The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population.

BACKGROUND: To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children's Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. METHODS: We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). RESULTS: Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. CONCLUSIONS: Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

Prediction of breath-holding spells based on electrocardiographic parameters using machine-learning model.

BACKGROUND: Breath-holding spells (BHS) are common in infancy and early childhood and may appear like seizures. Factors such as autonomic dysfunction and iron deficiency anemia are thought to contribute to the incidence of BHS. In this study, electrocardiographic (ECG) parameters of patients with BHS were compared to those of healthy, normal children. Logistic regression and machine-learning (ML) models were then created to predict these spells based on ECG characteristics. METHODS: In this case-control study, 52 BHS children have included as the case and 150 healthy children as the control group. ECG was taken from all children along with clinical examinations. Multivariate logistic regression model was used to predict BHS occurrence based on ECG parameters. ML model was trained and validated using the Gradient-Boosting algorithm, in the R programming language. RESULTS: In BHS and control groups, the average age was 11.90 ± 6.63 and 11.33 ± 6.17 months, respectively (p = .58). Mean heart rate, PR interval, and QRS interval on ECGs did not differ significantly between the two groups. BHS patients had significantly higher QTc, QTd, TpTe, and TpTe/QT (all p-values < .001). Evaluation of the ML model for prediction of BHS, fitting on the testing data showed AUC, specificity, and sensitivity of 0.94, 0.90, and 0.94 respectively. CONCLUSION: There are repolarization changes in patients with BHS, as the QTc, QTd, TpTe, and TpTe/QT ratio were significantly higher in these patients, which might be noticeable for future arrhythmia occurrence. In this regard, we developed a successful ML model to predict the possibility of BHS in suspected subjects.

High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry.

Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.

Effects of live and autolyzed yeast supplementation during transition period on ruminal fermentation, blood attributes, and immune response in dairy cows under heat stress condition.

This study was conducted to compare nutrient digestibility, performance and immune response of dairy cows received live and autolyzed yeast during the transition period in high ambient temperature. Cows (n = 25) were randomly divided and received a basal diet with or without live yeast or autolyzed yeast as on top three weeks pre-parturition until three weeks post-parturition. The Control group received a basal diet without yeast products; other groups received 0.5 g live yeast; 1.0 g live yeast; 10 g autolyzed yeast and 20 g/d/head autolyzed yeast. Live yeast resulted in higher nutrient digestibility compared with autolyzed yeast and the control. Methane production was the highest in autolyzed yeast and the lowest in live yeast. Average milk production was the highest in cows that received live yeast. The highest IgG level was for cows that received autolyzed yeast at a dose of 20 g/d/head. Live yeast had no significant effect, but autolyzed yeast increased the relative expression of γ-Interferon and interleukin-2 as compared with the control group. It was concluded that live yeast at a dose of 1.0 g/d/head could influence ruminal fermentation and milk production, but autolyzed yeast at a dose of 20 g/d/head could influence the immune response of dairy cows during the transition period and heat stress.

The impact of LncRNA dysregulation on clinicopathology and survival of pancreatic cancer: a systematic review and meta-analysis (PRISMA compliant).

PURPOSE: An increasing number of studies have reported a significant association between long non-coding RNAs (lncRNAs) dysregulation and pancreatic cancers. In the present study, we aimed to gather articles to evaluate the prognostic value of long non coding RNA in pancreatic cancer. EXPERIMENTAL DESIGN: We systematically searched all eligible articles from databases of PubMed, Web of Science, and Scopus to meta-analysis of published articles and screen association of multiple lncRNAs expression with clinicopathology and/or survival of pancreatic cancer. The pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were used to analysis of overall survival, disease-free survival and progression-free survival were measured with a fixed or random effects model. RESULTS: A total of 39 articles were included in the present meta-analysis. Our results showed that dysregulation of lncRNAs were linked to overall survival (39 studies, 4736 patients HR = 0.41, 95% CI 0.25 ± 0.58, random-effects in pancreatic cancer. Moreover, altered lncRNAs were also contributed to progression-free survival (8 studies, 1180 patients HR: 1.88, 95% CI (1.35-2.62) and disease-free survival (2 studies, 285 patients, HR: 6.07, 95% CI 1.28-28.78). In addition, our findings revealed the association between dysregulated RNAs and clinicopathological features in this type of cancer. CONCLUSIONS: In conclusion, dysregulated lncRNAs could be served as promising biomarkers for diagnosis and prognosis of pancreatic cancer.

The alleviating effects of sesame oil on diazinon-induced toxicity in male wistar rats.

