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Background: Glioma grading transformed in World Health Organization (WHO) 2021 CNS tumor classification, integrating molecular markers. However, the impact of this change on radiomics‐based machine learning (ML) classifiers remains unexplored. Purpose: To assess the performance of ML in classifying glioma tumor grades based on various WHO criteria. Study Type: Retrospective. Subjects: A neuropathologist regraded gliomas of 237 patients into WHO 2016 and 2021 from 2007 criteria. Field Strength/Sequence: Multicentric 0.5 to 3 Tesla; pre‐ and post‐contrast T1‐weighted, T2‐weighted, and fluid‐attenuated inversion recovery. Assessment: Radiomic features were selected using random forest‐recursive feature elimination. The synthetic minority over‐sampling technique (SMOTE) was implemented for data augmentation. Stratified 10‐fold cross‐validation with and without SMOTE was used to evaluate 11 classifiers for 3‐grade (2, 3, and 4; WHO 2016 and 2021) and 2‐grade (low and high grade; WHO 2007 and 2021) classification. Additionally, we developed the models on data randomly divided into training and test sets (mixed‐data analysis), or data divided based on the centers (independent‐data analysis). Statistical Tests: We assessed ML classifiers using sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC). Top performances were compared with a t‐test and categorical data with the chi‐square test using a significance level of P < 0.05. Results: In the mixed‐data analysis, Stacking Classifier without SMOTE achieved the highest accuracy (0.86) and AUC (0.92) in 3‐grade WHO 2021 grouping. The results of WHO 2021 were significantly better than WHO 2016 (P‐value<0.0001). In the 2‐grade analysis, ML achieved 1.00 in all metrics. In the independent‐data analysis, ML classifiers showed strong discrimination between grade 2 and 4, despite lower performance metrics than the mixed analysis. Data Conclusion: ML algorithms performed better in glioma tumor grading based on WHO 2021 criteria. Nonetheless, the clinical use of ML classifiers needs further investigation. Level of Evidence: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Key Clinical Message: Homozygous variants of Calcium Voltage‐Gated Channel Subunit Alpha1 S (CACNA1S) gene mutation were previously identified as causes of periodic paralysis and congenital early‐onset myopathy, while it could be manifested as a late‐onset congenital core myopathy. Calcium Voltage‐Gated Channel Subunit Alpha1 S (CACNA1S) gene mutation has been linked to various neuromuscular conditions in recent years. Congenital myopathy with core‐like features is one of the cardinal associations reported previously, causing severe respiratory insufficiency and death in neonates. Informed consent was received from the patients. Subsequently, peripheral blood leukocytes were utilized to extract genomic DNA. Moreover, exome enrichment was implemented through the Twist Human Core Exome Kit (Twist Bioscience) and exome sequenced using Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA). Sanger sequencing using BIG Dye Terminators confirmed the presence of the final variant. Finally, the candidate variants were classified based on the American College of Medical Genetics and Genomics (ACMG) guidelines. In this report, we describe two siblings, who presented with childhood and late‐onset progressive muscle weakness, and had a homozygous variant in exon 2 of the CACNA1S gene defined as c.188C > A (p.Ala63Asp) (NM_000069.3). The SIFT, Polyphen2, CADD PHRED, and Mutation Taster analysis tools classified the variant as pathogenic/damaging. The muscle biopsy of the younger brother revealed intermyofibrillar network pattern disruption as cytoplasmic core‐like lesions. The muscle magnetic resonance imaging (MRI) reported grade IIa and IIb fatty changes. Finally, the electromyography (EMG) findings suggested a myopathic change pattern. This report illustrates the clinical variability in CACNA1S‐related myopathy by reviewing prior reports and adding newly found aspects, additionally expanding the gene defects associated with core myopathy. [ABSTRACT FROM AUTHOR]

