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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.

Objective: This study was conducted to explore the expression levels of HTR1A gene in a sample of Egyptian autistic children. Methods: Thirty autistic patients (18 boys, 12 girls) and 20 controls were enrolled in the study. From each child, we isolated RNA samples from whole blood. Quantitative Real-Time PCR (qRT-PCR) was used to measure the gene expressions of HTR1A and normalized to the house keeping gene, beta-actin. Results: The HTR1A gene expression of healthy controls and ASD subjects were varied significantly (p =0.0062). As compared to control healthy subjects, the HTR1A expressions were greatly reduced in samples of ASD. Conclusion: HTR1A gene expression level is a candidate gene for further studies to explore its potential roles in ASD related pathways.

The present research was carried out to elucidate the role of zinc (Zn) supplementation on the plasma concentration and gene expression, as well as the effects on cognitive-motor performance, in a cohort of children with autism spectrum disorder (ASD). The study was performed on a cohort of 30 pediatric subjects with ASD, encompassing an age range of 3–8 years. The impact of Zn supplementation was investigated in 3 months (or 12 weeks) on the ASD children. Each daily dosage of Zn was calculated as being equal to the body weight in kg plus 15–20 mg. The effect of Zn was also evaluated on the serum level of metallothionein 1 (MT-1A), and the severity of autism via scores on the Childhood Autism Rating Scale. The effect of Zn was investigated on the gene expression of MT1-A before and after Zn supplementation. The data of the present study showed an increase in cognitive-motor performance and an increased serum metallothionein concentration, as well as a significant lowering in the circulating serum levels of copper (Cu) following Zn supplementation. In the cohort of ASD patients, the genetic expression of MT-1 was higher after Zn therapy than before the treatment. In conclusion, Zn supplementation might be an important factor in the treatment of children with ASD.

BackgroundDown syndrome (DS) is one of the commonest causes of developmental delay in children, with equilibrium problems being an integral part of the syndrome. This leads to further impairment of cognitive and concentration abilities.Material and MethodsIn our study, 30 DS children were categorized into 3 groups: bilateral normal middle ear pressure, bilateral abnormal middle ear pressure, and unilateral abnormal middle ear pressure. Sensory components of balance (somatosensory, visual, and vestibular) were assessed using computerized dynamic posturographyResultsResults showed a statistically significant decrease in composite score, visual ratio, and vestibular ratio among DS children compared to normal children. No significant differences in sensory parameters between the various DS groups (with various tympanogram types) were encountered.ConclusionsThis might lead one to suspect central and proprioceptive causes behind balance problems in DS, but further extended studies are needed to confirm this. Bedside screening tests for visual and vestibular functioning of balance are recommended, e.g. past pointing and Fukuda for early detection and intervention.

Importance Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. Objectives To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Design, Setting, and Participants Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Results Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH , CBS , MTHFR , CYP27A1 , and HIBCH ), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7 , STX1A , CCAR2 , EEF1D , GALNT2 , SLC44A1 , LRRIQ3 , AMZ2 , CLMN , SEC23IP , INIP , NARG2 , FAM234B , and TRAP1 . The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). Conclusions and Relevance Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.

Background: Autism is among the commonest neurodevelopmental childhood disorders worldwide; its aetiology is still unknown. Iron metabolism alteration in the central nervous system is recently implicated as a risk factor for several neurodegenerative disorders.Haemochromatosis HFE gene polymorphisms (p.H63D and p.C282Y) have shown significant association with several neurological diseases. Some evidences show altered iron related proteins in serum of autistic children. The aim of this work is to conduct a preliminary pilot study for the association of HFE polymorphisms and autism.Methods: All cases were referred from the clinic of special needs, National Research Centre, Cairo. Clinical diagnosis was based on the criteria for autistic disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR).Whole genome DNA was extracted; p.H63D and p.C282Y genotyping was studied using specific sequence amplification followed by restriction enzyme digestion on a sample of autism patients (25 cases) and twenty controls.Results: The p.H63D is more abundant than the C282Y among both autism and control samples. No significant association of p.H63D nor p.C282Y polymorphism and autism was revealed.Conclusion: We here report on the first pilot study of the possible genetic association between autism and HFE gene polymorphisms among Egyptians. Although our results do not prove the role of HFE polymorphisms as risk factors for autism, yet this does not exclude the role of iron in this prevalent disorder. Further extended studies are recommended to include other iron metabolism genes.

