Whole exome screening of neurodevelopmental regression disorders in a cohort of Egyptian patients.

Developmental regression describes a child who begins to lose his previously acquired milestones skills after he has reached a certain developmental stage and though affects his childhood development. It is associated with neurodegenerative diseases including leukodystrophy and neuronal ceroid lipofuscinosis diseases (NCLs), one of the most frequent childhood-onset neurodegenerative disorders. The current study focused on screening causative genes of developmental regression diseases comprising neurodegenerative disorders in Egyptian patients using next-generation sequencing (NGS)-based analyses as well as developing checklist to support clinicians who are not familiar with these diseases. A total of 763 Egyptian children (1 to 11 years), mainly diagnosed with developmental regression, seizures, or visual impairment, were studied using whole exome sequencing (WES). Among 763 Egyptian children, 726 cases were early clinically and molecularly diagnosed, including 482 cases that had pediatric stroke, congenital infection, and hepatic encephalopathy; meanwhile, 192 had clearly dysmorphic features, 31 showed central nervous system (CNS) malformation, 17 were diagnosed by leukodystrophy, 2 had ataxia telangiectasia, and 2 were diagnosed with tuberous sclerosis. The remained 37 out of 763 candidates were suspected with NCLs symptoms; however, 28 were confirmed to be NCLs patients, 1 was Kaya-Barakat-Masson syndrome, 1 was diagnosed as infantile neuroaxonal dystrophy, and 7 cases required further molecular diagnosis. This study provided an NGS-based approach of the genetic causes of developmental regression and neurodegenerative diseases as it comprised different variants and de novo mutations with complex phenotypes of these diseases which in turn help in early diagnoses and counseling for affected families.

Kynurenine and oxidative stress in children having learning disorder with and without attention deficit hyperactivity disorder: possible role and involvement.

BACKGROUND: The etiological and pathophysiological factors of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) are currently not well understood. These disorders disrupt some cognitive abilities. Identifying biomarkers for these disorders is a cornerstone to their proper management. Kynurenine (KYN) and oxidative stress markers have been reported to influence some cognitive abilities. Therefore, the aim was to measure the level of KYN and some oxidative stress indicators in children with LD with and without ADHD and to investigate their correlations with the abilities of children with LD. METHODS: The study included 154 participants who were divided into 3 groups: one for children who have LD (N = 69); another for children with LD and ADHD (N = 31); and a group for neurotypical (NT) children (N = 54). IQ testing, reading, writing, and other ability performance evaluation was performed for children with LD. Measuring plasma levels of KYN, malondialdehyde, glutathione peroxidase, and superoxide dismutase by enzyme-linked immunosorbent assay was performed for all participants. RESULTS: Some IQ measures and learning skills differed between the first two groups. The biochemical measures differed between children with LD (with and without ADHD) and NT children (p < 0.001). However, the biochemical measures did not show a significant statistical difference between the first two groups. KYN and glutathione peroxidase levels were correlated with one-minute writing and at-risk quotient, respectively (p = 0.03;0.04). KYN and malondialdehyde showed the highest sensitivity and specificity values. CONCLUSION: These biochemical measures could be involved or have a role in the abilities' performance of children with specific learning disorder.

Study of the Effect of Bisphenol A on Oxidative Stress in Children with Autism Spectrum Disorders.

The role of bisphenol A (BPA) in autism was investigated in 49 children (mean age = 5.950 ± 1.911 years) with autism spectrum disorders (ASDs) and 40 comparable age and sex matched children used as controls (mean age = 5.333 ± 2.279 years). In addition, 8-Hydroxydeoxyguanosine (8-oxodG) was also studied as a biomarker of oxidative stress in the same set of two selected groups. The results showed that both BPA and 8-oxodG were significantly higher in children with autism than those of control children (p values = 0.025 and 0.0001, respectively). There were positive correlations between both BPA and 8-oxodG with ASDs severity (r = 0.400 and 0.805, respectively), these correlations were highly significant (p values = 0.004 and 0.001, respectively). There was a significance positive correlation between BMI and BPA, but the correlation between BMI and 8-oxodG was not significant in children with autism. The observed results revealed that BPA may increase oxidative stress resulting in mitochondrial dysfunction that affecting the behavior and functioning of ASDs children.

