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.

First description of a patient with Vici syndrome due to a mutation affecting the penultimate exon of EPG5 and review of the literature.

Vici syndrome is a rare autosomal recessively inherited multisystem disorder characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, psychomotor delay, and hypopigmentation. Cullup et al. recently identified mutations in the gene EPG5 as the cause of Vici syndrome. EPG5 is involved in autophagy, an evolutionarily conserved lysosomal degradation process that is essential for cell homeostasis. Following the first description in 1988 by Vici et al., 24 other cases of Vici syndrome have been published with variable expression of the defining features. Here, we report on a further case of Vici syndrome with a homozygous truncating mutation of EPG5, identified by whole-exome sequencing. The mutation in our patient is the first reported affecting the penultimate exon of EPG5 and presenting with typical clinical manifestations of Vici syndrome. Additionally, we present a detailed clinical analysis of Vici syndrome comprising all cases previously described in the literature.

Safety and efficacy of levetiracetam and carbamazepine monotherapy in the management of pediatric focal epilepsy: a randomized clinical trial.

Due to the limited number of studies in children with focal epilepsy and the importance of choosing the most suitable drug to control seizures in children, the administration of the most effective medication with the most negligible adverse events is vital. This study aimed to evaluate the effectiveness and adverse events of carbamazepine vs. levetiracetam monotherapy in children with focal seizures. A monocentric, randomized, controlled, double-blind, parallel-group clinical trial was designed. This study was approved by the Iranian Registry of Clinical Trials (registration number: IRCT20170216032603N2) on June 19, 2020, and conducted at the neurology department of Imam Ali Hospital, Karaj, Iran, from February 2020 to March 2021. This study assessed 120 patients with recently diagnosed focal seizures aged 2 to 14. Patients were randomly divided into two groups, who received carbamazepine (CBZ) 15 to 20 mg/kg and levetiracetam (LEV) 20 to 40 mg/kg daily, respectively. Patients were evaluated for improvement and complications at weeks 4, 12, and 24. Out of 120 patients included in the study, six patients were excluded due to various complications of CBZ. The mean number of seizures at the end of the fourth, twelfth, and twenty-fourth weeks were 1.09 ± 0.75, 0.62 ± 0.27, and 0.39 ± 0.12 in the carbamazepine group and 1.11 ± 0.63, 0.52 ± 0.21, and 0.37 ± 0.11 in the LEV group, respectively (P > 0.05). Similarly, the number of seizure-free patients was 34, 44, and 48 in the CBZ group compared to 41, 50, and 54 in the LEV group, respectively (P > 0.05). On the other hand, the frequency of somnolence, dermatologic complications, and agitation was considerably higher in the CBZ group (P < 0.05). Although both medicines were equally effective in seizure control, CBZ was associated with considerably more adverse events and less patient compliance. Physicians should be aware of this difference to prevent unwanted consequences.

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.

Novel disease-causing variants in a cohort of Iranian patients with metachromatic leukodystrophy and in silico analysis of their pathogenicity.

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.

COVID-19: A New Horizon in Congenital Heart Diseases.

Objective: Previous studies have demonstrated that both children and adult patients with a history of congenital heart disease (CHD) are at high risk for coronavirus disease 2019 (COVID-19) infection. This study investigates the status of COVID-19 infection among children undergoing surgical repair within the past 2 years. Methods: All alive patients operated on in a tertiary referral center between March 2018 and March 2020 were recruited in the present study. Detailed demographics, past medical and surgical history, and physical examination were reviewed for each patient. During the COVID-19 pandemic, data regarding the patient's status were collected by telephone survey from April 15 to April 30, 2020. Results: A total number of 210 patients are analyzed in this study. Participants' median age was 21.59 months [interquartile range (IQR) = 12-54.67], and 125 (59.5%) were female. The median interval between surgery and COVID-19 assessment was 305 days (IQR = 215-400). In addition, 67 (32%) patients used angiotensin receptor blocker (ARB)/angiotensin-converting enzyme (ACE) inhibitor (spironolactone and/or captopril). Sixteen patients (7.6%) were symptomatic and had positive chest CT results and/or RT-PCR compared to the previously reported prevalence of COVID-19 among the pediatric population (2.4% of children with <18 years of age); the prevalence of COVID-19 among the patients operated on due to CHD in the present study was significantly higher (p = 0.00012). Two patients were admitted to the intensive care unit (ICU); one patient was discharged 2 weeks later with acceptable status, and one patient died 2 days after ICU admission due to cardiac and respiratory arrest and myocarditis. The complexity of the underlying cardiac disorders was not different between patients with low risk (p = 0.522), suspicious patients (p = 0.920), and patients positive for COVID-19 (p = 0.234). The ARB/ACE inhibitor consumption was not associated with the COVID-19 infection [p = 0.527, crude odds ratio (OR) = 1.407, 95% CI = 0.489-4.052]. Conclusion: Children with a history of previous CHD surgery are more susceptible to infections, especially those infections with pulmonary involvements, as the lung involvement could cause worsening of the patient's condition by aggravating pulmonary hypertension. The results of the current study indicate that these patients are more prone to COVID-19 infection compared to the healthy children population.

