Onset Of Delay Research Articles

Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion.

Biallelic mutations in BRAT1 result in lethal neonatal rigidity and multifocal seizure syndrome and a milder neurodevelopmental disorder of cerebellar atrophy with or without seizures (NEDCAS, MIM 618056). Combining linkage analysis and whole-genome sequencing (WGS), we identified a novel deep intronic BRAT1 variant, NC_000007.14 (NM_152743.4):c.128-1585 T > G, in 3 siblings of a consanguineous Bedouin family exhibiting NEDCAS. In silico analyses followed by molecular studies demonstrated this variant's impact on splice regulatory elements, forming a cryptic exon, resulting in a deleterious frameshift and aberrant transcript. Previously reported pathogenic BRAT1 splice-site mutations were adjacent to exons, affecting canonical consensus splice sites, and identifiable by whole-exome sequencing. The deep intronic BRAT1 disease-causing variant is thus unique and underscores the potential of intronic splice regulatory elements in BRAT1 disease pathogenesis, demonstrating the utility of WGS in identifying noncoding variants in unresolved cases. The affected individuals (deep into their twenties) are among the longest-surviving patients described to date-delineating the NEDCAS phenotype at these ages. Although sharing homozygosity of the same variant, they show varying penetrance of nystagmus and extreme variability in the extent of ataxia and age of onset of developmental delay. Notably, we summarize all documented BRAT1 splice variants reported to date and their phenotypic associations.

Myopia and Environmental Risk Factors: A Comprehensive Study

Background: The global rise in the prevalence of myopia calls for evidence-based strategies to be devised to reduce the incidence and delay the progression of Myopia. The aim is to determine the relationship between myopia incidence and some environmental factors. Methods: A cross-section observational study was conducted at Alzahraa Teaching Hospital from May 2023 to December 2023. Primary school students of both genders. All students were enrolled in the study after an agreement with their parents/guards. Data was collected using a pre-constructed data collection sheet (questionnaire) including three sections, the first section was sent to the families to fill and sign the consent for participation and provide the required data including the demographic variables, family history and medical history of the students, time outdoors, prolonged near work/increased study hours, high BMI, use of LED lamps for homework, less sleeping hours, low Vitamin D levels, less participation in sports and low socioeconomic status. The second part included the general examination of the students, school grades and education performance (assessed according to the student school Cards). The third section involved the ophthalmological examination, visual acuity and ophthalmoscopic examination. Results: A total of 100 students were enrolled in this study, they were equally distributed according to gender, 50 boys and 50 girls. The age of students ranged between 6 and 12 years. Only 12 students had positive past medical and surgical history. A family history of myopia was reported in 20% of the studied group, 20 children were wearing spectacles and a history of past eye complaints was reported in 9 (9%) of children. The refractive errors were 45% hypermetropia, 39% myopia and 16% astigmatism. Abnormal visual acuity was detected in 35%. Myopia was significantly higher in children with family history (p=0.007). A statistically significant relationship was found between large time outdoors and myopia (OR=4.52, p=0.02). A statistically significant relationship was found between prolonged near-work/increased study hours and myopia (OR=4.52, p=0.02). A statistically significant relationship was found between using LED lamps for homework and myopia (OR=10.33, p<0.0001). A statistically significant relationship was found between fewer sleeping hours and myopia (OR=7.5, p<0.0001). Conclusion: Prevention of the onset of myopia and delay in the progression of myopia can be altered by modifying the contributing environmental risk factors. Raise outdoor time with adequate sunlight exposure, rural environment, less duration of near work, use of incandescent lamp and normal sleeping rhythms with adequate regular sleeping hours can prevent the onset and progression of myopia. Myopia is associated with high BMI, watching television and playing digital devices. High socioeconomic status associated with more indoor activity, increased academic pressure, sedentary lifestyle contribute to the prevalence of myopia.

Predictors of academic delay post-pediatric kidney transplant in the USA.