Background: Glutaric aciduria type II (GA2) is a rare genetic disorder inherited in an autosomal recessive manner. Double dosage mutations in GA2 corresponding genes, ETFDH, ETFA, and ETFB, lead to defects in the catabolism of fatty acids, and amino acids lead to broad‐spectrum phenotypes, including muscle weakness, developmental delay, and seizures. product of these three genes have crucial role in transferring electrons to the electron transport chain (ETC), but are not directly involve in ETC complexes. Methods: Here, by using exome sequencing, the cause of periodic cryptic gastrointestinal complications in a 19‐year‐old girl was resolved after years of diagnostic odyssey. Protein modeling for the novel variant served as another line of validation for it. Results: Exome Sequencing (ES) identified two variants in ETFDH: ETFDH:c.926T>G and ETFDH:c.1141G>C. These variants are likely contributing to the crisis in this case. To the best of our knowledge at the time of writing this manuscript, variant ETFDH:c.926T>G is reported here for the first time. Clinical manifestations of the case and pathological analysis are in consistent with molecular findings. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant. ETFDH:c.926T>G is reported here for the first time in relation to the causation GA2. Conclusion: Given the milder symptoms in this case, a review of GA2 cases caused by compound heterozygous mutations was conducted, highlighting the range of symptoms observed in these patients, from mild fatigue to more severe outcomes. The results underscore the importance of comprehensive genetic analysis in elucidating the spectrum of clinical presentations in GA2 and guiding personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Glycogen storage diseases (GSDs) are a group of metabolic disorders affecting glycogen metabolism, with polyglucosan body myopathy type 1 (PGBM1) being a rare variant linked to RBCK1 gene mutations. Understanding the clinical diversity of PGBM1 aids in better characterization of the disease. Two unrelated Iranian families with individuals exhibiting progressive muscle weakness underwent clinical evaluations, genetic analysis using whole exome sequencing (WES), and histopathological examinations of muscle biopsies. In one case, a novel homozygous RBCK1 variant was identified, presenting with isolated myopathy without cardiac or immune involvement. Conversely, the second case harbored a known homozygous RBCK1 variant, displaying a broader phenotype encompassing myopathy, cardiomyopathy, inflammation, and immunodeficiency. Histopathological analyses confirmed characteristic skeletal muscle abnormalities consistent with PGBM1. Our study contributes to the expanding understanding of RBCK1‐related diseases, illustrating the spectrum of phenotypic variability associated with distinct RBCK1 variants. These findings underscore the importance of genotype–phenotype correlations in elucidating disease mechanisms and guiding clinical management. Furthermore, the utility of next‐generation sequencing techniques in diagnosing complex neurogenetic disorders is emphasized, facilitating precise diagnosis and enabling tailored genetic counseling for affected individuals and their families. [ABSTRACT FROM AUTHOR]

Background: Brain tumors in children can involve different parts of the brain and cause high mortality. These tumors have different types, and they cause different conflicts and complications. So far, limited studies have been conducted in Iran on children's brain tumors. This study aimed to evaluate radiographic, neuropathological, and demographic findings in children aged 1 to 18 years with brain tumors. Materials and Methods: In this descriptive study, which was conducted for children aged 1 to 18 years with brain tumors admitted to the children's ward of Shohada Hospital (Iran-Tehran) in 2012-2018, 64 children were evaluated. Patient information was extracted from patients' files, including basic data radiological and clinical findings. A significance level was considered less than 0.05. Results: Twenty-six patients (40.6%) were girls, and 38 (59.4%) were boys. 96.9% of the children were term, and the mortality rate was 40.6%. 57.8% were diagnosed in less than one month from the onset of symptoms. 47.6% of patients had a positive family history, and none of them had a history of brain infection. The most common clinical complaint was N/V. The most common location of the tumor was the fourth ventricle (31.3%), and acute hydrocephalus was also seen in 19 patients (29.7%). The most common tumor was medulloblastoma (93.8%), and the most common stage was grade 4 (98.4%). Desmoplastic medulloblastoma was the most common form of medulloblastoma. 9.4% of patients were positive for tumor marker P53. None of the patients were positive for Beta-Catenin. Conclusion: The findings have shown that being a boy, involvement of the fourth ventricle and medulloblastoma are the most common characteristics of brain tumor involvement in Iranian children. [ABSTRACT FROM AUTHOR]

