Journal articles on the topic 'Intellectual disability Genetic aspects'
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Kępińska Walczak, Zofia. "Genetic diagnosis of intellectual disability and its ethical aspect." Warszawskie Studia Pastoralne 1, no. 34 (January 1, 2018): 187. http://dx.doi.org/10.21697/wsp.2017.12.1.34.10.
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The article presents a reflection on the genetic diagnosis of intellectual disability. Attention was drawn to the moral aspect of genetic testing and it was emphasized that genetic diagnosis must not become an instrument in the implementation of bio-utilitarianism or the concept of wrongful life, according to which, whether a person can be considered a human being, and thus have the right to life, depends on certain factors, and is not self-evident by the very fact of belonging to the human species.
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Iuhas, Alin Remus, Claudia Jurca, and Marius Bembea. "Epidemiological aspects in phenylketonuria patients from a region in northwestern Romania." Romanian Journal of Pediatrics 71, no. 2 (June 30, 2022): 55–61. http://dx.doi.org/10.37897/rjp.2022.2.2.
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Introduction. Phenylketonuria (PKU), a genetic disease with autosomal dominant transmission, is the most frequent inborn error in aminoacidic metabolism. The variations in phenylalanine-hydroxylase (PAH) gene lead to a lowered enzymatic activity causing hyperphenylalaninemia. PKU has a mean European prevalence of 1:10,000 newborns, with a large variation in different ethnicities and geographic regions. The large genetic variability (over 1200 genetic variants known) as well as other factors determines a wide spectrum of metabolic phenotypes. Untreated, PKU leads to irreversible intellectual disability, low stature, hypopigmentation, motor deficits, seizures, but the early diagnosis and treatment enables almost normal somatic and mental development. Aim. The aim of this study is the determination of the impact of non-genetic factors over the clinical phenotype of PKU patients in a region of north-west Romania. Material and method. The study group is formed from 44 patients diagnosed with phenylketonuria in the 1981 – 2021 period, found in the database of Bihor Regional Center for Medical Genetics, Emergency Clinical County Hospital, Oradea, Romania. The collected data was referring to the age, sex and domicile of the patients, the age of the diagnosis and the beginning of the treatment, also the metabolic control over the years, the metabolic phenotype of the patients and its impact on the clinical phenotype (IQ, the presence or absence of intellectual disability or the existence of a specific clinical phenotype). Results. The majority of patients (66%) were diagnosticated with phenylketonuria in the first 4 months of life, although there were cases with a late diagnosis, 20.5% of the patients were diagnosticated after the age of 1 year. Based on the pre-treatment plasmatic levels of phenylalanine, the majority of cases (72.7%) had a severe metabolic phenotype (classic PKU - cPKU), 20.5% of cases had a milder form of PKU (mPKU) and 6.8% of patients were found with a mild hyperphenylalaninemia (HPA). In the case of 23 patients, an optimal metabolic control was not obtained. The specific phenotype (blonde hair, light skin, blue eyes) was found in 22.7% of cases, 77.3% not having these features. At 68.2% of cases intellectual disability was found, with different levels of severity: 5 patients (11.5%) had liminal intellect, 9 patients (20.5%) had mild mental retardation, 6 patients (13.6%) had moderate mental retardation, 9 cases (20.5%) were with severe mental retardation and 1 patient (2.3%) had profound mental retardation; 31.8% of cases had normal intellect. The prevalence in Bihor county is 1:7,843 newborns. Discussions. A partial or, in rare cases, total lack of dietetic treatment was observed in all patients over 20 years old (current age). The delay in treatment initiation or an insufficient treatment, with a suboptimal metabolic control, will affect patient’s intellect, regardless of metabolic phenotype. If in 20 years old patients, or older, the main reason for mental retardation is the lack of dietetic treatment availability in the first years of life, for the younger patients the reason for mental retardation is usually a lack of compliance with the treatment. The majority of metabolic phenotypes is cPKU, in concordance with the literature data; the mild phenotype (HPA) was observed in a small percentage of patients, smaller than the data reported in the literature. In the first two studied decades the mild phenotypes were seldom observed. In the absence of screening tests or suggestive clinical manifestation it can be assumed that HPA patients remained undiagnosed, which would explain the small HPA percentage in the study group. A significant improvement in metabolic control in younger patients compared with older ones was observed, which denotes a better access to specific alimentation on one side, and o the other side, a better understanding of the disease from the patients and their families. Also, this study confirms a known fact that the diet in PKU is of great importance in the disease evolution. In this study there were included patients with severe metabolic phenotype with good metabolic control which reached adulthood without intellectual deficits, with higher education, social integrated and also patients with mild metabolic phenotype but with a poor metabolic control which developed intellectual deficiency. Conclusions. The PKU prevalence in Bihor county is higher than the estimated national value. The late diagnosis and treatment or the poor metabolic control led to intellectual disability, regardless of the metabolic phenotype. PKU screening and the better access to treatment allows younger generations of patients to enjoy a superior quality of life than the patients from the first two studied decades.
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Gavril, Eva-Cristiana, Alina Costina Luca, Alexandrina-Stefania Curpan, Roxana Popescu, Irina Resmerita, Monica Cristina Panzaru, Lacramioara Ionela Butnariu, Eusebiu Vlad Gorduza, Mihaela Gramescu, and Cristina Rusu. "Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review." Children 8, no. 9 (August 30, 2021): 751. http://dx.doi.org/10.3390/children8090751.
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Wolf–Hirschhorn syndrome (WHS), a rare disorder determined by distal 4p deletion, is characterized by a pre and postnatal growth retardation, hypotonia, intellectual disability, epilepsy, craniofacial dysmorphism, and congenital fusion anomalies. The clinical aspects are dependent on the deletion’ size. Our aim was to identify rare specific characteristics in a cohort of seven cases with 4p deletion and to assess the utility of Multiplex ligation-dependent probe amplification (MLPA) (cheap and sensitive test)—combined kits—as a diagnostic test and selection tool for cases that require other investigations (chromosomal microarray analysis—CMA, karyotype). For all cases we conducted a clinical examination with the main features identified: facial dysmorphism, intellectual disability, postnatal development delay, cardiac defects and hypotonia. In some cases, we observed seizures, structural brain abnormalities, immunodeficiencies, and renal anomalies. Prenatal growth retardation was detected in a relatively small number of cases, but postnatal growth failure was a constant feature. In all cases, the clinical diagnosis was confirmed by genetic analyses: karyotype and/or MLPA. In conclusion, renal and brain defects, as well as immunodeficiency are rare manifestations and should be looked for. Although CMA is the standard test, in our experience, MLPA is also a reliable screening method as the identified cases were either confirmed by MLPA or selected for further investigations.
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Cammarata-Scalisi, Francisco, Michele Callea, Diego Martinelli, Colin Eric Willoughby, Antonio Cárdenas Tadich, Maykol Araya Castillo, María Angelina Lacruz-Rengel, et al. "Clinical and Genetic Aspects of Phelan–McDermid Syndrome: An Interdisciplinary Approach to Management." Genes 13, no. 3 (March 12, 2022): 504. http://dx.doi.org/10.3390/genes13030504.
