The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population.

BACKGROUND: To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children's Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. METHODS: We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). RESULTS: Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. CONCLUSIONS: Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

COLQ-related congenital myasthenic syndrome: An integrative view.

Congenital myasthenic syndromes are inherited disorders caused by mutation in components of the neuromuscular junction and manifest early in life. Mutations in COLQ gene result in congenital myasthenic syndrome. Here, we present the analysis of data from 209 patients from 195 unrelated families highlighting genotype-phenotype correlation. In addition, we describe a COLQ homozygous variant a new patient and discuss it utilizing the Phyre2 and I-TASSER programs. Clinical, molecular genetics, imaging (MRI), and electrodiagnostic (EEG, EMG/NCS) evaluations were performed. Our data showed 89 pathogenic/likely pathogenic variants including 35 missenses, 21 indels, 14 nonsense, 14 splicing, and 5 large deletions variants. Eight common variants were responsible for 48.46% of those. Weakness in proximal muscles, hypotonia, and generalized weakness were detected in all individuals tested. Apart from the weakness, extensive clinical heterogeneity was noted among patients with COLQ-related patients based on their genotypes-those with variants affecting the splice site exhibited more severe clinical features while those with missense variants displayed milder phenotypes, suggesting the role of differential splice variants in multiple functions within the muscle. Analyses and descriptions of these COLQ variants may be helpful in clinical trial readiness and potential development of novel therapies in the setting of established structure-function relationships.

High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry.

Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.

Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.

Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: an Iranian Case Series Expanding the Genetic and Neuroimaging Spectra.

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.

Molecular characterization of a large cohort of mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis study (IMPRESsion).

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

Characteristics of disease progression and genetic correlation in ambulatory Iranian boys with Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations of this disease include progressive muscle weakness, gait dysfunction, and motor impairment, leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is the standard diagnostic tool for DMD. This study aimed to investigate disease progression and genetic patterns in Iranian ambulant boys and to find the correlation between genotypes and motor function phenotypes. METHODS: This study was performed on 152 DMD patients. Clinical history, including the disease phenotype, steroid therapy, and the North Star Ambulatory Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses were confirmed by multiplex ligation-dependent probe amplification and next-generation sequencing tests. RESULTS: A total of 152 Iranian DMD patients were examined in this study. The mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years. Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual changes in the NSAA score were determined for all cases, based on the mutation type and exon site. Deletion mutation was found in 79.1% of cases, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon deletion was exon 44 (5.3%), and the most common multiexon deletions were attributed to exons 45-50 and exons 45-52 (4.6%). The results did not indicate any correlation between the mutation type and age at the time of disease onset, loss of ambulation age, and wheelchair dependence; however, a significant association was found between contracture and mutation type. The results showed a significant difference in the NSAA score between the deletion and nonsense groups at the age of 3 years (P = 0.04). No significant correlation was found between the phenotype and exon site. Overall, 91.1% of the study population had a history of corticosteroid use, and 54.1% showed compliance with rehabilitation therapy. CONCLUSION: This study demonstrated the phenotypes and mutational features of Iranian DMD boys and provided information regarding the natural motor history of the disease, disease progression, diagnosis, and status of DMD management in Iran. The present findings can promote the development of clinical trials and future advanced molecular therapies in Iran.

The safety and efficacy of umbilical cord blood mononuclear cells in individuals with spastic cerebral palsy: a randomized double-blind sham-controlled clinical trial.

INTRODUCTION: The current multi-center, randomized, double-blind study was conducted among children with cerebral palsy (CP) to assess the safety and efficacy of umbilical cord blood mononuclear cell (UCB-MNC). We performed the diffusion tensor imaging to assess the changes in the white matter structure. METHODS: Males and females aged 4 to 14 years old with spastic CP were included. Eligible participants were allocated in 4:1 ratio to be in the experimental or control groups; respectively. Individuals who were assigned in UCB-MNC group were tested for human leukocyte antigen (HLA) and fully-matched individuals were treated with UCB-MNCs. A single dose (5 × 106 /kg) UCB-MNCs were administered via intrathecal route in experimental group. The changes in gross motor function measure (GMFM)-66 from baseline to one year after treatment were the primary endpoints. The mean changes in modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also evaluated and compared between groups. The mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR) were the secondary endpoints. Adverse events were safety endpoint. RESULTS: There were 72 included individuals (36 cases in each group). The mean GMFM-66 scores increased in experimental group; compared to baseline (+ 9.62; 95%CI: 6.75, 12.49) and control arm (ß: 7.10; 95%CI: 2.08, 12.76; Cohen's d: 0.62) and mean MAS reduced in individuals treated with UCB-MNCs compared to the baseline (-0.87; 95%CI: -1.2, -0.54) and control group (ß: -0.58; 95%CI: -1.18, -0.11; Cohen's d: 0.36). The mean PEDI scores and mean CP-QoL scores in two domains were higher in the experimental group compared to the control. The imaging data indicated that mean FA increased and MD decreased in participants of UCB-MNC group indicating improvements in white matter structure. Lower back pain, headaches, and irritability were the most common adverse events within 24 h of treatment that were related to lumbar puncture. No side effects were observed during follow-up. CONCLUSIONS: This trial showed that intrathecal injection of UCB-MNCs were safe and effective in children with CP. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov ( NCT03795974 ).

