KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

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

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.

Expanding the Allelic spectrum in ATP1A3-related disorders with 3 novel mutations and clinic features.

OBJECTIVES: To describe the complex phenotype of ATP1A3 and second to report new mutation of ATP1A3. METHODS: This is a retrospective chart review of 7 patients who was diagnosed with ATP1A3 mutation based on whole exome sequencing (WES) result and the following information were collected; age, age of onset, developmental ability, seizure type, family history, MRI, WES report. The data collection started a year ago January 2021 in King Faisal Specialist Hospital and Research Centre, Riyadh, KSA. This has been cleared for publication by the Office of Research Affairs, and the Publication Number is 2225429. RESULTS: Five females and 2 males had onset ages of 0-3 years (mean=18 months). All had some degree of intellectual dysfunction, 6 had seizures (85%), 4 had neurologic abnormalities, 1 had autistic features and one had mild dystonia. CONCLUSION: Our small-cohort observations confirm that ATP1A3 mutations express a wide range of phenotypes, usually including some degree of cognitive-behavioral dysfunction (100% of patients), seizures (85% of patients), and AHC (71% of patients). Moreover, they further expand the evolving allelic spectrum of these disorders by identifying 3 novel mutations.

Exposure of preterm neonates to toxic metals during their stay in the Neonatal Intensive Care Unit and its impact on neurodevelopment at 2 months of age.

BACKGROUND: Premature neonates might be exposed to toxic metals during their stay in the neonatal intensive care unit (NICU), which could adversely affect neurodevelopment; however, limited evidence is available. The present study was therefore designed to assess the exposure to mercury, lead, cadmium, arsenic, and manganese of preterm neonates who received total parenteral nutrition (TPN) and/or red blood cell (RBC) transfusions during their NICU stay and the risk of neurodevelopment delay at the age of 2 months. METHODS: We recruited 33 preterm neonates who required TPN during their NICU admission. Blood samples were collected for metal analysis at two different time points (admission and before discharge). Metals in the daily TPN received by preterm neonates were analyzed. Neurodevelopment was assessed using the Ages and Stages Questionnaire Edition 3 (ASQ-3). RESULTS: All samples of TPN had metal contamination: 96% exceeded the critical arsenic limit (0.3 µg/kg body weight/day); daily manganese intake from TPN for preterm neonates exceeded the recommended dose (1 µg/kg body weight) as it was added intentionally to TPN solutions, raising potential safety concerns. All samples of RBC transfusions exceeded the estimated intravenous reference dose for lead (0.19 µg/kg body weight). Levels of mercury, lead and manganese in preterm neonates at discharge decreased 0.867 µg/L (95% CI, 0.76, 0.988), 0.831 (95%CI, 0.779, 0.886) and 0.847 µg/L (95% CI, 0.775, 0.926), respectively. A decrease in ASQ-3-problem solving scores was associated with higher levels of blood lead in preterm neonates taken at admission (ß = -0.405, 95%CI = -0.655, -0.014), and with plasma manganese (ß = -0.562, 95%CI = -0.995, -0.172). We also observed an association between decreased personal social domain scores with higher blood lead levels of preterm neonates before discharge (ß = -0.537, 95%CI = -0.905, -0.045). CONCLUSION: Our findings provide evidence to suggest negative impacts on the neurodevelopment at 2 months of preterm infants exposed to certain metals, possibly related to TPN intake and/or blood transfusions received during their NICU stay. Preterm neonates may be exposed to levels of metals in utero.

Exposure of preterm neonates receiving total parenteral nutrition to phthalates and its impact on neurodevelopment at the age of 2 months.

This prospective study assessed the exposure to phthalates of preterm neonates who received total parenteral nutrition (TPN) during their stay in the neonatal intensive care unit (NICU) and the risk of neurodevelopment delays at the age of 2 months. Our study recruited 33 preterm neonates who required TPN upon NICU admission. Urine samples for analyzing phthalate metabolites were obtained at admission and then daily until the last day of receiving TPN. Phthalates in the daily TPN received by the preterm neonates were analyzed. The neurodevelopment of the neonates was assessed using the Ages and Stages Questionnaire Edition 3 (ASQ-3). Diethyl phthalate and butyl benzyl phthalate were found in all TPN samples, while 27% and 83% contained dibutyl phthalate and di-(2-ethylhexyl) phthalate (DEHP), respectively. Yet, the daily dose of each phthalate that our preterm neonates received from TPN was much lower than the recommended tolerable limit. Urinary levels of monobenzyl phthalate and four metabolites of DEHP [i.e., mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)] and the sum of four DEHP metabolites (∑4DEHP) increased significantly in preterm neonates before discharge. However, these levels were not correlated with their phthalate parent compounds in TPN, suggesting other sources of exposure in the NICU. At 2 months, we found that urinary levels of mono-iso-butyl phthalate (MiBP), MECPP, MEHP, and ∑4DEHP were inversely related to fine motor skills. After adjusting for head circumference, the inverse relationships remained significant, suggesting direct effects from phthalates. Given the extreme vulnerability of our population, it is critical to minimize exposure to phthalates during their NICU stay.