Effect of anti-epileptic drugs on serum immunoglobulin levels in children.

Epilepsy is one of the most frequent neurological disorders. Despite the advances and improvements in treatment of seizure disorders, immunologic alterations related to anticonvulsant drugs have been described. The aim of this paper is to assess the effect of some antiepileptic drugs on serum immunoglobulin levels in epileptic patients. Seventy-one patients with epilepsy were included in the study. Participants were divided into three groups based on their treatment with carbamazepine (n=33), sodium valproate (n=22) or phenobarbital (n=16) as monotherapy. Three samples were taken from each patient and serum immunoglobulin levels were measured before treatment, 3 months and 6 months after therapy. Overall, eleven patients out of 71 (15.5%) had a decrease in at least one serum immunoglobulin level (more than 2SD below age-matched control). In the patients receiving carbamazepine, 8 patients (24.2%) showed significant decline in at least one immunoglobulin (3 cases in IgA and 5 cases in IgG). In the group of treated with sodium valproate, 2 patients showed significant decrease in serum IgA level. Results of the last group indicated a significant reduction in serum IgG concentration only in one patient. No patient at all showed significant decrease in serum IgM level. This study suggests that anti-epileptic drugs could reduce serum immunoglobulins, especially IgA and IgG; among them carbamazepine effect is of more concern.

SZT2 mutation in a boy with intellectual disability, seizures and autistic features.

The seizure threshold 2 (SZT2) gene has been shown to confer a low seizure threshold and may enhance epileptogenesis in mice. However, its biological function is still not known. Mutations in SZT2 have been reported in very few patients and features range from mild to moderate intellectual disability without seizures to severe intellectual disability with epileptic encephalopathies with severe developmental delay. Here, we report a six-year-old boy with a novel homozygous mutation in SZT2 gene with intellectual disability, seizures, absent speech and autistic features. We are reporting the first patient with autistic features including very little or no eye contact, arm flapping and repetitive behaviour.

Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency.

Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine nucleoside phosphorylase is an enzyme in the purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy.

A Novel Mutation in Aspartoacylase Gene; Canavan Disease.

Objective Canavan disease (CD) is a type of vacuolating leukodystrophy with autosomal recessive inheritance. Aspartoacylase deficiency results in decrease of myelin biosynthesis, dysmyelination and brain edema. Although CD is a very common in Ashkenazi Jews patients, several cases have been reported from non-Jewish population. This report is based on a homozygous C.202G>A mutation in the ASPA gene identified from an Iranian patient. To our knowledge, this type of mutation has not been reported in non-Jewish population in the literature.

Evaluation of Educational Environment for Medical Students of a Tertiary Pediatric Hospital in Tehran, Using DREEM Questionnaire.

BACKGROUND: Tertiary pediatric hospitals usually provide excellent clinical services, but such centers have a lot to do for educational perfection. OBJECTIVES: This study was performed to address under-graduate educational deficits and find feasible solutions. PATIENTS AND METHODS: This cross-sectional study was done in a target population of 77 sixth year undergraduate medical students (response rate = 78%) who spent their 3-month pediatric rotation in the Children's Medical Center, the Pediatrics Center of Excellence in Tehran, Iran. The Dundee ready educational environment measure (DREEM) instrument was used for assessing educational environment of this subspecialized pediatric hospital. RESULTS: Among 60 students who answered the questionnaires, 24 were male (40%). Participants' age ranged from 23 to 24 years. The mean total score was 95.8 (48%). Comparison of scores based on students' knowledge showed no significant difference. Problematic areas were learning, academic self-perception, and social self-perception. CONCLUSIONS: Having an accurate schedule to train general practitioner, using new teaching methods, and providing a non-stressful atmosphere were suggested solutions.

Alexander Disease: Report of Two Unrelated Infantile Form Cases, Identified by GFAP Mutation Analysis and Review of Literature; The First Report from Iran.