Pediatric patients with kidney failure often experience cognitive delays. However, academic delay (being more than one grade level below age-appropriate grade, or in special education) after pediatric kidney transplantation (KTx) has not been explored. We sought to identify patient characteristics associated with a higher risk of academic delay 1year post-KTx. We used the United Network for Organ Sharing (UNOS) database to identify children aged 6-17years who received a primary KTx between 2014 and 2021 and had a functioning graft 1year after KTx. The primary outcome was the patient's academic progress at 1year post-transplant. The secondary outcome was change in academic progress between transplant and 1-year follow-up: onset of new delay, resolution of pre-existing delay, persistence of delay, or no delay at either timepoint. Binomial and multinomial mixed effects logistic regression models were used to predict each outcome based on patient characteristics. The study included 2197 patients, of whom 14% demonstrated academic delay at 1year post-KTx, 4% demonstrated a new onset of academic delay, 5% demonstrated a resolution of academic delay, and 10% demonstrated persistent academic delay. Patients undergoing transplantation at a younger age, receiving a deceased donor kidney, experiencing longer waitlist times, and undergoing KTx for vascular or other disease indications for KTx were more likely to experience academic delays, including new-onset academic delays. Academic delays are frequently reported among pediatric KTx recipients. Additional academic support may help resolving or preventing academic delay for at-risk subgroups of children undergoing KTx.

Case analysis of epilepsy, neurodevelopmental disorder, and motor disorders associated with mutations in the dehydrodolichyl diphosphate synthase gene

The objective of this study is to analyze the role of dehydrodolichyl diphosphate synthase (DHDDS), a crucial enzyme in the mevalonate pathway, and its encoded mutations in the onset of developmental delay and seizures, with or without movement abnormalities. Its genotype-phenotype characteristics are still inconclusive. We analyzed the clinical characteristics of epilepsy, and neurodevelopmental and motor disorders related to DHDDS gene mutations and report the genotype-phenotype characteristics of a child with epilepsy caused by DHDDS gene mutation, providing a summary and a statistical analysis of epilepsy cases associated with DHDDS gene mutation up until February 2022.Methods: Using "DHDDS; epilepsy; neurodevelopmental disorder" as the keywords, the literature relevant to DHDDS gene mutations up until February 2022 was reviewed. A total of 25 cases were retrieved, among which 21 cases with complete data were included in the chi-squared test. The clinical characteristics of DHDDS gene-related cases were summarized and analyzed.Results: The onset of epilepsy caused by mutations of the DHDDS gene typically occurs during infancy. Predominantly, the mutation occurs in the locus of c.632G>A p.R211Q. Myoclonus is frequently the initial manifestation of epilepsy; it frequently coexists with neurodevelopmental disorder and intellectual disability, and patients have no specific type of motor disorder. Cranial magnetic resonance imaging (MRI) reveals no abnormalities, whereas electroencephalogram (EEG) frequently exhibits abnormalities. Valproic acid (VPA) yields good curative effects.Conclusion: Mutations in the DHDDS gene are associated with congenital glycosylation disorder, autosomal recessive retinitis pigmentosa, and epilepsy. According to statistical analysis using the chi-squared test, for pediatric patients with mutations in this gene locus, most of the epilepsy types are myoclonic epilepsies with intellectual disability and neurodevelopmental disorders. They have normal brain MRIs and abnormal EEGs. VPA produces beneficial therapeutic results and the differences are all statistically significant. The current diagnosis still relies on next-generation sequencing or whole-exome sequencing.

Factors Leading to Diagnostic and Therapeutic Delay of Rheumatoid Arthritis and Their Impact on Disease Outcome.

