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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., (© 2024. The Author(s).)

Objective: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies., Methods: This study summarizes the clinical, imaging, and molecular data of these patients for five years., Results: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis., Conclusions: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Congenital myasthenic syndromes are inherited disorders caused by mutation in components of the neuromuscular junction and manifest early in life. Mutations in COLQ gene result in congenital myasthenic syndrome. Here, we present the analysis of data from 209 patients from 195 unrelated families highlighting genotype-phenotype correlation. In addition, we describe a COLQ homozygous variant a new patient and discuss it utilizing the Phyre2 and I-TASSER programs. Clinical, molecular genetics, imaging (MRI), and electrodiagnostic (EEG, EMG/NCS) evaluations were performed. Our data showed 89 pathogenic/likely pathogenic variants including 35 missenses, 21 indels, 14 nonsense, 14 splicing, and 5 large deletions variants. Eight common variants were responsible for 48.46% of those. Weakness in proximal muscles, hypotonia, and generalized weakness were detected in all individuals tested. Apart from the weakness, extensive clinical heterogeneity was noted among patients with COLQ-related patients based on their genotypes-those with variants affecting the splice site exhibited more severe clinical features while those with missense variants displayed milder phenotypes, suggesting the role of differential splice variants in multiple functions within the muscle. Analyses and descriptions of these COLQ variants may be helpful in clinical trial readiness and potential development of novel therapies in the setting of established structure-function relationships., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There is growing evidence that prevalence rates of autism spectrum disorder (ASD) are increasing. A number of factors appear to contribute to this increase, including excessive screen time. Screen time seems to be linked to the severity of the symptoms of ASD. Given this, the aim of the present cross-sectional study was to investigate the association between early screen time and ASD symptoms severity in the first 36 months of life. To this end, sixty-eight Iranian toddlers (mean age: 27.09 months; 22.1% females) with ASD were recruited. Parents completed the modified checklist for autism in toddlers (M-CHAT), the Repetitive Behavior Scale-Revised (RBS-R), and a lifestyle checklist. Next, parents rated children's daily exposure to content specifically designed (foreground media) and not specifically designed (background media) for children, along with their daily exposure to social interaction. Per day, toddlers spent 5.12 h (±3.77) with foreground media, 3.72 h (±3.57) with background media, and 2.89 h (±2.74) in interaction with other people (parents). To test the hypotheses, we performed a series of Pearson's correlations and multiple regression analyses. Toddlers' higher severity scores for ASD symptoms were associated with longer foreground (r = 0.234, p = 0.001) and longer background (r = 0.180, p = 0.012) media duration, and with shorter duration of interaction with others (r = 0.192, p = 0.009). Toddlers spending 1 h more in foreground screen time and background screen time have 0.38 and 0.29 more units in the ASD symptom severity scale, respectively, while toddlers spending 1 h more in social interactions have 0.42 fewer units in the ASD symptom severity scale. The screen time and interaction duration are related to ASD symptoms severity of toddlers. The cross-sectional study design precludes causal associations, although bi-directional relationships appear plausible.

Purpose: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities., Methods: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells., Results: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells., Conclusion: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities., Competing Interests: Conflict of Interest H.Z.E. and H.Y. are employees of GeneDx, LLC. R.D.G. is a consultant for Minovia Therapeutics. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Insufficient amounts of survival motor neuron protein is leading to one of the most disabling neuromuscular diseases, spinal muscular atrophy (SMA). Before the current study, the detailed characteristics of Iranian patients with SMA had not been determined., Objective: To describe the key demographic, clinical, and genetic characteristics of patients with SMA registered in the Iranian Registry of SMA (IRSMA)., Methods: IRSMA has been established since 2018, and the demographic, clinical, and genetic characteristics of patients with SMA were recorded according to the methods of treat neuromuscular disease (TREAT-NMD) project., Results: By October 1, 2022, 781 patients with 5q SMA were registered. Of them, 164 patients died, the majority of them had SMA type 1 and died during the first 20 months of life. The median survival of patients with type 1 SMA was 23 months. The consanguinity rate in 617 alive patients was 52.4%, while merely 24.8% of them had a positive family history. The most common type of SMA in live patients was type 3. Morbidities were defined as having scoliosis (44.1%), wheelchair dependency (36.8%), tube feeding (8.1%), and requiring mechanical ventilation (9.9%). Most of the registered patients had a homozygous deletion of SMN1, while the frequency of patients with higher copy numbers of SMN2, was less in more severe types of the disease. Earlier onset of the disease was significantly seen in patients with lower copy numbers of SMN2. The neuronal apoptosis inhibitory protein (NAIP) gene deletion was associated with a higher incidence of more severe types of SMA, higher dependency on ventilators, tube feeding, and earlier onset of the disease., Conclusions: The IRSMA is the first established Iranian nationwide registry of patients with SMA. Using this registry, decision-makers, researchers, and practitioners can precisely understand the epidemiology, characteristics, and genetics of patients with SMA in Iran.

Objectives: This study aimed to analyze the health-related quality of life (HRQoL) of patients with spinal muscular atrophy (SMA) based on the type of SMA, demographic and clinical features and compare HRQoL of these patients with a matched healthy control group.  METHODS: This was a case-control study of Patients with SMA in Iran. Sixty-six patients with SMA type II and III aged 8-18 years and also 264 healthy age, sex, and socio-economic matched individuals were enrolled. To assess the quality of life, we used the Persian version of the KIDSCREEN-27., Results: The health-related quality of life between children with type II and type III SMA was not significant in all 5 subscales. However, HRQoL in healthy children was significantly higher than in SMA children in all 5 subscales., Conclusion: The quality of life in children with SMA was lower than the healthy control group in all subscales, and physical well-being and psychosocial aspects are the main domains of life impaired by SMA disease. However, no significant difference between the quality of life in children with SMA type II and type III was observed., (© 2022. The Author(s).)

