DLG3 Impairment Caused by Missense Variants in Non-Syndromic X-Linked Mental Retardation

2021 ◽  
Author(s):  
Meryem Alagoz ◽  
Nasim Kherad ◽  
Huseyin Avni Solgun ◽  
Alper Ozkılıc ◽  
Elif Sibel Aslan ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Cognitive Impairment ◽  
Neural Development ◽  
Conclusive Evidence ◽  
Adaptive Behaviour ◽  
Missense Mutations ◽  
Significant Deterioration ◽  
Familial Transmission ◽  
Functional Studies ◽  
Unrelated Male

Abstract X-lined intellectual disability (XLID), formerly known as X-lined mental retardation, is defined as genetically heterogeneous disorders with remarkable cognitive impairment and abnormal adaptive behaviour skills. This study demonstrates the Disc-large homolog 3 (DLG3) gene impairment in 2 different unrelated male probands. The results detected two missense mutations in the DLG3 gene, c.2267 G > A (p.Arg756Gln) and c.2359G > A p. (Gly787Ser) using by NGS. Both mutations were run in the PolyPhen2 program for mutation sensitivity check and showed to have 0.709 and 1, respectively. The familial transmission pattern of MR detected both mothers to be heterozygote. The mutations were shown to have caused non-syndromic XLMR (NS-XLMR) as both males did not show any abnormal facial or physiological features. Based on the IQ measurement, proband 1 and 2’ IQs were measured 40 and 33, and they were diagnosed with moderate and severe XLMR, respectively. Both affected males showed significant deterioration in neural development and behaviour abilities, which indicates the significant impact of the mutation on neurotransmitters and maintenance of NMDA receptors in neural functions. However, further molecular and functional studies are necessary to provide more conclusive evidence of the detailed abnormalities caused by the reported mutations.

Identification of new ARMC5 missense mutations in Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) and their functional studies in vitro

2018 ◽  
Author(s):  
Anna Vaczlavik ◽  
Stephanie Espiard ◽  
Marie-Odile North ◽  
Ludivine Drougat ◽  
Marthe Rizk-Rabin ◽  
...  
Keyword(s):  
Missense Mutations ◽  
Adrenal Hyperplasia ◽  
Functional Studies

scholarly journals Fragile X Mental Retardation 1 (FMR1) Intron 1 Methylation in Blood Predicts Verbal Cognitive Impairment in Female Carriers of Expanded FMR1 Alleles: Evidence from a Pilot Study

2012 ◽  
Vol 58 (3) ◽  
pp. 590-598 ◽  
Author(s):  
David E Godler ◽  
Howard R Slater ◽  
Quang M Bui ◽  
Elsdon Storey ◽  
Michele Y Ono ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Cognitive Impairment ◽  
Fragile X ◽  
Cognitive Status ◽  
Verbal Iq ◽  
Fragile X Mental Retardation ◽  
Cpg Sites ◽  
Cgg Repeats ◽  
Intron 1 ◽  
Study Participants

Abstract BACKGROUND Cognitive status in females with mutations in the FMR1 (fragile X mental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X–related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55–200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ <70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS A methylation analysis of intron 1 CpG sites 10–12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10−5) after adjustment for multiple measures. CONCLUSIONS The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment in FM females, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.

SMITH-LEMLI-OPITZ SYNDROME WITH CARDIOVASCULAR ABNORMALITY

PEDIATRICS ◽  
1971 ◽  
Vol 47 (5) ◽  
pp. 844-847
Author(s):  
Carl D. Robinson ◽  
Lowell W. Perry ◽  
Amnat Barlee ◽  
Gordon W. Mella
Keyword(s):  
Congenital Heart Disease ◽  
Mental Retardation ◽  
Heart Disease ◽  
Congenital Heart ◽  
Failure To Thrive ◽  
Neuromuscular System ◽  
Cardiac Lesion ◽  
Cardiovascular Abnormality ◽  
Opitz Syndrome ◽  
Unrelated Male

Smith, Lemli, and Opitz in 1964 described in three unrelated male children a syndrome consisting of failure to thrive, mental retardation, microcephaly, disorders of the neuromuscular system, typical facies with anteverted nares, micrognathia, broad maxillary ridge, and low set ears. Over 95% of males with the syndrome have hypospadias with or without cryptorchidism. Females have normal genitalia. Cutaneous syndactyly of the second and third toes commonly occurs. Chromosome karyotype is normal. The present case represents the fortieth to be reported. Of the 40 reported cases, eight or 20% had congenital heart disease which would appear to be emerging as a common feature of the syndrome. No specific cardiac lesion is predominantly seen.