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Phelan–McDermid syndrome (PMS) is a rare, heterogeneous, and complex neurodevelopmental disorder. It is generally caused by a heterozygous microdeletion of contiguous genes located in the distal portion of the long arm of chromosome 22, including the SHANK3 gene. Sequence variants of SHANK3, including frameshift, nonsense mutations, small indels and splice site mutations also result in PMS. Furthermore, haploinsufficiency in SHANK3 has been suggested as the main cause of PMS. SHANK3 is also associated with intellectual disability, autism spectrum disorder and schizophrenia. The phenotype of PMS is variable, and lacks a distinctive phenotypic characteristic, so the clinical diagnosis should be confirmed by genetic analysis. PMS is a multi-system disorder, and clinical care must encompass various specialties and therapists. The role of risperidone, intranasal insulin, insulin growth factor 1, and oxytocin as potential therapeutic options in PMS will be discussed in this review. The diagnosis of PMS is important to provide an appropriate clinical evaluation, treatment, and genetic counseling.
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Fragoso, D. C., D. M. Nunes, A. C. M. Maia, L. A. L. Garcia, H. C. B. R. Alves, C. J. da Silva, and C. C. Leite. "What We Should Not Forget about Down Syndrome." Neurographics 11, no. 3 (May 1, 2021): 149–65. http://dx.doi.org/10.3174/ng.2000043.
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Down syndrome is the foremost common genetic cause of intellectual disability. The additional copy of chromosome 21 confers potential changes in virtually all organ systems, including the brain, neck structures, and spine. Neuroradiologists should be aware of the multitude of imaging findings in patients with Down syndrome to correctly identify and diagnose life-altering conditions associated with this syndrome. In particular, the high prevalence of age-related cognitive decline and dementia stands out more clearly in recent decades due to the notable increase in these individuals' survival. Although the early and timely diagnosis of cognitive decline in patients with varying degrees of intellectual disability has not been an easy task from the clinical point of view, anatomic and functional brain studies have shown an essential role because they allow the early recognition of abnormalities that precede the cognitive decline. Furthermore, the similarities and differences in neuropathologic, genetic, and imaging aspects in patients with Down syndrome have allowed extrapolation for a better understanding of the mechanisms linked to Alzheimer disease development.Learning Objective: To review and systematize the distinctive characteristics and abnormalities of the head and neck, vertebral column, and CNS present in Down syndrome
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MacMahon, Kenneth, and Ricky McClements. "Working together: making the case for integrated forensic services for people with intellectual disabilities." Journal of Intellectual Disabilities and Offending Behaviour 6, no. 3/4 (December 14, 2015): 204–10. http://dx.doi.org/10.1108/jidob-08-2015-0021.
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Purpose – There is a general consensus that healthcare for people with intellectual disabilities should be provided by multi-disciplinary teams. Within a forensic setting, recommendations are often made for separate or “parallel” forensic teams, operating independently of generic mental health or intellectual disability teams. An alternative to this model is an “integrated” service, where specialist forensic clinicians work within the general intellectual disability service, to provide support for clients with forensic needs. For clients with intellectual disabilities and forensic needs, there may be advantages to providing access to a wider multi-disciplinary team, through the application of an integrated model. The purpose of this paper is to illustrate the working of an integrated forensic service within a learning disability team, to identify positive aspects of this model, and how potential shortcomings may be overcome. Design/methodology/approach – Literature review, description of service outline with case example. Findings – Although some studies have compared parallel and integrated forensic models within mental health services, there are no evaluations that compare models of forensic services for individuals with intellectual disabilities. However, specific advantages of an integrated model may include availability of multi-disciplinary clinicians, development of forensic skills across wider groups of clinicians, reduction in stigma and avoidance of delay in transfer of care between services. In addition, in areas with smaller populations, parallel services may not be feasible due to low case numbers. Originality/value – There has been no formal evaluation of parallel vs integrated forensic services within an intellectual disability setting. However, the authors describe a fully integrated service and suggest means by which the potential shortcomings of an integrated model may be overcome.
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Robb, Nigel, Annalu Waller, and Kate A. Woodcock. "Developing a Task Switching Training Game for Children With a Rare Genetic Syndrome Linked to Intellectual Disability." Simulation & Gaming 50, no. 2 (March 6, 2019): 160–79. http://dx.doi.org/10.1177/1046878119834319.
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Background. The ability to rapidly switch between tasks is important in a variety of contexts. Training in task switching may be particularly valuable for children with intellectual disability (ID), specifically ID linked to genetic syndromes such as Prader-Willi syndrome (PWS). We have developed a cognitive training game for children with PWS and performed a pilot evaluation of the programme to inform future game development. Here, we describe and critically reflect on the development and pilot evaluation process. Methods. Several novel aspects of our approach are highlighted in this paper, including the involvement (in various roles) of children with a rare genetic syndrome (PWS) in the development and evaluation of the software (participatory design) and the development of a matched control, or placebo version of the game for use in the pilot evaluation. Results. Children with PWS were capable of contributing to the design and development of a cognitive training game in various roles. In the subsequent pilot evaluation, playing the active version of the game was associated with greater improvement in task switching performance than playing the matched control (placebo) version of the game. However, attrition was an issue during both the design phase and the pilot evaluation. Conclusions. The lessons learned from our work have relevance in a wide range of contexts, such as the development of future cognitive training games; the evaluation of serious games in general; and the involvement of end-users with cognitive disabilities and/or rare syndromes in the design and development of software.
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Subramanian, L., Y. Wei, C. Nguyen, R. Hicks, P. Chitra, and C. Campbell. "P.074 Myopathic aspects of Mowat-Wilson Syndrome." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 44, S2 (June 2017): S32. http://dx.doi.org/10.1017/cjn.2017.158.
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Background: Mowat-Wilson Syndrome (MWS) is a genetic syndrome (ZEB2, OMIM: 235730) that occurs in 1 in 50000 births. It is characterized by microcephaly, intellectual disability, dysmorphisms (prominent chin, cupped ears, broad nasal bridge) and Hirschsprung’s disease. Although motor delay and hypotonia are common components, a myopathy has not been described in MWS literature. A childhood case with myopathic features prompted further study of this rare disease. Methods: Patients were recruited from the Mowat-Wilson Foundation via email or social media to complete a survey. Results: Thirteen surveys were returned to date. Although 54% of the patients reported motor delay, none of the patients had myopathy investigations. The index patient, presented at 1 year old, with hypotonia and developmental delay. Pregnancy and family history were unremarkable. Investigations revealed high CK levels (range 300 to 500 U/L), EMG confirmed myopathic motor units, and muscle biopsy showed type 1 fibre predominance. Single gene sequencing revealed pathogenic mutations of ZEB2, confirming a diagnosis of MWS. Conclusions: The description of myopathic features expands the spectrum of this rare syndrome and adds to the differential diagnosis of hyperCKemia in early childhood.