Background: By affecting about 50 million people worldwide, epilepsy is considered a global concern in neurology. Intolerable enough, up to ¼ of all patients do not respond to antiepileptic drugs and have recurring seizures. Therefore, revealing the underlying etiology is quite demanding in a clinical context to improve diagnosis and disease management., Methods: Initially, 85 patients suspected of epilepsy underwent thorough clinical and paraclinical evaluation and 24 individuals with drug-resistant epilepsy entered the study. Using whole-exome sequencing, the genetic etiology of drug-resistant epilepsy was investigated and discerned whether this method could facilitate the management of drug-resistant epilepsy through personalized medicine. Eventually, functional annotation was performed and drug-gene interaction networks were constructed to find potential therapeutic targets., Results: We found eleven novel variants in various genes including IRF2BPL, ST3GAL3, and GPAA1, for which a few epilepsy-related variants are available in public databases. The overall diagnostic yield for likely pathogenic and pathogenic variants and the detection rate of novel variants were 25% and 84.6%, respectively. Based on the results, two patients were considered potential candidates for personalized medicine. The highest number of interaction with drugs was demonstrated for SCN1A, SCN2A, and GRIN2A genes., Conclusions: This study highlighted the importance of consanguineous marriage in drug-resistant epilepsy and suggested the possibility of reduced penetrance and variable expressivity in some of the autosomal dominant cases. We also suggest that whole-exome sequencing could facilitate personalized management of drug-resistant epilepsy. Regarding drug-gene interactions, some genes such as SCN1A and SCN2A might serve as therapeutic targets in drug-resistant epilepsy., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Excessive exposure of young children to digital devices has increased in recent years. Much research has shown that early excessive screentime is associated with autistic-like symptoms. This study aimed to differentiate children with Post-Digital Nannying Autism Syndrome (PDNAS) from children with autism spectrum disorders (ASD) and typically developing children (TDC), both behaviorally and cognitively. This study is comparative and cross-sectional and included three groups of children. The first group consisted of 15 young children with subthreshold autism symptoms. They had not received a formal diagnosis of ASD and had been exposed to digital devices for more than half of their waking time. The second group consisted of 15 young children with ASD, and the third group consisted of 15 young TDC. A lifestyle checklist, a modified checklist for autism in toddlers (M-CHAT), a behavioral flexibility rating scale-revised (BFRS-R), the Gilliam autism rating scale (GARS-2), and a behavior rating inventory of executive functioning-preschool version (BRIEF-P) were used to compare the three groups. The results showed that executive functions and behavioral flexibility were more impaired in children with ASD than in children with PDNAS and in TDC. Also, we found that there was no significant difference in the severity of autism symptoms between the children with ASD and the children with PDNAS. Early excessive exposure to digital devices may cause autism-like symptoms in children (PDNAS). Children with PDNAS are different from children with ASD in executive functions and behavioral flexibility. Further research is needed in this area.

Background: The CEP104 gene (OMIM: 616,690) encodes the centrosome protein 104 (CEP104) that is involved in cilia function. Pathogenic variants in this gene have been described in four patients diagnosed with Joubert syndrome (JBTS) 25. Here, we challenged the concept that pathogenic variants in CEP104 gene are only involved in the development of JBTS 25., Methods and Results: In a clinical setting, whole-exome sequencing (WES) was applied to investigate pathogenic variants in patients with unexplained developmental delay or intellectual disability (DD/ID).WES revealed a novel homozygous nonsense variant (c.643C > T) in CEP104 (NM _014704.3) in a girl with mild intellectual disability, hypotonia, and imbalanced gait. Her brain MRI data did not show molar tooth sign (MTS) or any other brain anomalies., Conclusion: Our study introduced a novel variant in the CEP104 gene that results in an ID phenotype other than JBTS25. Comparison of her phenotype with that of eight previously published DD/ID patients harboring pathogenic variants in CEP104 gene revealed that more than half of them did not show JBTS related symptoms. Therefore, we suggest that the CEP104 gene might also be involved in a disorder other than JBTS 25, a point that deserves to be emerged in the OMIM database., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations of this disease include progressive muscle weakness, gait dysfunction, and motor impairment, leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is the standard diagnostic tool for DMD. This study aimed to investigate disease progression and genetic patterns in Iranian ambulant boys and to find the correlation between genotypes and motor function phenotypes., Methods: This study was performed on 152 DMD patients. Clinical history, including the disease phenotype, steroid therapy, and the North Star Ambulatory Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses were confirmed by multiplex ligation-dependent probe amplification and next-generation sequencing tests., Results: A total of 152 Iranian DMD patients were examined in this study. The mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years. Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual changes in the NSAA score were determined for all cases, based on the mutation type and exon site. Deletion mutation was found in 79.1% of cases, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon deletion was exon 44 (5.3%), and the most common multiexon deletions were attributed to exons 45-50 and exons 45-52 (4.6%). The results did not indicate any correlation between the mutation type and age at the time of disease onset, loss of ambulation age, and wheelchair dependence; however, a significant association was found between contracture and mutation type. The results showed a significant difference in the NSAA score between the deletion and nonsense groups at the age of 3 years (P = 0.04). No significant correlation was found between the phenotype and exon site. Overall, 91.1% of the study population had a history of corticosteroid use, and 54.1% showed compliance with rehabilitation therapy., Conclusion: This study demonstrated the phenotypes and mutational features of Iranian DMD boys and provided information regarding the natural motor history of the disease, disease progression, diagnosis, and status of DMD management in Iran. The present findings can promote the development of clinical trials and future advanced molecular therapies in Iran., (© 2022. The Author(s).)

