Mental Retardation Syndrome Research Articles

Aplastic Anemia, Mental Retardation, and Dwarfism Syndrome Associated with Aldh2 and Adh5 Mutations

Aplastic Anemia, Mental Retardation, and Dwarfism Syndrome Associated with <i>Aldh2</i> and <i>Adh5</i> Mutations

Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families

BackgroundIntellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome.MethodsExome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing.ResultsIn an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family.ConclusionsThe investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Successful Management of Velopharyngeal Insufficiency in WAGR syndrome with Deletion of Chromosome 11p14.3

Deletions in the 11p region can lead to severe outcomes, such as WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome. However, velopharyngeal insufficiency is little known, and its treatment guideline is yet to be established. Here, we present a velopharyngeal insufficiency case of a Korean patient with a 493kb deletion of chromosome 11p14.3. The patient was successfully managed with a posterior pharyngeal flap. Posterior pharyngeal flap should be considered in velopharyngeal insufficiency patients with WAGR syndrome.

Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

L1 Syndrome-Associated Phenotypes and a Novel L1CAM Variant: A Clinical Report

AbstractL1 syndrome is a group of X-linked diseases caused by pathogenic variants in the human L1 cell adhesion molecule gene (L1CAM; OMIM 308840). The L1CAM gene is expressed primarily in the nervous system, where it plays important roles in neuronal development, including the guidance of neurite outgrowth, neuronal cell migration, axon bundling, synaptogenesis, myelination, neuronal cell survival, and long-term potentiation. L1 syndrome comprises a group of overlapping phenotypes including partial agenesis of corpus callosum, congenital X-linked hydrocephalus, and mental retardation, aphasia, shuffling gait, and adducted thumbs syndrome. Molecular analysis was performed in four patients with congenital hydrocephalus (CH) and adducted thumbs. Three pathogenic variants were identified in the L1CAM gene, novel c.539dupA (p.Gln181Alafs*46) common to the two siblings, c.791G &gt; A (p.Cys264Tyr) and c.1453C &gt; T (p.Arg485*) variants. A correlation between genotype and phenotype has been reported in L1-related disorders. Two families with intrafamilial variability are presented and a novel pathogenic variant in the L1CAM gene has been reported. L1 syndrome should be considered primarily in patients with CH and adducted thumbs.

Rare Case of a Dyggve-Melchior-Clausen Syndrome Revealed by a Spinal Cord Compression

Dyggve-Melchior-Clausen syndrome (DMSC) is an rare autosomal recessive skeletal disorder that belongs to the category of spondyloepiphyseal dysplasia. The present work reports a case of DMCS in a nine- year-old kid who was admitted for spinal cord compression accompanied by mental retardation and dysmorphic syndrome. The patient had shown a C1-C2 dislocation with compression of the bulbo-medullary junction, platyspondyly with double ondulation of all the vertebral endplates, widely open acetabulums and epi- metaphyseal dysplasia of the femoral heads. Discussion: The syndrome is clinically characterized by a staturo- ponderal delay of varying severity. Radiological characteristics consist of a scalloped appearance of the iliac wings, spondyloepimetaphyseal dysplasia and platyspondyly. The diagnosis of Dyggve-Melchior-Clausen syndrome can be suspected after a clinical evaluation, a detailed patient history, and identification of characteristic clinical and radiological signs.

Analysis of clinical features and ATRX gene variants in a Chinese pedigree affected with X-linked alpha thalassemia mental retardation (ATR-X) syndrome

To explore the clinical characteristics and genetic basis of two brothers featuring X-linked alpha thalassemia mental retardation (ATR-X) syndrome. An infant who had presented at the Qilu Children's Hospital in 2020 for unstable upright head and inability to roll over and his family were selected as the study subjects. The clinical features of the child and one of his brothers were summarized, and their genomic DNA was subjected to targeted capture and next generation sequencing (NGS). The brothers had presented with mental retardation and facial dysmorphisms. NGS revealed that they had both harbored a hemizygous c.5275C>A variant of the ATRX gene located on the X chromosome, which was inherited from their mother. The siblings were diagnosed with ATR-X syndrome. The discovery of the c.5275C>A variant has enriched the mutational spectrum of the ATRX gene.