Childhood Apraxia of Speech: Exploring Gluten Sensitivity and Changes in Glutamate and Gamma-Aminobutyric Acid Plasma Levels.

BACKGROUND: Individuals with childhood apraxia of speech (CAS) were reported to have genetic variations related to gluten sensitivity and some neuroanatomic changes, which could be associated with alterations in neurotransmitters levels such as glutamate and gamma-aminobutyric acid (GABA). The aim was to measure the levels of antigliadin immunoglobulin A (IgA) antibody, glutamate, and GABA in the plasma of children with CAS compared with children with delayed language development (DLD) and neurotypical (NT) children. METHODS: The participants (N = 120) were in three groups: Group I for CAS (N = 30), Group II for DLD (N = 60), and Group III for NT (N = 30). The abilities of children in Groups I and II were evaluated. The plasma levels of antigliadin IgA, glutamate, and GABA were determined by enzyme-linked immunosorbent assay. RESULTS: The intelligence quotient and expressive language age in Group I were low compared with Group II (P = 0.001; 0.004). The levels of antigliadin IgA and glutamate in Group I were higher compared with the other two groups, whereas the level of GABA was lower (P < 0.0001). An imbalance between glutamate and GABA was found in Group I. In Group II, no measures differed from NTs except lower GABA levels (P = 0.0007). CONCLUSIONS: The elevated levels of antigliadin IgA antibody and glutamate demonstrated high sensitivity and specificity, differentiating children with CAS from children with DLD and NT children. The low levels of GABA contributed to the imbalance between the excitatory and inhibitory neurotransmitters' levels detected in children with CAS.

BDNF Val66Met Polymorphism: Suggested Genetic Involvement in Some Children with Learning Disorder.

Brain-derived neurotrophic factor (BDNF) plays an essential role in neuronal survival, especially in areas responsible for memory and learning. The BDNF Val66Met polymorphism has been described as a cognitive modifier in people with neuropsychiatric disorders. BDNF levels have been found to be low in children with learning disorder (LD). However, Val66Met polymorphism has not been studied before in such children. The aim was to investigate the presence of BDNF val66Met polymorphism in a group of children with specific LD and to verify its impact on their cognitive abilities. The participants in this cross-sectional study (N = 111) were divided into two groups: one for children with LD and the other for neurotypical (NT) ones. Children with LD (N = 72) were diagnosed according to the DSM-5 criteria. Their abilities were evaluated using Stanford-Binet Intelligence Scale, dyslexia assessment test, Illinois Test of Psycholinguistic Abilities, and phonological awareness test. Genotyping of BDNF Val66Met polymorphism was performed for all participants. The frequency of the Met allele was 26% among children with LD (6 children had homozygous, 26 had heterozygous genotype). The percentage of participants with deficits in reading, writing, and phonemic segmentation was higher in Met allele carriers when compared to non-Met allele carriers in LD group. The frequency of Met allele among NT children was 3.85% (0 homozygous, 3 children had heterozygous genotype) (p = 0.00001). The high frequency of Val66Met polymorphism among children with LD introduces the BDNF gene as a genetic modifier of learning performance in some children who manifest specific learning disorder (developmental dyslexia).

Dyslexia with and without Irlen syndrome: A study of influence on abilities and brain-derived neurotrophic factor level.