CEP104 gene may involve in the pathogenesis of a new developmental disorder other than joubert syndrome.

BACKGROUND: The CEP104 gene (OMIM: 616,690) encodes the centrosome protein 104 (CEP104) that is involved in cilia function. Pathogenic variants in this gene have been described in four patients diagnosed with Joubert syndrome (JBTS) 25. Here, we challenged the concept that pathogenic variants in CEP104 gene are only involved in the development of JBTS 25. METHODS AND RESULTS: In a clinical setting, whole-exome sequencing (WES) was applied to investigate pathogenic variants in patients with unexplained developmental delay or intellectual disability (DD/ID).WES revealed a novel homozygous nonsense variant (c.643C > T) in CEP104 (NM _014704.3) in a girl with mild intellectual disability, hypotonia, and imbalanced gait. Her brain MRI data did not show molar tooth sign (MTS) or any other brain anomalies. CONCLUSION: Our study introduced a novel variant in the CEP104 gene that results in an ID phenotype other than JBTS25. Comparison of her phenotype with that of eight previously published DD/ID patients harboring pathogenic variants in CEP104 gene revealed that more than half of them did not show JBTS related symptoms. Therefore, we suggest that the CEP104 gene might also be involved in a disorder other than JBTS 25, a point that deserves to be emerged in the OMIM database.

The quality of life in children with spinal muscular atrophy: a case-control study.

OBJECTIVES: This study aimed to analyze the health-related quality of life (HRQoL) of patients with spinal muscular atrophy (SMA) based on the type of SMA, demographic and clinical features and compare HRQoL of these patients with a matched healthy control group.  METHODS: This was a case-control study of Patients with SMA in Iran. Sixty-six patients with SMA type II and III aged 8-18 years and also 264 healthy age, sex, and socio-economic matched individuals were enrolled. To assess the quality of life, we used the Persian version of the KIDSCREEN-27. RESULTS: The health-related quality of life between children with type II and type III SMA was not significant in all 5 subscales. However, HRQoL in healthy children was significantly higher than in SMA children in all 5 subscales. CONCLUSION: The quality of life in children with SMA was lower than the healthy control group in all subscales, and physical well-being and psychosocial aspects are the main domains of life impaired by SMA disease. However, no significant difference between the quality of life in children with SMA type II and type III was observed.

Nonsyndromic Early-Onset Epileptic Encephalopathies: Two Novel KCTD7 Pathogenic Variants and a Literature Review.

Early-onset epileptic encephalopathies (EOEE) affect cognitive, sensory, and motor development. Genetic variations are among the identifiable primary causes of these syndromes. However, some patients have been reported to be affected by EOEE without any other clinical symptoms and signs. We study the genotype and phenotype of patients with nonsyndromic early-onset epileptic encephalopathy (NSEOEE) and report 2 novel patients from Iran. A comprehensive search was conducted in PubMed, John Willy, Springer, Elsevier, and Google Scholar databases to collect related information of all the previously reported cases with KCTD7 mutations. Fifty-four patients (from 40 families) were investigated. Using trio-whole-exome sequencing (trio-WES) and Sanger sequencing, the possible genetic causes of the disorder were checked. The probable impacts of the identified variants on the KCTD7 protein structure and function were predicted. This study provided a detailed overview of all published KCTD7 mutations and 2 de novo ones. We identified 2 novel homozygous variants of uncertain significance, c.458 G > A p. Arg153His and c.529C > T (p.Arg177Cys), in KCTD7 (NM_153033.4) (Chr7(GRCh37)). There is a significant wide distribution of the KCTD7 gene causing NSEOEE among different populations. In conclusion, KCTD7 mutations demonstrate a diverse geographical distribution alongside a wide range of ethnicities. This highlights the importance of careful consideration in the WES data analysis. Mutations of this gene may be a common cause of NSEOEE. Also, this study imprints targeted therapeutic opportunities for potassium channelepsies such as KCTD7-related NSEOEE.