Derivation of Induced Pluripotent Stem Cells Line (RCPCMi009-A-1) with Knockout of the &lt;i&gt;UBE2A&lt;/i&gt; Gene by CRISPR/Cas9 Genome Editing

The deletions and mutations in the UBE2A gene cause X-linked mental retardation syndrome of Nascimento type first described in 2006 (Nascimento et al., 2006). To study the role of the UBE2A gene in neurodevelopment, we generated a human iPSC line with knockout of the UBE2A gene (RCPCMi009-A-1) using genome editing CRISPR/Cas9 technology. The knockout of the UBE2A gene was confirmed by Western blotting. The pluripotent state of the RCPCMi009-A-1 iPSCs line was confirmed by typical stem cell morphology, normal male karyotype maintenance, expression of pluripotency markers and the ability to differentiate into three germ layers.

RAGAM ANAK BERKEBUTUHAN KHUSUS (ABK) DAN PROBLEMATIKA ANAK TUNARUNGU SERTA CARA MENGATASINYA DI SEKOLAH ALAM MAHIRA BENGKULU

&#x0D; The research objective with this study is to explore the Variety of Children with Special Needs (ABK) and the Problems of Deaf Children and How to Overcome Them in the Alam Mahira School Bengkulu. This study uses descriptive qualitative research where direct research is spaciousness. The informants in this study were 2 teacher and 1 student from the Alam Mahira Bengkulu School. This research addresses children with special needs by showing photos, videos, letter cards, sentence cards, ear anatomy, miniature objects, finger alphabet, ear models, half body torsos, fruit puzzles, animal puzzles, construction puzzles, cylinders, models. geometry, triangular tower, ring tower, rectangular tower, atlas, globe, wall map, custom house miniature. The results of the study show that there are several types of children with special needs (ABK) found in the field, including learning dyslexia (learning difficulties), ADHD (difficulty focusing), Autism (nervous disorder), Speech Delay (speech delay), Down Syndrome (physical and mental retardation). ), Mental Impairment (abnormalities below average – IQ), Deaf (hearing impairment). In this study it was more focused on children with special needs of the deaf. The results of the research show that deaf children need learning media in the form of visual aids to enrich their language vocabulary. The visual aids include miniature animals, miniature humans, relevant pictures, illustrated library books, and children's play equipment.

Analysis of CNNM2 gene variant in a child with Hypomagnesemia, seizures, and mental retardation syndrome

To explore the genetic etiology of a child with Hypomagnesemia, epilepsy and mental retardation syndrome (HSMR). A child who was admitted to the Children's Hospital of Shandong University on July 9, 2021 due to repeated convulsions for 2 months was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child, a 1-year-and-7-month-old male, had presented with epilepsy and global developmental delay. Serological testing revealed that he has low serum magnesium. Genetic testing showed that the child has harbored a heterozygous c.1448delT (p.Val483GlyfsTer29) variant of the CNNM2 gene, which was de novo in origin. The variant has caused substitution of the Valine at position 483 by Glycine and formation of a termination codon after 29 amino acids at downstream. As predicted by Swiss-Model online software, the variant may alter the protein structure, resulting in a truncation. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1448delT (p.Val483GlyfsTer29) was predicted as a pathogenic variant (PVS1+PS2+PM2_Supporting+PP4). The heterozygous c.1448delT variant of the CNNM2 gene probably underlay the HSMR in this child. Above finding has enriched the phenotype-genotype spectrum of the CNNM2 gene.

The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.

The vacuolar H+-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely ATP6V0C, ATP6V1A, ATP6V0A1, and ATP6V1B2, have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated Atp6v1b2emR506* mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of Atp6v1b2emR506* mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in ATP6V1B2 can cause seizures and that the Atp6v1b2emR506* heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.

Understanding the molecular profiling of diffuse gliomas classification: A brief overview.

