Mental Retardation Research Articles

FMRP protects breast cancer cells from ferroptosis by promoting SLC7A11 alternative splicing through interacting with hnRNPM

Ferroptosis is a unique modality of regulated cell death that is driven by iron-dependent phospholipid peroxidation. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. However, it remains elusive whether m6A reader Fragile X Mental Retardation Protein (FMRP) are involved in the modulation of ferroptosis in breast cancer (BC). In this study, we found that FMRP expression was elevated and associated with poor prognosis and pathological stage in BC patients. Overexpression of FMRP induced ferroptosis resistance and exerted oncogenic roles by positively regulating a critical ferroptosis defense gene SLC7A11. Mechanistically, upregulated FMRP catalyzes m6A modification of SLC7A11 mRNA and further influences the SLC7A11 translation through METTL3-dependent manner. Further studies revealed that FMRP interacts with splicing factor hnRNPM to recognize the splice site and then modulated the exon skip splicing event of SLC7A11 transcript. Interestingly, SLC7A11-S splicing variant can effectively promote FMRP overexpression-induced ferroptosis resistance in BC cells. Moreover, our clinical data suggested that FMRP/hnRNPM/SLC7A11 expression were significantly increased in the tumor tissues, and this signal axis was important evaluation factors closely related to the worse survival and prognosis of BC patients. Overall, our results uncovered a novel regulatory mechanism by which high FMRP expression protects BC cells from undergoing ferroptosis. Targeting the FMRP–SLC7A11 axis has a dual effect of inhibiting ferroptosis resistance and tumor growth, which could be a promising therapeutic target for treating BC.

Клинические популяционно-генетические исследования наследственных болезней среди детского населения Северной Осетии – Алании

Currently, there is limited understanding about the cumulative prevalence, diversity, and frequency of distinct orphan hereditary diseases (OHDs) in the pediatric population, both within the Russian Federation and in the global literature. This gap exists despite a significant demand for such knowledge in healthcare and society. Variability and heterogeneity of the above indicators are common across different populations, reflecting significant genetic heterogeneity of OHDs. The study aimed to assess OHDs in the pediatric population of the Republic of North Ossetia – Alania (RNO-A). A total of 543,817 people were evaluated, including 145,560 children aged 0–18 years. The cumulative prevalence of autosomal recessive (AR), autosomal dominant (AD), and X-linked (XL) OHDs was determined. The findings indicate an overall prevalence of OHDs among children of the RNO-A of 1 : 119, meaning that approximately 1% of children are diagnosed with these conditions. Notably, the total burden in children of all types of OHDs in rural areas exceeds that in urban areas and district centers by more than twofold. We identified 1,241 patients from 1,037 families with 241 distinct OHDs (109 with AD inheritance, 102 with AR inheritance, and 30 with XL inheritance). Three diseases were particularly prevalent in this population and have not been documented in similar studies: congenital myasthenia type 12, a rare form of congenital adrenal cortex dysfunction (3-beta-hydroxysteroid dehydrogenase deficiency), and brachydactyly E — amelogenesis — mental retardation — nanism syndrome. Thus, the population of the RNO-A exhibits a unique spectrum of OHDs caused by rare mutations, some of which are infrequent in other populations of the world and the Russian Federation. The significantly higher prevalence of these disorders in rural populations is noteworthy, underscoring the need for tailored, region-specific programs aimed at preventing childhood disability and/or mortality.

Proboscis Lateralis of the Nose

Abstract Proboscis lateralis (PL) of the nose is a very uncommon craniofacial anomaly characterized by a rudimentary tubular nose-like structure seen a little away from the midline of the face. It may be associated with other anomalies such as heminasal aplasia, mental retardation, callosal agenesis, microphthalmia, heminasal hypoplasia, and atypical clefting syndrome. Patients with this congenital craniofacial malformation need proper evaluation with the help of a computed tomography scan to assess the growth of facial and skull bones. The esthetic aspects and psychological problems are often a concern for patient’s families. The cartilaginous part or bony support of the nose can be reconstructed following proper growth of the face. Here, we presented a male neonate of 15 days with PL of the nose. There was no evidence of cleft lip or cleft palate. Parents were counseled for staged repair at an early age to avoid anxiety and to allow proportionate growth of the nose and face.