Levetiracetam for prophylactic treatment of pediatric migraine: A randomized double-blind placebo-controlled trial.

INTRODUCTION: Few drugs are available for migraine prophylaxis in children. Levetiracetam is a broad-spectrum anti-seizure drug that has been suggested to be effective in reducing adult migraine episodes. We assessed the safety and efficacy of levetiracetam in the prevention of pediatric migraine. METHODS: A randomized double-blind placebo-controlled trial was performed. Eligible participants were aged 4-17 years old with at least four migrainous episodes monthly or had severe disabling or intolerable episodes. Primary endpoints were the mean changes in monthly frequency and intensity of headaches from the baseline phase to the last month of the double-blind phase. Safety endpoint was the adverse effects reported. RESULTS: Sixty-one participants (31 taking levetiracetam and 30 taking placebo) completed the study. All had a significant reduction in frequency and intensity of episodes that was significantly greater in the levetiracetam arm. Sixty eight percent of individuals in the treatment group reported more than 50% reduction of episodes at the end of the trial compared with 30% in the placebo group (p-value: 0.007). Irritability, day-time sedation, and mild tic were reported. CONCLUSION: Levetiracetam may be useful in migraine prevention and may decrease migraine episodes and severity. TRIAL REGISTRATION: The study is prospectively registered with Iranian Registry of Clinical Trials; IRCT.ir, number IRCT2017021632603N1.

Impacts of the international economic sanctions on Iranian patients with epilepsy.

PURPOSE: On May 8, 2018, the United States announced that it was withdrawing from the Iran nuclear deal. This has resulted in reimposition of the economic hardship on Iran. We investigated the patients' perceptions of hardship in obtaining their antiepileptic drugs (AEDs) after the reimposition of sanctions. METHODS: We surveyed patients with epilepsy visiting three centers in Iran on February 2nd to 6th (easy sampling) on their perceptions on two issues: RESULTS: Two hundred and forty-four patients participated. Ninety-two patients (37.7%) claimed that they have had significant difficulty obtaining their AEDs, and 37 patients (15.2%) said that their AED(s) was not accessible. Ninety-six people (72%) of those receiving imported AEDs and 33 patients (30%) of those receiving homemade AEDs had significant hardship obtaining their drugs (p = 0.00001). Forty-seven patients (36%) of those who reported significant hardship obtaining their AEDs and 25 (22%) of those who did not, perceived worsening of their seizures (p = 0.017). CONCLUSION: Sanctions have affected ordinary people, especially those who are vulnerable the most (i.e., patients), significantly.

Short-term and long-term efficacy of classical ketogenic diet and modified Atkins diet in children and adolescents with epilepsy: A systematic review and meta-analysis.

OBJECTIVES: Classical ketogenic diet (KD) and modified Atkins diet (MAD) are two types of KD commonly used for the treatment of intractable epilepsy throughout the world. Studies have shown the efficacy of these diets. However, no systematic review and meta-analysis study has to date compared the efficacy of KD and MAD in a time trend. Therefore, the objectives of the present study were to compare the short-term and long-term efficacy of classical KD and MAD in children and adolescents with epilepsy and to determine the efficacy of classical KD and MAD at multiple time points and in a time trend. METHODS: Main electronic literature databases, including MEDLINE/PubMed, Web of Science, Scopus, and EMBASE, were searched in November 2016. Rate difference and random effects model were used to compare the efficacy of the classical KD and MAD. RESULTS: Overall, 70 studies were eligible for inclusion. Meta-analysis revealed a non-significant trend toward a higher efficacy of MAD at month-3 and month-6 (P > 0.05). In the classical KD group, the percentage of responder patients achieving ≥50% seizure reduction was 62, 60, 52, 42, and 46% at month-1, 3, 6, 12 and 24 and for the MAD group was 55, 47, 42, and 29% at month-1, 3, 6, and 12, respectively. DISCUSSION: Classical KD does not differ substantially from MAD in ≥50% and ≥90% reduction of seizure frequency at month-3 and month-6. Overall, the number of patients achieving seizure freedom increases over time.

A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies.

OBJECTIVE: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. METHODS: This study summarizes the clinical, imaging, and molecular data of these patients for five years. RESULTS: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. CONCLUSIONS: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. Highlights: AIRIM variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.

Associations between Symptom Severity of Autism Spectrum Disorder and Screen Time among Toddlers Aged 16 to 36 Months.

