Standardization of an Arabic-Language Neuropsychological Battery for Epilepsy Surgical Evaluations.

OBJECTIVES: This study provides a standardized Arabic language neuropsychological test battery and tests its ability to distinguish patients with left and right hemisphere epileptic foci who are candidates for surgical resection. METHODS: An Arabic language battery of 15 tests was developed based on the neuropsychological test battery used at the Johns Hopkins Hospital for surgical evaluation of patients undergoing temporal lobe resection. With modifications where culturally required, 11 tests were translated to Arabic by the principal investigator and back-translated by two bilingual health professionals; four tests were available in Arabic and added to the battery. The battery was administered to 21 Arabic-speaking patients with left temporal epileptic foci, 21 with right temporal epileptic foci, and 46 neurologically and psychiatrically healthy adults. RESULTS: Nearly all the Arabic test versions were capable of differentiating healthy controls and the temporal lobe epilepsy (TLE) groups. Tests known to distinguish left and right temporal lobectomy candidates, such as wordlist memory and prose recall, were able to do so as accurately as the English versions. Also, a roughly "culturally free" task (the Baltimore Board) and a newly developed version of the Boston Naming Test demonstrated some sensitivity to left temporal lobe involvement. CONCLUSIONS: Arabic-language neuropsychological tests for epilepsy surgical evaluations are made available, demonstrate cultural sensitivity and clinical validity, and require further psychometric property and normative research. (JINS, 2019, 25, 761-771).

The extent of mercury (Hg) exposure among Saudi mothers and their respective infants.

A total of 1016 healthy Saudi mothers and their respective infants (aged 3-12 months) were recruited from 57 Primary Health Care Centers (PHCCs) in Riyadh, Saudi Arabia, to evaluate the extent of mercury (Hg) exposure and predict its sources in the healthy Saudi population. Total Hg levels were measured in maternal urine, breast milk, blood, and hair and in the infants' urine and hair. Only 1.9% of the mothers had urinary Hg (UHg)>10 µg/l, the limit for asymptomatic adults recommended by the World Health Organization, but the median (0.99 µg/l) was higher than in other countries. Also, 49.3% of the mothers had UHg>1 µg/l, the German reference value for adults. Median infant UHg was 0.729 µg/l, and 77 and 93 % of the infants had levels higher than 0.4 and 0.1 µg/l, the reference values of the Centers for Disease Control and Prevention and for Germany, respectively. The median Hg level in breast milk was 0.884 µg/l. Even though 43.2% of the milk samples were above the background level for Hg in human milk (1 µg/l), our results were lower than those reported from other countries. Median maternal total Hg in blood was 0.637 µg/l, and only 0.4 and 6.9% of samples were higher than the Hg reference levels of 5.8 µg/l of the Environmental Protection Agency (EPA) and of 2 µg/l for Germany, respectively. Total Hg levels in hair (HHg) varied widely among mothers and infants, but only 3.9% of the mothers and 2.8% of the infants had HHg>1 µg/g (the EPA reference level). Median HHg values were 0.117 µg/g dry weight in mothers and 0.1 µg/g dry weight in infants; both were lower than in other countries. The Hg levels in mothers and their respective infants were relatively low, but our results were consistent with other studies indicating that dental amalgam fillings and fish consumption were the main predictors of maternal Hg exposure. Among the several biomarkers of Hg exposure, Hg levels in maternal hair and urine were the strongest predictors of infant exposure. The lack of an association between Hg in breast milk and Hg in infant urine and hair suggested that the infants were exposed to Hg predominately during pregnancy rather than during breastfeeding. We expect that our data can serve as a baseline for further biomonitoring and follow-up studies, particularly of the long-term impact of Hg on childhood neurodevelopment.

Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development.

We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.

A novel X-linked disorder with developmental delay and autistic features.

