Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants

This study evaluates the genetic spectrum of leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13), Canavan disease (12; 8), Tay-Sachs disease (11; 7), megalencephalic leukodystrophy with subcortical cysts (7; 5), X-linked adrenoleukodystrophy (8; 5), Pelizaeus�Merzbacher-like disease type 1 (8; 5), Sandhoff disease (6; 4), Krabbe disease (5; 3), and vanishing white matter disease (4; 3). Whole exome sequencing (WES) revealed 90 leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75. This unique study presents a national genetic data of leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning. © 2021, The Author(s)

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)

Seizure as the early and main manifestation of infantile vanishing white matter disease: A case report

Introduction: Vanishing white matter disease (VWM) is considered as one of the most frequent types of inherited childhood leukoencephalopathies. Various neurological and non-neurological manifestations have been reported in this type of leukodystrophy; however, seizures are rarely described in infantile type of VWM. Case Presentation: To patient is a 12 months old boy who experienced frequent seizures at 4th month of age. The seizures were resistant to anti-epileptic drugs and caused 3 periods of hospitalization. Magnetic resonance imaging (MRI) demonstrated demyeli-nating pattern and whole exome sequencing (WES) reported homozygous mutation (c.922G > A) in EIF2B2 gene in exon 8 leading to an amino-acid substitution (p.Val308Met). Conclusions: Infantile onset of vanishing white matter disease can be considered as one of few childhood leukodystrophies that are associated with early onset seizures. © 2018, Iranian Journal of Pediatrics

Effects of diets enriched with fish oil, vitamin A and vitamin E on experimental ulcerative colitis in rat's

Background: There are controversial reports about the therapeutic effects of fish oil in patients with ulcerative colitis. Polyunsaturated fatty acids cause an oxidative injury at the site of inflammation because of a decrease in the colonic antioxidant defense system. Vitamins A and E inhibit lipid peroxidation in the tissues. The aim of the present study was to evaluate possible useful effects of fish oil, vitamin A and vitamin E enriched diets on the improvement of colonic damage and reduction of inflammation in experimental acute ulcerative colitis.Materials and Methods: Eighty adult Wistar rats were randomly divided into treatment and pretreatment groups. Rats in the treatment groups received intrarectal saline (control group, n=10) or acetic acid (1 ml, 4) to induce acute ulcerative colitis. After the induction of colitis, rats were fed for 1 wk with standard diet (colitis group, n= 10), diet enriched with fish oil (10) and 1.2 mg/Kg vitamin A (FA group n=10), or diet enriched with fish oil (10) and 2 gr/Kg vitamin E (FE group, n=10). The control group was fed with standard diet. After 1 wk the degree of tissue injuries was assessed by macroscopical and histopathological scores of colonic mucosa. In pretreatment groups, rats were fed for 1 wk with standard diet (colitis group, n=10), diet enriched with fish oil (10) and 1.2 mg/Kg vitamin A (PFA group n=10) and or diet enriched with fish oil (10) and 2 gr/Kg vitamin E (PFE group, n=10) and then they received intrarectal acetic acid to induce ulcerative colitis. The control group was fed with standard diet and received intrarectal saline. Two days after the induction of colitis the degree of tissue injuries was assessed by macroscopical and histopathological scores of colonic mucosa.Results: Acetic acid administration induced severe macroscopic (Total score=5.0±0.0) and microscopic damages to mucosal tissue (Total score=9.7±1.3). The Rats with colitis in the treated group FE at 1wk showed significantly less macroscopic (Total score=1.0±0.3) and microscopic colonic damage (Total score=2.7±0.7) compared with those in colitis group. However in the FA group with macroscopic (Total score=3.2±0.7) and microscopic colonic damage (Total score=7.8±.8) there was no significant difference with colitis group. Pretreatment of acetic acid-treated rats with FA and FE diets did not result in any improvements in macroscopic and microscopic scores. Conclusion: These results may reflect that fish oil and vitamin E enriched diets could be beneficial in the treatment of ulcerative colitis