Introduction: Coenzyme Q10 deficiency can be due to mutations in Coenzyme Q10-biosynthesis genes (primary) or genes unrelated to biosynthesis (secondary). Primary Coenzyme Q10 deficiency-4 (COQ10D4), also known as autosomal recessive spinocerebellar ataxia-9 (SCAR9), is an autosomal recessive disorder caused by mutations in the ADCK3 gene. This disorder is characterized by several clinical manifestations such as severe infantile multisystemic illness, encephalomyopathy, isolated myopathy, cerebellar ataxia, or nephrotic syndrome., Methods: In this study, whole-exome sequencing was performed in order to identify disease-causing variants in an affected girl with developmental regression and Epilepsia Partialis Continua (EPC). Next, Sanger sequencing method was used to confirm the identified variant in the patient and segregation analysis in her parents., Case Presentation: The proband is an affected 11-year-old girl with persistent seizures, EPC, and developmental regression including motor, cognition, and speech. Seizures were not controlled with various anticonvulsant drugs despite adequate dosing. Progressive cerebellar atrophy, stroke-like cortical involvement, multifocal hyperintense bright objects, and restriction in diffusion-weighted imaging (DWI) were seen in the brain magnetic resonance imaging (MRI)., Conclusions: A novel homozygous missense variant [NM_020247.5: c.814G>T; (p.Gly272Cys)] was identified within the ADCK3 gene, which is the first mutation in this gene in the Iranian population. Bioinformatics analysis showed this variant is damaging. Based on our patient, clinicians should consider genetic testing earlier to instant diagnosis and satisfactory treatment based on exact etiology to prevent further neurologic sequelae., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants., (© 2022 Wiley Periodicals LLC.)

Introduction: The current multi-center, randomized, double-blind study was conducted among children with cerebral palsy (CP) to assess the safety and efficacy of umbilical cord blood mononuclear cell (UCB-MNC). We performed the diffusion tensor imaging to assess the changes in the white matter structure., Methods: Males and females aged 4 to 14 years old with spastic CP were included. Eligible participants were allocated in 4:1 ratio to be in the experimental or control groups; respectively. Individuals who were assigned in UCB-MNC group were tested for human leukocyte antigen (HLA) and fully-matched individuals were treated with UCB-MNCs. A single dose (5 × 10 6 /kg) UCB-MNCs were administered via intrathecal route in experimental group. The changes in gross motor function measure (GMFM)-66 from baseline to one year after treatment were the primary endpoints. The mean changes in modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also evaluated and compared between groups. The mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR) were the secondary endpoints. Adverse events were safety endpoint., Results: There were 72 included individuals (36 cases in each group). The mean GMFM-66 scores increased in experimental group; compared to baseline (+ 9.62; 95%CI: 6.75, 12.49) and control arm (β: 7.10; 95%CI: 2.08, 12.76; Cohen's d: 0.62) and mean MAS reduced in individuals treated with UCB-MNCs compared to the baseline (-0.87; 95%CI: -1.2, -0.54) and control group (β: -0.58; 95%CI: -1.18, -0.11; Cohen's d: 0.36). The mean PEDI scores and mean CP-QoL scores in two domains were higher in the experimental group compared to the control. The imaging data indicated that mean FA increased and MD decreased in participants of UCB-MNC group indicating improvements in white matter structure. Lower back pain, headaches, and irritability were the most common adverse events within 24 h of treatment that were related to lumbar puncture. No side effects were observed during follow-up., Conclusions: This trial showed that intrathecal injection of UCB-MNCs were safe and effective in children with CP., Trial Registration: The study was registered with ClinicalTrials.gov ( NCT03795974 )., (© 2022. The Author(s).)

Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene which can lead to a loss or shortage of the FMR1 protein. This protein interacts with specific miRNAs and can cause a range of neurological disorders. Therefore, miRNAs could act as a novel class of biomarkers for common CNS diseases. This study aimed to test this theory by exploring the expression profiles of various miRNAs in Iranian using deep sequencing-based technologies and validating the miRNAs affecting the expression of the FMR1 gene. Blood samples were taken from 15 patients with FXS (9 males, 6 females) and 12 controls. 25 miRNAs were differentially expressed in individuals with FXS compared to controls. Levels of 9 miRNAs were found to be significantly changed (3 upregulated and 6 downregulated). In Patients, the levels of hsa-miR-532-5p, hsa-miR-652-3p and hsa-miR-4797-3p were significantly upregulated while levels of hsa-miR-191-5p, hsa-miR-181-5p, hsa-miR-26a-5p, hsa-miR-30e-5p, hsa-miR-186-5p, and hsa-miR-4797-5p exhibited significant downregulation; and these dysregulations were confirmed by RT-qPCR. This study presents among the first evidence of altered miRNA expression in blood samples from patients with FXS, which could be used for diagnostic, prognostic, and treatment purposes. Larger studies are required to confirm these preliminary results., (© 2022. The Author(s).)