There is growing evidence that prevalence rates of autism spectrum disorder (ASD) are increasing. A number of factors appear to contribute to this increase, including excessive screen time. Screen time seems to be linked to the severity of the symptoms of ASD. Given this, the aim of the present cross-sectional study was to investigate the association between early screen time and ASD symptoms severity in the first 36 months of life. To this end, sixty-eight Iranian toddlers (mean age: 27.09 months; 22.1% females) with ASD were recruited. Parents completed the modified checklist for autism in toddlers (M-CHAT), the Repetitive Behavior Scale-Revised (RBS-R), and a lifestyle checklist. Next, parents rated children's daily exposure to content specifically designed (foreground media) and not specifically designed (background media) for children, along with their daily exposure to social interaction. Per day, toddlers spent 5.12 h (±3.77) with foreground media, 3.72 h (±3.57) with background media, and 2.89 h (±2.74) in interaction with other people (parents). To test the hypotheses, we performed a series of Pearson's correlations and multiple regression analyses. Toddlers' higher severity scores for ASD symptoms were associated with longer foreground (r = 0.234, p = 0.001) and longer background (r = 0.180, p = 0.012) media duration, and with shorter duration of interaction with others (r = 0.192, p = 0.009). Toddlers spending 1 h more in foreground screen time and background screen time have 0.38 and 0.29 more units in the ASD symptom severity scale, respectively, while toddlers spending 1 h more in social interactions have 0.42 fewer units in the ASD symptom severity scale. The screen time and interaction duration are related to ASD symptoms severity of toddlers. The cross-sectional study design precludes causal associations, although bi-directional relationships appear plausible.

The First Report of Iranian Registry of Patients with Spinal Muscular Atrophy.

BACKGROUND: Insufficient amounts of survival motor neuron protein is leading to one of the most disabling neuromuscular diseases, spinal muscular atrophy (SMA). Before the current study, the detailed characteristics of Iranian patients with SMA had not been determined. OBJECTIVE: To describe the key demographic, clinical, and genetic characteristics of patients with SMA registered in the Iranian Registry of SMA (IRSMA). METHODS: IRSMA has been established since 2018, and the demographic, clinical, and genetic characteristics of patients with SMA were recorded according to the methods of treat neuromuscular disease (TREAT-NMD) project. RESULTS: By October 1, 2022, 781 patients with 5q SMA were registered. Of them, 164 patients died, the majority of them had SMA type 1 and died during the first 20 months of life. The median survival of patients with type 1 SMA was 23 months. The consanguinity rate in 617 alive patients was 52.4%, while merely 24.8% of them had a positive family history. The most common type of SMA in live patients was type 3. Morbidities were defined as having scoliosis (44.1%), wheelchair dependency (36.8%), tube feeding (8.1%), and requiring mechanical ventilation (9.9%). Most of the registered patients had a homozygous deletion of SMN1, while the frequency of patients with higher copy numbers of SMN2, was less in more severe types of the disease. Earlier onset of the disease was significantly seen in patients with lower copy numbers of SMN2. The neuronal apoptosis inhibitory protein (NAIP) gene deletion was associated with a higher incidence of more severe types of SMA, higher dependency on ventilators, tube feeding, and earlier onset of the disease. CONCLUSIONS: The IRSMA is the first established Iranian nationwide registry of patients with SMA. Using this registry, decision-makers, researchers, and practitioners can precisely understand the epidemiology, characteristics, and genetics of patients with SMA in Iran.

Differentiating Post-Digital Nannying Autism Syndrome from Autism Spectrum Disorders in Young Children: A Comparative Cross-Sectional Study.

Excessive exposure of young children to digital devices has increased in recent years. Much research has shown that early excessive screentime is associated with autistic-like symptoms. This study aimed to differentiate children with Post-Digital Nannying Autism Syndrome (PDNAS) from children with autism spectrum disorders (ASD) and typically developing children (TDC), both behaviorally and cognitively. This study is comparative and cross-sectional and included three groups of children. The first group consisted of 15 young children with subthreshold autism symptoms. They had not received a formal diagnosis of ASD and had been exposed to digital devices for more than half of their waking time. The second group consisted of 15 young children with ASD, and the third group consisted of 15 young TDC. A lifestyle checklist, a modified checklist for autism in toddlers (M-CHAT), a behavioral flexibility rating scale-revised (BFRS-R), the Gilliam autism rating scale (GARS-2), and a behavior rating inventory of executive functioning-preschool version (BRIEF-P) were used to compare the three groups. The results showed that executive functions and behavioral flexibility were more impaired in children with ASD than in children with PDNAS and in TDC. Also, we found that there was no significant difference in the severity of autism symptoms between the children with ASD and the children with PDNAS. Early excessive exposure to digital devices may cause autism-like symptoms in children (PDNAS). Children with PDNAS are different from children with ASD in executive functions and behavioral flexibility. Further research is needed in this area.