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Endocrine, Metabolic & Immune Disorders... 2021Intellectual disability (ID), previously called mental retardation, is the most common neurodevelopmental disorder characterized by life-long intellectual and adaptive... (Review)
Review
Intellectual disability (ID), previously called mental retardation, is the most common neurodevelopmental disorder characterized by life-long intellectual and adaptive functioning impairments that have an impact on individuals, families, and society. Its prevalence is estimated to 3% of the general population and its etiology is still insufficiently understood. Besides the involvement of genetic and environmental factors, immunological dysfunctions have been also suggested to contribute to the pathophysiology of ID. Over the years, immune biomarkers related to ID have gained significant attention and researchers have begun to look at possible cytokine profiles in individuals suffered from this disorder. In fact, in addition to playing crucial physiological roles in the majority of normal neurodevelopmental processes, cytokines exert an important role in neuroinflammation under pathological conditions, and interactions between the immune system and central nervous system have long been under investigation. Cytokine levels imbalance has been reported associated with some behavioral characteristics and the onset of some syndromic forms of ID. In this review, we will focus on immunological biomarkers, especially the cytokine profiles that have been identified in people with ID. Thus, data reported and discussed in the present paper may provide additional information to start further studies and to plan strategies for early identification and managing of ID.
Topics: Animals; Biomarkers; Blood-Brain Barrier; Brain; Cytokines; Humans; Inflammation Mediators; Intellectual Disability
PubMed: 32600239
DOI: 10.2174/1871530320666200628024944 -
Orphanet Journal of Rare Diseases May 2020Glycosylphosphatidylinositol biosynthesis defects cause rare genetic disorders characterised by developmental delay/intellectual disability, seizures, dysmorphic... (Review)
Review
Glycosylphosphatidylinositol biosynthesis defects cause rare genetic disorders characterised by developmental delay/intellectual disability, seizures, dysmorphic features, and diverse congenital anomalies associated with a wide range of additional features (hypotonia, hearing loss, elevated alkaline phosphatase, and several other features). Glycosylphosphatidylinositol functions as an anchor to link cell membranes and protein. These proteins function as enzymes, adhesion molecules, complement regulators, or co-receptors in signal transduction pathways. Biallelic variants involved in the glycosylphosphatidylinositol anchored proteins biosynthetic pathway are responsible for a growing number of disorders, including multiple congenital anomalies-hypotonia-seizures syndrome; hyperphosphatasia with mental retardation syndrome/Mabry syndrome; coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies/epilepsy syndrome; and early infantile epileptic encephalopathy-55. This review focuses on the current understanding of Glycosylphosphatidylinositol biosynthesis defects and the associated genes to further understand its wide phenotype spectrum.
Topics: Abnormalities, Multiple; Glycosylphosphatidylinositols; Humans; Intellectual Disability; Muscle Hypotonia; Mutation; Spasms, Infantile
PubMed: 32466763
DOI: 10.1186/s13023-020-01401-z -
American Journal of Medical Genetics.... Feb 2023The causal link between variants in the SCAF4 gene and a syndromic form of intellectual disability (ID) was established in 2020 by Fliedner et al. Since then, no...
The causal link between variants in the SCAF4 gene and a syndromic form of intellectual disability (ID) was established in 2020 by Fliedner et al. Since then, no additional cases have been reported. We performed exome sequencing in a 16-year-old Brazilian male presenting with ID, epilepsy, behavioral problems, speech impairment, facial dysmorphisms, heart malformations, and obesity. A de novo pathogenic variant [SCAF4(NM_020706.2):c.374_375dup(p.Glu126LeufsTer20)] was identified. This is the second study reporting the involvement of SCAF4 in syndromic ID, and the description of the patient's clinical features contributes to defining the phenotypic spectrum of this recently described Mendelian disorder.