OBJECTIVE: Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa. METHODS: We evaluated the affected individuals, all maternally related, using childhood autism rating scale (CARS) and Vineland Adaptive scales, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain, electroencephalography (EEG), electromyography (EMG), muscle biopsy, high-resolution molecular karyotype arrays, Giemsa banding (G-banding) and fluorescent in situ hybridization (FISH) experiments, mitochondrial DNA (mtDNA) sequencing, X-chromosome inactivation study, global gene expression analysis on Epstein-Barr virus (EBV)-transformed lymphoblasts, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). RESULTS: We have identified a novel Xq12-q13.3 duplication in an extended family. Clinically normal mothers were completely skewed in favor of the normal chromosome X. Global transcriptional profiling of affected individuals and controls revealed significant alterations of genes and pathways in a pattern consistent with previous microarray studies of autism spectrum disorder patients. Moreover, expression analysis revealed copy number-dependent increased messenger RNA (mRNA) levels in affected patients compared to control individuals. A subset of differentially expressed genes was validated using qRT-PCR. INTERPRETATION: Xq12-q13.3 duplication is a novel global developmental delay and autism-predisposing chromosomal aberration; pathogenesis of which may be mediated by increased dosage of genes contained in the duplication, including NLGN3, OPHN1, AR, EFNB1, TAF1, GJB1, and MED12.

Genomic and transcriptomic analyses distinguish classic Rett and Rett-like syndrome and reveals shared altered pathways.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by derangements in nervous system especially in cognition and behavior. The present study aims to understand the molecular underpinnings of two subtypes of RTT, classic RTT and Rett-like, and to elucidate common pathways giving rise to common RTT phenotype using genomic and transcriptomic approaches. Mutation screening on selected nuclear genes revealed only MECP2 mutations in a subset of classic RTT patients. MLPA assays and mtDNA screenings were all negative. Genome-wide copy number analysis indicated a novel duplication on X chromosome. Transcriptional profiling revealed blood gene signatures that clearly distinguish classic RTT and RTT-like patients, as well as shared altered pathways in interleukin-4 and NF-κB signaling pathways in both subtypes of the syndrome. To our knowledge, this is the first report on investigating common regulatory mechanisms/signaling pathways that may be relevant to the pathobiology of the "common RTT" phenotype.

Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII.

We define the neurological characteristics of familial cases from multiple branches of a large consanguineous family with cerebellar ataxia, mental retardation (MR), and dysequilibrium syndrome type 3 caused by a mutation in the recently cloned CA8 gene. The linkage analysis revealed a high logarithm of the odds (LOD) score region on 8q that harbors the CA8 in which a novel homozygous c.484G>A (p.G162R) mutation was identified in all seven affected members. The patients had variable cerebellar ataxia and mild cognitive impairment without quadrupedal gait. The brain MRI showed variable cerebellar volume loss and ill-defined peritrigonal white matter abnormalities. The Fluorodeoxyglucose Positron Emission Tomography (FDG PET) revealed hypometabolic cerebellar hemispheres, temporal lobes, and mesial cortex. This report expands the neurological and radiological phenotype associated with CA8 mutations. CA8 involvement should be considered in the differential diagnosis of other genetically unresolved autosomal recessive cerebellar ataxias.

Adapting evidence-based clinical practice guidelines for people with attention deficit hyperactivity disorder in Saudi Arabia: process and outputs of a national initiative.

BACKGROUND: We recently adapted the published National Institute for Health and Care Excellence (NICE) Attention deficit hyperactivity disorder (ADHD) diagnosis and management guideline to the Saudi Arabian context. It has been postulated that adaptation of evidence-based clinical practice guidelines to the local healthcare context rather than de-novo development will improve their adoption and implementation without imposing a significant burden on resources. The objective of this paper is to describe the adaptation process methodology utilized for the generation of the first national guideline for management of people with ADHD in Saudi Arabia. METHODS: We used the KSU-Modified-ADAPTE methodology for the guideline adaptation process. We describe the full process in detail including the three phases of set-up, adaptation, and finalization. The process was conducted by a multidisciplinary guideline adaptation group in addition to an external review for the clinical content and methodology. RESULTS: The group adapted ten main categories of recommendations from one source CPG (NICE). The recommendations include: (i) service organisation and training, (ii) recognition, identification and referral, (iii) diagnosis, (iv) support, (v) managing ADHD, (vi) dietary advice, (vii) medication, (viii) maintenance and monitoring, (ix) adherence to treatment, and (x) review of medication and discontinuation. Several implementation tools were compiled and developed to enhance implementability including a clinical algorithm, quality measures, coding system, medication tables, translations, patient information, and online resources. CONCLUSIONS: The finalized clinical practice guideline provides healthcare providers with applicable evidence-based guidance for the management of people with ADHD in Saudi Arabia. The project also demonstrated the effectiveness of KSU-Modified-ADAPTE, and emphasized the value of a collaborative clinical and methodological expert group for adaptation of national guidelines.