White matter lesions (WML) or leukoaraiosis is a major feature in cerebral imaging of older people, and their prevalence increases with age. The clinical effects of WML vary with the main impairment being detected in the cognitive functions, increased risk of severe depression and motor impairment. Although vascular comorbidities have been found to be the main changes in these brains, increased production of reactive oxygen species (ROS) could represent a risk factor for these lesions with elemental iron being a potential factor for ROS production. This study focuses on changes in iron, iron-regulating proteins and RNA expression of iron metabolism genes. Three groups of samples were used: WML, normal areas from lesional WM [NAWM (L)] as disease control and normal WM from control brains [NAWM(C)]. Ferric iron staining was undertaken using known Perl's reaction. Immunohistochemistry (IHC) of white matter for ceruloplasmin (Cp), haemochromatosis (HFE) and transferrin receptor (TfR) was done. Cellular localization of HFE and Cp was performed using dual-antibody IHC. Whole-genome RNA was extracted from WML, NAWM (L) and NAWM(C), and QPCR for HFE, TF, TfR, ceruloplasmin, ferritin and ferroportin was performed. Ferric iron staining shows increased diffuse iron staining among WML, followed by NAWM (L) and the least group being NAWM(C). IHC shows increased HFE and CP expression in lesional WM, while TfR shows no changes among the groups. HFE colocalized with vascular endothelium and microglia in WML and control samples, while Cp colocalized with microglia and some expression was shown by astrocytes. The mRNA expression using QPCR suggests a pattern that favours decreased intracellular iron influx, increased ferrous oxidation and increased iron export from the cells. Iron metabolism seems to be changed in brains with WML, increased elemental iron in these brains and in turn increased production of free oxidative radicals could represent a potentiating factor for the development of ageing WML.

Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens' scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.

Background Learning disorder (LD) is manifested by significant difficulties in the acquisition and use of reasoning, reading, writing, or mathematical abilities, despite average intelligence and proper education. Its etiological factors were suggested to be related to neurodevelopmental alterations. Measurement of the levels of brain-derived neurotrophic factor (BDNF) and coenzyme Q10 (CoQ10) was targeted in children with LD in comparison with typically developing (TD) ones. Materials and methods This study included 82 Egyptian Arabic-speaking children matched for age and sex and socioeconomic status, comprising 42 with specific LD (group I) and 40 TD children (group II). All participants were subjected to clinical and full neurological examination after reporting a full medical history. Furthermore, LD group was subjected to Stanford–Binet intelligence scale, dyslexia assessment test, and phonological awareness test, which evaluates cognitive and learning aptitudes. The levels of BDNF and CoQ10 were determined in serum by enzyme-linked immunosorbent assay. Results All children with LD obtained a score of 1 or more as at-risk quotient by the dyslexia assessment test, which indicated a specific reading disorder. The BDNF and CoQ10 levels in the LD group were significantly less than those in the TD group. No correlations were found between the measured markers and each other or between them and the measured factors of the used tests. Conclusion The detected low levels of BDNF and CoQ10 in children with specific LD with impairment in reading would be suspected to be related to etiological or exaggerating factors for the deficits in such children.

Autistic spectrum disorders (ASD) is now considered a multifactorial neurodevelopmental disorder, with increasing prevalence worldwide. Many evidences had showed a role of disturbed folate metabolism in increasing risk for autism, with methylenetetrahydrofolate reductase (MTHFR) being a pivotal enzyme controlling it. This study aims at examining two polymorphisms in MTHFR gene as they are linked to decreased enzyme activity. MTHFR C677T and A1298C polymorphisms are studied in Egyptian ASD children and their mothers in addition to control group. We examined MTHFR 677 C/T and 1298 A/C in 24 autistic children and their mothers and 30 control children and 42 control mothers. Genotype frequency of MTHFR 1298 AC/CC is significantly higher in autistic children; compared to controls. It was also significantly higher in autism mothers compared to control mothers with 3.2, and 2.1 increased fold risk for MTHFR 1298 AC, and AC+CC genotypes, respectively. No significant changes in C677T genotyping was found in neither autism children nor their mothers. Conclusion: These data supports an increased risk for ASD in association with MTHFR 1298 AC/CC polymorphism and hence a role of folate/methylation cycle disturbances is suspected in autism.

Cerebral white matters lesions (WML) are seen in 94% of the population aged 64 and over and are associated with cognitive decline and depression. We used immunohistochemistry and stereological methods on post mortem brain samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) cohort to investigate the axonal density within deep subcortical lesions. There was no significant difference between the lesional and control white matter, therefore, we conclude that there is axonal preservation within these lesions that are characterized by demyelination.

Background: Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. Materials and Methods: We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. Results: Plasma serotonin was significantly low in autistic children compared to control ( P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. Conclusion: Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident.

Microtia is a congenital anomaly that is found with different prevalence among various populations. The exact etiology of ear anomalies is still unknown. We describe a new additional family with this rare disorder; Johnson-McMillin syndrome (JMS) where mother, son, and distant grandmother have multiple features of JMS in the form of microtia, facial asymmetry, ear malformation, hearing defect, and hypotrichosis. Variable presentations in this family could be referred to phenotype variation supporting an autosomal dominant pattern of inheritance. We observed that the mother was very sad and suffered from feelings of guilt. We found that she had isolated herself from family and community out of fear of being stigmatized and hurt. We concluded that the occurrence of microtia is of public health importance, adhering to traditional marriage customs in Egypt increases women's risk of giving birth to a disabled child, yet the mothers are blamed and shamed for their children's birth defects by their husbands, families, and communities, while the fathers are not stigmatized.