Dramatic Improvement in down Syndrome—Associated Cognitive Impairment with Donepezil

2005 ◽  
Vol 39 (3) ◽  
pp. 563-566 ◽  
Author(s):  
Tatsuro Kondoh ◽  
Nagisa Amamoto ◽  
Tomoki Doi ◽  
Hitomi Hamada ◽  
Yoji Ogawa ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mental Retardation ◽  
Cognitive Impairment ◽  
Adverse Effects ◽  
Junior High School ◽  
Dramatic Improvement ◽  
Progressive Dementia ◽  
Severe Cognitive Impairment ◽  
Soft Stool

OBJECTIVE: To report 2 cases of patients with Down syndrome and severe cognitive impairment who gained dramatic improvements in quality of life (QOL) upon donepezil treatment. CASE SUMMARIES: Case 1. A 38-year-old woman with Down syndrome, diagnosed with secondary progressive dementia when her mental state had deteriorated rapidly after graduation from junior high school, started donepezil treatment. The loading dose was 3 mg/day and was increased to 5 mg/day for maintenance. One month after the dose was increased, adverse effects such as soft stool and urinary incontinence appeared. These adverse effects disappeared when the dose was decreased again to 3 mg/day. Her QOL improved dramatically with this minimal dose. She recovered verbal and written communication skills that she had lost for the past 21 years. Case 2. A 22-year-old man with Down syndrome, who had been diagnosed as having severe mental retardation, was put on donepezil therapy. Both loading and maintenance doses were 3 mg/day. His QOL had also dramatically improved, with some recovery in verbal communication. Transient agitation/violence and transient muscle weakness appeared during the first few months of treatment. DISCUSSION: Patients with Down syndrome may be more sensitive to donepezil therapy than others and may benefit from this medicine, although they may also have adverse effects more frequently. CONCLUSIONS: Donepezil may be a useful medicine for some patients with Down syndrome with severe cognitive impairment or mental retardation if the adverse effects are manageable.

scholarly journals PRACTICAL ADAPTIVE BEHAVIOR OF CHILDREN WITH MENTAL RETARDATION

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Victoria Jyothi ◽  
Sudhakar Venukapalli
Keyword(s):  
Mental Retardation ◽  
Adaptive Behavior ◽  
Gender Discrimination ◽  
Research Work ◽  
Adaptive Behaviour ◽  
Practical Skills ◽  
External Reality ◽  
Moderate Mental Retardation ◽  
Domestic Lives ◽  
Verbal Prompts

How do the children with mild and moderate mental retardation recognize and comprehend the external reality? How do they communicate their abilities of representation and exhibit their competencies? What kind of Practical skills do they possess? With what practical skills do they interact? These are some of the seminal questions in the contemporary discourse on children with mental retardation. This study is an attempt to grapple with some of the above questions, related to the practical adaptive behaviour of children with mental retardation. In social and domestic lives, the practical skills are important, and this article is to study the comparison of various domains of mentally retarded individuals with different degrees of retardation such as mild, moderate, severe, and profound. To carry out this research work a sample of 60 children with mental retardation are randomly selected, from two sub-populations i.e., mild and moderate children with mental retardation. This article mainly focuses on the practical adaptive behavior of children with mild and moderate mental retardation to their level of mental retardation, gender, level of the parent's education, and years of schooling. This research helped us to identify certain gaps in the existing knowledge. It was found based on the conducted research that the majority of the children with mild mental retardation exhibited practical behavior most frequently by participating in most of the classroom practical activities. It is also very important for us to realize that these children whose exceptionalities and disabilities can also be helped with good suggestions so, that they can lead a happy and productive life. From the analysis and testing of the hypothesis, it is evident that the variable 'gender' does not have any influence on children's practical skills. Irrespective of various backgrounds both the boys and girls are equally getting involved in the different practical activities, this may be the reason for the absence of gender discrimination in this context. It can be concluded that children with mental retardation exhibit delays in all aspects of practical skills management compared to non-retarded children and it is felt that if some verbal and non-verbal prompts are provided, these children can manage practical acts well in familiar situations. <p> </p><p><strong> Article visualizations:</strong></p><p><img src="/-counters-/edu_01/0776/a.php" alt="Hit counter" /></p>

scholarly journals Analysis of the prevalence of mental and speech disorders in children in the Srednekolymsky Ulus of Yakutia (based on the results of a screening examination)