Effects of early and recent mercury and lead exposure on the neurodevelopment of children with elevated mercury and/or developmental delays during lactation: A follow-up study.

This follow-up study of 82 children investigated the potential impact of early and recent exposure to mercury and lead on their neurodevelopmental performance at 5-8 years of age (2017-2018). Early exposure of these children to mercury, methylmercury, and lead was assessed during lactation at 3-12 months old, as well as their mother's exposure using measurements from a cross-sectional study (2011-2013). Only infants who failed to pass the neurodevelopment screening tools and/or had elevated mercury were included in this study. Urine and hair were sampled during the follow-up study to assess the children's recent exposure to mercury, methylmercury, and lead. Their cognitive performance and visual-motor integration were also measured using the Test of Non-Verbal Intelligence (TONI) and the Beery-Visual-Motor Integration (Beery VMI), respectively. The association between alterations in urinary porphyrins excretion and exposure to metals was analyzed and their influence on the children's neurodevelopment was explored. Linear regression models revealed a significant negative association between the infants' mercury exposure during lactation and the TONI Quotient (ß = -0.298, 95%CI = -4.677, -0.414) and Beery VMI Age Equivalent scores at age 5-8 (ß = -0.437, 95%CI = -6.383, -1.844). The mothers' blood methylmercury was inversely and significantly associated with their children's TONI Quotient (ß = -0.231, 95%CI = -8.184, -0.331). In contrast, the children's Beery VMI Age Equivalent scores were positively and significantly associated with the hair methylmercury of the mothers (ß = 0.214, 95%CI = 0.088, 3.899) and their infants (ß = 0.256, 95%CI = 0.396, 4.488). These relationships suggest the presence of negative confounding that we did not take into account. Unlike mercury, there was some evidence that lead in breast milk had an inverse relationship with the children's visual-motor coordination skills. Our study did not show a clear association between children's recent exposure to metals and neurodevelopment. However, a significant inverse association was observed between the TONI Quotient and the interaction of hair methylmercury × ∑porphyrins (ß = -0.224, 95%CI = -0.86, -0.049), implying that porphyrins are a sensitive measure of low body-mercury burden. Although lead induced higher ∑porphyrins excretion in urine (ß = 0.347, 95%CI = 0.107, 0.525), their interaction did not influence children's neurodevelopmental scores. The interactions between metals and porphyrins might provide insights into their potential contributory role in the pathogenesis associated with neurological disorders or other diseases. Despite the small sample size of the present study, its findings about the association between toxic metal exposure and the high risk of poor neurodevelopmental performance are worrying, particularly at an early age, and additional research is needed using larger sample sizes.

First report of two successive deletions on chromosome 15q13 cytogenetic bands in a boy and girl: additional data to 15q13.3 syndrome with a report of high IQ patient.

15q13.3 syndrome is associated with a wide spectrum of neurological disorders. Among a cohort of 150 neurodevelopmental cases, we identified two patients with two close proximity interstitial hemizygous deletions on chromosome 15q13. Using high-density microarrays, we characterized these deletions and their approximate breakpoints. The second deletion in both patients overlaps in a small area containing CHRNA7 where the gene is partially deleted. The CHRNA7 is considered a strong candidate for the 15q13.3 deletion syndrome's pathogenicity. Patient 1 has cognitive impairment, learning disabilities, hyperactivity and subtle dysmorphic features whereas patient 2 has mild language impairment with speech difficulty, mild dysmorphia, heart defect and interestingly a high IQ that has not been reported in 15q13.3 syndrome patients before. Our study presents first report of such two successive deletions in 15q13.3 syndrome patients and a high IQ in a 15q13.3 syndrome patient. Our study expands the breakpoints and phenotypic features related to 15q13.3 syndrome.

