings further enrich the known variant spectrum of the NALCN gene and may expand the range of clinical options for treating NALCN-related disorders.