Genotype, phenotype and in silico pathogenicity analysis of HEXB mutations: Panel based sequencing for differential diagnosis of gangliosidosis

Objectives: Gangliosidosis is an inherited metabolic disorder causing neurodegeneration and motor regression. Preventive diagnosis is the first choice for the affected families due to lack of straightforward therapy. Genetic studies could confirm the diagnosis and help families for carrier screening and prenatal diagnosis. An update of HEXB gene variants concerning genotype, phenotype and in silico analysis are presented. Patients and Methods: Panel based next generation sequencing and direct sequencing of four cases were performed to confirm the clinical diagnosis and for reproductive planning. Bioinformatic analyses of the HEXB mutation database were also performed. Results: Direct sequencing of HEXA and HEXB genes showed recurrent homozygous variants at c.509G>A (p.Arg170Gln) and c.850C>T (p.Arg284Ter), respectively. A novel variant at c.416T>A (p.Leu139Gln) was identified in the GLB1 gene. Panel based next generation sequencing was performed for an undiagnosed patient which showed a novel mutation at c.1602C>A (p.Cys534Ter) of HEXB gene. Bioinformatic analysis of the HEXB mutation database showed 97 consistency of in silico genotype analysis with the phenotype. Bioinformatic analysis of the novel variants predicted to be disease causing. In silico structural and functional analysis of the novel variants showed structural effect of HEXB and functional effect of GLB1 variants which would provide fast analysis of novel variants. Conclusions: Panel based studies could be performed for overlapping symptomatic patients. Consequently, genetic testing would help affected families for patients� management, carrier detection, and family planning's. © 2018 Elsevier B.V

Genotype, phenotype and in silico pathogenicity analysis of HEXB mutations: Panel based sequencing for differential diagnosis of gangliosidosis

Objectives: Gangliosidosis is an inherited metabolic disorder causing neurodegeneration and motor regression. Preventive diagnosis is the first choice for the affected families due to lack of straightforward therapy. Genetic studies could confirm the diagnosis and help families for carrier screening and prenatal diagnosis. An update of HEXB gene variants concerning genotype, phenotype and in silico analysis are presented. Patients and Methods: Panel based next generation sequencing and direct sequencing of four cases were performed to confirm the clinical diagnosis and for reproductive planning. Bioinformatic analyses of the HEXB mutation database were also performed. Results: Direct sequencing of HEXA and HEXB genes showed recurrent homozygous variants at c.509G>A (p.Arg170Gln) and c.850C>T (p.Arg284Ter), respectively. A novel variant at c.416T>A (p.Leu139Gln) was identified in the GLB1 gene. Panel based next generation sequencing was performed for an undiagnosed patient which showed a novel mutation at c.1602C>A (p.Cys534Ter) of HEXB gene. Bioinformatic analysis of the HEXB mutation database showed 97 consistency of in silico genotype analysis with the phenotype. Bioinformatic analysis of the novel variants predicted to be disease causing. In silico structural and functional analysis of the novel variants showed structural effect of HEXB and functional effect of GLB1 variants which would provide fast analysis of novel variants. Conclusions: Panel based studies could be performed for overlapping symptomatic patients. Consequently, genetic testing would help affected families for patients� management, carrier detection, and family planning's. © 2018 Elsevier B.V

A novel missense variant in GPT2 causes non-syndromic autosomal recessive intellectual disability in a consanguineous Iranian family