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Di Stefano, Vincenzo, Marianna Gabriella Rispoli, Noemi Pellegrino, Alessandro Graziosi, Eleonora Rotondo, Christian Napoli, Daniela Pietrobon, Filippo Brighina, and Pasquale Parisi. "Diagnostic and therapeutic aspects of hemiplegic migraine." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 7 (May 19, 2020): 764–71. http://dx.doi.org/10.1136/jnnp-2020-322850.
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Hemiplegic migraine (HM) is a clinically and genetically heterogeneous condition with attacks of headache and motor weakness which may be associated with impaired consciousness, cerebellar ataxia and intellectual disability. Motor symptoms usually last <72 hours and are associated with visual or sensory manifestations, speech impairment or brainstem aura. HM can occur as a sporadic HM or familiar HM with an autosomal dominant mode of inheritance. Mutations in CACNA1A, ATP1A2 and SCN1A encoding proteins involved in ion transport are implicated. The pathophysiology of HM is close to the process of typical migraine with aura, but appearing with a lower threshold and more severity. We reviewed epidemiology, clinical presentation, diagnostic assessment, differential diagnosis and treatment of HM to offer the best evidence of this rare condition. The differential diagnosis of HM is broad, including other types of migraine and any condition that can cause transitory neurological signs and symptoms. Neuroimaging, cerebrospinal fluid analysis and electroencephalography are useful, but the diagnosis is clinical with a genetic confirmation. The management relies on the control of triggering factors and even hospitalisation in case of long-lasting auras. As HM is a rare condition, there are no randomised controlled trials, but the evidence for the treatment comes from small studies.
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Atli, Emine Ikbal, Engin Atli, Sinem Yalcintepe, Selma Demir, Cisem Mail, Damla Eker, Yasemin Ozen, and Hakan Gurkan. "Clinical Features of Aberrations Chromosome 22q: A Pilot Study." Global Medical Genetics 09, no. 01 (November 9, 2021): 042–50. http://dx.doi.org/10.1055/s-0041-1739496.
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Abstract Objective A significant number of genetic variations have been identified in chromosome 22, using molecular genetic techniques. Various genomic disorders on chromosome 22, including cat's eye syndrome caused by extra copies of the proximal region of the 22q chromosome, are now well-defined. Our aim in the study was to show phenotypic variability associated with rearrangements of the 22q chromosomal region. Methods We focused our study on clinical aspects of these disorders, including genetic testing, genotype-phenotype correlation, and potential treatments. A total of 998 patients were referred for genetic analysis (Karyotyping, MLPA, array-CGH) during January 2015 to February 2020 because of intellectual deficiency, behavior issues, and/or multiple congenital abnormalities in several genetics departments. Informed consent was obtained from all the patients and/or their parents. Results 22q11.21 or 22q13.33 microdeletions and 22q11.22-q11.23 microduplication were identified in 31 patients out of referrals. The 22q aberrations were detected in 31/998 patients, giving a prevalence of 3.1%. In this study, 18 patients with 22q11.2 (LCR22A-H) deletion, three patients with 22q13.31 deletion, 9 patients with 22q11.2 duplication and one patient with 22q13.31 duplication were identified. We report on the clinical and molecular characterization of 31 individuals with distal deletions and duplications of chromosome 22q. Conclusions The current study demonstrated in the largest postnatal case series reporting the whole spectrum of atypical phenotypic and genotypic variations at 22q. We believe that when all the phenotypic differences are taken into account, various anomalies including developmental delay and intellectual disability might be considered as an indication to search for aberrations of 22q along with congenital heart diseases.
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Lombardo, Barbara, Daniela Esposito, Sandra Iossa, Andrea Vitale, Francesco Verdesca, Carla Perrotta, Luca Di Leo, Valerio Costa, Lucio Pastore, and Annamaria Franzé. "Intragenic Deletion in MACROD2: A Family with Complex Phenotypes Including Microcephaly, Intellectual Disability, Polydactyly, Renal and Pancreatic Malformations." Cytogenetic and Genome Research 158, no. 1 (2019): 25–31. http://dx.doi.org/10.1159/000499886.
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Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology.
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McClimens, Alex, and Frances Gordon. "Presentation of Self in E-veryday Life: How People Labelled with Intellectual Disability Manage Identity as They Engage the Blogosphere." Sociological Research Online 13, no. 4 (July 2008): 40–52. http://dx.doi.org/10.5153/sro.1774.
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Very little is known about the online habits of people labelled with intellectual disability. What little information there is focuses more on demographic descriptors rather than any analyses of issues specific to that group. Hence the vast majority of the literature is firmly focused on more generic issues as they affect the general population. Some very few disability dedicated studies, however, have examined homepages maintained by individuals who live with Down syndrome. Here at least is evidence of a field of inquiry that recognises there may be particular aspects of web based communications that deserve special interest. The dynamics of web based communications are fast moving and the relatively static homepage has subsequently given way to Web 2.0 technologies. Here the recent and exponential increase in the popularity of blogging as a means of mass communication has attracted much comment in both popular and specialist quarters. Its ease of use and near universal availability has prompted massive sociological inquiry. But again the profile of people living with intellectual disability is absent from the debate. Our study reports on a project in which adults with intellectual disability were assisted to access the web in general, and the ‘blogosphere’ in particular. Our focus is on the means and methods by which the participants were able to manage their off and online identities. We look at the language employed, the layouts used and the way the online messages and postings reflected or distorted the actual lived experiences of these proto-bloggers. Notions of authorship and audience also contribute to the debate as these issues raise questions about sense of self, disability as a cultural construct and our ability to negotiate the increasingly important virtual world of the web.
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Boniel, Snir, Krystyna Szymańska, Robert Śmigiel, and Krzysztof Szczałuba. "Kabuki Syndrome—Clinical Review with Molecular Aspects." Genes 12, no. 4 (March 25, 2021): 468. http://dx.doi.org/10.3390/genes12040468.
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Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.
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Fahn, Chia Wei. "Perfecting Bodies: Who Are the Disabled in Andrew Niccol’s Gattaca?" Philosophies 5, no. 2 (April 1, 2020): 6. http://dx.doi.org/10.3390/philosophies5020006.
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This paper will examine the impact of genetic technologies on the corporeal and economical aspects of human lives while emphasizing the ambiguity of disability under these subversive circumstances. In 2013, the world was introduced to CRISPR genetic editing technology, followed by the controversial announcement in 2018 from Chinese scientist He Jiankui, who claims to have genetically engineered twins that were born HIV-immune. The possible social outcome of genetic treatment leading to the alteration of human embryos to create physically and intellectually superior offspring, as well as its impact on the social treatment of disabled bodies, is clearly illustrated in Andrew Niccol’s directive debut Gattaca. Here, I will discuss Niccol’s utilization of disabled characters in interrogating the employment of disabled characters as a narrative vehicle to reflect upon social paradigms. I examine both the subversion and expansion of the social construct of disability in Gattaca’s narrative, emphasizing the film’s portrayal of economic differences as a disabling factor in a world of augmentative technology.
