Cause Of Developmental Delay Research Articles

Behavioural and neurodevelopmental characteristics of SYNGAP1

BackgroundSYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID.MethodsParticipants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4–16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires.ResultsOur results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p = < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p = .35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p = .49) or oppositional defiant disorder (7.7%;0%; p = .15).ConclusionFor the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management.

Consider CUX1 variants in children with a variation of sex development: a case report and review of the literature

BackgroundThe Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented.Case presentationThe proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4–10 of the CUX1 gene.ConclusionsOur review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development.

Quality of life in Down syndrome in Brazil: a cross-sectional study.

Down syndrome is the most commonly genetic cause of developmental delay and intellectual disability, affecting 1:700 live births. It is associated with heart disease and recurrent infections, among other complications that greatly impair the patient's quality of life. To evaluate the major factors associated with quality of life in a cohort of patients with Down syndrome. We assessed 1,187 patients with Down syndrome, older than 4 years old, with an adaptation of the Personal Outcomes Scale validated for Portuguese language, interviewing patients, parents, and caregivers. A bad quality of life was reported in 56.4% of the sample. The main factors associated with better quality of life were female sex, first medical visit before 4 months old, higher parental education, a professionally active mother, and prenatal care. The main factors associated with worse quality of life were family history of alcohol abuse and psychiatric disorders and comorbidity with autism and epilepsy. Clinical comorbidities such as autism and epilepsy carry a heavy burden among patients with Down syndrome, while factors related to family support, such as employment status and educational background of the parents, enhance quality of life. The factors associated with quality of life among patients with Down syndrome should be adequately evaluated in medical consultation and targeted in public health policies.

The effect of intensive rehabilitation treatment on sleep disorder in children with motor delays

BackgroundAlthough the importance of sleep problems has been increasingly emphasized due to the effects on children's development and children's and families' daytime behaviors, physical health, and quality of life, they have been overlooked in clinical practice. However, there have been few studies on the effects of rehabilitation on sleep problems. Therefore, in this study, we investigated the effects of an intensive rehabilitation program on sleep problems in children with developmental delays (DD).MethodsWe included 36 children with DD (30 outpatients, 6 inpatients) and their caregivers who completed all items on the Sleep Disturbance Scale for Children. Of the children with DD, 19 (59.3%) had cerebral palsy (CP) and 13 (40.7%) had DD of non-CP origins, of which 6 (18.8%) had prematurity, 4 (12.5%) had genetic causes, and 3 (9.4%) had an unknown origin. Changes in sleep problems after the intensive rehabilitation program were evaluated using a paired or unpaired t-test, depending on the distribution of the continuous variables.ResultsAfter the intensive rehabilitation program, in 36 children with DD, there was a significant improvement in the difficulty in initiating and maintaining sleep (DIMS) sub-score (p < 0.05). However, there was no significant improvement in the total score or other sub-scores, such as those for sleep breathing disorders (SBD), disorders of arousal (DA), sleep–wake transition disorders (SWTD), disorders of excessive somnolence (DOES), and sleep hyperhidrosis (SH). In the subgroup analysis according to the cause of DD, children with CP had a significant improvement in DIMS and DOES sub-scores (p < 0.05).ConclusionThe intensive rehabilitation program, consisting of more than two sessions per day, effectively alleviated sleep problems in children with DD, especially in those with CP. Among the sleep problems, the intensive rehabilitative program was most effective at improving the DIMS. However, further prospective studies with a larger number of patients with DD and a more standardized protocol are necessary to generalize this effect.