Intellectual disability (ID) affects 1�3 of the general population worldwide. Genetic factors play an undeniable role in the etiology of Non-Syndromic Intellectual disability (NS-ID). Nowadays, whole-exome sequencing (WES) technique is used frequently to identify the causative genes in such heterogeneous diseases. Herein, we subjected four patients with initial diagnostics of NS-ID in a consanguineous Iranian family. To find the possible genetic cause(s), Trio-WES was performed on the proband and his both healthy parents. Sanger sequencing was performed to confirm the identified variant by WES and also investigate whether it co-segregates with the patients� phenotype in the family. Using several online in-silico predictors, the probable impacts of the variant on structure and function of GPT2 protein were predicted. A novel variant, c.266A>G; p.(Glu89Gly), in exon 3 of GPT2 (NM133443.3) was identified using Trio-WES. The candidate variant was also verified by Sanger sequencing. All affected members showed the common clinical features suffering from a non-progressive mild-to-severe ID. Also, different clinical observations compared to previously reported cases such as no facial features, no obvious structural malformations, ability to speak but with difficulty, and lack of any morphological defects were noted for the first time in this family. The c.266A>G; p.(Glu89Gly) variant reported here is the sixth variant identified up to now in the GPT2 gene, to be associated with NS-ID. Our data support the potential malfunction of the substituted GPT2 protein resulted from the novel variant, however, we strongly suggest confirming this finding more by doing functional analysis. © 2020 Elsevier Masson SA

GFAP variants leading to infantile Alexander disease: Phenotype and genotype analysis of 135 cases and report of a de novo variant

Objectives: Alexander disease (AxD) is a rare autosomal dominant disorder due to GFAP mutations; infantile AxD is the most common severe form which usually results in death. In this study, phenotype and genotype analysis of all reported cases with IAxD are reported as well as a de novo variant. Methods: We conduct a comprehensive review on all reported Infantile AxD due to GFAP mutation. Clinical data and genetics of the reported patients were analyzed. Clinical evaluations, pedigree drawing, MRI and sequencing of GFAP were performed. Results: 135 patients clinically diagnosed with IAxD had GFAP mutations. A total of fifty three variants of GFAP were determined; 19 of them were located at 1A domain. The four common prevalent variants (c 0.715C>T, c 0.236G�A, c 0.716G�A, and c 0.235C�T) were responsible for 64/135 (47.4) of the patients. Seizure was the dominant clinical symptom (62.3) followed by macrocephaly (41), developmental delay (23.9) and spasticity (23.9). A de novo variant c 0.715C�T was found in the presented Iranian case. Discussion: The majority of GFAP variant are located in a specific domain of the protein. Seizure as the most common symptom of IAxD could be considered. This study highlighted the role of genetic testing for diagnosing AxD. © 2021 Elsevier B.V

The efficacy of cerebrolysin in improvement of spasticity in children with cerebral palsy: A clinical trial

Background: Cerebral Palsy (CP) constitutes a heterogeneous group of developmental disorders resulting from damage to the brain which affects motor system. Cerebrolysin, as a neurotrophic peptide has been used for improving symptoms of patients suffering from neurodegenerative disorders. Objectives: Due to the presence of limited information about the usefulness of Cerebrolysin in CP, this study was performed for the evaluation of Cerebrolysin in the management of spasticity in children with CP. Methods: 26 Spastic CP patients aged between 2 and 6 years entered this study. At the first visit, Modified Ashworth scale for assessment of spasticity was used. Then Cerebrolysin was administered at a dose of 0.1 cc/kg intramuscularly (IM) for 3 months. In the first month, the medication was injected 5 times per week. In the second month of therapy, injections were performed as follows: 4 injections in the first week, 3 injections in the second week, 2 injections in the third week and a single one in the fourth week. In the third month of therapy, Cerebrolysin was continued as weekly injections. The spasticity of the patients was evaluated at the end of the first and third month of therapy. Results: Modified Ashworth score at baseline was 20.62 ± 9.65 which reached 15.19 ± 7.30 after 1 month of treatment. This figure was 14.81 ± 3.77 at month 3. Total decline in Modified Ashworth Scale was 5.42 ± 5.33 at the first month and 5.81 ± 2.74 at the third month in comparison to baseline. The difference between Modified Ashworth Scale at baseline and 1 month after therapy was significant (P = 0.000) but there was no significant difference between first month and third month of therapy. (P = 0.755). Also analysis indicates that there was an association between absolute reduction of Modified Ashworth score and the age at beginning of treatment (P = 0.037). Conclusions: Using Cerebrolysin as a neurotrophic peptide may improve spasticity of children with CP and should be considered as a possible useful treatment in CP cases. © 2018, Iranian Journal of Pediatrics