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Ganesan, Shiva, Peter D. Galer, Katherine L. Helbig, Sarah E. McKeown, Margaret O’Brien, Alexander K. Gonzalez, Alex S. Felmeister, Pouya Khankhanian, Colin A. Ellis, and Ingo Helbig. "A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation." Genetics in Medicine 22, no. 12 (August 10, 2020): 2060–70. http://dx.doi.org/10.1038/s41436-020-0923-1.
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Abstract Purpose Childhood epilepsies have a strong genetic contribution, but the disease trajectory for many genetic etiologies remains unknown. Electronic medical record (EMR) data potentially allow for the analysis of longitudinal clinical information but this has not yet been explored. Methods We analyzed provider-entered neurological diagnoses made at 62,104 patient encounters from 658 individuals with known or presumed genetic epilepsies. To harmonize clinical terminology, we mapped clinical descriptors to Human Phenotype Ontology (HPO) terms and inferred higher-level phenotypic concepts. We then binned the resulting 286,085 HPO terms to 100 3-month time intervals and assessed gene–phenotype associations at each interval. Results We analyzed a median follow-up of 6.9 years per patient and a cumulative 3251 patient years. Correcting for multiple testing, we identified significant associations between “Status epilepticus” with SCN1A at 1.0 years, “Severe intellectual disability” with PURA at 9.75 years, and “Infantile spasms” and “Epileptic spasms” with STXBP1 at 0.5 years. The identified associations reflect known clinical features of these conditions, and manual chart review excluded provider bias. Conclusion Some aspects of the longitudinal disease histories can be reconstructed through EMR data and reveal significant gene–phenotype associations, even within closely related conditions. Gene-specific EMR footprints may enable outcome studies and clinical decision support.
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Egger, J., L. Van Dongen, C. Stumpel, E. Wingbermuehle, and T. Kleefstra. "Kbg Syndrome and the Establishment of its Neuropsychological Phenotype." European Psychiatry 41, S1 (April 2017): S157—S158. http://dx.doi.org/10.1016/j.eurpsy.2017.01.2026.
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ObjectiveKBG syndrome is caused by a mutation in the ANKRD11 gene, characterized by short stature and specific dental, craniofacial and skeletal anomalies. Scarce literature on the phenotypical presentation mention delayed speech and motor development as well as mild to moderate intellectual disabilities. As to psychopathology, often, autism and ADHD are mentioned but not yet substantiated in terms of neurocognitive variables.AimAim of the current study was to investigate neurocognitive aspects of KBG syndrome.Participants and Methods Seventeen patients (aged 6–66 years; ten females) with a proven ANKRD11 mutation were compared with two different groups of patients with a genetic disorder and similar developmental ages (n = 14 and n = 10). Neuropsychological assessment was performed focusing on the level of intellectual functioning and on attention, memory, executive functioning, and social cognition.ResultsIn KBG patients, mild to moderate intellectual disabilities (WAIS IV Total IQ = 63.5 ± 10.7, range: 45–84) were established with a mental age that was lower than mean chronological age (6.4 ± 2.6 years versus 11 ± 5.7 years, respectively). When compared to both control groups, results indicated a relatively strong processing speed and social cognitive functioning of patients with KBG while direct recall of auditory memory was relatively poor most probably due to attentional dysfunction.ConclusionsThe cognitive profile of this group of 17 patients with KBG is characterized by mild intellectual disability and diminished sustained attention in verbal tasks. Implications for diagnostic procedures and clinical management of the syndrome are discussed, also with regard to the question how this relates to classificatory diagnosis of ADHD.
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Yang, Lili, Xiaoli Shu, Shujiong Mao, Yi Wang, Xiaonan Du, and Chaochun Zou. "Genotype–Phenotype Correlations in Angelman Syndrome." Genes 12, no. 7 (June 28, 2021): 987. http://dx.doi.org/10.3390/genes12070987.
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Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11–q13, paternal uniparental disomy of chromosome 15q11–q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11–13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype–phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype–phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype–phenotype correlations based on larger data should be carried out for identifying new treatment modalities.
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Ashraf, Maham, Muhammad Azzam Khan, Bareera Saeed, Saba Aziz, Fahad Masood, Muhammad Ahmed, and Arslan Saleem Chugtai. "Perspective of Parental Satisfaction with Academia of Children with Down Syndrome and Intellectual Disability." Pakistan Journal of Medical and Health Sciences 16, no. 8 (August 31, 2022): 518–20. http://dx.doi.org/10.53350/pjmhs22168518.
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Background: Down syndrome is the disorder in which physical, mental, and functional deformity is present due to trisomy twenty one, the existence of three chromosomes instead of two normal chromosomes in human genome. Children who have intellectual disability they have neurodevelopmental deficit regards to limited in intellectual operation and adaptive behaviors. One of the safeguards variables as a favorable adaptability to a challenging conditions, like managing a handicapped kid, is marital satisfaction. Higher levels of marital happiness are linked to reduce depression levels, less parenting stress, and better parental planning (Kersh, Hedvat, Hauser-Cram, & Warfield, 2006) Objective(s): To find out parental satisfaction with academia of Down syndrome and Intellectual disability in Pakistan. Methodology: A standardized tool PSCDDI is used and data were collected from special education school of Lahore and Gujranwala city. Data were collected from 385 parents of down syndrome and intellectual disable child parents through questionnaire which were provided to parents and take their opinion. After data collected we analyze the data and concluded the results. Results: In this study we find out that parents are unsatisfied to academic performance of their child most of child and most of the parents are not sure and disagree. Down syndrome child are 38.9% and 60.9% child were intellectual disable and they are all in pre to 3rd grade. Most of the child were in the age range of 5- 8 years. The parents of DS and ID child have non-Consaginous marriage is 53.6% and 46.4% are Consaginous marriage. Conclusion(s): The overall study of parental satisfaction towards the developmental disability of their children shows unsatisfaction. . In Pakistan parents who have their children with disability faced many challenges in society. Keyword: Down syndrome, intellectual disability, parental satisfaction, academia
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Martínez-Cué, Carmen, and Noemí Rueda. "Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome." International Journal of Molecular Sciences 21, no. 18 (September 20, 2020): 6906. http://dx.doi.org/10.3390/ijms21186906.
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Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.
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Merrick, Joav, Carmit Cahana, Meir Lotan, Isack Kandel, and Eli Carmeli. "Snoezelen or Controlled Multisensory Stimulation. Treatment Aspects from Israel." Scientific World JOURNAL 4 (2004): 307–14. http://dx.doi.org/10.1100/tsw.2004.30.