The presence of comorbid Irlen syndrome (IS) in children with developmental dyslexia (DD) may have an impact on their reading and cognitive abilities. Furthermore, the brain-derived neurotrophic factor (BDNF) was reported to be expressed in brain areas involved in cognitive and visual processing. The aim of this study was to evaluate some cognitive abilities of a group of dyslexic children with IS and to measure and compare the plasma BDNF level to dyslexic children without IS and neurotypical (NT) children. The participants were 60 children with DD (30 in the DD + IS group; 30 in the DD group) and 30 NT children. The Irlen reading perceptual scale, the Stanford Binet intelligence scale, 4th ed, the dyslexia assessment test, and the Illinois test of psycholinguistic abilities were used. The BDNF level was measured using the enzyme-linked immunosorbent assay. One-minute writing and visual closure deficits were more prevalent, while phonemic segmentation deficits were less prevalent in the DD + IS group compared to the DD group. The BDNF level in the DD groups was lower than that in NT children (p < 0.001). Some reading and non-reading tasks were influenced by the presence of a coexisting IS. The reduced BDNF level could play a role in the deficits noticed in the abilities of children with DD.

The role of duloxetine in reducing opioid consumption after thoracotomy: a prospective, randomized, double-blinded, placebo-controlled pilot trial.

BACKGROUND: Exploration of the thoracic cavity through a thoracotomy incision for thoracic malignancies is accompanied by severe, excruciating acute postoperative pain. The objective of this study is to evaluate the efficacy of perioperative duloxetine when given as part of a multimodal analgesia in reducing the dose of opioids needed to treat acute postoperative pain after thoracotomy. METHODS: Sixty patients scheduled for thoracotomy were randomly assigned to one of two treatment groups. The duloxetine group (D) received duloxetine 60 mg orally two hours before the surgical procedure and 24 hours after surgery, and the placebo group (P) received oral equivalent placebo capsules during the same time schedule. The primary outcome was the postoperative consumption of narcotics. Secondary outcome measures were assessment of postoperative pain scores (VAS) during rest, walking and coughing, hemodynamic variables and development of any side effects. RESULTS: Total dose of morphine needed to treat postoperative pain in first 48 hours, intraoperative isoflurane concentrations, intra- and postoperative epidural infusion rates all were significantly lower in group D (P<0.001). Postoperative pain at rest (VAS-R) was significantly less frequent in group D compared to group P at all-time intervals so as during walking (VAS-W) (P<0.001). While during cough (VAS-C), it was comparable at all time point except at 12 hours which was significantly low in group D (P<0.001). The intra-, postoperative mean blood pressure and development of side effects were comparable between the two groups. CONCLUSIONS: Oral duloxetine used perioperatively during thoracic surgery may play an important role as multimodal analgesia for acute postoperative pain without any added side effects.

Variable predicted pathogenic mechanisms for novel MECP2 variants in RTT patients.

BACKGROUND: Methyl CpG binding protein 2 (MeCP2) is essential for the normal function of mature neurons. Mutations in the MECP2 gene are the main cause of Rett syndrome (RTT). Gene mutations have been identified throughout the gene and the mutation effect is mainly correlated with its type and location. METHODS: In this study, a series of in silico algorithms were applied for analyzing the functional consequences of 3 novel gene missense mutations (D121A, S359Y, and P403S) and a rarely reported one with suspicious effect (R133H) on RettBASE. Besides, a ROC curve analysis was performed to investigate the critical factors affecting variant pathogenicity. RESULTS: (1) The ROC curve analysis for a retrieved set of MeCP2 variants showed that physicochemical characters do not significantly affect variant pathogenicity; (2) PREM PDI tool revealed that both D121A and R133H mainly contribute to disease progression via reducing MeCP2 affinity to DNA; (3) GPS v5.0 software indicated that P403S may correlate with altered protein phosphorylation; however, no defective protein interaction has been already documented. (4) The applied computational algorithms failed to explore any informative pathogenic mechanism for the S359Y variant. CONCLUSION: The conducted approach might provide an efficient prediction model for the effect of MECP2 variants that are located in MBD and CTD.

The Role of Double Modality Ultrasonographic and Fluoroscopic Guided Superior Hypogastric Plexus Neurolysis in Treating Intractable Pelvic Cancer Pain: A Comparative Study.