Trisomy 21 Testing in Second Trimester: Reliability Comparison of Triple and Quadruple Testing in Pakistan

Objectives: Down syndrome is a disorder that affects one in every 700 babies born, and it is one of the most frequent causes of developmental delay (DS). In Pakistan, prenatal screening for Down syndrome is not being practised according to any approved protocol. The biochemical screening that takes place during the second trimester is still carried out using the triple test. Although the quadruple test has a better sensitivity and specificity than other diagnostic methods, its usage in routine medical settings is not advised. The purpose of this study was to explore the second trimester screening for trisomy 21 (quadruple test with genetic sonogram) in order to determine its sensitivity and accuracy in comparison to biochemical testing. Place of Study: District Headquarters Hospital, Gujranwala Duration of Study: January 2021 to December 2021 Methods: This retrospective observational study was carried out in a Fetal Medicine Centre with the purpose of analysing the odds of being affected with Down syndrome, given a positive risk (OAPR) upon screening in the quadruple test; triple test and quadruple test plus a genetic sonogram for highrisk singleton pregnancies (in view of advanced maternal age; an anomaly scan showing some abnormality, etc.). Given the presence of a positive risk factor, the goal of this study was to ascertain the likelihood of having a child impacted by Down syndrome. Practical Implication: To explore the second trimester screening for trisomy 21 (quadruple test with genetic sonogram) in order to determine its sensitivity and accuracy in comparison to biochemical testing. Results: The discovery of trisomies was made after an investigation into 3,042 highrisk pregnancies with a singleton baby. 327 pregnant women who have received positive findings from a triple test, quadruple test, or quadruple test in addition to a genetic ultrasonography opt to have an amniocentesis. This decision was made after the ladies learned that their unborn child may have a genetic disorder. It was discovered that 20 of the developing babies were affected by Down syndrome. The OAPR for the quadruple test was demonstrated to be significantly higher when compared to the OAPR for the triple test (1:29.1 as compared to 1:39.2). It was found that the combination of the triple test and the genetic sonogram had the highest OAPR of 1:7. Conclusions: The triple test combined with a genetic sonogram is the most effective tool for screening for trisomy 21, and it has the potential to cut down on the number of unnecessary amniocentesis operations carried out in high-risk populations. Keywords: Down syndrome, genetic, quadruples test, second trimester screening, triple test,ultrasound

Expanding the phenotypic spectrum of Chromosome 16p13.11 microduplication: A multicentric analysis of 206 patients

IntroductionRecurrent chromosome 16p13.11 microduplication has been characterised in the literature as a cause of developmental delay, learning difficulties and behavioural abnormalities. It is a neurosusceptibility locus and has incomplete penetrance and variable expression. Other clinical features, such as cardiac abnormalities have also been reported. The duplicated region contains the MYH11 gene, which encodes the protein myosin-11 and is a component of the myosin heavy chain in smooth muscle. Recent literature has suggested 16p13.11 microduplication as one of the possible risk factors for thoracic aortic aneurysms and dissection (TAAD). Therefore, we studied the detailed phenotype of cases of chromosome 16p13.11 microduplication from seven centres in the United Kingdom (UK) to expand the phenotype, focusing on the cardiac abnormalities. MethodsAll individuals with a chromosome 16p13.11 microduplication seen in Clinical Genetics prior to June 2017 in 6 centres (prior to 2018 in the seventh centre) were identified through the regional genetics laboratory databases. A Microsoft Excel® proforma was created and clinical data was collected retrospectively from clinical genetics databases from the seven genetics services in the UK. The data was collated and analysed collectively. ResultsThe majority of the individuals presented with (72%) developmental delay and (62%) behavioural abnormalities, in keeping with the published literature. 27% had some dysmorphic features, 14% had visual impairment and 8% had congenital cardiac abnormalities. Echocardiograms were performed in 50% of patients, and only 3.8% patients had aortic dilatation and no one had aortic dissection. 9.7% of patients were found to have a second genetic/chromosomal diagnosis, especially where there were additional phenotypic features. Conclusion16p13.11 microduplication is a neurosusceptibility locus and is associated with variable expression. It may be helpful to refer children with 16p13.11 microduplication for a cardiac review for congenital cardiac abnormalities and also for ophthalmological assessment. Further prospective studies with cardiac assessments are recommended in this cohort of patients to determine whether ongoing aortic surveillance is indicated. Guidelines about the frequency of surveillance are indicated, especially in individuals with normal cardiac findings. We also highlight the importance of considering a second diagnosis if the phenotype is inconsistent with that reported.