The cumulative risk assessment of phthalates exposure in preterm neonates.

Phthalates are widely used plasticizers in various consumer products and medical devices, with some reporting as having estrogenic and anti-androgenic endocrine-disrupting effects. Premature neonates may be exposed to high levels of specific phthalates during hospitalization in the neonatal intensive care unit (NICU) because of reliance on multiple medical procedures that pose a possible health risk. The present study utilized seven urinary phthalate metabolites of dibutyl phthalate isomers [(di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)], butylbenzyl phthalate (BBzP), and di(2-ethylhexyl) phthalate (DEHP) that had been previously measured in 33 preterm neonates sampled at hospital admission (N = 23) and daily during their NICU stay (N = 260). We aimed to perform: (1) cumulative risk assessment (CRA) using the volume and creatinine-adjusted models; (2) examine the temporal variability of CRA from repeated measures and (3) estimate the risk of cumulative exposure to phthalates based on their anti-androgenic and/or estrogenic properties. We multiplied the relative activity of individual phthalates exhibiting estrogenic or anti-androgenic effects by daily intake. For each preterm neonate, CRA was assessed based on the hazard index (HI) metric [the sum of hazard quotients] based on three reference doses for anti-androgenicity: the tolerable daily intake (TDI) from the European Food Safety Authority, the reference dose (RfD-AA) published in 2010 and newly revised published in 2020 (NRfD-AA). The metabolites of BBzP and DEHP were 2-23 fold higher in preterm neonates during their NICU stay. Median HIs increased in the order of HINRfDAA > HIRfDAA > HITDI. In the creatinine-based model, 87% (92%), 87% (96%), and 100% (100%) of preterm neonates at admission (during NICU stay) showed HITDI, HIRfD-AA, and HINRfD-AA exceeding 1, respectively with DEHP the most prevalent. The temporal reproducibility of HI (based on three reference doses) during preterm neonate stay in the NICU was high, with intra-class correlation coefficients ranging between 0.77 and 0.97, suggesting persistent exposure to phthalates. The four phthalates that preterm neonates were exposed to in the NICU exhibited estrogenic binding and anti-androgenic effects with median values (creatinine-based) of 98.7 and 56.9 µg/kg body weight/day, respectively. This was especially true for DEHP. The results indicate that preterm neonates in this NICU setting are probably at high risk of cumulative phthalate exposure with anti-androgenic properties that may have long-term adverse reproductive and developmental effects.

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.

Saudi Expert Consensus-Based Autism Spectrum Disorder Statement: From Screening to Management.

BACKGROUND: There is a large gap between the needs of individuals diagnosed with autism spectrum disorder (ASD) and the currently available services in Saudi Arabia. Services are often difficult to access, inconsistent in quality, incomplete, unsatisfactory, and costly. As such, there is a national need for expert consensus on the appropriate standards for the assessment and management of children on the autism spectrum. METHODOLOGY: A guideline development group (GDC) was formed by professionals representing all related specialties and institutions involved in the management of individuals on the autism spectrum in Saudi Arabia. They met on a regular basis over 21 months. The guideline development process consisted of five steps starting from reviewing existing guidelines and ending with discussing and writing this manuscript. A formal voting process was utilized and recommendations were discussed until a consensus was reached. RESULTS: There was consensus on the following: A specialized diagnostic assessment needs to be carried out by an experienced multidisciplinary team for children referred to assess for ASD. They should be assessed for medical etiology, their behavioral history carefully reviewed, and symptoms directly observed. Longitudinal assessments are encouraged to reflect the effects of symptoms on the individual's ability to function while with their family, among peers, and in school settings. An additional formal assessment of language, cognitive, and adaptive abilities as well as sensory status is essential to complete the diagnostic process. Interventions should be individualized, developmentally appropriate, and intensive, with performance data relevant to intervention goals to evaluate and adjust interventions. Target symptoms must be identified to address and develop monitoring systems to track change. CONCLUSION: ASD is a complex condition with widely varying clinical manifestations, thus requiring evaluation and intervention by a range of professionals working in coordination. Behavioral and environmental interventions are the key to optimal outcomes, in conjunction with medications when indicated for specific symptoms. Parental involvement in interventions is vital to sustaining therapeutic gains.

Case Report: ASI intervention on a child with autism in Saudi Arabia.