Gliomas represent almost 30% of all primary brain tumors and account for 80% of malignant primary ones. In the last two decades, significant progress has been made in understanding gliomas' molecular origin and development. These advancements have demonstrated a remarkable improvement in classification systems based on mutational markers, which contribute paramount information in addition to traditional histology-based classification. We performed a narrative review of the literature including each molecular marker described for adult diffuse gliomas used in the World Health Organization (WHO) central nervous system 5. The 2021 WHO classification of diffuse gliomas encompasses many molecular aspects considered in the latest proposed hallmarks of cancer. The outcome of patients with diffuse gliomas relies on their molecular behavior and consequently, to determine clinical outcomes for these patients, molecular profiling should be mandatory. At least, the following molecular markers are necessary for the current most accurate classification of these tumors: (1) isocitrate dehydrogenase (IDH) IDH-1 mutation, (2) 1p/19q codeletion, (3) cyclin-dependent kinase inhibitor 2A/B deletion, (4) telomerase reverse transcriptase promoter mutation, (5) α-thalassemia/ mental retardation syndrome X-linked loss, (6) epidermal growth factor receptor amplification, and (7) tumor protein P53 mutation. These molecular markers have allowed the differentiation of multiple variations of the same disease, including the differentiation of distinct molecular Grade 4 gliomas. This could imply different clinical outcomes and possibly impact targeted therapies in the years to come. Physicians face different challenging scenarios according to the clinical features of patients with gliomas. In addition to the current advances in clinical decision-making, including radiological and surgical techniques, understanding the disease's molecular pathogenesis is paramount to improving the benefits of its clinical treatments. This review aims to describe straightforwardly the most remarkable aspects of the molecular pathogenesis of diffuse gliomas.

Retromer Chaperones: Potential Therapeutics for Treatment of Skin Disease?

Retromer Chaperones: Potential Therapeutics for Treatment of Skin Disease?

Novel USP9X Mutation in A Lebanese Patient with Delay and Microcephaly: Case Report and Review of Literature

Introduction: USP9X gene is located on the X-chromosome and encodes for an enzyme that regulates important substrates involved in neuronal growth and development. Thus, rare USP9X mutations were identified as directly causative of neurodevelopmental disorders (NDDs) and Intellectual Disability (ID) in homozygous males and more rarely in heterozygous females. In males, USP9X variants have been linked to an X-linked mental retardation syndrome that includes; central nervous system (CNS) abnormalities (white matter disturbances, thin corpus callosum, widened ventricles, and cerebellar defects), global delay with significant alteration of speech, language and behavior, hypotonia, joint hypermobility, digital abnormalities, gastro-intestinal symptoms, visual system defects and dysmorphic facial features. Patient Data: We report the rare case of a 3 years old and 8 months male patient presenting with NDD, ID, speech delay, progressive aggressive behavioral changes and CNS abnormalities (microcephaly, left periventricular lesion). He was found to have a USP9X variant carrying a missense mutation: USP9X, c.1870A&gt;T p.(Met624Leu) on Whole-Exome Sequencing (WES). Discussion: Our patient had most of the important features of the previously described X-linked mental retardation syndrome but some were absent such as dysmorphic features, digital or visual abnormalities and hypotonia. Microcephaly rather than macrocephaly was noted, which could be an additional potential CNS malformation, expanding the spectrum of phenotypic characteristics of the USP9X variants. No associated congenital anomalies were noted that are usually more common in female subjects. Conclusion: This is to our knowledge the first reported case of a USP9X variant in Lebanon. The clinical characteristics matched most of the previously described features in the literature. Microcephaly was a new clinical feature not previously described and could be a new possible phenotypic characteristic of the disease.

