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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.

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.