Introduction: With the increasing rate of COVID-19, particularly in developing countries such as Iran, a high number of frontline service providers, including doctors and nurses, have died, making frontline healthcare workers (HCWs) more vulnerable to psychological disorders and fear and anxiety of secondary transmission to others, especially their family members. In this study, we aimed to report the incidence of COVID-19 infection among HCWs in an Iranian referral pediatrics hospital between April 2020 and July 2020., Materials and Methods: In this retrospective cross-sectional study, HCWs and hospital staff working at Children's Medical Center, Tehran, Iran, with positive SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) test results were evaluated between April 2020 and July 2020., Results: Sixty-one out of the 1085 personnel (5.6%) including 14 pediatricians (23%), 24 nurses (39%), 9 paramedics (15%), and 14 HCWs without direct patient contact (23%) had a nasopharyngeal specimen positive SARS-CoV-2 RT-PCR test. The mean age was 39.8±10.6 years. Eleven cases (18%) had underlying diseases such as hypertension and asthma. The most common symptoms were fatigue (67%, n=41), dry cough (61%, n=37), fever (52%, n=32), headache (46%, n=28), dyspnea (43%, n=24), anosmia (28%, n=17), chills (26%, n=16), sore throat (26%, n=16), gastrointestinal symptoms (23%, n=14), and productive cough (3%, n=2). Eleven cases (18%) showed lung involvement in their chest X-rays and/or CT scans. Eighteen cases (29.5%) had lymphopenia, and 20 individuals (33%) had a high level of C-reactive protein., Conclusion: In conclusion, in the early phase of the COVID-19 outbreak, a substantial proportion of HCWs with fever, respiratory, and other prevalent symptoms including fatigue and headache were infected with SARS-CoV-2. Therefore, implementation of infection prevention measures, isolation of confirmed HCWs, disinfection of the environment, and regular COVID-19 prevention training for HCWs are strongly recommended for the wellbeing of health workers and minimizing the spread of infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: This study assessed the safety and efficacy of intrathecal injection of umbilical cord tissue mesenchymal stem cells (UCT-MSC) in individuals with cerebral palsy (CP). The diffusion tensor imaging (DTI) was performed to evaluate the alterations in white-matter integrity., Methods: Participants (4-14 years old) with spastic CP were assigned in 1:1 ratio to receive either UCT-MSC or sham procedure. Single-dose (2 × 10 7 ) cells were administered in the experimental group. Small needle pricks to the lower back were performed in the sham-control arm. All individuals were sedated to prevent awareness. The primary endpoints were the mean changes in gross motor function measure (GMFM)-66 from baseline to 12 months after procedures. The mean changes in the modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also assessed. Secondary endpoints were the mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR)., Results: There were 36 participants in each group. The mean GMFM-66 scores after 12 months of intervention were significantly higher in the UCT-MSC group compared to baseline (10.65; 95%CI 5.39, 15.91) and control (β 8.07; 95%CI 1.62, 14.52; Cohen's d 0.92). The increase was also seen in total PEDI scores (vs baseline 8.53; 95%CI 4.98, 12.08; vs control: β 6.87; 95%CI 1.52, 12.21; Cohen's d 0.70). The mean change in MAS scores after 12 months of cell injection reduced compared to baseline (-1.0; 95%CI -1.31, -0.69) and control (β -0.72; 95%CI -1.18, -0.26; Cohen's d 0.76). Regarding CP-QoL, mean changes in domains including friends and family, participation in activities, and communication were higher than the control group with a large effect size. The DTI analysis in the experimental group showed that mean FA increased (CST 0.032; 95%CI 0.02, 0.03. PTR 0.024; 95%CI 0.020, 0.028) and MD decreased (CST -0.035 × 10 -3 ; 95%CI -0.04 × 10 -3 , -0.02 × 10 -3 . PTR -0.045 × 10 -3 ; 95%CI -0.05 × 10 -3 , -0.03 × 10 -3 ); compared to baseline. The mean changes were significantly higher than the control group., Conclusions: The UCT-MSC transplantation was safe and may improve the clinical and imaging outcomes., Trial Registration: The study was registered with ClinicalTrials.gov ( NCT03795974 )., (© 2021. The Author(s).)

The aim of the current study was to investigate the opinions of neurologists and psychiatrists in Iran on the necessity of COVID-19 vaccination in patients with epilepsy (PWE). These data can help policy makers understand the concerns of these healthcare professionals. This was a survey study. On September 1 st , 2020 we sent a questionnaire (using Google-forms) to all neurologists and psychiatrists in Iran via WhatsApp. The survey included three general questions (age, sex, and discipline) and six COVID-specific questions. In total, 202 physicians participated in this study (116 neurologists and 86 psychiatrists). Of the participants, 27% believed that PWE are at increased risk of contracting COVID-19. The majority (74%) of the participants would confidently recommend COVID-19 vaccine to their patients. However, only 49% of the physicians would recommend such a vaccine to all patients; others would consider it in special populations only. The overwhelming majority (91%) of the participants would recommend COVID-19 vaccine only when a reliable vaccine becomes available. Many physicians would trust a vaccine that is approved by the World Health Organization (WHO) (46%) or a vaccine that is approved by the Food and Drug Administration (FDA-USA) (34%). Physicians have concerns on the issue of the necessity of (a future) COVID-19 vaccine in PWE. The most important concern is the reliability of a vaccine and in this regard, two health agencies, the WHO and the FDA, are the most trusted organizations to approve a vaccine against COVID-19.

Background: Celiac disease is the inflammatory entropy caused by hypersensitivity to gluten, which occurs in susceptible individuals. Some studies have suggested a link between celiac disease and epilepsy in children. Our aim was to screen for clinical and paraclinical features of celiac disease in children with intractable epilepsy., Methods: This was a cross-sectional study. Children aged 2 to 18 years with refractory epilepsy that referred to the pediatric neurology clinic within one year (2018-2019) were enrolled. Demographic and clinical characteristics of patients, especially clinical manifestations of celiac disease, were recorded in a questionnaire. A venous blood sample was sent to determine the total IgA, anti-tTG (IgA), and anti-endomysial antibody (IgA). Endoscopy was performed in cases where the celiac serological test was positive., Results: Seventy children with idiopathic drug-resistant epilepsy (44 boys) were evaluated. The height-for-age index was 49.2% and the weight-for-age index was 38.2% less than normal. Constipation (48.6%), anorexia (25.7%), and abdominal pain (21.4%) were the most common gastrointestinal symptoms. Celiac serological tests were negative in all children. Therefore, endoscopy and bowel biopsy were not performed in any case., Conclusion: Celiac disease was not found in any patient with intractable epilepsy. Gastrointestinal symptoms and growth disorders in this group may be related to the underlying disease or medications and not to celiac disease., Competing Interests: The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2021 Golnaz Ghazizadeh Esslami et al.)