Pesticides are introduced into the environment in a variety of ways and constitute a wide group of environmental pollutants. To evaluate the attenuating effects of sesame oil on the toxicity of diazinon (DZN), male Wistar rats were exposed to DZN and/or sesame oil by gavage at different dosages for 8 weeks. DZN in a concentration of 30 mg/kg caused an increase in the number of white blood cell (WBCs), and the combination of DZN and sesame oil raised the number of platelets; the number of red blood cells, however, did not change. In addition, DZN caused a drastic decrease in the sperm count in a dose-dependent manner and in a concentration of 50 mg/kg, the sperm count decreased by more than 50%, but the combination of sesame oil in a dose of 4 ml/kg with DZN reversed the effect of this pesticide. The evidence presented here suggests that in addition to antioxidants, such as olive oil, intermittent exposure with sufficient intervals can decrease the toxicity of pesticides.

Atypical Kawasaki Disease Presenting with Hemiparesis and Aphasia: A Case Report.

Kawasaki disease (KD) is an inflammatory vasculitis. KD is classified into two groups based on clinical characteristics criteria, namely classic and incomplete. Cerebral vascular abnormality, especially arterial ischemic stroke (AIS) is very rare and unusual in KD. Here, we report a 4-year-old boy who was referred to our tertiary pediatric center with abrupt right hemiparesis and aphasia. At admission time, he had febrile illness and was toxic. On physical examination, we found unilateral left submandibular lymphadenopathy. On neurologic examination, we obtained right sided hemiparesis with hemiparetic gait and aphasia. His deep tendon reflexes (DTRs) of right extremities were exaggerated and his sensory system was intact. Based on these features, some differential diagnoses were suggested, such as acute encephalitis with focal signs, brain abscess, cerebral vasculitis, hemorrhagic insults, and ischemic stroke, etc. After a complete evaluation, especially brain MRI and MRA, our diagnosis was arterial ischemic stroke (AIS) following atypical KD. Based on these findings, we administered intravenous immunoglobulin (IVIG 2 gm/kg) and oral high dose aspirin (100 mg/kg/d). He responded to these anti-inflammatory treatments dramatically.

The protective effect of Borago Officinalis extract on amyloid ß (25-35)-induced long term potentiation disruption in the dentate gyrus of male rats.

Alzheimer's disease (AD) begins with impairment in synaptic functions before developing into later neurodegeneration and neural loss. In the present study we have examined the protective effects of Borago Officinalis (borage) extract on amyloid ß (Aß)--Induced long term potentiation (LTP) disruption in hippocampal dentate gyrus (DG). Wistar male rats received intrahippocampal (IHP) injection of the Aß (25-35) and borage extract throughout gestation (100 mg/kg). LTP in perforant path- DG synapses was assessed using electrophysiology method and field excitatory post- synaptic potential (fEPSP) slope and population spike (PS) amplitude were measured by 400 Hz tetanization. Finally, the total thiol content of hippocampus was measured using colorimetric reaction based on the Ellman's method. The results showed that Aß (25-35) significantly decreased fEPSP slope and SP amplitude comparing with the control and sham group, whereas borage extract administration increased these parameters compared to the Aß group. Aß induced a remarkable decrease in total thiol content of hippocampus and borage prevented the decrease of the hippocampal total sulfhydryl (SH) groups. This data suggest that Aß (25-35) can effectively inhibit LTP in the granular cells of the DG in hippocampus, and borage supplementation reverse the synaptic plasticity in DG following Aß treatment and that borage consumption may lead to an improvement of AD-induced cognitive dysfunction.

Marangoni flows triggered by cationic-anionic surfactant complexation.

HYPOTHESIS: The gradients in surfactant distribution at a fluid-fluid interface can induce fluid flow known as the Marangoni flow. Fluid interfaces found in biological and environmental systems are seldom clean, where mixtures of various surfactants are present. The presence of multi-component surfactant mixtures introduces the possibility of interactions among constituents, which may impact Marangoni flows and alter flow dynamics. EXPERIMENTS: We employed flow visualization, surface tension and reaction kinetic measurements, and numerical simulations to quantitatively investigate the Marangoni flows induced by the reacting surfactant mixtures. Different binary surfactant mixtures were utilized for comparative analysis. FINDINGS: The impact of surfactant interactions on Marangoni flows is confirmed through the observation of diverse complex flow patterns that result from the combination of oppositely charged surfactants in varying composition ratios and concentrations. Unique flow patterns originate from the composition-dependent interfacial phenomena upon mixing surfactants. Our findings provide vital insights that could be used to guide the development of effective oil remediation or the spreading of waterborne pathogens in contaminated regions.