Topics: Humans; Male; Adolescent; Intellectual Disability; Epilepsy; Problem Behavior; Exome Sequencing; Syndrome; Phenotype; Serine-Arginine Splicing Factors
PubMed: 36333968
DOI: 10.1002/ajmg.a.63032 -
Disease Models & Mechanisms Feb 2023The fragile X-related disorders are an important group of hereditary disorders that are caused by expanded CGG repeats in the 5' untranslated region of the FMR1 gene or... (Review)
Review
The fragile X-related disorders are an important group of hereditary disorders that are caused by expanded CGG repeats in the 5' untranslated region of the FMR1 gene or by mutations in the coding sequence of this gene. Two categories of pathological CGG repeats are associated with these disorders, full mutation alleles and shorter premutation alleles. Individuals with full mutation alleles develop fragile X syndrome, which causes autism and intellectual disability, whereas those with premutation alleles, which have shorter CGG expansions, can develop fragile X-associated tremor/ataxia syndrome, a progressive neurodegenerative disease. Thus, fragile X-related disorders can manifest as neurodegenerative or neurodevelopmental disorders, depending on the size of the repeat expansion. Here, we review mouse models of fragile X-related disorders and discuss how they have informed our understanding of neurodegenerative and neurodevelopmental disorders. We also assess the translational value of these models for developing rational targeted therapies for intellectual disability and autism disorders.
Topics: Animals; Mice; Trinucleotide Repeat Expansion; Intellectual Disability; Neurodegenerative Diseases; Fragile X Mental Retardation Protein; Fragile X Syndrome; Mutation; Disease Models, Animal
PubMed: 36692473
DOI: 10.1242/dmm.049485 -
International Journal of Developmental... Nov 2019SYNGAP1 is a gene that encodes the cytosolic protein SYNGAP1 (SYNaptic GTPase Activating Protein), an essential component of the postsynaptic density at excitatory... (Review)
Review
SYNGAP1 is a gene that encodes the cytosolic protein SYNGAP1 (SYNaptic GTPase Activating Protein), an essential component of the postsynaptic density at excitatory glutamatergic neurons. SYNGAP1 plays critical roles in synaptic development, structure, function, and plasticity. Mutations in SYNGAP1 result in a neurodevelopmental disorder termed Mental retardation-type 5 (MRD5, OMIM #612621) with a phenotype consisting of intellectual disability, motor impairments, and epilepsy, attesting to the importance of this protein for normal brain development. Here we review the clinical and pathophysiological aspects of SYNGAP1 mutations with a focus on their effect on synaptogenesis, neural circuit function, and cellular plasticity. We conclude by comparing the molecular pathogenesis of SYNGAP1 mutations with those of another neurodevelopmental disorder that affects dendritic function and cellular plasticity, fragile X syndrome. Insights into the molecular similarities and differences underlying these disorders could lead to rationale therapy development.
Topics: Epilepsy; Humans; Intellectual Disability; Mutation; Neurodevelopmental Disorders; Neuronal Plasticity; Phenotype; ras GTPase-Activating Proteins
PubMed: 31454529
DOI: 10.1016/j.ijdevneu.2019.08.003 -
Scientific Reports Sep 2023To compare the anterior segment indices between mentally retarded and normal children. The current study was conducted as a cohort. In this study, 73 mentally retarded...
To compare the anterior segment indices between mentally retarded and normal children. The current study was conducted as a cohort. In this study, 73 mentally retarded and 76 normal children were selected from normal school and special schools for mentally retarded children using random cluster sampling method. Mental retardation in children was confirmed by a psychologist. Optometry examinations including visual acuity and refraction were performed for all participants, and ultimately, corneal imaging measurements were taken by Pentacam. The mean age of mentally retarded and normal children was of 13.30 ± 1.83 and 13.05 ± 1.82 years, respectively (P = 0.180). A multiple generalized estimating equations model demonstrated that there is a significant association between central corneal thickness (CCT) (coef = 1.011, P < 0.001), corneal diameter (CD) (coef = 0.444, P = 0.046), anterior chamber depth (ACD) (coef = 0.23), P < 0.001) and index of vertical asymmetry (IVA) (coef = 0.12, P < 0.001) and mental retardation. Cerebral palsy children had higher keratoconus index (KI), central keratoconus index (CKI), index of height asymmetry(IHA), and index of height decentration (IHD) compared to those without cerebral palsy (P < 0.05). Children with moderate mental retardation had higher index of surface variance (ISV), IVA, IHA, and IHD than those with mild mental retardation (P < 0.05). The mean and standard deviation of CCT, CD, ACD and IVA index in mentally retarded children were 535.3 ± 46.68 micron, 11.87 ± 0.42 mm, 3.29 ± 0.24 mm and 0.25 ± 0.18 mm, respectively. These indices in the normal group were 525.53 ± 47.52 micron, 11.84 ± 0.38 mm, 3.15 ± 0.28 mm and 0.17 ± 0.05 mm, respectively. The findings of this study showed that some anterior segment indices were different in mentally retarded compared to normal children. Moreover, some keratoconus indicators were worse in cerebral palsy children and children with higher grade mental retardation. So, it is important to consider keratoconus screening in these children.