Background: The role of biallelic variants in the NRCAM gene underlying a neurodevelopmental disorder has been defined recently. The phenotype is mainly recognized by varying severity of global developmental delay/intellectual disability, hypotonia, spasticity, and peripheral neuropathy. Methods: Here, we describe a patient with an initial diagnosis of motor‐predominant axonal polyneuropathy or a form of distal SMA. Whole‐exome sequencing (WES), in parallel with WES‐based CNV detection and assessment of homozygosity runs, was performed to identify this patient's possible genetic cause. Results: Whole exome sequencing revealed a homozygous variant, c.73C > T (p.Gln25*), in the NRCAM gene, while the patient manifests a mild range of phenotypes compared to NRCAM‐related disorder. He presented only motor‐predominant axonal polyneuropathy with no other signs of central nervous system involvement. Conclusions: This study is the second report of an association between biallelic NRCAM gene variants and a Mendelian disorder. The obtained clinical data, together with the molecular findings in this patient, expands the clinical and molecular spectrum of NRCAM‐related disorder and highlights its phenotypic complexity. Although patients with loss of function variants in this gene have previously presented severe clinical features, we show that type of the pathogenic variant does not necessarily determine the severity of this phenotype. [ABSTRACT FROM AUTHOR]

Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease's severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 paediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty-seven per cent of the patients had consanguineous parents. Ninety-one per cent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in five patients (21.7%) and four patients (17.4%) required non-invasive ventilation. Sixty per cent of patients were wheelchair-bound since early teens (median age of 12.0 years). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy. [ABSTRACT FROM AUTHOR]

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Aim: Considering the allergic basis of Eosinophilic esophagitis (EoE), this study was conducted to evaluate peripheral blood Tregs in children with EoE. Background: Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of gastrointestinal tract. Regulatory T cells (Tregs) have a confirmed role in allergic disorders. Methods: Children with EoE, gastroesophageal reflux disease (GERD) and healthy controls (HC) (10 subjects in each group) were recruited after diagnosis by a pediatric gastroenterologist and allergist. After obtaining informed written consent, peripheral blood was obtained. Peripheral blood mononuclear cells were isolated by Ficoll gradient centrifugation. Flowcytometry was used to enumerate peripheral blood Tregs (CD4+CD25+FOXP3+ gated lymphocytes were considered as Tregs). Results: CD4+ gated lymphocytes significantly increased in EoE and GERD groups compared to HC group (p= 0.018). Tregs also was significantly increased in EoE in comparison to HC group (p=0.016). There were no statistically significant differences in Tregs of EoE as compared to GERD subjects (p=0.085). Conclusion: Peripheral blood Tregs increase in patients with EoE as compared to healthy controls, which may be indicative of a feedback mechanism to regulate inflammatory responses. [ABSTRACT FROM AUTHOR]

Background: Hirschsprung's disease (HSCR) may be accompanied by other anomalies, including congenital heart disease (CHD), resulting in additional complications. This study was performed to evaluate the prevalence and type of concomitant CHD in hospitalized children with HSCR. Methods: All HSCR patients (n=129) admitted to Mofid Children's Hospital in Tehran, Iran, from April 2016 to August 2019 were investigated in a descriptive cross-sectional study. Two-dimensional, M-mode and pulsed, continuous, and color Doppler provided echocardiography were applied to evaluate cardiac structure and function. Results: CHD was observed in 48 (37.2%) cases, and the most common anomalies were Atrial Septal Defect (ASD) in 20 (15.5%), Ventricular Septal Defect (VSD) in 1 (0.8%), Patent Ductus Arteriosus (PDA) in 2 (1.6%), Tetralogy of Fallot in 3 (2.3%), ASD and Pulmonary stenosis in 2 (1.6%), ASD and PDA in 7 (5.4%), ASD and VSD in 3 (2.3%), as well as VSD and PDA in 2 (1.6%) patients. Conclusion: Cardiac anomalies are relatively prevalent in the Iranian HSCR population participating in the present study. In addition, early echocardiographic evaluation in the setting of HSCR is recommended. [ABSTRACT FROM AUTHOR]