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In Israel today, with a total population of over 6 million persons, the Division for Mental Retardation (DMR) provides services to 23,000 persons with intellectual disability (ID). Of the 23,000, residential services are provided to more than 6,000 in close to 60 residential centers, another 2,000 are provided residential care in hostels or group homes in the community in about 50 locations, while the rest are served with day-care kindergarten, day-treatment centers, sheltered workshops, or integrated care in the community. The first Snoezelen room (controlled multisensory stimulation) in the DMR was established at the Bnei Zion residential care center in 1995. The Snoezelen method is now used in Israel in more than 30 residential care centers and 3 community settings. Since the year 2000, a physiotherapist has been employed in order to supervise the treatment and development of the method nationally. Professional staff meetings take place every 4 months. A certification course has been established on a national basis for individuals from different professions (occupational therapists, physiotherapists, teachers, music therapists, nurses, speech therapists, or caregivers). Snoezelen has proved to be an important instrument and a powerful therapeutic tool among the various treatment modules employed in Israel for persons with ID. This paper presents the concept illustrated with two case stories.
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Tenorio-Castaño, Jair, Beatriz Morte, Julián Nevado, Víctor Martinez-Glez, Fernando Santos-Simarro, Sixto García-Miñaúr, María Palomares-Bralo, et al. "Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review." Genes 12, no. 5 (May 13, 2021): 738. http://dx.doi.org/10.3390/genes12050738.
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Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50–74%), infrequent (26–49%) and rare (less than ≤25%).
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Biswas, Dayita, Whitney Cary, and Jan A. Nolta. "PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder." International Journal of Molecular Sciences 21, no. 4 (February 14, 2020): 1286. http://dx.doi.org/10.3390/ijms21041286.
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Protein Phosphatase 2 Regulatory Subunit B′ Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the PPP2R5D gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer’s disease, and Parkinson’s-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine/threonine dephosphorylations in different tissues. The specificity for a wide variety of substrates is determined through nearly 100 different PP2A holoenzymes that are formed by at least 23 types of regulatory B subunits, and two isoforms each of the catalytic subunit C and the structural subunit A. In the mammalian brain, PP2A-mediated protein dephosphorylation plays an important role in learning and memory. The PPP2R5D subunit is highly expressed in the brain and the PPP2A–PPP2R5D holoenzyme plays an important role in maintaining neurons and regulating neuronal signaling. From 2015 to 2017, 25 individuals with PPP2R5D-related developmental disorder were diagnosed. Since then, Whole-Exome Sequencing (WES) has helped to identify more unrelated individuals clinically diagnosed with a neurodevelopmental disorder with pathological variants of PPP2R5D. In this review, we discuss the current understanding of the clinical and genetic aspects of the disorder in the context of the known functions of the PP2A–PPP2R5D holoenzyme in the brain, as well as the pathogenic mutations in PPP2R5D that lead to deficient PP2A–PPP2R5D dephosphorylation and their implications during development and in the etiology of autism, Parkinson’s disease, Alzheimer’s disease, and so forth. In the future, tools such as transgenic animals carrying pathogenic PPP2R5D mutations, and patient-derived induced pluripotent stem cell lines need to be developed in order to fully understand the effects of these mutations on different neural cell types.
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Vasic, Verica, Mattson S. O. Jones, Denise Haslinger, Lisa S. Knaus, Michael J. Schmeisser, Gaia Novarino, and Andreas G. Chiocchetti. "Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment." Genes 12, no. 11 (October 30, 2021): 1746. http://dx.doi.org/10.3390/genes12111746.
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Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.
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Rad, Abolfazl, Umut Altunoglu, Rebecca Miller, Reza Maroofian, Kiely N. James, Ahmet Okay Çağlayan, Maryam Najafi, et al. "MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)." Journal of Medical Genetics 56, no. 5 (November 28, 2018): 332–39. http://dx.doi.org/10.1136/jmedgenet-2018-105623.
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BackgroundPutative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.ObjectiveA homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families.ResultsWe identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly.ConclusionThis report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.
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Hofmeister, Benedikt, Celina von Stülpnagel, Cornelia Betzler, Francesca Mari, Alessandra Renieri, Margherita Baldassarri, Edda Haberlandt, et al. "Epilepsy in Nicolaides–Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects." Neuropediatrics 52, no. 02 (February 12, 2021): 109–22. http://dx.doi.org/10.1055/s-0041-1722878.
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AbstractNicolaides–Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via “Network Therapy of Rare Epilepsies (NETRE)” and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.
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Morisse, Filip, Eleonore Vandemaele, Claudia Claes, Lien Claes, and Stijn Vandevelde. "Quality of Life in Persons with Intellectual Disabilities and Mental Health Problems: An Explorative Study." Scientific World Journal 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/491918.
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The field of intellectual disability (ID) is strongly influenced by the Quality of Life paradigm (QOL). We aimed at investigating whether or not the QOL paradigm also applies to clients with ID and cooccurring mental health problems. This paper aims at stimulating a debate on this topic, by investigating whether or not QOL domains are universal. Focus groups with natural and professional network members were organized to gather qualitative data, in order to answer two questions: (1) Are the QOL dimensions conceptualized in the model of Schalock et al. applicable for persons with ID and mental health problems? (2) What are indicators relating to the above-mentioned dimensions in relation to persons with ID and mental health problems? The results offer some proof for the assumption that the QOL construct seems to have universal properties. With regard to the second question, the study revealed that the natural and professional network members are challenged to look for the most appropriate support strategies, taking specific indicators of QOL into account. When aspects of empowerment and regulation are used in an integrated manner, the application of the QOL paradigm could lead to positive outcomes concerning self-determination, interdependence, social inclusion, and emotional development.
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Hamburg, S., C. M. Startin, and A. Strydom. "The Relationship Between Sound–Shape Matching and Cognitive Ability in Adults With Down Syndrome." Multisensory Research 30, no. 6 (2017): 537–47. http://dx.doi.org/10.1163/22134808-00002579.
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Down syndrome (DS), the most common genetic cause of intellectual disability, is characterised by a pattern of cognitive deficits hypothesised as relating to later developing neural systems. Multisensory integration (MSI) has been shown to benefit cognitive performance on numerous tasks in the typically developing population and is implicated in the early development of various cognitive processes. Given these developmental links of both MSI and DS it is important to determine the relationship between MSI and DS. This study aimed to characterise sound–shape matching performance in young adults with DS as an indicator of MSI (correct response rate around 90% in typically developing individuals). We further investigated the relationship between task performance and estimated cognitive ability (verbal and non-verbal) in addition to everyday adaptive behavior skills. Those answering correctly (72.5%) scored significantly higher across cognitive and adaptive behavior measures compared to those answering incorrectly. Furthermore, 57.1% of individuals with estimated cognitive ability scores below the median value answered correctly compared to 89.5% of individuals scoring above the median, with similar values found for adaptive behavior skills (57.9% vs. 94.4%). This preliminary finding suggests sound–shape matching deficits are relatively common in DS but may be restricted to individuals of lower ability as opposed to being a general characteristic of DS. Further studies investigating aspects of MSI across a range of modalities are necessary to fully characterise the nature of MSI in DS and to explore underlying neural correlates and mechanisms.
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Bhattacharyya, Anita. "Advancing Knowledge of Down Syndrome Brain Development and Function With Human Stem Cells." American Journal on Intellectual and Developmental Disabilities 125, no. 2 (March 1, 2020): 90–92. http://dx.doi.org/10.1352/1944-7558-125.2.90.