Objective To identify the factors which leadto delay in diagnosis and initiation of disease-modifying anti-rheumatic drugs (DMARDs) inrheumatoid arthritis (RA) patients and their impact on disease outcome and functional ability. Methodology This cross-sectional study was conducted from June 2021 to May 2022 at the Department of Rheumatology and Immunology, Sheikh Zayed Hospital, Lahore. Inclusion criteria were patients aged >18 years who were diagnosed with RA, based on American College of Rheumatology (ACR) criteria 2010. Delay was defined as any sort of delay which leads to delay in diagnosis or initiation of treatment of more than three months. The factors and impact on disease outcome were measured by using Disease Activity Score-28 (DAS-28) for disease activity and Health Assessment Questionnaire-Disability Index (HAQ-DI) for functional disability. The collected data were analyzed with Statistical Package for Social Sciences (SPSS) version 24 (IBM Corp., Armonk, NY, USA). Results One hundred and twenty patients were included in the study. Mean delay in referral to a rheumatologist was 36.75±61.07 weeks. Fifty-eight (48.3%) patients with RA were misdiagnosed before presentation to a rheumatologist. Sixty-six(55%) patients had the perception that RA is a non-treatable disease. Delay in diagnosis of RA from onset of symptoms (lag 3) and delay in start of DMARDs fromonset of symptoms (lag 4) were significantly associated with increased DAS-28 and HAQ-DI scores (p-value 0.001). Conclusion The factors which led to diagnostic and therapeutic delay were delayed consultation with a rheumatologist, old age, low education status and low socioeconomic status. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies had no role in diagnostic and therapeutic delay. Many RA patients were misdiagnosed with gouty arthritis and undifferentiated arthritis before consulting a rheumatologist. This diagnostic and therapeutic delay compromises RA management leading to high DAS-28 and HAQ-DI in RA patients.

A Global Survey of Ethnic Indian Women Living with Polycystic Ovary Syndrome: Co-Morbidities, Concerns, Diagnosis Experiences, Quality of Life, and Use of Treatment Methods

Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is highly prevalent in women of Indian ethnicity. Clinical practice guidelines do not adequately consider ethnic-cultural differences in the diagnosing and care of women with PCOS. This study aimed to understand co-morbidities, key concerns, quality of life (QoL), and diagnosis experiences of ethnic Indian women living with PCOS. Global online survey of ethnic Indian women of reproductive age living with PCOS. Respondents (n = 4409) had a mean age of 26.8 (SD 5.5) years and reported having a family history of type 2 diabetes (43%) and PCOS (18%). Most of them (64%) were diagnosed with one or more co-morbidities (anxiety/depression being the most common). Irregular periods, cysts on the ovaries, and excess unwanted facial hair growth were their three top concerns. On average, women experienced symptoms of PCOS at the age of 19.0 (SD 5.0) and were diagnosed at the age of 20.8 years (SD 4.8). We report a one-year delay in seeking medical help and a seven-month diagnostic delay, which were associated with poor satisfaction with the information provided related to PCOS and its treatment options (p < 0.01). Women living outside India reported difficulty losing weight as their most key concern; however, they had higher dissatisfaction with the information provided on diet (OR, 0.74; 95% CI, 0.6 to 0.8; p = 0.002), exercise (OR, 0.74; 95% CI, 0.6 to 0.9; p = 0.002) and behavioural advice (OR, 0.74; 95% CI, 0.6 to 0.9; p = 0.004) than women living in India. Most women reported poor QoL in weight and emotion domains. Ethnic Indian women experience early onset of PCOS symptoms and delay in seeking professional help. Timely diagnosis, providing cultural-specific education related to lifestyle and weight management, and improving psycho-emotional support are key areas that should be addressed in clinical practice and future research.

Novel application of a force sensor during sit-to-stands to measure dynamic cerebral autoregulation onset.

Current sit‐to‐stand methods measuring dynamic cerebral autoregulation (dCA) do not capture the precise onset of the time delay (TD) response. Reduced sit‐to‐stand reactions in older adults and individuals post‐stroke could inadvertently introduce variability, error, and imprecise timing. We applied a force sensor during a sit‐to‐stand task to more accurately determine how TD before the onset of dCA may be altered. Middle cerebral artery blood velocity (MCAv) and mean arterial pressure (MAP) were measured during two sit‐to‐stands separated by 15 min. Recordings started with participants sitting on a force‐sensitive resistor for 60 s, then asked to stand for 2 min. Upon standing, the force sensor voltage immediately dropped and marked the exact moment of arise‐and‐off (AO). Time from AO until an increase in cerebrovascular conductance (CVC = MCAv/MAP) was calculated as TD. We tested the sensor in four healthy young adults, two older adults, and two individuals post‐stroke. Healthy young adults stood quickly and the force sensor detected a small change in TD compared to classically estimated AO, from verbal command to stand. When compared to the estimated AO, older adults had a delayed measured AO and TD decreased up to ~53% while individuals post‐stroke had an early AO and TD increased up to ~14%. The stance time during the sit‐to‐stand has the potential to influence the TD before the onset of dCA metric. As observed in the older adults and participants with stroke, this response may drastically vary and influence TD.