BACKGROUND: Superior hypogastric neurolytic block is performed to block visceral pelvic pain. This could be performed through the anterior approach guided by CT or ultrasound and through a posterior approach, guided by fluoroscopy or CT. METHODS: Sixty adult patients with severe visceral pelvic pain (VAS>70 mm) were randomly divided into two groups. Group S: SHP block was done ultrasound guided using the anterior approach and confirmed by fluoroscopy. Group F: SHP block was done fluoroscopic guided using the posterior oblique approach. The VAS (visual analog scale), duration of the technique, time of X-ray exposure, patient satisfaction score, patient global impression of change (PGIC), quality of life score, and daily morphine consumption (mg/day) were measured pre-procedure and at the 1st, 4th, 8th, and 12th week after the procedure. In addition, any side effects of the procedure were recorded. RESULTS: There was a significant difference in VAS between the two groups (P<0.01) (better in group S). The quality of life score was improved from the pre-procedure in both groups (P<0.05), and morphine consumption was significantly lower in group S than in group F (P<0.05) at the 1st, 4th, and 8th week and not significant at the 12th week. The two groups show a statistically significant difference as regards the duration of the procedure and X-ray exposure (P<0.01). There was a statistically significant difference in the satisfactory score between the two groups at the 1st, 4th, 8th, and 12th week (P<0.01). As regards the PGIC score, there was no statistically significant difference between the two groups (P>0.05). In group S, no back pain was reported, while 11 patients of group F complained from post-procedure back pain (P<0.001). CONCLUSION: The anterior ultrasound guided SHPB aided by fluoroscopy is suggested to be more superior to the standard fluoroscopic guided technique in relieving pelvic cancer pain and decreasing morphine consumption.

Investigating the influence of ubiquinone blood level on the abilities of children with specific learning disorder.

BACKGROUND: Ubiquinone has antioxidant properties and has been linked to cognitive performance in some neuropsychiatric disorders. Its role in specific learning disorder manifestations has not been previously investigated. Therefore, the aim of this study was to measure the blood levels of ubiquinone in a group of children with specific learning disorder in comparison to typically developing children and to investigate the correlation between ubiquinone levels in children with specific learning disorder and some of their intellectual capabilities, reading, spelling and writing performance. METHODS: The study included 71 native Arabic speaking children: 31 in the specific learning disorder group and 40 in the typically developing (TD) group. The abilities of the children with specific learning disorder were evaluated by the Stanford-Binet Intelligence Scale-4th edition, the Dyslexia Assessment Test, and the Illinois Test of Psycholinguistic Abilities. The level of ubiquinone was measured in both groups by ELISA. Correlation between some aptitudes of children with specific learning disorder and the ubiquinone level was performed. RESULTS: The blood levels of ubiquinone in the children with specific learning disorder group were less than those in the TD group. Correlation analysis revealed a significant positive correlation between ubiquinone and the scores of backward digit span abilities. CONCLUSIONS: Ubiquinone has a role in the auditory working memory performance of children with specific learning disorder (with impairment in reading). The decreased levels of ubiquinone in this sample of children with specific learning disorder could have participated in the pathogenesis of this disorder.

Clinical Spectrum of Cerebral Palsy and Associated Disability in South Egypt: A Local Survey Study.

BACKGROUND: Cerebral palsy is the most common cause of motor disability in children with a prevalence of 2-10/1,000 live births in the developing areas. AIM: The epidemiology, clinical picture, and associated comorbidities in CP have been extensively studied in high-resource countries, but in low-resource areas, including Africa, those studies are still lacking. METHODS: Cerebral palsy cases were prospectively recruited from every physiotherapy centre in Bani-Mazar city, Egypt, in a cross-sectional study from May 2015 to November 2015. RESULTS: Two hundred cases were enrolled with a prevalence of 1 per 1000 live births. Within the study population, 72.5% were the spastic type, 16% were dyskinetic, 7% were ataxic, and 4.5% were hypotonic. The most common comorbidities were cognitive impairment and epilepsy affecting 77% and 38%, respectively. CONCLUSION: Cerebral palsy in developing countries has a higher prevalence and different clinical profile regarding severity and associated disability. The perinatal and high-quality neonatal care together with physical therapy and rehabilitation programs is still lacking in developing countries.

Acute aortic occlusion presenting as flaccid paraplegia.