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Abstract Our bodies are made up of over 250 specific cell types, and all initially arise from stem cells during embryonic development. Stem cells have two characteristics that make them unique: (1) they are pluripotent, meaning that they can differentiate into all cell types of the body, and (2) they are capable of self-renewal to generate more of themselves and are thus able to populate an organism. Human pluripotent stem cells were first isolated from human embryos twenty years ago (Thomson et al., 1998) and more recently, technology to reprogram somatic cells, such as skin and blood, to induced pluripotent stem cells has emerged (Park et al., 2008; Takahashi et al., 2007; Yu et al., 2007). Induced pluripotent stem cells, or iPSCs, are particularly valuable as disease specific iPSCs can be generated from individuals with specific genetic mutations diseases. Researchers have harnessed the power of stem cells to understand many aspects of developmental biology in model organisms (e.g. worms, mice) and more recently, in humans. Human stem cells in culture recapitulate development. For example, formation of the brain occurs prenatally and follows a specific pattern of timing and cell generation. Human stem cells in the culture dish follow a similar pattern when exposed to developmental cues and can thus be used to understand aspects of prenatal human brain development that are not accessible by other means. Disease-specific iPSCs are a valuable tool to model neural development in specific neurodevelopmental disorders like Down syndrome. Down syndrome is a classic developmental disorder; mistakes that are made during development of a particular organ system result in the characteristics of the disorder. In the brain, mistakes during prenatal brain development lead to intellectual disability. Trisomy 21 (Ts21) iPSCs generated from somatic cells of Down syndrome individuals may enable us to understand the mistakes made during Down syndrome brain development.
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Ghirardini, Elsa, Francesco Calugi, Giulia Sagona, Federica Di Vetta, Martina Palma, Roberta Battini, Giovanni Cioni, Tommaso Pizzorusso, and Laura Baroncelli. "The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development." Genes 12, no. 8 (July 24, 2021): 1123. http://dx.doi.org/10.3390/genes12081123.
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Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.
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Karalis, Vasiliki, and Helen S. Bateup. "Current Approaches and Future Directions for the Treatment of mTORopathies." Developmental Neuroscience 43, no. 3-4 (2021): 143–58. http://dx.doi.org/10.1159/000515672.
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The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.
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Vorsanova, Svetlana G., Yuri B. Yurov, Irina A. Demidova, Victor S. Kravets, Alexey D. Kolotii, Kirill S. Vasin, Ilia V. Soloviev, and Ivan Y. Iourov. "Chromosome 18p deletion syndrome (18p-) in children: the value of cytogenetic and molecular cytogenetic diagnosis." RESEARCH RESULTS IN BIOMEDICINE 7, no. 3 (September 30, 2021): 257–71. http://dx.doi.org/10.18413/2658-6533-2021-7-3-0-5.
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Chromosome 18p deletion syndrome (18p-) is associated with a loss of chromosomal material of the short arm (partial monosomy); however, the whole short arm is lost in the majority of cases. The frequency of 18p- syndrome is 1:60000. The syndrome is cytogenetically and clinically heterogeneous. The clinical manifestations vary extremely from mild forms with congenital anomalies and developmental delays to severe brain malformations. Rare cases demonstrate epilepsy and autism spectrum disorders. The deletion breakpoints are also variable. Accordingly, the syndrome needs the analysis of large groups of diseased children by current genomic technologies. Aim of the study: The evaluation of cytogenetic and molecular- cytogenetic technologies for defining critical breakpoints and possible phenotype- genotype correlations. Results: Here, we describe our observations of 15 patients (9 boys and 6 girls) with 18p deletion syndrome, revealed in a large cohort of patients (n=8536). The mean age was 5.1 years; the sex ratio was in favor of boys (1.5:1) in contrast to the literature data. Critical breakpoints associated with this syndrome within the short arm of chromosome 18 were not revealed. It is possible that the clinical features of the syndrome are associated with many breakpoints in chromosome 18 short arm (p11.1->pter). The frequency of 18p- syndrome in children with intellectual disability, developmental delays, and congenital anomalies was 0.2%. The diagnostic aspects of this pathology and the value of molecular cytogenetic methods in studying the syndrome are discussed. Conclusion: We highlight personalized approach to diagnosis of the syndrome for correct genetic counseling for the improvement the life quality and establishing phenotype-karyotype correlations.
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Vasko, Ashley, Theodore G. Drivas, and Samantha A. Schrier Vergano. "Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome." Genes 12, no. 6 (June 19, 2021): 937. http://dx.doi.org/10.3390/genes12060937.
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Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad.
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Underwood, Adam, Daniel T. Rasicci, David Hinds, Jackson T. Mitchell, Jacob K. Zieba, Joshua Mills, Nicholas E. Arnold, et al. "Evolutionary Landscape of SOX Genes to Inform Genotype-to-Phenotype Relationships." Genes 14, no. 1 (January 14, 2023): 222. http://dx.doi.org/10.3390/genes14010222.
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The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype–phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 gnomAD, 485 ClinVar, 1174 Geno2MP, and 4313 COSMIC human variants. We identified, within the HMG (High Mobility Group)- box, twenty-seven amino acids with changes in multiple SOX proteins annotated to clinical pathologies. These sites were screened through Geno2MP medical phenotypes, revealing novel SOX15 R104G associated with musculature abnormality and SOX8 R159G with intellectual disability. Within gnomAD, SOX18 E137K (rs201931544), found within the HMG box of ~0.8% of Latinx individuals, is associated with seizures and neurological complications, potentially through blood–brain barrier alterations. A total of 56 highly conserved variants were found at sites outside the HMG-box, including several within the SOX2 HMG-box-flanking region with neurological associations, several in the SOX9 dimerization region associated with Campomelic Dysplasia, SOX14 K88R (rs199932938) flanking the HMG box associated with cardiovascular complications within European populations, and SOX7 A379V (rs143587868) within an SOXF conserved far C-terminal domain heterozygous in 0.716% of African individuals with associated eye phenotypes. This SOX data compilation builds a robust genotype-to-phenotype association for a gene family through more robust ortholog data integration.
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Bhatti, Nadeem Ahmad, Sara Mumtaz, and Sajid Malik. "Epidemiological study of congenital and hereditary anomalies in Sialkot District of Pakistan revealed a high incidence of limb and neurological disorders." Asian Biomedicine 13, no. 2 (December 19, 2019): 49–60. http://dx.doi.org/10.1515/abm-2019-0040.