Nitric oxide synthase system in the brain development of neonatal hypothyroid rats

Thyroid hormones play an important morphogenetic role during the fetal and neonatal periods and regulate numerous metabolic processes. In the central nervous system, they control myelination and overall brain development, regional gene expression, and regulation of oxygen consumption. Their deficiency in the fetal and neonatal periods causes severe mental retardation, due to lack of thyroid function, or to iodine deficiency. At the same time, nitric oxide is an atypical neurotransmitter that also has special relevance in neuronal development and plasticity and functions as a vasodilator, regulating cerebral blood flow. Although under physiological conditions it functions as a neuroprotector, in excess it can be neurotoxic. We have studied, by immunocytochemical and Western blot techniques, the evolution of the expression of neuronal and inducible isoforms of the enzyme nitric oxide synthase, and of nitrotyrosine as a marker of protein nitration produced by the presence of nitric oxide, during the early stages of postnatal brain development. We induced hypothyroidism by administering mercaptomethylimidazole to pregnant mothers, from the seventh day of gestation until the sacrifice of the offspring. The results show a delay in the evolution of the expression of the two isoforms of the enzyme nitric oxide synthase in hypothyroid animals, followed by an anomalous overexpression in later stages. Finally, the expression of nitrotyrosine follows an evolution that is synchronized with that shown by both isoenzymes in control and hypothyroid animals.

Research on the Rehabilitation Effect of Repetitive Transcranial Magnetic Stimulation Combined with Cognitive Training on Children with Mental Retardation

This study investigated the rehabilitation effect of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training on children with mental retardation (MR). Through a randomized controlled trial design, 40 children aged 2–6 years with mental retardation were selected as study subjects and randomly divided into two groups: conventional treatment group and rTMS combined with cognitive training treatment group. The results showed that compared with the conventional treatment group, the rTMS combined with cognitive training treatment group exhibited more significant effects in improving children’s cognitive function, social adaptability, and quality of life. This study not only enriched the theoretical basis of rehabilitation treatment for children with mental retardation but also provided strong evidence support for clinical practice.

ВЛИЯНИЕ ИНТЕРАКТИВНОГО ФИЗКУЛЬТУРНОГО КОМПЛЕКСА НА РЕАБИЛИТАЦИЮ ДЕТЕЙ С ЗАДЕРЖКОЙ ПСИХИЧЕСКОГО РАЗВИТИЯ

An urgent issue today is the increase in the number of children with mental retardation. Statistics from the last five years show that more than 20% of children are born with lesions of the central nervous system. Perinatal pathology leads to a delay in mental and motor development and subsequently contributes to the risk of children's academic failure, maladjustment and social deviation. For a comprehensive solution to the problem, rehabilitation methods should be correctly selected, aimed at improving mental functions, developing physical qualities and forming motor skills. The purpose of the study is to study the effectiveness of an interactive physical education complex in the rehabilitation of children with mental retardation. The results obtained made it possible to identify the effectiveness of the use of a non–drug rehabilitation method - an interactive physical education complex for the development of cognitive functions and physical qualities of primary school children with mental retardation. To identify the level of logical thinking, the "Exclusion of excess" method was used, dexterity of movements was assessed by the "Darts" test, communicative activity was identified using a questionnaire for parents using the Makarchuk A.V., Gorinova E.V. method, large hand motor skills were assessed by a functional motor test, fine hand motor skills were assessed by the Grizik T.I., Tymoshchuk L.F. method. In the study of logical thinking in children after the rehabilitation course, an increase in the average values of the indicator was revealed in the main group, there were no changes in the control group. The results of the dexterity assessment test showed that after rehabilitation, the average values of the indicator increased only in the main group where the interactive complex was used. When evaluating communicative activity, it was revealed that when comparing groups, no changes were found in the average values of the indicator, however, the level of social interaction in the main group moved from "average" to "high" on a point scale, in the control group the level remained the same. When evaluating large hand motor skills, it was revealed that after rehabilitation in the main group, in which an interactive physical education complex was used, the average values of the indicator increased and began to correspond to the assessment "good", in the control group the indicator did not change – the assessment "satisfactory". In the study of fine motor skills, an increase in the average values in the main group was revealed: from the level of "poor development" to the level of "insufficiently good development", there were no changes in the control group. Thus, the interactive physical education complex increases the indicators of logical thinking, dexterity of movements, large and small hand motor skills and improves the level of communicative activity.