Objective: Metachromatic leukodystrophy (MLD) is an autosomal recessive leukodystrophy caused by deficiency of aryl sulfatase A (ASA) activity affecting the nervous system. MLD and mutations in ARSA have not been widely studied in non-European cohorts. The genotype-phenotype spectrum of MLD patients was investigated in this study of a cohort of Iranian leukodystrophy patients. In silico analysis was performed to investigate the pathogenicity of the variants., Methods: Genetic analysis for 25 patients was performed with direct sequencing of the ARSA gene. The missense variants underwent in silico analysis to characterize the pathogenicity based on predicted structural and stability changes., Results: 19 patients had variants in ARSA genes, including 18 homozygotes and one compound heterozygote individual. In 6 individuals no mutations were found in ARSA gene, suggesting an alternative cause of their leukodystrophy. We found 5 novel disease causing variants: p.Phe64Ile, p.Ser292Alafs*34, p.Arg99Profs*35, p.Phe400Leu and p.Leu429Pro. 32 % of the patients had p.Gly311Ser substitution and resulted in juvenile MLD type. Different in silico analysis showed variable pathogenic effect for the variants., Conclusion: c.931 G > A (p.Gly311Ser) and c.465 + 1 G > A variants are the most frequent alleles among Iranian MLD patients and five mutations appear to be confined to the Iranian patients. Population screening for these variants may be helpful to reduce the burden of the disease in this part of the world., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Early-onset epileptic encephalopathies (EOEE) affect cognitive, sensory, and motor development. Genetic variations are among the identifiable primary causes of these syndromes. However, some patients have been reported to be affected by EOEE without any other clinical symptoms and signs. We study the genotype and phenotype of patients with nonsyndromic early-onset epileptic encephalopathy (NSEOEE) and report 2 novel patients from Iran. A comprehensive search was conducted in PubMed, John Willy, Springer, Elsevier, and Google Scholar databases to collect related information of all the previously reported cases with KCTD7 mutations. Fifty-four patients (from 40 families) were investigated. Using trio-whole-exome sequencing (trio-WES) and Sanger sequencing, the possible genetic causes of the disorder were checked. The probable impacts of the identified variants on the KCTD7 protein structure and function were predicted. This study provided a detailed overview of all published KCTD7 mutations and 2 de novo ones. We identified 2 novel homozygous variants of uncertain significance, c.458 G > A p. Arg153His and c.529C > T (p.Arg177Cys), in KCTD7 (NM_153033.4) (Chr7(GRCh37)). There is a significant wide distribution of the KCTD7 gene causing NSEOEE among different populations. In conclusion, KCTD7 mutations demonstrate a diverse geographical distribution alongside a wide range of ethnicities. This highlights the importance of careful consideration in the WES data analysis. Mutations of this gene may be a common cause of NSEOEE. Also, this study imprints targeted therapeutic opportunities for potassium channelepsies such as KCTD7-related NSEOEE., (© 2021 S. Karger AG, Basel.)

Objective: One of the difficulties to conduct electroencephalography (EEG) in pediatric patient population is that they are not always cooperative during the procedure. Different medications are used to induce sedation during EEG recording. In order to find a medication with the least adverse effects and high efficacy, the current study aimed at comparing clonidine and chloral hydrate as a premedication prior to EEG recording in pediatric population., Materials & Methods: A prospective, randomized, single-blinded, controlled trial was conducted on 198 children (9 to 156 months old) to investigate the sedative and adverse effects of clonidine and chloral hydrate. Patients, partially sleep-deprived the night before, were randomly divided into two groups of clonidine (n=100) and chloral hydrate (n=98) on an alternative day basis., Results: The average sleep onset latency was significantly longer in the clonidine group than chloral hydrate group (the Mann-Whitney test, p <0.0001). Sleep duration ranged 15 to 150 minutes and it was not significantly different between the two groups (the Mann-Whitney test, p = 0.2). Drowsiness terminated faster with chloral hydrate than clonidine.Drowsiness after arousal was observed in 58% and 26.1% of patients in the clonidine and chloral hydrate groups, respectively; the difference between the groups was significant (the Mann-Whitney test, p = 0.058). EEG results were reported normal in 77 subjects in the chloral hydrate group (77%) and 69 subjects (69%) in the clonidine group (p = 0.161). Generalized epileptiform discharges were significant in the clonidine group (the Mann-Whitney test, p = 0.006)., Conclusion: The results of the current study showed that both 5% chloral hydrate (1 mL/kg) and clonidine (4 μg/kg) could be administered as a premedication prior to EEG recording in children, although drowsiness after arousal was higher with clonidine than chloral hydrate. However, the yield of generalized epileptiform discharges in the clonidine group was greater than that of the chloral hydrate group., Competing Interests: The authors declare that there is no conflict of interest

Mutations in the dystrophin gene could cause Duchenne muscular dystrophy (DMD), which is the most common muscular disorder in pediatrics. Considering the growing evidence on appropriateness of gene therapies for DMD, precise genetic diagnosis seems essential. Hence, we conducted a study to determine mutational patterns in Iranian children with DMD. To detect all probable large mutations in the dystrophin gene, 314 DMD patients were evaluated using the multiplex ligation-dependent probe amplification (MLPA). Subjects who were MLPA-negative underwent the next generation sequencing (NGS) to identify potential point mutations. MLPA detected deletions (79.93%) and duplications (5.41%) along the dystrophin gene of 268 patients. Distribution of large mutations was heterogeneous and followed hotspot pattern throughout the gene. From 46 patients who were MLPA-negative, 43 exhibited point mutations including nonsense in 7.64%, frameshifts in 4.77%, splicing in 0.96%, and missense variations in 0.32% of participants. Most of the point mutations were located between exons 19 and 40. In three patients (1%), no mutation was found using either MLPA or NGS. Two subjects had novel nonsense mutations (L1675X and E1199X) in their dystrophin gene, which were considered as the possible reason for elimination of major domains of the gene. The results of this study provided invaluable information regarding the distribution of various large and small mutations in Iranian individuals with DMD. Besides, the novel nonsense mutations L1675X and E1199X were identified within the highly conserved residues, leading to elimination of significant domains of the dystrophin gene.