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Abstract Background Pakistan faces high incidence of congenital anomalies (CA) and hereditary anomalies due to various factors, including a high rate of consanguinity, early marriages, and predominance of extended families. There is a paucity of epidemiological studies that could provide a baseline for management strategies for these anomalies. Objectives We aimed to elucidate the pattern, as well as the clinical and genetic aspects, of CA prevalence among the general population in Sialkot District of Pakistan. Methods In a cross-sectional sampling design, subjects and families with a certain type of CA were recruited from hospitals and medical centers in Sialkot District. Subjects were also selected from various towns and remote villages by visiting public places. Phenotypic and descriptive data were obtained, pedigrees were constructed, and parental and demographic attributes were recorded. Results A total of 241 independent subjects and/or families with CA were recruited. The malformations were classified into five major and 56 minor categories. Limb defects had the highest representation (n = 113; proportion = 0.469; 95% confidence interval (CI) = 0.406–0.532), followed by neurological anomalies (n = 76; proportion = 0.315; 95% CI = 0.257–0.374). Among the limb defects, polydactyly and talipes were most prevalent while, among neurological disorders, intellectual disability and cerebral palsy were more frequent. In this cohort, sporadic occurrence was customary compared to the familial presentation (n = 144 vs 97). Analyses of various attributes, such as gender differences, parental consanguinity, and paternal ages, as well as pedigree analyses, revealed marked heterogeneity among the major and minor categories of CA. Conclusion The pattern of anomalies witnessed in this cohort and a high occurrence of sporadic cases point to a substantial role of nongenetic etiological factors, which could be minimized by strengthening the health-care system.
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Fetta, Anna, Luca Soliani, Alessia Trevisan, Rosa Pugliano, Emilia Ricci, Veronica Di Pisa, Veronica Pignataro, et al. "Cognitive, Behavioral, and Sensory Profile of Pallister–Killian Syndrome: A Prospective Study of 22 Individuals." Genes 13, no. 2 (February 16, 2022): 356. http://dx.doi.org/10.3390/genes13020356.
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Background: Developmental delay and intellectual disability are two pivotal elements of the phenotype of Pallister–Killian Syndrome (PKS). Our study aims to define the cognitive, adaptive, behavioral, and sensory profile of these patients and to evaluate possible correlations between the different aspects investigated and with the main clinical and demographic variables. Methods: Individuals of any age with genetically confirmed PKS were recruited. Those ≤ 42 months were administered the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III), and those > 42 months the Vineland Adaptive Behavior Scales—Second Edition (Vineland-II). Stereotyped behaviors (Stereotypy Severity Scale, SSS) and aggressive behaviors (Behavior Problems Inventory—Short Version, BPIs) were assessed in all subjects > 1 year; sensory profile (Child Sensory Profile 2, C-SP2) in all aged 2–18 years. Results: Twenty-two subjects were enrolled (11 F/11 M; age 9 months to 28 years). All subjects ≤ 42 months had psychomotor developmental delay. Of the subjects > 42 months, 15 had low IQ deviation, and 1 in the normal range. Stereotypies were frequent (median SSS-total score 25/68). Lower Vineland-II values corresponded to greater intensity and frequency of stereotypies (p = 0.004 and p = 0.003), and self-injurious behaviors (p = 0.002 and p = 0.002). Patients with severe low vision had greater interference of stereotypies (p = 0.027), and frequency and severity of aggressive behaviors (p = 0.026; p = 0.032). The C-SP2, while not homogeneous across subjects, showed prevalence of low registration and sensory seeking profiles and hypersensitivity to tactile and auditory stimuli. Lower Vineland-II scores correlated with higher Registration scores (p = 0.041), while stereotypies were more frequent and severe in case of high auditory sensitivity (p = 0.019; p = 0.007). Finally, greater sleep impairment correlated with stereotypies and self-injurious behaviors, and lower Vineland-II scores. Conclusions: The present study provides a further step in the investigation of the etiopathogenesis of the syndrome. Furthermore, these aspects could guide rehabilitation therapy through the identification of targeted protocols.
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Ronzoni, Luisa, Susanna Esposito, and Donatella Milani. "Genetic Advances in Intellectual Disability." Journal of Pediatric Genetics 04, no. 03 (December 15, 2015): 125–27. http://dx.doi.org/10.1055/s-0035-1564438.
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Ellison, Jay W., Jill A. Rosenfeld, and Lisa G. Shaffer. "Genetic Basis of Intellectual Disability." Annual Review of Medicine 64, no. 1 (January 14, 2013): 441–50. http://dx.doi.org/10.1146/annurev-med-042711-140053.
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Vitriolo, Alessandro, Michele Gabriele, and Giuseppe Testa. "From enhanceropathies to the epigenetic manifold underlying human cognition." Human Molecular Genetics 28, R2 (August 14, 2019): R226—R234. http://dx.doi.org/10.1093/hmg/ddz196.
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Abstract A vast portion of intellectual disability and autism spectrum disorders is genetically caused by mutations in chromatin modulators. These proteins play key roles in development and are also highly expressed in the adult brain. Specifically, the pivotal role of chromatin regulation in transcription has placed enhancers at the core of neurodevelopmental disorders (NDDs) studies, ushering in the coining of the term enhanceropathies. The convergence of these disorders is multilayered, spanning from molecular causes to pathophysiological traits, including extensive overlaps between enhanceropathies and neurocristopathies. The reconstruction of epigenetic circuitries wiring development and underlying cognitive functions has gone hand in hand with the development of tools that increase the sensitivity of identifying regulatory regions and linking enhancers to their target genes. The available models, including loop extrusion and phase separation, have been bringing into relief complementary aspects to interpret gene regulation datasets, reinforcing the idea that enhancers are not all the same and that regulatory regions possess shades of enhancer-ness and promoter-ness. The current limits in enhancer definition, within the emerging broader understanding of chromatin dynamics in time and space, are now on the verge of being transformed by the possibility to interrogate developmentally relevant three-dimensional cellular models at single-cell resolution. Here we discuss the contours of how these technological advances, as well as the epistemic limitations they are set to overcome, may well usher in a change of paradigm for NDDs, moving the quest for convergence from enhancers to the four-dimensional (4D) genome.
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UNGUREAN, B. C. "THEORETICAL ASPECTS OF INTELLECTUAL DISABILITY - DEFINITION, CLASSIFICATION." Series IX Sciences of Human Kinetics 14(63), no. 1 (June 10, 2021): 247–52. http://dx.doi.org/10.31926/but.shk.2021.14.63.1.31.
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The onset of intellectual disability is marked by impairment of all parts that contribute to an individual's intelligence, such as the functions of socialization, knowledge, speech, and motor function. Intellectual disability is also defined, involving significant limitations in both intellectual functioning and adaptive behavior, which cover many daily social, motor, and practical skills. The most commonly accepted definition of intellectual disability is that provided by AAIDD: “Intellectual disability is a disability characterized by significant reductions in both mental functioning and adaptive behavior, covering many daily social and practical skills. This disability originates before the age of 18.”
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Edwards, S. D. "Prenatal genetic screening for intellectual disability." Journal of Intellectual Disability Research 47, no. 7 (October 2003): 526–32. http://dx.doi.org/10.1046/j.1365-2788.2003.00531.x.
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Poplawski, NK. "Investigating intellectual disability: A genetic perspective." Journal of Paediatrics and Child Health 39, no. 7 (September 2003): 492–506. http://dx.doi.org/10.1046/j.1440-1754.2003.00201.x.