Background: Ayres Sensory Integration (ASI) is widely employed by occupational therapists working with clients who experience challenges in sensory integration, including those with autism spectrum disorder (ASD). However, there is a dearth of research examining the feasibility of ASI outside of Western nations. This study documented the barriers associated with ASI in Saudi Arabia and assessed whether the intervention could improve process and participation skills. Methods: A pre-test/post-test case study design was used. The participant was a 4-year-old girl with ASD from Saudi Arabia. Data were gathered on sensory processing, motor skills, and participation in activities of daily living. The study used semi-structured interviews and assessments (Sensory Integration and Praxis Tests, the Sensory Processing Measure-Preschool, and the Peabody Developmental Motor Scale-2) to develop goals, identify outcome measures, and plan an ASI intervention. Results: Despite the limited availability of resources (e.g., toys, treatment spaces) and Arabic measures, improvements were observed on motor and sensory tasks and in occupational performance. Conclusion: ASI that adheres to the ASI fidelity tool can be of value for Saudi Arabian children with ASD. Additionally, the study provides a stepping-stone to further research for occupational therapists in Saudi Arabia working with children with ASD.

Multiple Recurrent Copy Number Variations (CNVs) in Chromosome 22 Including 22q11.2 Associated with Autism Spectrum Disorder.

Introduction: Autism spectrum disorder (ASD) is a developmental disorder that can cause substantial social, communication, and behavioral challenges. Genetic factors play a significant role in ASD, where the risk of ASD has been increased for unclear reasons. Twin studies have shown important evidence of both genetic and environmental contributions in ASD, where the level of contribution of these factors has not been proven yet. It has been suggested that copy number variation (CNV) duplication and the deletion of many genes in chromosome 22 (Ch22) may have a strong association with ASD. This study screened the CNVs in Ch22 in autistic Saudi children and assessed the candidate gene in the CNVs region of Ch22 that is most associated with ASD. Methods: This study included 15 autistic Saudi children as well as 4 healthy children as controls; DNA was extracted from samples and analyzed using array comparative genomic hybridization (aCGH) and DNA sequencing. Results: The aCGH detected (in only 6 autistic samples) deletion and duplication in many regions of Ch22, including some critical genes. Moreover, DNA sequencing determined a genetic mutation in the TBX1 gene sequence in autistic samples. This study, carried out using aCGH, found that six autistic patients had CNVs in Ch22, and DNA sequencing revealed mutations in the TBX1 gene in autistic samples but none in the control. Conclusion: CNV deletion and the duplication of the TBX1 gene could be related to ASD; therefore, this gene needs more analysis in terms of expression levels.

Factors associated with age of diagnosis of autism spectrum disorder among children in Saudi Arabia: new insights from a cross-sectional study.

OBJECTIVES: Research examining the age of diagnosis of autism spectrum disorder (ASD) and its influencing factors mostly originate from developed Western countries, providing little to no systematic information about the understanding and management of ASD in the rest of the world. The present exploratory study examined the influence of child and family characteristics on the age of ASD diagnosis in Saudi Arabia. RESULTS: The median age at diagnosis was 3.0 years and was associated with some child and family characteristics. A 1 year increase in child's age was associated with a 0.1 year increase in age of diagnosis (95% CI 0.05, 0.12). Children who did not respond to their name were diagnosed 0.3 years earlier than other children (95% CI - 0.60, - 0.05), and engaging in challenging behavior was associated with a 0.5 year increase in age of diagnosis (95% CI 0.20, 0.81). A lack of comorbidity was associated with a 0.6 year increase in the age of diagnosis compared to the diagnosis age of children with comorbidity (95% CI 0.13, 1.01). Finally, those residing outside of Saudi Arabia were diagnosed with ASD 0.9 years earlier than those residing in Saudi Arabia (95% CI - 0.171, - 0.11).

DNA Methylation Level of Transcription Factor Binding Site in the Promoter Region of Acyl-CoA Synthetase Family Member 3 (ACSF3) in Saudi Autistic Children.

BACKGROUND: DNA methylation (DNAm) is one of the main epigenetic mechanisms that affects gene expression without changing the underlying DNA sequence. Aberrant DNAm has an implication in different human diseases such as cancer, schizophrenia, and autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder that affects behavior, learning, and communication skills. Acyl-CoA synthetase family member 3 (ACSF3) encodes malonyl-CoA synthetase that is involved in the synthesis and oxidation of fatty acids. The dysregulation in such gene has been reported in combined malonic and methylmalonic aciduria associated with neurological symptoms such as memory problems, psychiatric diseases, and/or cognitive decline. This research aims to study DNAm in the transcription factor (TF) binding site of ACSF3 in Saudi autistic children. To determine whether the DNAm of the TF-binding site is a cause or a consequence of transcription regulation of ACSF3. METHODS: RT-qPCR and DNA methylight qPCR were used to determine the expression and DNAm level in the promoter region of ACSF3, respectively. DNA and RNA were extracted from 19 cases of ASD children and 18 control samples from their healthy siblings. RESULTS: The results showed a significant correlation between the gene expression of ACSF3 and specificity protein 1 (SP1) in 17 samples of ASD patients, where both genes were upregulated in 9 samples and downregulated in 8 samples. CONCLUSION: Although this study found no DNAm in the binding site of SP1 within the ACSF3 promoter, the indicated correlation highlights a possible role of ACSF3 and SP1 in ASD patients.