Introduction: Guillain-Barré syndrome is an immune-mediated peripheral neuropathy characterized by different clinical manifestations. We aimed to describe the clinical features, seasonal distribution, subtypes, and electrodiagnostic characteristics of Iranian children with Guillain-Barré syndrome., Methods: In this prospective study, a total of 30 children with Guillain-Barré syndrome were evaluated. All demographic features were collected and electrodiagnostic study was assessed., Results: Twelve participants were diagnosed with acute inflammatory demyelinating polyradiculoneuropathy and 18 patients were identified with acute motor axonal neuropathy. The initial findings showed that a significant number of patients (23 cases, P = .003) resided in rural areas. Our results showed a higher incidence of Guillain-Barré syndrome in summer and autumn months. No significant difference was observed between the seasonal distribution of acute inflammatory demyelinating polyradiculoneuropathy and acute motor axonal neuropathy subtypes. Antecedent history of pulmonary infections was recorded in 14 children with Guillain-Barré syndrome. Electrophysiological findings revealed a pattern of prolonged F wave latency with reduced persistency, absence of sensory nerve action potential, reduced compound muscle action potential amplitude, prolonged distal motor latency, reduced nerve conduction velocity, and abnormal temporal dispersion or conduction block in most patients with acute inflammatory demyelinating polyradiculoneuropathy. However, reduced compound muscle action potential amplitude, F wave with normal latency and reduced persistency, normal sensory nerve action potential amplitude, normal distal latency, normal sensory nerve conduction velocity, and conduction block or temporal dispersion were observed in most acute motor axonal neuropathy patients., Conclusion: The data support a correlation between Guillain-Barré syndrome incidence with seasonal variation and living area. Further studies should assess the Guillain-Barré syndrome features in pediatric population.

Monosomy 18p syndrome is one of the prototypical examples of autosomal terminal deletions. This deletion can be the consequence of de novo deletions, malsegregation of a balanced parental translocation, cryptic subtelomeric deletions or ring chromosome 18. The present case is a rare cytogenetic variant of monosomy 18 as a consequence of whole-arm translocation between chromosomes 13 and 18 which has been reported only three times previously., (© 2019 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Objective: Major birth defects are inborn structural or functional anomalies with long-term disability and adverse impacts on individuals, families, health-care systems, and societies. Approximately 20% of birth defects are due to chromosomal and genetic conditions. Inspired by the fact that neonatal deaths are caused by birth defects in about 20 and 10% of cases in Iran and worldwide respectively, we conducted the present study to unravel the role of chromosome abnormalities, including microdeletion/microduplication(s), in multiple congenital abnormalities in a number of Iranian patients., Materials and Methods: In this descriptive cross-sectional study, 50 sporadic patients with Multiple Congenital Anomalies (MCA) were selected. The techniques employed included conventional karyotyping, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridisation (array-CGH), according to the clinical diagnosis for each patient., Results: Chromosomal abnormalities and microdeletion/microduplication(s) were observed in eight out of fifty patients (16%). The abnormalities proved to result from the imbalances in chromosomes 1, 3, 12, and 18 in four of the patients. However, the other four patients were diagnosed to suffer from the known microdeletions of 22q11.21, 16p13.3, 5q35.3, and 7q11.23., Conclusion: In the present study, we report a patient with 46,XY, der(18)[12]/46,XY, der(18), +mar[8] dn presented with MCA associated with hypogammaglobulinemia. Given the patient's seemingly rare and highly complex chromosomal abnormality and the lack of any concise mechanism presented in the literature to justify the case, we hereby propose a novel mechanism for the formation of both derivative and ring chromosome 18. In addition, we introduce a new 12q abnormality and a novel association of an Xp22.33 duplication with 1q43q44 deletion syndrome. The phenotype analysis of the patients with chromosome abnormality would be beneficial for further phenotype-genotype correlation studies., Competing Interests: There is no conflict of interest in this study., (Copyright© by Royan Institute. All rights reserved.)

Introduction: Few drugs are available for migraine prophylaxis in children. Levetiracetam is a broad-spectrum anti-seizure drug that has been suggested to be effective in reducing adult migraine episodes. We assessed the safety and efficacy of levetiracetam in the prevention of pediatric migraine., Methods: A randomized double-blind placebo-controlled trial was performed. Eligible participants were aged 4-17 years old with at least four migrainous episodes monthly or had severe disabling or intolerable episodes. Primary endpoints were the mean changes in monthly frequency and intensity of headaches from the baseline phase to the last month of the double-blind phase. Safety endpoint was the adverse effects reported., Results: Sixty-one participants (31 taking levetiracetam and 30 taking placebo) completed the study. All had a significant reduction in frequency and intensity of episodes that was significantly greater in the levetiracetam arm. Sixty eight percent of individuals in the treatment group reported more than 50% reduction of episodes at the end of the trial compared with 30% in the placebo group ( p -value: 0.007). Irritability, day-time sedation, and mild tic were reported., Conclusion: Levetiracetam may be useful in migraine prevention and may decrease migraine episodes and severity., Trial Registration: The study is prospectively registered with Iranian Registry of Clinical Trials; IRCT.ir, number IRCT2017021632603N1.