Longitudinal study of prenatal and postnatal lead exposure and early cognitive development in Al-Kharj, Saudi Arabia: a preliminary results of cord blood lead levels.

Extensive data shows a direct link between low-level lead exposure during early development and deficits in neurobehavioral-cognitive performance evident late in childhood through adolescence. Our previous studies confirmed the transfer of lead from the mother to the fetus as well as the effect of low lead exposure on neuropsychological behavior in school children. Such results led us to design a longitudinal survey to evaluate the effect of prenatal and/or postnatal lead exposure on early cognitive development among selected group of children from birth to 2 years of age. During the first stage of this study (between March and July 2004), we measured lead levels in 653 umbilical cord blood samples taken from healthy Saudi mothers delivering at King Khalid Hospital, Al-Kharj. This gave a good opportunity to look at the prevalence of increased blood lead levels in umbilical cord blood and to identify risk factors for prenatal lead exposure. The mean cord lead levels were 2.21 +/- 1.691 microg/dl in the range of 0.284-17.276 microg/dl. Only 1.23% of the newborns had blood lead levels >10 microg/dl, the Center for Disease Control level of concern. To investigate risk factors affecting cord blood lead levels, only subjects with lead levels above the 75th percentile (2.475 microg/dl) were selected in the multiple regression models. We observed that cord blood lead levels were significantly influenced by maternal age, the location of residence and intake of prenatal supplements. Controlling for newborn's head circumferences confounders, it was found that cord blood lead levels were significantly and negatively associated with newborn's head circumference (beta = -0.158, p = 0.036). The negative association was seen between intake of prenatal supplements and cord blood lead levels emphasizing the role of prenatal supplementations during pregnancy. The significant reductions in newborns, head circumferences due to lead exposure may have serious implications for their future performance and achievement. This study reveals that even at low prenatal lead exposure, all possible measures to inspect lead sources in our environment and reduce lead exposure should be taken.

Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity. The interplay of de novo and inherited rare variants has been suspected in the development of ASD. Here, we applied whole exome sequencing (WES) on 19 trios from singleton Saudi families with ASD. We developed an analysis pipeline that allows capturing both de novo and inherited rare variants predicted to be deleterious. A total of 47 unique rare variants were detected in 17 trios including 38 which are newly discovered. The majority were either autosomal recessive or X-linked. Our pipeline uncovered variants in 15 ASD-candidate genes, including 5 (GLT8D1, HTATSF1, OR6C65, ITIH6 and DDX26B) that have not been reported in any human condition. The remaining variants occurred in genes formerly associated with ASD or other neurological disorders. Examples include SUMF1, KDM5B and MXRA5 (Known-ASD genes), PRODH2 and KCTD21 (implicated in schizophrenia), as well as USP9X and SMS (implicated in intellectual disability). Consistent with expectation and previous studies, most of the genes implicated herein are enriched for biological processes pertaining to neuronal function. Our findings underscore the private and heterogeneous nature of the genetic architecture of ASD even in a population with high consanguinity rates.

Alterations in biochemical markers due to mercury (Hg) exposure and its influence on infant's neurodevelopment.

