Review in Autism and Epilepsy

Autism is a neurodevelopmental disorder of undefined etiology characterized by social, communication deficits, and restricted interests/repetitive or isolated behaviors. The determination of autism is made in early life as the patients create unusual or decreased social interaction and communication, together with stereotypic movement. In most patients, a delay in verbal and nonverbal communication is watched, whereas a few patients never accomplish valuable language. Patients with autism and epilepsy may develop any type of seizure and maybe all type of seizures. Interestingly, not absolutely understood relationship between each and a lot of research in progress concerning these relations. In patients with autism, some they do not develop seizures; however, abnormal paroxysmal electroencephalographic “EEG” activity can be seen in up to 30%. For that reason, important investigation of patients with autistic spectrum disorders, and any kids with language regression, should always include sleep recording EEG in order to exclude acquired epileptic aphasia (Landau-Kleffner syndrome). The complex relationship between autism and epilepsy provides a bridge to further knowledge of shared neuronal networks for both the autisms and the epilepsies We review the literature to elucidate the relationships between epilepsy and autism

Challenges of Autism Spectrum Disorders Families Towards Oral Health Care in Kingdom of Saudi Arabia

Objective: To assess the knowledge, attitudes, and practice regarding oral health care among parents of autistic children and also the challenges faced by them in providing dental care for their Autism Spectrum Disorders (ASD) children’s in four regions of Kingdom of Saudi Arabia. Material and Methods:  In total, 263 parents of autistic children participated in this cross-sectional study who were enrolled from 4 major regions of Kingdom of Saudi Arabia. A self-administered questionnaire formulated in simple Arabic was distributed to parents of children diagnosed with autism or any form of ASD. The questionnaires consisted of demographic questions and also to assess their knowledge on oral health, child’s oral hygiene practices and visits to their dentist, oral hygiene, experience and challenges in waiting room area before the dental treatment, acceptance of treatment or rejection, accessibility to find non-dental centers either government or private for treatment and their recommendations. Results: All the parents brushed their child’s teeth using a toothbrush and fluoridated toothpaste. A total of 29.7% of the parents informed that their child never brushes teeth. A total of 41.4% of the parents visit the dental clinic when the child complains about dental problems and 54% find difficulty in locating appropriate dental clinic to deal with their ASD children. Most parents reported taking their child to a private office (38.8%). Only 3.8% of parents reported that their children had seizures during dental procedures. Conclusion:  The knowledge toward oral health was found to be inadequate among the majority of the parents. Parents of ASD children need to be educated about the consequences of oral health neglect and the importance of regular check-ups

Case report: Aromatic L-amino acid decarboxylase deficiency in three patient cases from the Kingdom of Saudi Arabia

Aromatic L-amino acid decarboxylase (AADC) deficiency is an ultra-rare and often severe neurometabolic disorder resulting from variants in the dopa decarboxylase (DDC) gene. A timely diagnosis is critical to prevent secondary complications, promote development, and optimize outcomes from future innovative treatment options, such as gene therapy. This article describes three patients with AADC deficiency managed in the Kingdom of Saudi Arabia (KSA). All three patients had homozygous variants within the DDC gene, including one novel gene variant (c.245G > A, p.Arg82Glu), and presented with symptoms from birth. In all cases, a diagnostic delay was observed owing to non-specific signs and symptoms, a lack of disease awareness among primary care physicians, and delays associated with outsourcing of genetic tests. All three patients were managed by a multidisciplinary team at a specialist tertiary center. Clinical outcomes for all three cases were poor, with one patient passing away at 3 years of age and the other two patients continuing to experience substantial disability and poor quality of life. There is an urgent need to raise awareness and improve diagnostic testing for rare diseases such as AADC deficiency in the KSA in order to improve outcomes, particularly as innovative disease-targeting therapies become available

KCNT1- related epilepsy: An international multicenter cohort of 27 pediatric cases