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Ramzan, Laraib, Amna Rashid, Saba Aziz, Sehar Batool, Saba Yaqoob, Muhammad Azzam Khan, and Arslan Saleem Chugtai. "Parental Stress of Pakistani Families with Children who Have Developmental Disabilities." Pakistan Journal of Medical and Health Sciences 16, no. 8 (August 31, 2022): 514–17. http://dx.doi.org/10.53350/pjmhs22168514.
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Background: The goal of this research was to find out what factors were associated with these parenting effects in Pakistani mothers and dads who had children with intellectual disability (ID) or autism spectrum disorders (ASD) A total of 191 parents agreed to take part in the study, 100 of whom had a child with ADS and 91 of whom had a child with ID. Each participant filled out standardized parenting stress scale rating scales and provided demographic data during the interview. Families who have children with Autism and ID have higher emotional state, according to structural equation modelling. Objective: To find out parental stress of Pakistani families with children who have developmental disabilities. Methodology: The cross-sectional study was conducted through five different organizations in Lahore, Pakistan (Bases, Rising sun, Dimensions, Autism resource center, Oasis) and from two hospitals (Mayo Hospital Lahore and Sheikh Zaid Hospital). Standardized questionnaire (Parental stress scale) was used. Data was collected through standardized questionnaire after taking inform consent and distributed among the parents with children that have special needs (ASD and ID) Parents were asked to complete a questionnaire. Result scores were recorded for every respondent. The data was analyzed by “Statistical Package for Social Sciences” SPSS (version 22.0). Results: Using a standardized questionnaire, it was shown that the emotional well-being of families with children with ASD and ID was much worse, with both mothers and fathers reporting emotional exhaustion. Stress was exacerbated by a lack of emotional well-being. ASD parents show high percentage of 72.2% and ID parents show highest percentage of 61.1% so according to the given standardized questionnaire points the higher the percentage the higher the stress level. While raising a kid with neurological disabilities has a roughly comparable effect on Pakistani families as it does on parents in other countries, there are evidence that children with ASD and ID provide particular challenges to these families. Conclusion: Parents of both children face higher stress level. High level of parent stress needs timely counselling of the parents about the circumstances that they need to be encountered with having an abnormal child. They shall be aware with the techniques to deviate their mind from the most recurring point of stress. Keywords: Autism spectrum disorder, Intellectual disability, Parental stress, Pakistan, Health, developmental disability
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de Villiers, Jana, and Mary Porteous. "Genetic testing of adults with intellectual disability." Psychiatrist 36, no. 11 (November 2012): 409–13. http://dx.doi.org/10.1192/pb.bp.111.038216.
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MethodPatients known to learning disability services in two health boards in southeast Scotland were cross-matched with the patients tested at the Western General Hospital in Edinburgh. Those with a positive genetic diagnosis were identified. Semi-structured interviews were conducted with senior learning disability psychiatrists and clinical genetics consultants.ResultsOf the 3323 patients with intellectual disability across both health boards, 41% have had genetic tests and 6% have an identified genetic abnormality as the cause for their intellectual disability. Of the 1349 patients who have been tested, a genetic abnormality was found in 14%. Psychiatrists named several benefits to genetic testing, but they also highlighted a number of non-medical reasons for not testing adults with intellectual disability.Clinical implicationsIdentifying genetic aetiology in intellectual disability has a number of benefits. Our study would indicate that genetic diagnoses are being missed due to a lack of genetic testing in this patient group. Adult learning disability services need to consider increasing genetic testing.
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Baker, Kate, F. Lucy Raymond, and Nick Bass. "Genetic investigation for adults with intellectual disability." Current Opinion in Neurology 25, no. 2 (April 2012): 150–58. http://dx.doi.org/10.1097/wco.0b013e328351820e.
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Anazi, Shams, Sateesh Maddirevula, Vincenzo Salpietro, Yasmine T. Asi, Saud Alsahli, Amal Alhashem, Hanan E. Shamseldin, et al. "Expanding the genetic heterogeneity of intellectual disability." Human Genetics 136, no. 11-12 (September 22, 2017): 1419–29. http://dx.doi.org/10.1007/s00439-017-1843-2.
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Puri, Ratna Dua, Moni Tuteja, and I. C. Verma. "Genetic Approach to Diagnosis of Intellectual Disability." Indian Journal of Pediatrics 83, no. 10 (September 13, 2016): 1141–49. http://dx.doi.org/10.1007/s12098-016-2205-0.
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Hinojosa, A. Blazquez, L. Rodríguez-Revenga Bodi, A. Sánchez Díaz, T. Armengué Salvador, and R. M. Calvo Escalona. "Genetic analysis of intellectual disability and autism." Neuroscience Applied 1 (2022): 100748. http://dx.doi.org/10.1016/j.nsa.2022.100748.
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Hoekstra, R. A., F. Happé, S. Baron-Cohen, and A. Ronald. "Association between extreme autistic traits and intellectual disability: insights from a general population twin study." British Journal of Psychiatry 195, no. 6 (December 2009): 531–36. http://dx.doi.org/10.1192/bjp.bp.108.060889.
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BackgroundAutism is associated with intellectual disability. The strength and origin of this association is unclear.AimsTo investigate the association between extreme autistic traits and intellectual disability in children from a community-based sample and to examine whether the association can be explained by genetic factors.MethodChildren scoring in the extreme 5% on measures of autistic traits, IQ and academic achievement were selected from 7965 7/8-year-old and 3687 9-year-old twin pairs. Phenotypic associations between extreme autistic traits and intellectual disability were compared with associations among the full-range scores. Genetic correlations were estimated using bivariate DeFries–Fulker extremes analyses.ResultsExtreme autistic traits were modestly related to intellectual disability; this association was driven by communication problems characteristic of autism. Although this association was largely explained by genetic factors, the genetic correlation between autistic traits and intellectual disability was only modest.ConclusionsExtreme autistic traits are substantially genetically independent of intellectual disability.
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Chiurazzi, Pietro, and Filomena Pirozzi. "Advances in understanding – genetic basis of intellectual disability." F1000Research 5 (April 7, 2016): 599. http://dx.doi.org/10.12688/f1000research.7134.1.
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Intellectual disability is the most common developmental disorder characterized by a congenital limitation in intellectual functioning and adaptive behavior. It often co-occurs with other mental conditions like attention deficit/hyperactivity disorder and autism spectrum disorder, and can be part of a malformation syndrome that affects other organs. Considering the heterogeneity of its causes (environmental and genetic), its frequency worldwide varies greatly. This review focuses on known genes underlying (syndromic and non-syndromic) intellectual disability, it provides a succinct analysis of their Gene Ontology, and it suggests the use of transcriptional profiling for the prioritization of candidate genes.
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Yim, Shin-Young. "Diagnostic approach for genetic causes of intellectual disability." Journal of Genetic Medicine 12, no. 1 (June 30, 2015): 6–11. http://dx.doi.org/10.5734/jgm.2015.12.1.6.
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