Purpose: On May 8, 2018, the United States announced that it was withdrawing from the Iran nuclear deal. This has resulted in reimposition of the economic hardship on Iran. We investigated the patients' perceptions of hardship in obtaining their antiepileptic drugs (AEDs) after the reimposition of sanctions., Methods: We surveyed patients with epilepsy visiting three centers in Iran on February 2nd to 6th (easy sampling) on their perceptions on two issues: RESULTS: Two hundred and forty-four patients participated. Ninety-two patients (37.7%) claimed that they have had significant difficulty obtaining their AEDs, and 37 patients (15.2%) said that their AED(s) was not accessible. Ninety-six people (72%) of those receiving imported AEDs and 33 patients (30%) of those receiving homemade AEDs had significant hardship obtaining their drugs (p = 0.00001). Forty-seven patients (36%) of those who reported significant hardship obtaining their AEDs and 25 (22%) of those who did not, perceived worsening of their seizures (p = 0.017)., Conclusion: Sanctions have affected ordinary people, especially those who are vulnerable the most (i.e., patients), significantly., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Classical ketogenic diet (KD) and modified Atkins diet (MAD) are two types of KD commonly used for the treatment of intractable epilepsy throughout the world. Studies have shown the efficacy of these diets. However, no systematic review and meta-analysis study has to date compared the efficacy of KD and MAD in a time trend. Therefore, the objectives of the present study were to compare the short-term and long-term efficacy of classical KD and MAD in children and adolescents with epilepsy and to determine the efficacy of classical KD and MAD at multiple time points and in a time trend., Methods: Main electronic literature databases, including MEDLINE/PubMed, Web of Science, Scopus, and EMBASE, were searched in November 2016. Rate difference and random effects model were used to compare the efficacy of the classical KD and MAD., Results: Overall, 70 studies were eligible for inclusion. Meta-analysis revealed a non-significant trend toward a higher efficacy of MAD at month-3 and month-6 (P > 0.05). In the classical KD group, the percentage of responder patients achieving ≥50% seizure reduction was 62, 60, 52, 42, and 46% at month-1, 3, 6, 12 and 24 and for the MAD group was 55, 47, 42, and 29% at month-1, 3, 6, and 12, respectively., Discussion: Classical KD does not differ substantially from MAD in ≥50% and ≥90% reduction of seizure frequency at month-3 and month-6. Overall, the number of patients achieving seizure freedom increases over time.

Low glycemic index treatment (LGIT) is one of the new kinds of ketogenic diet (KD), designed to simplify the implementation of the KD. To date, several studies have attempted to determine the efficacy of LGIT in patients with epilepsy; however, their results are debatable. This study aims to retrieve all the LGIT studies to shed light on LGIT efficacy in epileptic patients. Electronic literature databases including MEDLINE/PubMed, Web of Science, Scopus, EMBASE were searched in July 2017. Interventional or observational studies exploring the efficacy of LGIT were included in the study. The National Heart, Lung, and Blood Institute quality assessment tool was used for the quality assessment of included studies. Two hundred and eighteen records were retrieved through a literature search. Following the screening process, eight studies were included. According to the ratings of the quality assessment tool, four studies were classified as good and four were categorized as fair. The result of the current study reveals that LGIT has a beneficial effect in patients with intractable epilepsy. However, more high-quality studies are required to determine the efficacy of LGIT in patients with intractable epilepsy.

Objectives: Malignant Infantile Osteopetrosis (MIOP) is a rare inherited disorder with neurological complications, notably visual impairment and decrease of hearing level. Although Hematopoietic Stem Cell Transplantation (HSCT) has been approved as the only curative treatment for these patients, the exact impact of it on visual and hearing level is still unclear., Study Design: We analyzed the P2 latency and amplitude from Visual Evoked Potentials (VEP) of 10 patients (20 eyes) and the threshold of wave V from Auditory Brainstem Response (ABR) of 15 patients (30 ears) with MIOP before, 6 and 12 months after HSCT., Results: Before the HSCT, 10/30 ears demonstrated some degree of hearing loss; while only 3/20 eyes had P2 wave latencies in normal range for age. Using GEE models, it was shown that 12 months after HSCT, wave V threshold of ABR of the patients was significantly lower compared to its value from before the transplant (p value: 0.04). The analysis of latency and amplitude of P2 wave of VEPs showed no significant difference between before and after the transplant., Conclusion: This study clearly showed that HSCT can improve the hearing level of the patients in terms of ABR threshold. Although HSCT made no significant improvement in latency of P2 in VEP of the patients, it can be concluded that transplant can halt visual regression in these patients. Early diagnosis of MIOP with this objective tools and subsequently early HSCT in these patients can decrease the rate of neurological complications of MIOP and improve the quality of life in them., (Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Childhood leukodystrophies are a fast-growing field of pediatric neurology practice. Epidemiologic studies on the incidence of these disorders in children show different results. This is the first report of childhood leukodystrophies incidence from Iran. The enrolled patients were recruited from the neurometabolic bioregistry system that was organized in 2010 in the Children's Medical Center, Tehran, Iran. Herein is reported the incidence rate of leukodystrophies in those patients who were residents of 2 big popular provinces near Iran's capital city Tehran, with an average child population of 2 988 800 children. Ninety cases of leukodystrophies from Tehran and Alborz provinces who were registered between 2010 and 2016 in the bioregistry system were enrolled in this study. The annual incidence of inherited white matter disorders was 3.01/100 000, the highest number compared with those found in other studies using similar methods throughout the world. One of the main cause of this higher incidence could be the higher number of consanguineous marriages in Iran.