Метаболитная терапия в реабилитации детей с последствиями перинатальной гипоксии

Perinatal hypoxia is a common cause of developmental delays, disorders of the nervous and cardiovascular systems, and immune disorders. Early comprehensive rehabilitation of children with hypoxic lesions to the central nervous system can alleviate pathological manifestations and normalize the process of development. This review discusses different aspects of metabolic therapy for the rehabilitation of such children and describes the results of some studies assessing the efficacy of Glycine and Biotredin in children with various disorders. The combination of these two drugs proved to be effective in premature infants of various gestational age through normalizing their neurological status and improving weight and growth parameters. The article also describes the principles of metabolic correction of speech disorders in the critical preschool period, as well the mechanisms underlying the effect of the drugs on the cellular metabolism of the nervous system. Key words: hypoxia, metabolic therapy, preterm birth, glycine, speech disorders

Brainstem auditory pathway maturation in term neonates with congenital cytomegalovirus infection: a cohort study.

Congenital cytomegalovirus infection (cCMVi) is a leading cause of sensorineural hearing loss (SNHL) and developmental delay. Brainstem auditory evoked potentials (BAEPs) recording allows assessment of central auditory pathway maturation in neonates. We aimed to characterize the effect of cCMVi on the maturation of the brainstem auditory pathway in term neonates. We retrospectively reviewed medical records of neonates born with cCMVi in 2010-2018 and characterized their auditory pathway maturation using brainstem auditory-evoked potentials (BAEPs). We compared inter-peak latency differences (IPLDs) of the main BAEP components (I-V, I-III, and III-V) in terms of cCMVi patients and healthy controls and described their changes in cCMVi patients throughout the first year of life. Of 101 cCMVi patients, 57 (56.4%) were considered symptomatic, 6 (5.9%) were small for gestational age, 6 (5.9%) had microcephaly, 4 (4%) had thrombocytopenia, 5 (6.6%) had hepatitis, 2 (2.1%) had retinitis, 47 (49.5%) had typical abnormalities on head ultrasound, 9 (8.9%)developed SNHL, and 34 (59.6%) received antiviral therapy. No significant difference was found between IPLDs of full-term cCMVi patients compared to controls throughout the entire auditory pathway (I-III, III-V, and I-V IPLDs), for both ears (p > 0.05). On serial BAEP examinations, cCMVi patients presented decreased IPLDs throughout the first year of life (p < 0.05 ofcompared 1st, 2nd, and 3rd BAEPs in both ears). Conclusions: Intrauterine cytomegalovirus infection does not affect the auditory brainstem maturation process in term neonates. Our findings support previous studies noting the normal neurodevelopmental outcome of asymptomatic cCMVi patients, suggesting antiviral treatment is not warranted in these cases. What is Known: •cCMVi is a leading cause of developmental delay and hearing loss. Treatment is recommended for patients with symptomatic diseases who are at significant risk of long-term sequelae. • It is unknown whether cCMVi affects the central nervous system maturation process. What is New: •We performed a neurophysiological evaluation of brainstem conduction by recording the BAEPs. We found that cCMVi has no significant impact on central conduction times along the auditory pathways in the brainstem at birth nor changes the neuronal maturation process during the first year of life. •Our findings suggest that cCMVi does not universally affect central nervous system maturation, supporting a highly selective approach when considering the benefits of antiviral therapy.

Brain Magnetic Resonance Imaging Findings in Patients with Developmental Delay in Addis Ababa, Ethiopia.