Efficacy and Safety of Therapeutic Plasma Exchange in Children with Neuroimmunological Disorders: A Limited Unicentral Study.

Objectives: Therapeutic plasma exchange (TPE) is a plasmapheresis procedure whose Safety data for pediatric neuro-immunological disorders (PNID) is confined. The present research documents TPE's safety and feasibility data in these conditions. Materials & Methods: The current study involved six distinct groups of patients with PNID undergoing TPE: neuromyelitis optic spectrum disorder (NMOSD), autoimmune encephalitis (AIE), acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), Guillain-Barre syndrome (GBS), and optic neuritis (ON). This study documented complications related to each TPE process. In addition, TPE's efficacy was studied in these patients. Results: The present study recorded adverse effects in 18 patients with PNID that received 121 TPE cycles: five cycles (4.13%) in MS, three (2.48%) in AIE subgroup, one (0.82%) in ADEM, and two (1.65%) in GBS. No severe complications were observed among the patients. Conclusion: Patients with PNID tolerated therapeutic plasma exchange, which was a safe process.

Boswellic acids as promising agents for the management of brain diseases.

Boswellic acid (BA)s are pentacyclic triterpenic acids present in gum resin of Boswellia species (such as B. serrata and B. carterii). They possess a variety of pharmacological effects such as anti-inflammatory, anti-oxidant, and anti-excitotoxic effects. These properties may have potential therapeutic implication in neurological disorders. Notably, the BAs-induced neuroprotection is proposed to be associated with the ability to reduce neurotoxic aggregates, decrease oxidative stress, and improve cognitive dysfunction. Recently, BAs have been suggested as potential agents for the treatment of brain tumors due to their potential to attenuate cell proliferation, migration, metastasis, angiogenesis, and promote apoptosis during both in vitro and in vivo studies. The present review aims to address these studies and highlights the possible underlying mechanisms of the observed effects. Besides, novel formulations and improving pharmacokinetic properties may enhance the therapeutic efficacy of BAs.

Clinical and MRI characteristics of multiple sclerosis in Iranian Children and Adolescents.

Objective: To determine the clinical and MRI characteristics of multiple sclerosis (MS) in the children and adolescents. Material & Methods: In this cross-sectional study, information of 95 MS patients was obtained from the Iranian MS registry. Disease characteristics and imaging data were collected using medical records. Results: Ninety-five patients including 64 female and 31 male subjects with mean age of 13.97±2.4 years (range, 8-18) years were enrolled. The most frequent signs and symptoms were ophthalmic symptoms (n=61, 64.2%), brainstem signs (n=44, 46.3%), cerebellar signs (n=32, 33.6%) and pyramidal signs (n=26, 27.3%). Blurred vision (n=21, 34.4%) was the most common ophthalmic symptom and ataxia (n=24, 75%) the most prevalent cerebellar sign. The most common brainstem signs/symptoms were motor symptoms and vertigo (each n=14, 31.8%) and the most common pyramidal sign/symptom was right upper monoparesis (n=14, 23.3%). Active demyelinating lesions were reported in brain MRI of all patients, mostly appeared as periventricular (n=91, 95.8%) and pericallosal (n=55, 57.9%) lesions. Acute demyelinating spinal lesions were presented in 38 patients (51.3%) with a prominent involvement of the cervical spine (n=33, 86.8%). Conclusion: In our study, the most frequent signs and symptoms were eye symptoms, brainstem signs, cerebellar signs and pyramidal signs, respectively. Moreover, our results showed that MRI plays a critical role in the diagnostic evaluation of MS in children with presence of brain lesions in all patients and spinal lesion in a considerable portion of patients.

Neurological Involvements in COVID-19: A hospital-based study.

Objectives: The SARS-CoV-2 pandemic is the most challenging crisis in the contemporary world. Besides severe pulmonary involvement, the disease also has several extrapulmonary manifestations, and new signs and symptoms are associated with it every dayThe present study aimed to inquire about the frequency of neurological manifestations and risk factors of COVID-19. Materials & Methods: This retrospective, descriptive study included patients with neurological involvement admitted to the Alborz University of Medical Sciences academic hospitals from March 2020 to July 2020 with confirmed COVID-19 infection. The data included in the analysis were the patient's demographic information, underlying diseases, neurological manifestations, and laboratory findings. Results: The study included ninety-five patients with a mean age of fifty-nine. Neurological symptoms and signs were observed in 91.6% and 10.5% of the patients, respectively. The most frequently associated neurological symptoms of COVID-19 were fatigue (49.5%), headache (47.4%), and dizziness (45.3%). Furthermore, the most common neurological involvements included gait disorders (6.3%), cerebellar dysfunction (4.2%), and cerebrovascular accidents (3.15%). Positive troponin was shown to be the strongest predictor of neurological signs (OR=21, P=0.017), followed by WBC≥15,000 (OR = 20.75, P=0.018) and a history of respiratory disease (OR=7.42, P=0.007). Conclusion: Neurological symptoms were observed in more than 91% of the patients, while neurological signs were present in 10.5% of the COVID-19 patients. Additionally, positive troponin, WBC≥15,000, and a history of respiratory disease were the strongest predictors of neurological signs.