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy.

Objective SCN8A epileptic encephalopathy is caused predominantly by de novo gain‐of‐function mutations in the voltage‐gated sodium channel Nav1.6. The disorder is characterized by early onset of seizures and developmental delay. Most patients with SCN8A epileptic encephalopathy are refractory to current anti‐seizure medications. Previous studies determining the mechanisms of this disease have focused on neuronal dysfunction as Nav1.6 is expressed by neurons and plays a critical role in controlling neuronal excitability. However, glial dysfunction has been implicated in epilepsy and alterations in glial physiology could contribute to the pathology of SCN8A encephalopathy. In the current study, we examined alterations in astrocyte and microglia physiology in the development of seizures in a mouse model of SCN8A epileptic encephalopathy.MethodsUsing immunohistochemistry, we assessed microglia and astrocyte reactivity before and after the onset of spontaneous seizures. Expression of glutamine synthetase and Nav1.6, and Kir4.1 channel currents were assessed in astrocytes in wild‐type (WT) mice and mice carrying the N1768D SCN8A mutation (D/+).ResultsAstrocytes in spontaneously seizing D/+ mice become reactive and increase expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity. These same astrocytes exhibited reduced barium‐sensitive Kir4.1 currents compared to age‐matched WT mice and decreased expression of glutamine synthetase. These alterations were only observed in spontaneously seizing mice and not before the onset of seizures. In contrast, microglial morphology remained unchanged before and after the onset of seizures.SignificanceAstrocytes, but not microglia, become reactive only after the onset of spontaneous seizures in a mouse model of SCN8A encephalopathy. Reactive astrocytes have reduced Kir4.1‐mediated currents, which would impair their ability to buffer potassium. Reduced expression of glutamine synthetase would modulate the availability of neurotransmitters to excitatory and inhibitory neurons. These deficits in potassium and glutamate handling by astrocytes could exacerbate seizures in SCN8A epileptic encephalopathy. Targeting astrocytes may provide a new therapeutic approach to seizure suppression.

Relationship between onset of symptoms and diagnostic delay in women with endometriosis

Relationship between onset of symptoms and diagnostic delay in women with endometriosis

Peroxisomal acyl CoA oxidase deficiency: a rare inherited disorder of nervous system

Background: Peroxisomal acyl CoA oxidase deficiency is a very rare neurodegenerative disorder characterised by postnatal hypotonia, seizures, and neurological regression in early infancy. Case Presentation: Here, we present a case of two children in a family affected with peroxisomal acyl CoA oxidase deficiency. Early onset of hypotonia, seizures, and psychomotor delay was observed in both the sibs. Plasma levels of very long chain fatty acids showed normal levels of phytanic acid, pristanic acid, C22, C24, C26, C26/C22, and C24/C22 ratios. Here, we describe a case where women in her second trimester and with two affected siblings with peroxisomal acyl CoA oxidase deficiency was referred to institute for genetic counselling. Conclusion: Clinical exome analysis of the couple, two affected sibs and the fetus adds new insight into the clinical, neuroradiological, and molecular aspects of this disorder that represents one of the rarer inherited defects of peroxisomal function.