PARENTS’ COMMUNICATION PATTERNS TOWARDS CHILDREN WITH MENTAL DISORDERS

Communication is a necessity or means of social interaction for human life. However, some individuals, such as mentally retarded children, experience difficulties in communicating due to various factors and environments. This study aims to understand the communication patterns used by parents in interacting with children who suffer from mental retardation. The method used is Systematic Literature Review to explore insights into parents' communication patterns towards mentally retarded children. The researcher collected, summarized, evaluated, interpreted and synthesized information from journals published between 2019-2024. The results showed that communication patterns used by parents can affect learning outcomes and behavioral changes in children with mental retardation. The ideal communication pattern is interpersonal communication that involves direct interaction and feedback between parents and children. Parents need to have extra patience in communicating with mentally retarded children, and communication must be done regularly so that communication development for children can run well. Based on the author's understanding, interpretation and evaluation of various existing journals, it turns out that the communication pattern most favored by mentally retarded children is through audio and video-based multimedia interactive media and gross and fine motor skills through the puzzle game method.

Advancements in the Study of Clinical Features and Molecular Functions in Heterogeneous TAF1-associated Clinical Phenotypes

Purpose of review: TATA-binding protein (TBP)-associated factor 1 (TAF1) encodes the largest component of the transcription factor IID (TFIID) complex, which binds to core promoters and serves as a scaffold for assembly of the RNA polymerase II transcription complex. Variants in TAF1 are associated with X-linked dystonia-parkinsonism (XDP) and X-linked syndromic mental retardation-33 (MRXS33). This review provides a concise summary of the genetic and clinicopathological features of TAF1 variants related to phenotype. Recent findings: XDP is an adult-onset X-linked progressive neurodegenerative disorder presenting dystonia and parkinsonism and caused by a SINE-VNTR-Alu (SVA)-type retrotransposon within TAF1. TAF1/MRXS33 intellectual disability syndrome is characterized by global developmental delay, intellectual disability, facial dysmorphia, generalized hypotonia, and neurological abnormalities due to the missense variants in TAF1. Various symptoms of TAF1 missense mutations may be related to mutations in different functional regions of the protein. The clinical manifestations of XDP and MRXS33, both caused by variants of TAF1, present prominent heterogeneity, which could be influenced by whether the TAF1 mutation is located in the coding region, the time when TAF1 expression decreases, and the effect on downstream gene expression. Summary: TAF1 is linked to many different phenotypes because of its variable regulation of coding and noncoding elements, which makes its mechanistic roles in disease challenging to interpret. However, it is important to note that strategies to correct TAF1 splicing could provide therapeutic benefits in different diseases.

Digital learning: Differentiated teaching models using ICT in a Greek context – Good Practices "We give money, we buy things"

The importance of money in people's lives today is an important and useful skill for individuals in a transactional society. Money management is a communication, transaction, and socialization skill. People with special educational needs and especially people with mental retardation with the right training can develop the skill of recognizing and using money. Differentiated teaching with the help of ICTs is an educational approach to knowledge suitable for teaching people without or with special educational needs.

A Retrospective Evaluation of Patients Who Had Den¬tal Treatments Under General Anesthesia