Developmental delay is a major health problem throughout the world causing significant individual disability. Even though physical examination and patient history are the most important and basic evaluations of patients with developmental delay, additional investigations are usually required in supporting or reaching a diagnosis among which is neuroimaging. This study aims to assess brain Magnetic resonance imaging (MRI) patterns in patients presented with developmental delay. A retrospective analysis of 164 patients who had undergone brain Magnetic Resonance Imaging (MRI) evaluation for the developmental delay was done. The study was conducted between March to November 2021 G.C at Tikur Anbessa Specialized Hospital (TASH). The patients' clinical history and magnetic resonance imaging reports were reviewed from their medical records. All patients with developmental delay who had brain MRI evaluation at TASH and at one private diagnostic center in Addis Ababa were included in the study. A total of 164 patients were included in this study of which 95(57.9%) were male and 69(42.1%) female patients were seen. A total of 120 patients (73.2%) showed abnormal brain MRI studies. Previous neurovascular insults were the most common abnormalities seen in 75(45.7%) patients followed by imaging findings of congenital and developmental abnormalities seen in 20(12.2%) patients. Brain MRI is an important input in the evaluation of patients with developmental delay. It can give evidence for the cause of developmental delay, especially in the diagnosis of perinatal/hypoxic-ischemic insults, and congenital and developmental malformations.

Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder

Alterations in the TAOK1 gene have recently emerged as the cause of developmental delay with or without intellectual impairment or behavioral abnormalities (MIM # 619575). The 32 cases currently described in the literature have predominantly de novo alterations in TAOK1 and a wide spectrum of neurodevelopmental abnormalities. Here, we report four patients with novel pathogenic TAOK1 variants identified by research genome sequencing, clinical exome sequencing, and international matchmaking. The overlapping clinical features of our patients are consistent with the emerging core phenotype of TAOK1-associated syndrome: facial dysmorphism, feeding difficulties, global developmental delay, joint laxity, and hypotonia. However, behavioral abnormalities and gastrointestinal issues are more common in our cohort than previously reported. Two patients have de novo TAOK1 variants (one missense, one splice site) consistent with most known alterations in this gene. However, we also report the first sibling pair who both inherited a TAOK1 frameshift variant from a mildly affected mother. Our findings suggest that incomplete penetrance and variable expressivity are relatively common in TAOK1-associated syndrome, which holds important implications for clinical genetic testing.

Guanidinoacetate Methyltransferase Deficiency: A Treatable Cause of Developmental Delay Diagnosed by Magnetic Resonance Spectroscopy.

Guanidinoacetate Methyltransferase Deficiency: A Treatable Cause of Developmental Delay Diagnosed by Magnetic Resonance Spectroscopy.

Coat Color-Facilitated Efficient Generation and Analysis of a Mouse Model of Down Syndrome Triplicated for All Human Chromosome 21 Orthologous Regions.

Down syndrome (DS) is one of the most complex genetic disorders in humans and a leading genetic cause of developmental delays and intellectual disabilities. The mouse remains an essential model organism in DS research because human chromosome 21 (Hsa21) is orthologously conserved with three regions in the mouse genome. Recent studies have revealed complex interactions among different triplicated genomic regions and Hsa21 gene orthologs that underlie major DS phenotypes. Because we do not know conclusively which triplicated genes are indispensable in such interactions for a specific phenotype, it is desirable that all evolutionarily conserved Hsa21 gene orthologs are triplicated in a complete model. For this reason, the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ mouse is the most complete model of DS to reflect gene dosage effects because it is the only mutant triplicated for all Hsa21 orthologous regions. Recently, several groups have expressed concerns that efforts needed to generate the triple compound model would be so overwhelming that it may be impractical to take advantage of its unique strength. To alleviate these concerns, we developed a strategy to drastically improve the efficiency of generating the triple compound model with the aid of a targeted coat color, and the results confirmed that the mutant mice generated via this approach exhibited cognitive deficits.