Modifiable Environmental Risk Factors Affecting Myopia

Purpose: The global rise in the prevalence of myopia calls for evidence-based strategies to be devised to reduce the incidence and delay the progression of Myopia. The aim of this study is to review the current literature on modifiable risk factors that control the development and progression of Myopia, specifically in paediatric population. Method: A comprehensive literature review was conducted using PubMed, ScienceDirect, Elsevier, and Google Scholar databases, including keywords such as environmental risk factors; myopia; “outdoor activity”; “near work”; “high body mass index”; “LED lamps usage”; “watching television”; “digital devices”; “sleep”; “melatonin”; “low vitamin D levels”; “sports”; “socioeconomic status”; “COVID-19 and online education”. English language full-text articles published between Jan 2010 and Oct 2020 were included in the study. Studies were critically reviewed for study methodology and robustness of data. Thirty six studies are included in this literature review. Conclusion: Prevention of onset of myopia and delay in progression of myopia can be altered by modifying the contributing risk factors. Increase in outdoor time with adequate sunlight exposure, rural environment, less duration of near work, use of incandescent lamp, normal circadian rhythms with adequate regular sleeping hours can prevent the onset and progression of myopia. Myopia association with high BMI, watching television, playing digital devices, serum vitamin D levels, participation in sports yet to be established. High socioeconomic status associated with more indoor activity, increased academic pressure, sedentary life style contributes to prevalence of myopia. COVID-19 pandemic control measures with consequent online education resulted in increased digital screen time, near work, and limited outdoor activities, causing rise of myopia pandemic.

Tuberous Sclerosis Complex: Clinical Spectrum and Epilepsy: A Retrospective Chart Review Study.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic neurocutaneous disorder, with heterogeneous manifestations. We aimed to review the clinical presentation of TSC and its association with epilepsy among Saudi population. This was a retrospective chart review study of 88 patients diagnosed with TSC with or without epilepsy. In 38.6% of patients, symptoms began before 1 year of age. The most frequent initial manifestations of TSC were new onset of seizures (68.2%), skin manifestations (46.6%) and development delay (23.9%). During the evolution of the disease 65.9% had epilepsy, 17% facial angiofibromas, 13.6% Shagreen patch, 18.2% heart rhabdomyomas and 12.5% retinal hamartomas. The genetic study for TSC diagnosis was done for 44 patients, 42 (95,4%) of them were genetically confirmed, for whom 13 patients had TSC1 mutation (29.5%), 29 patients were carrying TSC2 gene mutation (65.9%), Genetic test for TSC 1 and TSC 2 were negative for 2 patients (4.5%) despite positive gene mutation in their relative with TSC. The most common manifestations were central nervous system (predominantly epilepsy) and dermatological manifestations. Most of the patients develop epilepsy with multiple seizure types. TSC 2 mutation is more common than TSC 1 mutation.

10 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIED SHARED METHYLOMIC CONTRIBUTIONS TO SUSCEPTIBILITY AND PROGRESSION IN PEDIATRIC CROHN'S DISEASE

Most Crohn’s Disease (CD) patients present with an inflammatory phenotype (B1), however, a subgroup rapidly progress to complicated disease behaviours such as stricturing (B2). Recent evidence suggests the involvement of gene-environmental interactions in CD. Epigenetic processes play a key role in mediating environmental influences. Therefore, we set out to examine the role of DNA methylation as a contributor to CD susceptibility and progression. We utilized a subset of pediatric subjects recruited under the RISK study. We generated genome-wide DNA methylation data using the Illumina HumanMethylationEPIC 850K array in whole blood DNA samples of 74 controls and 164 newly diagnosed CD cases (B1), of which 54 progressed to B2 at a later time point within 36 months from the day of diagnosis. β-values for each CpG site were modeled as a linear function of disease status with age, gender, and cell-type proportions as covariates. 1,043 CpGs exhibited significant association with CD susceptibility (FDR<0.05). Of these, 849 CpGs were hypermethylated and 194 were hypomethylated in cases compared to controls. CpGs in a long non-coding RNA, LOC100996291, showed the strongest association with CD. The 1,043 CpGs mapped to 627 unique genes, which were enriched for immune function-related TNF-alpha, Jak-STAT, Rap1 and PI3K-Akt signaling pathways. 142 of the 1,043 CD-susceptibility CpGs also exhibited association with disease progression (B1 vs B2), suggesting common epigenetic processes underlying both susceptibility and progression of CD. Using genetic association and the concept of Mendelian randomization, we identified CpGs that are potentially causal to CD rather than the consequence of the disease. Our findings suggest that dysregulated DNA methylation is associated with CD susceptibility and progression, and it may offer new pathophysiological insights and therapeutic targets to prevent the onset of CD and delay its progression.

Intermittent Explosive Disorder and Substance Use Disorder: Analysis of the National Comorbidity Survey Replication Sample.