Analysis of clinical features and genetic variant in a neonate with Au-Kline syndrome due to a de novo variant of the HNRNPK gene

To explore the clinical phenotype and genetic basis of a neonate with Au-Kline syndrome (AKS). Clinical data and result of genetic testing of a neonate with AKS who was admitted to the Affiliated Provincial Children's Hospital of Anhui Medical University in January 2021 were retrospectively analyzed. Relevant literature was searched from the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed databases using key words "Au Kline syndrome", "Au-Kline syndrome", "HNRNPK" and "AKS". The research period was set as from January 1, 2000 to December 31, 2020. The male newborn has manifested feeding difficulties, hypotonia, absence of the upper jaw to the uvula and facial dysmorphism. Trio-whole exome sequencing revealed that he has harbored a frameshift c.478dupA (p.Ile160AsnfsTer7) variant of the HNRNPK gene, which was varified by Sanger sequencing to have a de novo origin. The variant has not been included in the databases. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was rated as pathogenic (PVS1+PS2+PM2_Supporting). Literature retrieval has identified 14 children with AKS and de novo mutations of the HNRNPK gene. Their clinical manifestations have included growth and motor retardation, various degree of mental retardation, facial dysmorphism and a high frequency of congenital heart malformations. The AKS in this child may be attributed to the c478dupA frameshifting variant of the HNRNPK gene. Diagnosis of AKS should be suspected for children with mental retardation and multiple congenital malformation syndromes including Kabuki syndrome.

Mechanisms of action of cytoplasmic microRNAs. Part 6. MicroRNA-mediated translation activation

In the scientific review, the mechanisms of action of cytoplasmic miRNAs, namely miRNA-mediated activation of translation, are given. To write the article, information was searched using Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library databases. Examples of direct activation of mRNA translation by miRNA are presented. One of them is miRNA-mediated activation of translation, which is associated with the peculiarities of the state of the cell (resting cell effect). It has been shown that protein 1 of the fragile X mental retardation (FMR1) syndrome, depending on the stage of the cell cycle, can participate in both inhibition and enhancement of translation. It is known that microRNAs can influence the activity of RNP by binding to the RNA-binding sites of specific mRNAs or directly to RBP molecules, directly inhibiting their activity. Poly (rC) binding protein 2 (PCBP2) is a multifunctional adapter molecule that binds to RNA and DNA, competing with other RNA-binding factors. The PCBP2 protein limits translation initiation by preventing ribosome recruitment. The authors provided information on miR-346-mediated activation of the translation of receptor-interacting protein 140. It is emphasized that some miRNAs, preventing the degradation of the mRNA molecule, increasе the level of its stability, which is accompanied by an enhancement in their translation. MicroRNAs stabilize specific mRNA targets, preventing the association of the ARE element degradation factor, tristetraprolin, with mRNA. Data are presented on the activation of mRNA target translation by factors that sequester miRNAs or compete with miRNAs. Various intracellular factors and proteins can enter into a competitive relationship with miRNA and interfere with or remove it from the target mRNA. It is known that activation of translation can occur due to microRNA inhibition of repressor proteins. The authors indicate that increased miR-145 expression is accompanied by activation of myocardin translation, which induces the proliferation and migration of smooth muscle cells.

Epilepsy syndromes associated with hearing loss

Patients with epilepsy who have also hearing loss represent a distinct group of patients, often with aggravated medical history, comorbidities and high potential for disability. The etiopathogenetic factors of epilepsy and hearing loss may be common to these conditions (neuroinfections, craniocerebral injuries, cerebral circulatory disorders, perinatal pathology, etc.). In addition, these two syndromes may occur as part of hereditary diseases, so their timely recognition and genetic diagnosis are important for determining further medical and genetic prognosis. This article provides an overview of orphan genetic diseases associated with epilepsy and hearing loss - MERRF syndrome, MELAS syndrome, EAST syndrome, Ayme-Grippsyndrome, epilepsy, hearing loss and mental retardation syndromes, associated with mutations in SPATA5 gene, DOOR syndrome, Gustavson syndrome.