This study examined the role of oxidative stress due to mercury (Hg) exposure on infant's neurodevelopmental performance. A total of 944 healthy Saudi mothers and their respective infants (aged 3-12 months) were recruited from 57 Primary Health Care Centers in Riyadh City. Total mercury (Hg) was measured in mothers and infants urine and hair samples, as well as mother's blood and breast milk. Methylmercury (MeHg) was determined in the mothers and infants' hair and mother's blood. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and porphyrins were used to assess oxidative stress. The infant's neurodevelopment was evaluated using Denver Developmental Screening Test II (DDST-II) and Parents' Evaluation of Developmental Status. The median total Hg levels in mother's urine, infant's urine, mother's hair, infant's hair, and mother's blood and breast milk were 0.995µg/l, 0.716µg/l, 0.118µg/g dw, 0.101µg/g dw, 0.635µg/l, and 0.884µg/l respectively. The median MeHg levels in mother's hair, infant's hair, and mother's blood were 0.132µg/g dw, 0.091µg/g dw, and 2.341µg/l respectively. A significant interrelationship between mothers and infants Hg measures in various matrices was noted. This suggests that mother's exposure to different forms of Hg (total and/or MeHg) from various sources contributed significantly to the metal body burden of their respective infants. Even though Hg exposure was low, it induced high oxidative stress in mothers and infants. The influence of multiplicative interaction terms between Hg measures and oxidative stress biomarkers was tested using multiple regression analysis. Significant interactions between the urinary Hg levels in mothers and infants and oxidative stress biomarkers (8-OHdG and MDA) were noted. The MeHg levels in mother-infant hair revealed similar interaction patterns. The p-values for both were below 0.001. These observations suggest that the exposure of our infants to Hg via mothers either during pregnancy and/or neonatal life, promoted oxidative stress that might have played a role in infant neurodevelopmental delays that we reported previously. The results confirmed that the interaction between infant's MeHg in hair and 8-OHdG and MDA levels was significantly associated with a delay in DDST-II performance (ß=-0.188, p=0.028). This finding provides an insight into the potential consequences of Hg-induced oxidative stress to infant's cognitive neurodevelopment for the first time. This observation still needs future studies to be validated. Given the low MeHg levels in our population, these findings are of particular importance.

Mercury (Hg) exposure and its effects on Saudi breastfed infant's neurodevelopment.

This cross-sectional study analyzed mercury (Hg) levels in healthy Saudi mothers and their infants (age 3-12 months) and examined the influence of Hg on the infants' neurodevelopment using screening tools, such as the Denver Developmental Screening Test II (DDST-II) and Parents' Evaluation of Developmental Status (PEDS). A total of 944 mothers and their 944 infants were recruited from 57 Primary Health Care Centers (PHCCs) in Riyadh. The total Hg (THg) levels were measured in the mothers' and infants' urine (UTHg-M and UTHg-I) and hair (HTHg-M and HTHg-I) samples and in the breast milk and mothers' blood. Methylmercury (MeHg) levels were determined in hair samples from the mothers (MeHg-M) and infants (MeHg-I). Only 40.1% of the infants were breast-fed when enrolled, and 59.9% had stopped breastfeeding. Only 1.8% of the mothers and 0.3% of the infants had MeHg levels above the Environmental Proection Agency (EPA) reference dose (1 µg/g), with low medians of 0.132 and 0.091 µg/g dw, respectively, but the MeHg levels were significantly associated with infant DDST-II performance. The levels of corrected UTHg-M for creatinine (Cr), HTHg-M, HTHg-I, and HMeHg-M, however, displayed an association with infant PEDS performance. The medians and percentage of the tested population that exceeded the recommended limits for Hg in urine and hair set by the World Health Organization (5 µg/g Cr) and EPA (1 µg/g) were 0.695 µg/g Cr and 3% UTHg, 0.118 µg/g dw and 4.1% HTHg-M, 0.101 µg/g dw and 2.8% HTHg-I, and 0.132 µg/g dw and 1.8% HMeHg-M. Our study provides evidence of an association between some Hg measures and delays in infant neurodevelopment, despite their low levels and regardless of the infant's breastfeeding status. The results are of potential concern, because delayed psychomotor or mental performance in infants could be an indicator of later neurocognitive development in children, which may persist into adulthood, as shown in other studies. The absence of local standardization of the DDST-II and PEDS screening tools might raise some questions, although the DDST-II has been used in local institutions for a number of years. The development of effective standardized developmental screening tools is necessary to ensure that all children at risk of neurodevelopmental problems early in life are identified so that they can receive appropriate and timely intervention.

