Coronavirus, its neurologic manifestations, and complications

Context: We are going to face an epidemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus in our country. The main manifestation of this viral infection is respiratory and cardiovascular; however, up-to-date knowledge of its probable neurologic complications is highly needed. Evidence Acquisition: To provide up-to-date information on neurologic manifestation on coronaviruses, we concisely reviewed the neurologic manifestations and their complications. Using the keywords, coronavirus, corona, human coronaviruses (HCoVs), SARS, Middle East respiratory syndrome-related (MERS), coronavirus disease 2019 (COVID-19), manifestations, complications, and neurologic, all the relevant articles were retrieved from PubMed, reviewed, and critically analyzed. Results: Although the main clinical manifestation of human coronaviruses is respiratory involvement and the main cause of death is acute respiratory failure, extra respiratory manifestations such as neurologic findings have been reported. Fortunately, the neurologic manifestations in COVID-19 have not been reported yet. Conclusions: We need well-designed studies to monitor neurologic manifestations of COVID-19 in adults and children. © 2020, Author(s)

Investigation of chromosomal abnormalities and microdeletion/ microduplication(s) in fifty Iranian patients with multiple congenital anomalies

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), +mar8 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. © 2019 Royan Institute (ACECR). All rights reserved

Pathogenic significance of SCN1A splicing variants causing Dravet syndrome: Improving diagnosis with targeted sequencing for variants by in silico analysis

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. © 2018 Elsevier B.V

Pathogenic significance of SCN1A splicing variants causing Dravet syndrome: Improving diagnosis with targeted sequencing for variants by in silico analysis

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. © 2018 Elsevier B.V

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. © 2020 Elsevier B.V

The effects of classic ketogenic diet on serum lipid profile in children with refractory seizures

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. © 2016 Belgian Neurological Societ

Levetiracetam for prophylactic treatment of pediatric migraine: A randomized double-blind placebo-controlled trial

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. © International Headache Society 2019

The First Report of Iranian Registry of Patients with Spinal Muscular Atrophy

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