The molecular basis of the Fragile X syndrome

This analysis aimed to clarify the molecular basis of fragile X syndrome and explain the role of genetic material in the genetic disease's development and treatment. Fragile X syndrome is an X-linked mutation inheritance disorder. The mutated gene is called FMR-1. This is important for normal brain development and synaptic plasticity, which was verified and recognized in 1991, and this has become a hope for more clarification. FMR1 influences the translation of messenger RNA (mRNA), but identifying functional targets was complex and directly related to translational control and showed that dysregulated translation initiation signaling was observed for the FMR1 gene in the FMR1 knockout mouse model of FXS.&#x0D; Because of the epigenetic alteration, such as hypermethylated at the DNA promoter region, and chromatin modification, such as H3K9 methylation, the FMR1 gene can be imprinted. Still, their mechanisms of aberrant epigenetic marks play a role in the etiology of many neurodevelopmental disorders, some of which we still do not fully understand and need to show more. The opportunities for epigenetic markers to map and alter epigenetic marks and the potential for therapies based on epigenetics and noncoding manipulation. For neurodevelopmental and behavioral conditions, including mental retardation, autism, anxiety, and mood disturbance, FMR1 loss of control is a model.&#x0D; Most studies have focused on the new and effective approach for Fragile X syndrome, which is Gene therapy is unarguably the definitive way to treat and possibly cure genetic diseases. Many of them are under clinical trial, but more studies, such as the CRISPR/Cas9-based method, should be approved. Adeno-associated viral (AAV) vectors are highly effective for generating models. Most research is used in the mouse model of fragile X syndrome, where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. The vast expansions need southern blotting in myotonic dystrophy. Fragile X is diagnosed by a form of Southern blotting that relies on the size and the FRAXA gene's methylation status. Almost always, genetic testing is performed by PCR. The few Southern blotting uses include checking for significant destructive gene rearrangements and complete mutations of fragile X and myotonic dystrophy. Expansions suppress the expression of closely adjacent genes, causing loss of function. A named FMRI (fragile-X mental retardation syndrome) gene cDNA probe. Some unique molecular mechanisms, such as CGG expansion in Fragile-X syndrome, can make a particular sequence change in a gene far more probable than any other change.

Two South African patients with PGAP3-related Mabry syndrome with unusually low alkaline phosphatase levels

&#x0D; &#x0D; &#x0D; &#x0D; Hyperphosphatasia with mental retardation syndrome (HPMRS), also known as Mabry syndrome, is an autosomal recessive disease that is associated with inherited glycosylphosphatidylinositol (GPI) deficiencies. This genetically heterogeneous disorder can be caused by variants in seven genes that encode molecules of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, namely PIGL, PIGO, PIGV, PIGW, PIGY, PGAP2 and PGAP3. Recently, a pathogenic variant in PGAP3 was identified in 3 unrelated South African patients with HMPRS. Here, two further patients with the exact variant in PGAP3 are described. Classically, HMPRS is associated with elevated alkaline phosphatase (ALP) levels. Interestingly, these two patients had unusually low ALP levels at initial presentation. This is an important observation, as the ALP level is often used as a screening test to decide whether to proceed to confirmatory genetic testing. These patients illustrate that in PGAP3-related Mabry syndrome, ALP levels can be low, albeit a rare finding. Hence, a high suspicion for the disorder should be maintained in patients with typical facial dysmorphic features and severe neurodevelopmental delay, even in the absence of elevated ALP.&#x0D; &#x0D; &#x0D; &#x0D;

Treatment of Cornelia de Lange syndrome: Evidence-based medicine and expert opinion

Background: Cornelia de Lange syndrome is a rare genetic condition of highly variable phenotype making ranging from classic syndrome with many cardinal features to mild syndrome with less characteristic features. Materials and methods: The mother of a three and half years old boy brought her son to our clinic because of significant developmental delay and over-activity. The mother denied the presence of relevant family history. Results: The boy was mentally retarded and had facial dysmorphic features including thick eyebrows with synophrys, long or smooth philtrum, thin upper lip vermilion, and low set ears. The boy poor adaptive skills and has not achieved urine and bowel control and was unable to hold spoon appropriately to feed himself. He had no speech development and was not saying any word. At the clinic, he was very active, but he was responding to name and had acceptable eye contact and therefore, he was not considered to have autistic features. It was not possible to convince him to take a pen to scribble. Based on our extensive published experiences with treatment of mental retardation syndrome, we recommended an initial therapeutic course which included a course of intramuscular piracetam 600 mg given daily in the morning every third day (Ten doses over one month). Conclusion: An expert therapeutic recommendation for the condition is described.