Aim: This retrospective study aimed to evaluate the demographic and operational data of uncooperative healthy individuals and individuals with special needs who underwent dental treatments under sedation and general anesthesia. Methods: Data of 458 patients with special needs and 77 healthy noncooperative patients who were examined at XXX University Faculty of Dentistry between January 2022 and May 2023 and underwent dental treatments under general anesthesia were examined retrospectively. Demographic data of the patients, American Society of Anesthesiologists (ASA) scores, mallampati (MP) scores, disability status, if they have systemic diseases, type of anesthesia (sedation/general anesthesia), anesthetic agents and analgesia used, operation duration and dental treatments, were evaluated. Results: The average age of 535 patients who received dental treatment was 13.5±9.9 years and 58.1% (n=311) of the patients were male and 41.9% (n=224) were female. According to ASA scores, the distribution was 15.7% ASA I, 77.6% ASA II, and 6.7% ASA III. While 14.4% of the patients were systemically healthy, 16.7% had epilepsy, 12.9% had cerebral palsy, 12.1% had mental retardation, and 7.1% had Down syndrome. Of 7.1% had various comorbidities such as cardiological problems. Sedation was applied to 7.3% (n=39) of the patients, and general anesthesia was applied to 92.7% (n=496). The average anesthesia duration was 74.5±34.6 minutes. While the average restorative treatment applied to the patients was calculated as 6.45±3.9, tooth extraction 5.25±4.3, fissure sealant 2.44±2.5, pulp treatment 1.62±0.9; Trauma splint was applied to 3 patients. Conclusions: While pre-anesthesia evaluation is very important in determining the risks in dental general anesthesia and sedation applications, the operating conditions and the general and oral health of the patients are effective in the dental treatment decision.

Effects of EEG-Neurofeedback in children with Down syndrome

Background. Down syndrome (DS) is a genetic disorder characterized by varying degrees of mental retardation and neurological complications. Children with DS often experience difficulties with attention, concentration, learning, memory, speech, language, behavior, and physical balance. Methods. This study included 11 children with DS and 10 children with ADHD, aged 6 to 10 years who received treatment at the private clinic “Neyromed Servis” in Tashkent, Uzbekistan. Cognitive functions were analyzed by using Electroencephalography-neurofeedback (EEG-NFB) and the Forbrain headsets. The Wechsler Preschool and Primary Scale of Intelligence and Schulte table were used to assess the effectiveness of non-drug treatment. Results. The utilization of Forbrain headsets enhanced children’s attentiveness as listeners and improved the quality of their voice and speaking. Positive changes in EEG parameters were also registered: theta wave amplitude and theta-tobeta ratio in the frontal lobes decreased significantly. Conclusion. EEG-NFB treatment significantly improved cognitive function, particularly attention, without any side effects in observed children. Moreover, impulsivity as well as hyperactivity decreased gradually. Additionally, after using of the Forbrain method, vocabulary in children improved by 20-40% across all groups.

William M. Reynolds (1951-2024).

Memorializes William M. Reynolds (1951-2024). "Bill" served as director of the graduate program in school psychology at the University of Wisconsin-Madison and held appointments as principal investigator at the Waisman Center on Mental Retardation and Human Development and as discipline chief of Psychology of the University Affiliated Program at the Waisman Center. He developed the Reynolds Adolescent Depression Scale and the Reynolds Childhood Depression Scale, which are widely used both clinically and in research. Bill held a professorship at the University of British Columbia (1991-2000), serving as director of the School Psychology graduate program. In 2000, Dr. Reynolds returned to California as professor of Psychology at Cal Poly Humboldt. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

DDX5-Targeting Fragile X Mental Retardation Protein Regulates the Wnt/β-catenin Signaling Pathway to Promote Epithelial Mesenchymal Transition in Breast Cancer