Developmental regression and movement disorder as a phenotypic variant of POLR3A Mutation-Case report.

POLR3A is a main subunit encoding RNA polymerase III, which is involved in transcription of many RNA structures. Here, we report a new presentation of c.1771-6C > G intronic variant presenting as developmental regression, seizure, and dystonia in a 6-year-old boy associated with striatum involvement in the brain MRI.

Incidence of Pediatric Multiple Sclerosis in Iran within 2000-2019.

OBJECTIVES: Due to a lack of data on pediatric multiple sclerosis (MS) epidemiology in Iran, this study aimed to determine the incidence rate of pediatric MS in Iran. MATERIALS & METHODS:  All the data of the patients with MS registered in the Ministry of Health and Medical Education of Iran for 20 years were collected in this study; those born in 1982 and diagnosed with the disease and treated since 2000 were included in this study. Therefor The collected variables were patients' age at the time of diagnosis, gender, year of diagnosis, urban or rural residency, and province of residence. Additionally, age-specific incidence rates per 100,000 of the population were calculated. RESULTS: This study was performed on 4544 cases of pediatric MS within 2000-2019, of which 997 patients (21.9%) were male. The mean age of the patients with MS at the time of diagnosis was 14.3±4.6 years, and 4414 children (97.1%) lived in urban areas. The incidence rate of pediatric MS in Iran during 20 years increased from 0.26 per 100,000 of the population in 2000 to 1.53 in 2019. CONCLUSION: The incidence of pediatric MS in Iran is high, and the development of diagnostic practices in the past decade in Iran has contributed to the detection of this high incidence.

A Brief Review on the Role of Vesicular Monoamine Transporter2 Inhibitors in Hyperkinetic Movement Disorders.

Hyperkinetic movement disorders are a common group of movement abnormalities in children, characterized with repetitive unintended involuntary movements. Major hyperkinetic movements include tremor, tic, dystonia, myoclonus, and chorea. Although a number of drugs have been proven to be beneficial for these abnormalities, some patients may become resistant to conventional treatments. Vesicular monoamine transporter2 (VMAT2) inhibitors (Tetrabenazine, Deutetrabenazine, and Valbenazine) are new agents introduced in the last decade for treating some of movement disorders, in particular tardive dyskinesia, Huntington chorea, and Tourette syndrome. In this brief review, we discussed the role of these drugs in managing hyperkinetic movement disorders.

A case of diffuse leptomeningeal glioneuronal tumor in a 10-year-old boy: First report from Iran.

A 10-year-old boy who was referred due to acute hydrocephalus symptoms was diagnosed as the first case of pediatric DLGNT in Iran. The results suggested that using shunting for hydrocephaly and anti-seizure medicines, as well as chemotherapeutic agents, can be an effective treatment strategy for DLGNT. Although the patient was stable without a tumor recurrence for a limited follow-up period of 22 months, further studies are expected.

Serum Zinc Level in Children with Febrile Seizure.

OBJECTIVES: Febrile seizure (FS) is the most common type of seizure in children. FS is a genetic age-limited seizure, which only occurs with febrile illness. Today, it is known that genetic factors play a major role in the occurrence of FS. Nevertheless, some trace elements, such as zinc, may play an important role in the occurrence of FS. In this study, we investigated the serum level of zinc in patients with FS and febrile children without seizure (control group). MATERIALS &METHODS: This prospective case-control study was conducted on 41 patients with simple and complex FS as the case group and 41 febrile children without seizure as the age- and sex-matched control group. The participants were admitted to Best Hospital of Hamadan, Iran between January 2013 and January 2014 . The children's age ranged from six months to five years. Serum zinc levels were measured by atomic absorption spectroscopy in these groups. RESULTS: The mean serum zinc levels were 70.41±20.46 and 92.73±17.62 mcg/dL in the case and control groups, respectively (P=0.001). The results showed that the serum zinc level in children with FS was significantly lower than that of the control group. CONCLUSION: Based on the present results, serum zinc level was lower in children with febrile seizure. However, further basic research is needed to examine the efficacy of zinc supplements in the prevention of FS.