Variability in Neuropsychological Phenotypes in Patients with 22Q11.2 Deletion Syndrome: Case Series

ABSTRACT Children with 22q11.2 deletion syndrome (22q11.2DS) have diverse neurodevelopmental and mental health profiles involving cognitive impairments and behavioral symptomatology that evolve over the lifespan. 22q11.2DS is the second-most common cause of developmental delay in children. Frequent physical manifestations include impact to skeletal, cardiac, immunological, respiratory, renal, auditory, and gastrointestinal systems. Neuropsychological impact ranges from early developmental delay to learning disabilities to more global intellectual disability. This population is also at higher risk for psychiatric conditions including Attention Deficit Hyperactivity Disorder, Anxiety Disorder, Bipolar Disorder and early Schizophrenia. The present case series relays cross-sectional findings from a 3-year -old Black/Non-Hispanic male, a 5-year -old White/Hispanic/Latina female, and an 8-year -old White/Hispanic/Latina female, diagnosed with 22q11.2DS via whole exome sequencing. Based on the referral question, various components of intellectual, attention/executive, memory, language, visual-motor/fine-motor, academic, adaptive, and emotional/behavioral functioning were examined across cases. Results revealed cognitive scores that ranged from exceptionally low to below average, consistent with the variability in cognitive functioning documented in the literature. Their neurodevelopmental and mental health symptoms appear to be consistent with time points reported in the literature including Autism Spectrum Disorder in the youngest patient and elevated levels of anxiety and internalizing behaviors in the oldest patient, placing that patient at a greater risk for further psychiatric difficulties. Therefore, longitudinal documentation of linkages between clinical neuropsychological presentations and specific genetic characteristics in 22q11.2DS is warranted to identify consistent developmental differences across the lifespan.

Precision Therapy for Epilepsy Related to Brain Malformations.

Malformations of cortical development (MCDs) represent a range of neurodevelopmental disorders that are collectively common causes of developmental delay and epilepsy, especially refractory childhood epilepsy. Initial treatment with antiseizure medications is empiric, and consideration of surgery is the standard of care for eligible patients with medically refractory epilepsy. In the past decade, advances in next generation sequencing technologies have accelerated progress in understanding the genetic etiologies of MCDs, and precision therapies for focal MCDs are emerging. Notably, mutations that lead to abnormal activation of the mammalian target of rapamycin (mTOR) pathway, which provides critical control of cell growth and proliferation, have emerged as a common cause of malformations. These include tuberous sclerosis complex (TSC), hemimegalencephaly (HME), and some types of focal cortical dysplasia (FCD). TSC currently represents the best example for the pathway from gene discovery to relatively safe and efficacious targeted therapy for epilepsy related to MCDs. Based on extensive pre-clinical and clinical data, the mTOR inhibitor everolimus is currently approved for the treatment of focal refractory seizures in patients with TSC. Although clinical studies are just emerging for FCD and HME, we believe the next decade will bring significant advancements in precision therapies for epilepsy related to these and other MCDs.

Estimate of the contemporary live-birth prevalence of recurrent 22q11.2 deletions: a cross-sectional analysis from population-based newborn screening.