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency.

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature.

Background: SLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver. Pathogenic variants of the gene cause an autosomal recessive syndrome known as "developmental and epileptic encephalopathy 25 with amelogenesis imperfecta." Results: Here, we have investigated six patients from three different consanguineous Saudi families. The affected individuals presented with neonatal seizures, developmental delay, and significant defects in tooth development. Some patients showed other clinical features such as muscle weakness, motor difficulties, intellectual disability, microcephaly, and speech problems in addition to additional abnormalities revealed by electroencephalography (EEGs) and magnetic resonance imaging (MRI). One of the MRI findings was related to cortical thickening in the frontal lobe. To diagnose and study the genetic defects of the patients, whole exome sequencing (WES) coupled with confirmatory Sanger sequencing was utilized. Iterative filtering identified two variants of SLC13A5, one of which is novel, in the families. Families 1 and 2 had the same insertion (a previously reported mutation), leading to a frameshift and premature stop codon. The third family had a novel splice site variant. Confirmatory Sanger sequencing corroborated WES results and indicated full segregation of the variants in the corresponding families. The patients' conditions were poorly controlled by multiple antiepileptics as they needed constant care. Conclusion: Considering that recessive mutations are common in the Arab population, SLC13A5 screening should be prioritized in future patients harboring similar symptoms including defects in molar development.

Genetics of ataxia telangiectasia in a highly consanguineous population.

Ataxia telangiectasia (AT) is a rare autosomal recessive multisystemic disorder. It usually presents in toddler years with progressive ataxia and oculomotor apraxia, or less commonly, in the late-first or early-second decade of life with mixed movement disorders. Biallelic mutations in ataxia telangiectasia mutated gene (ATM) cause AT phenotype, a disease not well documented in Saudi Arabia, a highly consanguineous society. We studied several Saudi AT patients, identified ATM variants, and investigated associated clinical features. We included 17 patients from 12 consanguineous families. All patients had comprehensive clinical and radiological assessment, and most were examined through whole-exome sequencing (WES). Selected individuals were analyzed using various genetic approaches. We identified five different ATM variants in our patients: three previously reported mutations, and two novel variants. Nearly all patients had classical AT presentation except for two patients with a milder phenotype. Among the three known variants, a deletion causing truncation (c.381delA resulting in p.(Val128Ter)) was identified in 13 patients. Two patients harboured the other two truncating variants, (c.9001_9002delAG resulting in p.Ser3001Phefs*6) and (c.9066delA resulting in p.Glu3023Alafs*10) and two patients had novel compound heterozygous variants (NM_000051.3:Paternal Allele:c.8762C > G;p.Thr2921Arg and Maternal Allele:c.1057T > C;p.Cys353Arg). We speculate that c.381delA is a founder mutation in our population. This study provides a genotype-phenotype relationship in a previously unstudied consanguineous population. Our findings contribute to improve local clinical care, therapy, and genetic counseling.

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.

Sociodemographic, clinical characteristics, and service utilization of young children diagnosed with autism spectrum disorder at a research center in Saudi Arabia: The road to autism spectrum disorder diagnosis.

OBJECTIVES: To assess how clinical services are accessed and utilized by young children with suspected autism spectrum disorder (ASD) and identifying factors that prevent the early identification of developmental concerns and diagnosis. METHODS: This retrospective study examined the sociodemographic and clinical characteristics of a convenience sample of children diagnosed with ASD at the Center for Autism Research, Riyadh, Saudi Arabia between 2016 and 2018. The characteristics of ASD assessment and intervention service use were examined. Additionally, we examined the association between sociodemographic, clinical, and service use variables with the child's age at the time of the parent's initial concern and first ASD diagnosis, and the time from first concern to diagnosis. RESULTS: Out of 127 cases, 67 were diagnosed with ASD (mean: 46.88 months, SD: 18.88, median: 42.00, range, 19-93). Most ASD cases had one previous assessment (n=28, 41.8%). Higher sibling numbers were associated with a later age of first concern (p=0.0278). Applied behavior analysis service utilization was associated with later age of first ASD diagnosis (p=0.0336) and longer time to ASD diagnosis (p=0.0301). CONCLUSION: Larger sample size is needed to further investigate whether these findings are representative of the national experience. Community-based intervention outcome studies should assess the quality of services being provided.

Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.