To investigate the role of fragile X mental retardation protein (FMRP) in promoting cell migration and epithelial-mesenchymal transition (EMT) in breast cancer (BC) and the potential mechanisms involved. The mRNA and protein expressions of FMRP in MCF-10A, a normal human breast epithelial cell line, and four breast cancer cell lines, including MCF-7, BT474, MDA-MB-231, and HCC1937, were analyzed by RT-PCR and Western blot. The expression of FMRP in BC tissues was measured by immunohistochemistry (IHC). FMRP expression in BC and its relationship with clinical prognosis were analyzed using GEO database. Lentiviral infection and siRNA interference were used to construct FMRP overexpression and interference vectors, respectively, and the human breast cancer cell line MCF-7 was subsequently transfected. A Control group, an interference empty vector group (the NC group), a knockdown vector group (the siFMRP group), an overexpression empty vector group (the Lv-NC group), and an overexpression vector group (the Lv-FMRP group) were set up. The migration and invasion abilities of the cells were assessed by scratch assay and Transwell assay. The expression of EMT markers, including E-cadherin, an epithelial marker, N-cadherin, an mesenchymal markers, vimentin, zinc finger E-box binding homeobox 1 (ZEB1), and snail family zinc finger 2 (Slug), in the cells of each group was determined by Western blot. The interaction between FMRP and DEAD-box RNA helicase-5 (DDX5) protein was analyzed by immunocoprecipitation combined with mass spectrometry (IP-MS). The regulatory effect of FMRP on DDX5 protein expression was assessed using the protein synthesis inhibitor cycloheximide (CHX) and proteasome inhibitor MG132. In addition, transfection with siDDX5 vector was conducted to observe whether DDX5 could reverse the effects of FMRP overexpression on cell migration and EMT. The localization and expression of β-catenin were determined by immunofluorescence staining, and the expression of core markers of Wnt/β-catenin signaling pathway was examined by Western blot. FMRP was highly expressed in BC tissues and cells (P<0.05), and overall survival (OS) and recurrence-free survival (RFS) of the FMRP high expression group were significantly lower than those of the FMRP low expression group (P<0.05). The migration ability of MCF-7 cells was weakened after FMRP knockdown, while overexpression of FMRP promoted cell migration (P<0.05). After FMRP knockdown, the expression of E-cadherin was increased, while the expression levels of N-cadherin, vimentin, ZEB1, and Slug were decreased, which inhibited the occurrence of EMT. In contrast, the overexpression of FMRP promoted the EMT process (P<0.05). FMRP interacted with DDX5 protein and promoted DDX5 protein stability by blocking the ubiquitin-proteasome pathway. DDX5 knockdown reversed the effect of FMRP overexpression to promote cell migration and EMT (P<0.05), effectively inhibited β-catenin nuclear translocation, and decreased β-catenin nuclear distribution. Furthermore, it was found that the expression of p-β-catenin, GSK3β and Axin2 protein was increased and the expression of C-myc protein was decreased after DDX5 downregulation (P<0.05). On the other hand, the expression of these proteins was reversed by combined FMRP overexpression (P<0.05). FMRP targets DDX5 and promotes BC cell migration and EMT via the activation of the Wnt/β-catenin signaling pathway.

Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome

BackgroundDefective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT.MethodsRimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed.ResultsmtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice.LimitationsThe lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions.ConclusionsThe present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with the possible benefits of a scheduled feeding intervention using the Fmr1 knockout (KO) mouse model. These mutants displayed clear evidence for sleep and circadian disturbances including delay in the onset of sleep and fragmented activity rhythms with increases in cycle-to-cycle variability. The Fmr1 KO mice exhibited deficits in their circadian behavioral response to light with reduced masking, longer time to resetting to shifts in the LD cycle, altered synchronization to a skeleton photoperiod and lower magnitude light-induced phase shifts of activity rhythms. Investigation of the retinal input to the surprachiasmatic nucleus (SCN) with the neurotracer cholera toxin (β subunit) and quantification of the light-evoked cFos expression in the SCN revealed an abnormal retinal innervation of the SCN in the Fmr1 KO, providing a possible mechanistic explanation for the observed behavioral deficits. Interestingly, disruptions in social and repetitive behavior correlated with sleep duration and fragmentation. Understanding the nature of the deficits, we decided to apply a scheduled feeding regimen (6-hr/18-hr feed/fast cycle) as a circadian-based strategy to boast circadian rhythms independently of light. This intervention significantly improved the activity rhythms and sleep in the mutants. Strikingly, the scheduled feeding ameliorated social interactions and reduced repetitive behaviors as well as the levels of Interferon-gamma and Interleukin-12 in the Fmr1 KO mutants, suggesting that timed eating may be an effective way to reduce inflammation. Collectively, this work adds support to efforts to develop circadian based interventions to help with symptoms of neurodevelopmental disorders.

Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion.

MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome. KEY MESSAGES: A missense AP1S1 c.269T > C (σ1A L90P) variant causes full MEDNIK syndrome. The σ1A L90P variant is largely unable to assemble into the AP-1 complex. The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs. The σ1A L90P variant results in loss-of-function of the protein.