Homozygosity analysis in subjects with autistic spectrum disorder.

Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder that results in social and communication impairments, as well as repetitive and stereotyped patterns. Genetically, ASD has been described as a multifactorial genetic disorder. The aim of the present study was to investigate possible susceptibility loci of ASD, utilizing the highly consanguineous and inbred nature of numerous families within the population of Saudi Arabia. A total of 13 multiplex families and 27 affected individuals were recruited and analyzed using Affymetrix GeneChip(®) Mapping 250K and 6.0 arrays as well as Axiom arrays. Numerous regions of homozygosity were identified, including regions in genes associated with synaptic function and neurotransmitters, as well as energy and mitochondria-associated genes, and developmentally-associated genes. The loci identified in the present study represent regions that may be further investigated, which could reveal novel changes and variations associated with ASD, reinforcing the complex inheritance of the disease.

Variable expression pattern in Donnai-Barrow syndrome: Report of two novel LRP2 mutations and review of the literature.

Donnai-Barrow syndrome (DBS; MIM 222448) is characterized by typical craniofacial anomalies (major hypertelorism with bulging eyes), high grade myopia, deafness and low molecular weight proteinuria. The disorder results from mutations in the low density lipoprotein receptor-related protein 2 gene LRP2 that maps to chromosome 2q31.1. LRP2 encodes megalin, a multi-ligand endocytic receptor. Herein, we describe the clinical presentation of 4 patients from 2 unrelated Saudi families. Two novel LRP2 mutations, a homozygous nonsense mutation (c.4968C>G; p.Tyr1656*) and a missense mutation (c.12062G>A; p.Cys4021Tyr), were detected in the first and second family respectively. Interestingly, intrafamilial phenotypic variability was observed in one family, while DBS features were atypical in the second family. Differential diagnosis of DBS includes several syndromes associating hypertelorism with high grade myopia, and several syndromal forms of CDH, which are briefly summarized in this study.

Prenatal and postnatal lead exposure and early cognitive development: longitudinal study in Saudi Arabia.

The goal of this study was to assess the effect of prenatal and postnatal lead exposure on early cognitive development of infants using the Bayley Scale of Infant Development (BSID-I) at the age of 6, 12, 18, and 24 months in a longitudinal study. Based on the results of 653 cord blood lead levels, infants were classified into three groups for neuropsychological assessments: low lead risk (<10th percentile) and high lead risk (>10th percentile) of the distribution of cord blood lead level were designated as low (< or = 1.045 microg/dL) and high (> or = 3.466 microg/dL) lead risk groups. Blood lead levels in between the <10th and >90th percentile were designated as mid lead risk group. A total of 66 infants were supposed to be selected from each group for a follow-up study. Of these, only 106 participated 6 months after the study. During the follow-up study, the dropout was very high with attrition rates of 74.5%, 52.8%, and 39.6% during the 12, 18, and 24 months. Mean blood lead levels increased from 3.36 to 4.45 microg/dL between the ages of 6 and 24 months, but the standardized Mental Development Index (MDI) and Psychomotor Development Index (PDI) decreased from 99.26 and 98.13 (6 months old) to 93.29 and 82.52, respectively (24 months old). Due to the high rate of attrition, most of the infants in the low group were lost. Therefore, we used the 75th percentile of blood lead levels as a cutoff in the statistical analyses. After adjustment for a large number of confounding variables, prenatal lead exposure was found to be significantly associated with the standardized MDI and PDI scores at the age of 6 months old with a P value of 0.02 for both. A borderline significant effect of prenatal lead exposure was also seen on standardized PDI scores at the age of 24 months (P = 0.09). On the other hand, no relationship was seen between postnatal blood lead levels and concurrent cognitive development scores. Such an observation is not conclusive because of low statistical power due to small sample size. Our results provide additional evidence for low prenatal lead exposure effects on cognitive development in Saudi infants living in a rural area.