2020 ◽  
Vol 11 (5) ◽  
pp. 21-29
Author(s):  
Vera V. Pozdnyak ◽  
Severin V. Grechanyy
Keyword(s):  
Eating Disorders ◽  
Mental Retardation ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Mental Disorders ◽  
Age Groups ◽  
Speech Disorders ◽  
Preschool Age ◽  
Wide Range ◽  
The Republic

The article is devoted to the analysis of mental, including speech, disorders among children in the villages of the Srednekolymsky ulus of the Republic of Sakha (Yakutia). The purpose of the survey was to analyze the diagnosed mental, including speech, disorders among the children of the villages of the Srednekolymsky ulus of the Republic of Sakha (Yakutia). 501 children aged 2 to 18 years were examined. Clinically significant disorders were detected in 187 children (37.4%). The structure of mental disorders is described: the first place is occupied by specific speech and language disorders (F80), the second is mental retardation (F83) and the third is mild cognitive impairment (F06.7). The data on the prevalence of mental disorders in various age groups are presented: most often, mental disorders occur in adolescence (51.0% of all examined children). Less disturbances are diagnosed in the early age group and the first period of childhood 22.0% of all children examined. In the group of preschool age, speech disorders are in the lead, in the group of primary school age mental retardation, speech disorders and mild cognitive impairment. In adolescence, a wide range of mental disorders is diagnosed, including adaptive reactions and eating disorders. Sexual differences in the nosological specificity of mental disorders were revealed: mental disorders prevail in boys. Speech disorders, stuttering, and behavioral disorders are significantly more common among boys. Among girls, adaptation disorders, emotionally labile disorders and eating disorders are significantly more common.

scholarly journals Mental retardation and oral health: An insight

2021 ◽  
Vol 2 (6) ◽  
Author(s):  
Pramod V Tatuskar ◽  
◽  
Vandana KL ◽  
Keyword(s):  
Mental Retardation ◽  
Oral Health ◽  
Genetic Disorder ◽  
Care Plan ◽  
Adaptive Skills ◽  
Adaptive Behaviour ◽  
Oral Health Promotion ◽  
Health Care Plan ◽  
Service Training ◽  
Health Situation

Mental Retardation (MR) is a genetic disorder mainfested in significantly below average overall intellectual functioning and deficits in adaptive behaviour. It is a particular state of functioning that begins in childhood and is characterized by decreased intelligence and adaptive skills and also is the most common developmental disorder, often missed by clinicians. The condition is present in 2 to 3 percent of the population, either as an isolated finding or as part of a syndrome or broader disorder. Looking at varies studies it was concluded that the oral health situation of these groups must be improved and a suitable system devised for delivery of preventive measures. Special consideration must be given to improving the oral health of these groups. Oral health should be included in each child’s individual health care plan with oral health promotion programmes aimed specifically at special needs schools and their parents. Children should be instructed to clean their teeth twice a day and oral hygiene should be practised at school and supervised by teachers. There should be a provision for in-service training for teachers, school staff and parents on how to promote good oral health specifically for these children with disabilities.

scholarly journals Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity

2021 ◽  
Vol 118 (4) ◽  
pp. e2010612118
Author(s):  
Robert Rauscher ◽  
Giovana B. Bampi ◽  
Marta Guevara-Ferrer ◽  
Leonardo A. Santos ◽  
Disha Joshi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Amino Acid ◽  
Time Window ◽  
Mrna Translation ◽  
Underlying Mechanism ◽  
Missense Mutations ◽  
Translation Speed ◽  
Functional Studies ◽  
Translation Velocity ◽  
And Function

Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)—the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease–causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain–domain interactions that are otherwise perturbed by each individual mutation.

scholarly journals Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly

2019 ◽  
Vol 116 (39) ◽  
pp. 19717-19726 ◽  
Author(s):  
Rui Yang ◽  
Kathryn K. Walder-Christensen ◽  
Samir Lalani ◽  
Haidun Yan ◽  
Irene Díez García-Prieto ◽  
...  
Keyword(s):  
Neural Development ◽  
Initial Segment ◽  
Intermediate Stage ◽  
Missense Mutations ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Close Apposition ◽  
Ankyrin G ◽  
Sites Of Action ◽  
Axon Initial Segments

Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and β4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of β4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of β4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of β4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.

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