Genetic and clinical analysis of two children with microcephaly and mental retardation due to a frameshifting variant of CASK gene

To explore the clinical and genetic characteristics of two children with mental retardation and microcephaly. Two children who had visited the Anhui Children's Hospital respectively on March 12 and June 22, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from them and their parents, and subjected to chromosomal karyotyping and whole exome sequencing analyses. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. Chromosomal karyotyping and copy number detection of the two children had found no abnormality. Whole exome sequencing revealed that child 1 has harbored a c.471delT (p.Pro157Profs*9) frameshifting variant of the CASK gene, whilst child 2 has harbored a c.1259_1269delCTGAGAATAAC (p.Pro420fs*27) frameshifting variant of the CASK gene. Sanger sequencing confirmed that both variants were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), both variants were rated as pathogenic (PVS1+PS2+PP3). The de novo variants of the CASK gene probably underlay the pathogenesis of mental retardation and microcephaly in both children.

Genetic analysis of a child with pachygyria due to variant of ADGRG1 gen

To explore the genetic basis for a child with pachygyria. A proband who had visited Qinzhou Maternal and Child Health Care Hospital for pachygyria and mental retardation in June 2020 was selected as the study subject. Clinical data was collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The proband, a 4-year-and-6-month-old female, was clinically diagnosed with megagyrus deformity. WES revealed that she has harbored compound heterozygous variants of the ADGRG1 gene, namely c.781G>T (p.E261*) in exon 6 and c.1369A>C (p.S457R) in exon 11, which were verified by Sanger sequencing to be derived from her mother and father, respectively. Her younger sister was also heterozygous for the c.1369A>C (p.S457R) variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1+PM2_ Supporting; PM1+PM2_Supporting+PM3+PP3). The c.781G>T (p.E261*) and c.1369A>C (p.S457R) compound heterozygous variants of the ADGRG1 gene probably underlay the pachygyria malformation in this child.

Helsmoortel-Van der Aa syndrome in a 13-year-old girl with autistic spectrum disorder, dysmorphism, a right solitary kidney, and polycystic ovaries: a case report

BackgroundHelsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis.Case presentationWe report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition.ConclusionsClinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.

Forming inflection and word-formation operations in preschoolers with mental retardation

Introduction. At the present stage of societal development, great attention is paid to issues affecting the psychological and pedagogical support in the educational process of children with disabilities. One general pattern of dysontogenetic development is violation of speech mediation. The most important areas of assistance to children with special educational needs are: identifying speech defect specifics and creating additional special conditions that will facilitate assimilation of educational programs and the social development of each student’s personality. The study aims to develop and test a program for forming inflection and word-formation operations in preschoolers with mental retardation. Materials and methods. The study involved 92 preschoolers aged 6-7 with mental retardation. The research methods were: Methodology of psycholinguistic study of oral speech disorders in children by R.I. Lalaeva, Diagnostics of oral speech of children aged 4-7 by N.V. Nishcheva; mathematical statistics: χ2-Pearson criterion. Results. The ascertaining experiment showed that preschoolers with mental retardation are characterized by predominantly low level of formation of inflection and word-formation operations. Specific difficulties were identified: omission or incorrect use of prepositions in speech; errors in changing nouns in indirect cases; deficiencies in the agreement of an adjective with a noun in the neuter gender; lexical substitutions of nouns, verbs when forming new words using suffixes and prefixes; replacement and incorrect use of suffixes while forming relative and possessive adjectives, etc. After the formative experiment, significant shifts occurred both in the level of noun inflection operations (χ2 = 19.739; p ≤ 0.05) where the number of children at a low level decreased from 64% to 32%, and in the level of verb word-formation operations (χ2 = 30.61; p ≤ 0.05) where the number of children at an average level increased from 39% to 58%. Conclusion. Preschoolers with mental retardation experience difficulties in grammatically designing speech utterances. The data obtained in the experiment show that speech difficulties are due to the delayed development of inflection and word-formation operations and the qualitative peculiarity of the manifestation of the defect. Studying grammatical operations in young children with mental retardation and the specifics of the manifestation of this disorder in written speech is a promising further direction.