Objectives: Genetic heterogeneity of epileptic encephalopathy (IEE) mandates the use of gene-panels for diagnosis., Patients and Methods: A 36-gene-panel next-generation sequencing was applied for IEE in two Iranian families. A literature search was performed using keywords to identify reported splicing mutations in SCN1A and perform genotype-phenotype correlation., Results: An update of splicing mutations revealed 147 variants with 65.75% of them de novo mutations. Most of the familial variants were of parental origin. The structure of the protein was often affected in the linker and transmembrane segments. 92% of intronic variants were pathogenic. A de novo heterozygous mutation was found in the first patient, but not in her sibling and parents. In the second family, a novel de novo heterozygous mutation was found at position c.1210insT leading to a truncated protein., Conclusion: Gene-panel sequencing is helpful for reducing the time and cost, guiding early treatment, and estimating the recurrence risks. The importance of characterization of intronic variants was noticed; though bioinformatics analysis of novel intronic variants should be of concern for rapid reporting the pathogenic effect of variants., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to assess the effect of parent report gross motor function level of cerebral palsy (CP) children on the parent report quality of life of CP children., Materials & Methods: Sampling of this cross-sectional study was done in occupational therapy clinics and CP children's schools in 2016 in Zanjan, Iran. Samples size was 60 CP children aged 6-12 yr and for sampling method, a non-probability convenience was used. For assessing the quality of life of CP children the cerebral palsy quality of life (CP QOL) questionnaire and for assessing the level of gross motor function of CP children the Gross Motor Function Classification System Family Report Questionnaire (GMFCSFRQ) were used., Results: The average age of children (22 males and 30 females) was 8.92 yr old (minimum 6 yr and maximum 12 yr). The relationship between the level of gross motor function and participation and physical health was direct and significant (r=0.65). The relationship between functioning, access to services and family health with the level of gross motor function was direct but was not significant ( P >0.05) and the relationship between pain and impact of disability and emotional well-being with the level of gross motor function was significant ( P <0.05)., Conclusion: There was no strong correlation between the level of gross motor function and quality of life of children with cerebral palsy. It means that the level of gross motor function cannot be used as a predictor of quality of life for children with cerebral palsy alone.

To evaluate the efficacy, safety, and tolerability of a classic 4:1 ketogenic diet using a formula-based powder in infants and children with refractory seizures who are reluctant to eat homemade foods. We conducted an open label trial and administered a ketogenic diet using formula-based power (Ketocal ® ). Twenty-seven infants and children aged between 12 months and 5 years were enrolled who had refractory seizures and were reluctant to eat homemade foods. Of 27 children, 5 were lost to follow-up and 22 were remained at the end of the study. After 4 months, the median frequency of seizures per week was reduced >50% in 68.2% of patients, while 9/22 children (40.9%) showed a 50-90% reduction in seizure frequency per week, and 6/22 children (27.3%) showed more than 90% reduction in seizure frequency per week. Over the study course, 6/22 (27%) children who continued to receive the diet developed constipation, one child developed gastroesophageal reflux, and one child developed hypercholesterolemia. None of these children discontinued the diet because of the complications. Thirteen children and their parents (59%) reported that the diet was palatable and tolerable enough. The ketogenic diet using a formula-based powder (Ketocal ® ) is effective, safe, and tolerable in infants and children with refractory seizures who are reluctant to eat homemade foods according to the rules of the ketogenic diet.

More than 25 % of children with epilepsy develop refractory seizures unresponsive to both old and new generation anticonvulsants. Since such seizures have a serious negative impact on the quality of life, other treatment options are considered. The ketogenic diet is a well-known treatment for managing refractory seizures, although its mechanism of action is unknown. Studies have shown that this diet is as good as, or better than, any of the newer medications in reducing seizure frequency. However, concerns about adverse effects have been raised. We conducted an open label trial to show the effects of this diet on serum lipid profile. Thirty-three children with refractory epilepsy were treated with the ketogenic diet and were followed for 6 months. Their serum lipid profile was assessed at baseline, and at 3 and 6 months after initiating the diet. Seizure frequency was reduced in 63 % of children (no seizures in 2/33 and reduced >50 % in 19/33). However, after 6 months of administering the diet, median triglyceride was significantly increased (from 84 to 180 mg/dl, P < 0.001), median total cholesterol was significantly increased (from 180 to 285 mg/dl, P < 0.001), median serum low-density lipoprotein (LDL) was significantly increased (from 91 to 175 mg/dl, P < 0.001), and median serum high-density lipoprotein (HDL) was significantly increased (from 51 to 58 mg/dl, P < 0.001). Results of this study indicate that a classic ketogenic diet in children with refractory seizures is effective in seizure reduction, but leads to development of hypercholesterolemia and hypertriglyceridemia.

Febrile seizures (FS) is the most common seizure disorder during childhood. This study was performed in 78 patients with FS and 137 control subjects to assess polymorphisms of the TNF-α gene at positions -308 and -238, using the polymerase chain reaction and the sequence specific primers method. The highest positive allelic association that made the patients susceptible to FS was seen for TNF-α -238/G (p<0.0001). The GG genotype at TNF-α -238 was significantly higher in the patients with FS, compared to the controls (p=0.0001). Also, GA genotype at the same position was significantly lower in patients than in controls (P=0.0001). The GG haplotype had a significant positive association at TNF-α (308, 238) while GA haplotype showed a negative association (P<0.001). Our data support the idea that TNF-α single-nucleotide polymorphisms play a role in the pathogenesis of FS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: At a time of increasing high risk neonates, an assessment method is needed that can reliably predict neurological deficits at an early age., Aims: The objective of this study was to determine whether the assessment of fidgety movements (FMs) will predict the neurological outcome of infants with hypoxic ischemic encephalopathy (HIE)., Study Design: This study employed a prospective and descriptive plan., Subjects: The study sample consisted of 15 infants (8 male and 7 female) born at term. Video recording of FMs were analyzed at 3 to 5 months' infants, who identified with perinatal asphyxia and neonatal HIE. FMs were classified as present or absent., Outcome Measures: At 12-18 months age, the infants' developmental outcome was classified as normal or abnormal according to the Infant Neurological International Battery test. "Abnormal outcome" was denoted as poor motor or neurological outcome such as cerebral palsy, whereas "Normal outcome" denotes normal motor and neurological outcomes., Results: The predictive values of FMs were: a sensitivity 0.80 (95% CI: 0.44-0.96), a specificity 1.00 (95% CI: 0.47-1.00), and the accuracy 0.87 (0.57 to 1.00)., Conclusions: FMs assessment improves our ability to predict later neurodevelopmental outcomes in term born children with neonatal HIE., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)