A 67-year-old male known to be hypertensive and diabetic had a sudden onset of severe low back pain and flaccid paraplegia with no sensory level or bladder affection and the distal pulsations were felt. Acute compressive myelopathy was excluded by MRI of the dorsal and lumbar spines. The nerve conduction study and CSF analysis was suggestive of acute demyelinating polyneuropathy. The patient developed ischemic changes of the lower limb and CT angiography revealed severe stenosis of the abdominal aorta and both common iliac arteries. We emphasize the importance of including acute aortic occlusion in the differential diagnosis of acute flaccid paraplegia especially in the presence of severe back pain even if the distal pulsations were felt.

Parkinsonism as a Complication of Bariatric Surgery.

BACKGROUND: The association between Parkinsonism and BS has already been reported in only three patients worldwide. CASE SUMMARY: We report a 39-years old Kuwaiti female who presented with parkinsonian features and mononeuropathy (carpal tunnel syndrome) 3 years after a vertical sleeve gastrectomy operation. CONCLUSION: We conclude that with the increasing popularity of bariatric surgery, clinicians will need to recognize and manage neurologic complications that may appear soon after or years to decades later. Thorough evaluation is essential for any patient who has undergone bariatric surgery and develops neurologic symptoms.

Association analysis of genetic variations of eNOS and α2ß1 integrin genes with type 2 diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus. It has been suggested that nitric oxide (NO) and α2ß1 integrin (a platelet receptor for collagen) play an important role in the pathogenesis of microvascular complications in DR. AIM: The aim of this study was to investigate the association of two candidate genes involved in the regulation of retinal vasculature, endothelial nitric oxide synthase (eNOS) and α2ß1 integrin (ITGA2) genes, with the development of DR in Egyptian patients with type 2 diabetes mellitus and to investigate whether genetic variants will affect the type of retinopathy (proliferative or nonproliferative). METHODS: In this study, 70 patients were enrolled and categorized into two groups: (1) a DR group consisting of 50 patients with DR, which was further subclassified into 25 patients with nonproliferative DR (NPDR group) and 25 patients with proliferative DR (PDR group) and (2) a diabetes without retinopathy (DWR) group, comprising 20 patients with type 2 diabetes of more than 10 years' duration who showed no signs of DR. Associations of the genetic polymorphisms of eNOS (G894T) and ITGA2 (BgI II) were studied. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed for all samples to evaluate the genotypes and correlate with the phenotype of the disease. RESULTS: The allele frequencies of both polymorphisms showed considerable differences between patients with and without DR. The GG genotype of G894T polymorphism of eNOS was associated with a 9.75-fold increased risk of DR (95% confidence interval 1.7-55.4) and the genotype ITGA2 BgI II (+/+) was associated with a 10.1-fold increased risk of DR (95% confidence interval 1.8-57.9), while the α2ß1 integrin gene polymorphism of genotype distribution of both eNOS and ITGA2 polymorphisms did not differ significantly between the proliferative and nonproliferative DR groups. CONCLUSION: A significant association between the G894T polymorphism of eNOS and BgI II polymorphism of ITGA2 genes and DR was observed, while there was no association between the genetic variants of those two polymorphisms and the type of retinopathy.

Elevated serum Bcl-2 in children with temporal lobe epilepsy.

Intractable temporal lobe epilepsy (TLE) is associated with alterations in expression of apoptosis-associated signaling molecules in the temporal lobe. Bcl-2 is an anti-apoptotic molecule which has previously been reported to be raised in patient's brain and serum. In the present study we examined serum Bcl-2 protein levels as a surrogate marker of apoptosis-associated signaling in children with non lesional TLE. Serum Bcl-2 levels were found to be higher in patients with TLE than controls. The serum level correlated to seizure variables including, duration of disease, frequency of seizures, and disease severity. The impact of epilepsy on cognition was assessed using total score intelligence quotient (IQ). IQ was found to be lower than controls and negatively correlated to serum Bcl-2. These findings support serum Bcl-2 levels as a marker of seizure burden and cognition in children with epilepsy.