ObjectiveThrough international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1- related epilepsy and explored genotype- phenotype correlations associated with frequently encountered variants.MethodsA cross- sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics.ResultsTwenty- seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two- thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray- white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%- 50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy.SignificanceOur cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence- based practice is still unavailable.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154940/1/epi16480_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154940/2/epi16480.pd

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Autism and ADHD in the Era of Big Data; An Overview of Digital Resources for Patient, Genetic and Clinical Trials Information

Even in the era of information “prosperity” in the form of databases and registries that compile a wealth of data, information about ASD and ADHD remains scattered and disconnected. These data systems are powerful tools that can inform decision-making and policy creation, as well as advancing and disseminating knowledge. Here, we review three types of data systems (patient registries, clinical trial registries and genetic databases) that are concerned with ASD or ADHD and discuss their features, advantages and limitations. We noticed the lack of ethnic diversity in the data, as the majority of their content is curated from European and (to a lesser extent) Asian populations. Acutely aware of this knowledge gap, we introduce here the framework of the Neurodevelopmental Disorders Database (NDDB). This registry was designed to serve as a model for the national repository for collecting data from Saudi Arabia on neurodevelopmental disorders, particularly ASD and ADHD, across diverse domains

Machine learning for distinguishing saudi children with and without autism via eye-tracking data

Abstract Background Despite the prevalence of Autism Spectrum Disorder (ASD) globally, there’s a knowledge gap pertaining to autism in Arabic nations. Recognizing the need for validated biomarkers for ASD, our study leverages eye-tracking technology to understand gaze patterns associated with ASD, focusing on joint attention (JA) and atypical gaze patterns during face perception. While previous studies typically evaluate a single eye-tracking metric, our research combines multiple metrics to capture the multidimensional nature of autism, focusing on dwell times on eyes, left facial side, and joint attention. Methods We recorded data from 104 participants (41 neurotypical, mean age: 8.21 ± 4.12 years; 63 with ASD, mean age 8 ± 3.89 years). The data collection consisted of a series of visual stimuli of cartoon faces of humans and animals, presented to the participants in a controlled environment. During each stimulus, the eye movements of the participants were recorded and analyzed, extracting metrics such as time to first fixation and dwell time. We then used these data to train a number of machine learning classification algorithms, to determine if these biomarkers can be used to diagnose ASD. Results We found no significant difference in eye-dwell time between autistic and control groups on human or animal eyes. However, autistic individuals focused less on the left side of both human and animal faces, indicating reduced left visual field (LVF) bias. They also showed slower response times and shorter dwell times on congruent objects during joint attention (JA) tasks, indicating diminished reflexive joint attention. No significant difference was found in time spent on incongruent objects during JA tasks. These results suggest potential eye-tracking biomarkers for autism. The best-performing algorithm was the random forest one, which achieved accuracy = 0.76 ± 0.08, precision = 0.78 ± 0.13, recall = 0.84 ± 0.07, and F1 = 0.80 ± 0.09. Conclusions Although the autism group displayed notable differences in reflexive joint attention and left visual field bias, the dwell time on eyes was not significantly different. Nevertheless, the machine algorithm model trained on these data proved effective at diagnosing ASD, showing the potential of these biomarkers. Our study shows promising results and opens up potential for further exploration in this under-researched geographical context

A Novel <i>GEMIN4</i> Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts

Pathogenic variants in GEMIN4 contribute to a hereditary disorder characterized by neurodevelopmental features, microcephaly, cataracts, and renal abnormalities (known as NEDMCR). To date, only two homoallelic variations have been linked to the disease. Moreover, clinical features associated with the variants have not been fully elucidated yet. Here, we identified a novel variant in GEMIN4 (NM_015721:exon2:c.440A>G:p.His147Arg) in two siblings from a consanguineous Saudi family by using whole exome sequencing followed by Sanger sequence verification. We comprehensively investigated the patients’ clinical features, including brain imaging and electroencephalogram findings, and compared their phenotypic characteristics with those of previously reported cases. In silico prediction and structural modeling support that the p.His147Arg variant is pathogenic