A relationship between aggression and substance use has been debated for many years. While substance use increases the risk of aggressive behavior, no studies have reported on the relationship between impulsive aggression and substance use/disorder, specifically. We analyzed data from the community-based National Comorbidity Survey Replication (N = 9,282 subjects) in order to examine the relationship between current DSM-5 intermittent explosive disorder (IED), a disorder of impulsive aggression, and current substance use disorders (SUDs), overall, and with regard to alcohol, tobacco, and cannabis use disorders and nondisordered use. Occurrence of current SUD was elevated in current IED versus non-IED adult subjects, and onset of IED preceded that of SUD in 92.5% of comorbid IED + SUD cases. This relationship was not due to the presence, or absence, of current depressive or anxiety disorders. Examination of the severity of IED and of SUD revealed that the presence of IED increases SUD severity but that the presence of SUD does not increase IED severity. Subjects with IED are at increased risk of developing SUD, compared with those without IED. This suggests that history of recurrent, problematic, impulsive aggression is a risk factor for the later development of SUD rather than the reverse. If so, effective treatment of impulsive aggression, before the onset of substance misuse, may prevent, or delay, the development of SUD in young people.

Clinical heterogeneity of glycine encephalopathy in three Palestinian siblings: A novel mutation in the glycine decarboxylase (GLDC) gene

IntroductionGlycine encephalopathy (GE), also known as non-ketotic hyperglycinemia (NKH), is a rare inborn error of glycine metabolism caused by a defect in glycine cleavage system, a multi-enzyme complex located in mitochondrial membrane. This defect results in elevated glycine concentration in plasma and cerebrospinal fluid (CSF). Clinical manifestations vary from severe lethargy, hypoactivity and apneic episodes in the neonatal form, mild or moderate psychomotor delay and seizures in the infantile form, and abnormal behaviors, ataxia and choreoathetoid movements in late onset form. More than 50 GLDC mutations were found, reflecting large heterogeneity of the gene. MethodsWe describe the clinical, biochemical and molecular characteristics of three Palestinian siblings who have distinct clinical phenotypes. Molecular study was performed utilizing standard Polymerase Chain Reaction (PCR) amplification then direct DNA sequencing for the affected family members. ResultsTheir phenotypes included severe symptoms in neonatal period, infantile onset of seizure and psychomotor delay and a mild late-onset form with speech delay at age 20months. All siblings were homozygous for a novel mutation Y164H in exon 4 of GLDC gene. The described novel homozygous variant in our study is predicted deleterious and pathogenic. ConclusionsThis article further expands the genetic spectrum of glycine encephalopathy and adds an evidence of the clinical heterogeneity of glycine encephalopathy even in siblings with identical mutation.

Epilepsy prevalence and severity predictors in MRI-identified focal cortical dysplasia

ObjectivesTo determine the prevalence of epilepsy and drug-resistant epilepsy in pediatric patients with focal cortical dysplasia (FCD) identified by magnetic resonance imaging (MRI). To determine clinical and imaging differences between those with drug-resistant epilepsy, drug-responsive epilepsy, and no epilepsy among children with MRI-identified FCD. MethodsA keyword search of a hospital radiology database identified 97 study participants for inclusion in this retrospective study. Participants were included if they were under 18 years of age at time of database query and had an MRI between 2004 and 2013 showing FCD. Exclusion was based on imaging and clinical characteristics. Data was gathered using a chart review and supplemental questionnaire. ResultsIn this cohort of patients with imaging findings compatible with FCD, 29% had not developed epilepsy. The prevalence of epilepsy and drug-resistant epilepsy was 71.13% (95% C.I.=61.05–79.89%) and 32.99% (95% C.I.=23.78–43.27%), respectively. Patients with epilepsy were more likely to have temporal (p=0.029) or frontal (p=0.044) lobe lesions and a family history of seizures (p=0.003) than those without epilepsy. Age of seizure onset was later in those with drug-responsive epilepsy than those with drug-resistant epilepsy (p=0.0002). A later age of seizure onset (OR=1.22, p=0.0441, 95% C.I.=1.00–1.486) and absence of developmental delay (OR=3.624, p=0.0497, 95% C.I.=1.002–13.110) predicted a less severe epilepsy phenotype. ConclusionsPrevious studies have only assessed patient cohorts with FCD and epilepsy, limiting the data on “asymptomatic” or “atypically presenting” FCD. Identifying a surprisingly large, novel cohort of children with FCD that had not developed epilepsy helps define prognosis and inform clinical management of children with FCD on imaging.