Background:Although pathogenic 22q11.2 deletions are an important cause of developmental delays and lifelong disease burden, their variable and complex clinical expression contributes to under-recognition, delayed molecular diagnosis and uncertainty about prevalence. We sought to estimate the contemporary live-birth prevalence of typical 22q11.2 deletions using a population-based newborn screening sample and to examine data available for associated clinical features.Methods:Using DNA available from an unbiased sample of about 12% of all dried blood spots collected for newborn screening in Ontario between January 2017 and September 2018, we prospectively screened for 22q11.2 deletions using multiplex quantitative polymerase chain reaction assays and conducted independent confirmatory studies. We used cross-sectional analyses to compare available clinical and T-cell receptor excision circle (TREC, used in newborn screening for severe combined immunodeficiency) data between samples with and without 22q11.2 deletions.Results:The estimated minimum prevalence of 22q11.2 deletions was 1 in 2148 (4.7 per 10 000) live births (95% confidence interval [CI] 2.5 to 7.8 per 10 000), based on a total of 30 074 samples screened, with 14 having confirmed 22q11.2 deletions. Of term singletons, samples with 22q11.2 deletions had significantly younger median maternal age (25.5 v. 32.0 yr, difference −6.5 yr, 95% CI −7 to −2 yr), a greater proportion with small birth weight for gestational age (odds ratio 7.00, 95% CI 2.36 to 23.18) and lower median TREC levels (108.9 v. 602.5 copies/3 μL, p < 0.001).Interpretation:These results indicate that the 22q11.2 deletion syndrome is one of the most common of rare genetic conditions and may be associated with relatively younger maternal ages and with prenatal growth abnormalities. The findings support the public health importance of early — prenatal and neonatal — diagnosis that would enable prompt screening for and management of well-known actionable features associated with 22q11.2 deletions.

A homozygous nonsense mutation in DCBLD2 is a candidate cause of developmental delay, dysmorphic features and restrictive cardiomyopathy

DCBLD2 encodes discodin, CUB and LCCL domain-containing protein 2, a type-I transmembrane receptor that is involved in intracellular receptor signalling pathways and the regulation of cell growth. In this report, we describe a 5-year-old female who presented severe clinical features, including restrictive cardiomyopathy, developmental delay, spasticity and dysmorphic features. Trio-whole-exome sequencing and segregation analysis were performed to identify the genetic cause of the disease within the family. A novel homozygous nonsense variant in the DCBLD2 gene (c.80G > A, p.W27*) was identified as the most likely cause of the patient’s phenotype. This nonsense variant falls in the extracellular N-terminus of DCBLD2 and thus might affect proper protein function of the transmembrane receptor. A number of in vitro investigations were performed on the proband’s skin fibroblasts compared to normal fibroblasts, which allowed a comprehensive assessment resulting in the functional characterization of the identified DCBLD2 nonsense variant in different cellular processes. Our data propose a significant association between the identified variant and the observed reduction in cell proliferation, cell cycle progression, intracellular ROS, and Ca2 + levels, which would likely explain the phenotypic presentation of the patient as associated with lethal restrictive cardiomyopathy.

CK syndrome: a rare cause of developmental delay in a young boy.

CK syndrome is a rare disorder caused by mutation in the NSDHL (NAD(P) dependent steroid dehydrogenase-like) gene at the Xq28 locus. It has expanded the spectrum of disorders associated with X-linked mental retardation and defects in sterol metabolism. There are only a few reports defining the phenotypic spectrum of this rare disorder. We describe a new patient from the Indian subcontinent who presented with dysmorphism, global developmental delay and epilepsy. We also add left ventricular concentric hypertrophy and sensory neuropathy, which have not been reported previously. Our report suggests that CK syndrome may be unrecognized due to limited clinical knowledge and restricted availability of genetic testing. The expansion of the phenotype may also lead to a better understanding of biochemical anomalies and management approaches.

Downregulated GPR30 expression in the epileptogenic foci of female patients with focal cortical dysplasia type IIb and tuberous sclerosis complex is correlated with 18 F-FDG PET-CT values.

Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are typical causes of developmental delay and refractory epilepsy. G‐protein‐coupled receptor 30 (GPR30) is a specific estrogen receptor that is critical in neurodevelopment, neuroinflammation, and neuronal excitability, suggesting that it plays a potential role in the epilepsy of patients with FCDIIb and TSC. Therefore, we investigated the role of GPR30 in patients with FCDIIb and TSC. We found that the expression of GPR30 and its downstream protein kinase A (PKA) pathway were decreased and negatively correlated with seizure frequency in female patients with FCDIIb and TSC, but not in male patients. GPR30 was widely distributed in neurons, astrocytes, and microglia, and its downregulation was especially notable in microglia. The GPR30 agonist G‐1 increased the expression of PKA and p‐PKA in cultured cortical neurons, and the GPR30 antagonist G‐15 exhibited the opposite effects of G‐1. The NF‐κB signaling pathway was also activated in the specimens of female patients with FCDIIb and TSC, and was regulated by G‐1 and G‐15 in cultured cortical neurons. We also found that GPR30 regulated cortical neuronal excitability by altering the frequency of spontaneous excitatory postsynaptic currents and the expression of NR2A/B. Further, the relationship between GPR30 and glycometabolism was evaluated by analyzing the correlations between GPR30 and 18F‐FDG PET‐CT values (standardized uptake values, SUVs). Positive correlations between GPR30 and SUVs were found in female patients, but not in male patients. Intriguingly, GPR30 expression and SUVs were significantly decreased in the epileptogenic tubers of female TSC patients, and ROC curves indicated that SUVs could predict the localization of epileptogenic tubers. Taken together, our results suggest a potential protective effect of GPR30 in the epileptogenesis of female patients with FCDIIb and TSC.

Genetic developmental disability diagnosed in adulthood: a case report

BackgroundDevelopmental disabilities (DD) are an umbrella term for conditions associated with functional impairments in physical, learning, language, or behavior areas. Intellectual disability (ID) is a type of developmental disability that results in delays in cognitive or intellectual functioning, such as reasoning, learning, and problem-solving, and adaptive behaviors including social and practical life skills. DD can be due to a variety of factors, ranging from environmental exposures to genetic mutations, and studies suggest that up to 40% of DDs may be caused by genetic issues.Case presentationIn this case study, we present an 18-year-old internationally adopted female Chinese American patient with a known history of developmental delay, intellectual disability, strabismus, and a congenital heart defect who had not been tested for genetic causes of her delay prior to presentation. When evaluated with chromosomal microarray, the patient demonstrated a deletion on the short arm of chromosome 5, an area associated with Cri-du-chat syndrome. This chromosomal deletion was a likely explanation for her history of developmental delays, intellectual disability, and congenital heart defect, in addition to her history of institutionalization and the trauma of multiple caregiver transitions in early childhood. The patient was referred for further evaluation by a geneticist and genetic counselor.ConclusionsThis case highlights that the underlying cause of developmental delay is often multifactorial, and underscores the importance of a full medical evaluation, including genetic testing, for children with intellectual disability. Using this approach, healthcare professionals can identify potential diagnoses and provide more targeted resources to families.

Developmental delay in congenital hypothyroidism.

We report the case of a 5-month-old male, born out of a nonconsanguineous marriage, who presented with an inability to hold neck. As per the parents, he had diminished spontaneous movements since birth and described him as lethargic. He was clinically diagnosed with cretinism by a pediatric neurologist. He was referred by to the department of physiotherapy for evaluation and advice for the associated motor delay. On observation, the infant displayed peculiar clinical features of sparse hair, periorbital edema and macroglossia (A). Irritability, hoarse cry, abdominal distension and frog leg position was observed in supine lying position (B). Examination revealed generalized hypotonia, wide fontanelles, feeding difficulties and global developmental delay. He was neither able to roll over from supine to prone nor was he able to hold neck adequately. He had head lag during pull to sit test. Due to financial constraints, they were not willing to attend physiotherapy sessions on a regular basis. Thus, parents were educated about the home exercise program that included active assisted rolling, neck extensor muscles facilitation against gravity while lying prone on forearm, active assisted reaching out for objects while lying, neck flexor muscles facilitation in gravity minimized plane and active neck rotations to look at objects of interest while side lying on forearm support. Congenital hypothyroidism is still a common cause of developmental delay in newborns of the developing countries. Awareness, universal newborn screening, prompt recognition and medical treatment along with physiotherapy can minimize adverse effect on the physical and neurocognitive development.