BACKGROUND: Alexander disease (AD) is a sporadic leukodystrophy that predominantly affects infants and children and usually results in death within ten years after onset. The infantile form comprises the most of affected individuals. It presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly and frontal bossing, seizures, pyramidal signs and ataxia. The diagnosis is based on magnetic resonance imaging (MRI) findings and confirmed by GFAP gene molecular testing. GFAP gene encodes glial fibrillary acidic protein, is the only gene in which mutation is currently known to cause AD which is inherited in autosomal dominant manner. CASE PRESENTATION: In this article we report the first two Iranian cases of infantile AD and their clinical, brain MRI and molecular findings. We report two novel mutations too in the GFAP gene that are associated with infantile form of AD. CONCLUSION: GFAP gene mutations are a reliable marker for infantile AD diagnosed according to clinical and MRI defined criteria. A genotype-phenotype correlation had been discerned for the two most frequently reported GFAP gene mutations in infantile type of AD (R79 and R239), with the phenotype of the R79 mutations appearing much less severe than that of the R239 mutations. Our findings confirm this theory.

Autism in a child with common variable immunodeficiency.

Autism is a neurodevelopmental disorder, characterized by poor social interaction and communication impairment and repetitive behavior. Autism is considered as a genetic and multifactorial disorder, with diverse risk factors involved.Herein, we report a 13-year-old male with common variable immunodeficiency (CVID), who was diagnosed with autism at the age of 3 years old. As there are some evidences about the role of the immune system defects in the pathogenesis of autism, specific primary antibody deficiency diseases such as CVID might predispose some affected cases to such neurodevelopmental disorders.

Clinical trial of vigabatrin as adjunctive therapy in children with refractory epilepsy.

OBJECTIVE: Approximately one-third of all children with epilepsy do not achieve complete seizure improvement. This study evaluated the efficacy of Vigabatrin in children with intractable epilepsy. METHODS: From November 2011 to October 2012, 73 children with refractory epilepsy (failure of seizure control with the use of two or more anticonvulsant drugs) who were referred to the Children's Medical Center and Mofid Children's Hospital were included in the study. The patients were treated with Vigabatrin in addition to their previous medication, and followed-up after three to four weeks to determine the daily frequency, severity, and duration of seizures in addition to any reported side effects. FINDINGS: Of the 67 children, 41 (61.2%) were males and 26 (38.8%) females, their age ranging from three months to 13 years with an average of 3.1 [standard deviation (SD), 2.6] years. The mean daily frequency of seizures at baseline was 6.61 (SD, 5.9) seizures per day. Vigabatrin reduced the seizure frequency ≤2.9 (SD, 5.2) (56% decline) and 3.0 (SD, 5.3) (54.5% decline) per day after three and six months of treatment, respectively. A significant difference was observed between seizure frequencies at three (P<0.001) and six months (P<0.001) after Vigabatrin initiation compared with the baseline. Somnolence [3 (4.5%)], horse laugh [1 (1.5%)], urinary stones [1 (1.5%)], increased appetite [1 (1.5%)], and abnormal electroretinographic pattern [3 (4.5%)] were the most common side effects in our patients. CONCLUSION: This study confirms the short-term efficacy and safety of Vigabatrin in children with refractory epilepsies.

Pelizaeus-merzbacher disease: the first genetically approved case report from iran.

BACKGROUND: Classic Pelizaeus-Merzbacher disease is a rare x-linked disorder of proteolipid protein expression first described clinically in 1885. This disease is characterized by abnormal eye movements, very slow motor development and involuntary movements. The causative gene is PLP1. CASE PRESENTATION: A 1-year-old boy was referred to our clinic due to abnormal eye movements. He had horizontal and flickering eye oscillation, psychomotor retardation, hypotonia and head nodding. We found hypomyelination in brain MRI. CONCLUSION: The possibility of Pelizaeus-Merzbacher disease should be considered in boys with abnormal eye movements, psychomotor retardation and hypotonia.

Effect of anti-epileptic drugs on serum level of IgG subclasses.

OBJECTIVE: There are some controversial studies on effects of anti-epileptic drugs (AEDs) on serum IgG subclasses; however, the role of these medications is still unclear. The aim of this study was evaluation the effects of anti-epileptic drugs on serum concentration of IgG and its subclasses METHODS: Serum IgG and IgG subclasses of 61 newly diagnosed epileptic patients were measured at the beginning of monotherapy with carbamazepine, sodium valproate, and phenobarbital, and 6 months later. Measurement of IgG and its subclasses was performed using nephlometry and ELISA techniques, respectively. FINDINGS: Reduction of at least one IgG subclass was found in 6 patients 6 months after treatment with AEDs. Among 27 patients receiving carbamazepine, decrease in at least one serum IgG subclass level was found in 5 patients. Among 20 patients using sodium valproate, only one patient showed decrease in IgG2 subclass. None of the 14 patients using phenobarbital revealed significant decrease in IgG subclasses. No infection was seen in the patients with reduction of subclasses. CONCLUSION: Although in our study, children with selective IgG subclass deficiency were asymptomatic, assessment of serum immunoglobulin levels could be recommended at starting the administration of AEDs and in serial intervals afterward in epileptic patients.