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis (OA) pathogenesis. In our study, a real-time PCR assay revealed that miR-483-5p was upregulated in articular cartilage from OA patients and experimental OA mice induced by destabilization of the medial meniscus compared to their controls. Overexpression of miR-483-5p by intra-articular injection of lentivirus LV3-miR-483-5p significantly enhanced the severity of experimental OA. Consequently, we synthesized antago-miR-483-5p to silence the endogenous miR-483-5p anddelivered it intra-articularly, which revealed that antago-miR-483-5p delayed the progression of experimental OA. To investigate the functional mechanism of miR-483-5p in OA development, we generated doxycycline-inducible miR-483 transgenic (TG483) mice. TG483 mice exhibited significant acceleration and increased severity of OA, and age-related OA occurred with higher incidence and greater severity in TG483 mice compared with their controls. Furthermore, our results revealed miR-483-5p directly targeted to the cartilage matrix protein matrilin 3 (Matn3) and tissue inhibitor of metalloproteinase 2 (Timp2) to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and cartilage angiogenesis, and itconsequently initiated and accelerated the development of OA. In conclusion, our findings reveal an miRNA functional pathway important for OA development. Targeting of miR-483-5p by intra-articular injection of antago-miR-483-5p represents an approach that could prevent the onset of OA and delay its progression.

The cost and impact of compulsivity: A research perspective

Compulsivity is the defining feature of various psychiatric disorders including Obsessive Compulsive Related Disorders (OCRDs), and other compulsive, impulsive, and addictive disorders. These disorders are disabling, chronic conditions with an early onset and high rates of comorbidity, misdiagnoses, and delay in treatment onset. Disorders of compulsivity are responsible for considerable socioeconomic burden to society. We review the costs and impacts of compulsivity. In order to facilitate earlier diagnosis and targeted treatments, we examine the overlapping mechanisms that underlie compulsivity. We reconceptualize psychiatric disorders based on core features of compulsivity, highlight challenges in harmonizing research in children and adults, describe newer research methodologies, and point to future directions that can impact the costs and impact of disorders of compulsivity.

A New Nonsense Mutation in CDKL5 Gene in a Male Patient with Early Onset Refractory Epilepsy: a Case Report

Background The X-linked cyclin-dependent kinase like 5 (CDKL5/STK9) gene has been shown to be responsible for a severe encephalopathy condition characterized by early onset of epilepsy and severe developmental delay. CDKL5 mutations have been shown to be more frequent among female patients. Results Here we report a 6- month male patient, second child of a healthy non consanguineous in the Iranian population. He has been affected by early onset epileptic refractory seizures and developmental delay. Whole-exome sequencing (WES) has revealed a base substitution c.173T>A in CDKL5 gene, resulting in the formation of stop codon p.L58X. This mutation resides in the catalytic domain of the corresponding protein and is expected to result in premature RNA break down with no CDKL5 resulting protein. Conclusion The present report highlights the importance of CDKL5 mutation analysis in male patients affected with early onset refractory epilepsy.

Progression of neuropsychiatric and cognitive features due to exons 2 to 5 deletion in the epsilon-sarcoglycan gene: a case report

ABSTRACTPhysical symptoms of myoclonus dystonia due to epsilon-sarcoglycan mutations are well documented; however, the progression of neuropsychiatric and cognitive symptoms remains unclear. We present a case of a 34-year-old woman with early childhood onset of myoclonic jerks, dystonic posture and developmental delay due to exons 2 to 5 deletion in the epsilon-sarcoglycan gene. Over time, she developed neuropsychiatric symptoms. She underwent bilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus for her motor symptoms, which greatly improved but she exhibited slow deterioration of her neuropsychiatric and cognitive symptoms, particularly apathy, aggression and severe executive dysfunction.