Topics: Humans; Child; Adolescent; Persons with Mental Disabilities; Intellectual Disability; Cerebral Palsy; Keratoconus; Physical Examination
PubMed: 37666932
DOI: 10.1038/s41598-023-41827-6 -
Annals of Human Genetics Sep 2021Alopecia-mental retardation syndrome (APMR) is a rare autosomal recessive neuro-dermal disorder. It is characterized by heterogeneous phenotypic features, that is,... (Review)
Review
Alopecia-mental retardation syndrome (APMR) is a rare autosomal recessive neuro-dermal disorder. It is characterized by heterogeneous phenotypic features, that is, absence of hair on the scalp, eyelashes, and eyebrows and mild to severe intellectual disability. So far, approximately 14 families (i.e., Iranian, Pakistani, and Swiss) with APMR have been reported in the scientific literature. Its precise prevalence is still unknown, but according to a predictive estimate, it prevails with the ratio of 1 in 1,000,000 persons worldwide. Until now, only four loci (two characterized and two uncharacterized) have been reported to be involved in APMR. The pathogenic variants in alpha-2-HS-glycoprotein [AHSG; APMR1 (MIM#203650)] and lanosterol synthase [LSS; APMR4 (MIM#618840)] are the characterized genetic factors associated with APMR. Among them, AHSG was reported in a consanguineous Iranian family and LSS gene in a Swiss origin family, while the remaining two uncharacterized loci, that is, APMR2 and APMR3, are reported in the Pakistani population. The current mini-report discusses the molecular genetics and mutational spectrum of APMR syndrome, its differential diagnosis from related disorders, and prediction of plausible candidate genes in two uncharacterized loci.
Topics: Alopecia; Humans; Intellectual Disability; Intramolecular Transferases; Iran; Mutation; Pakistan; Rare Diseases; Switzerland; alpha-2-HS-Glycoprotein
PubMed: 33881165
DOI: 10.1111/ahg.12425 -
Genes Feb 2021Dual-specificity tyrosine phosphorylation-regulated kinase 1A or contributes to central nervous system development in a dose-sensitive manner. Triallelic is implicated...
Dual-specificity tyrosine phosphorylation-regulated kinase 1A or contributes to central nervous system development in a dose-sensitive manner. Triallelic is implicated in the neuropathology of Down syndrome, whereas haploinsufficiency causes the rare -related intellectual disability syndrome (also known as mental retardation 7). It is characterised by intellectual disability, autism spectrum disorder and microcephaly with a typical facial gestalt. Preclinical studies elucidate a role for in eye development and case studies have reported associated ocular pathology. In this study families of the DYRK1A Syndrome International Association were asked to self-report any co-existing ocular abnormalities. Twenty-six patients responded but only 14 had molecular confirmation of a pathogenic variant. A further nineteen patients from the UK Genomics England 100,000 Genomes Project were identified and combined with 112 patients reported in the literature for further analysis. Ninety out of 145 patients (62.1%) with heterozygous variants revealed ocular features, these ranged from optic nerve hypoplasia (13%, 12/90), refractive error (35.6%, 32/90) and strabismus (21.1%, 19/90). Patients with variants should be referred to ophthalmology as part of their management care pathway to prevent amblyopia in children and reduce visual comorbidity, which may further impact on learning, behaviour, and quality of life.
Topics: Central Nervous System; Child; Child, Preschool; Down Syndrome; Eye; Eye Abnormalities; Female; Haploinsufficiency; Humans; Infant; Intellectual Disability; Male; Middle Aged; Optic Nerve; Optic Nerve Diseases; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Refractive Errors; Strabismus; Dyrk Kinases
PubMed: 33562844
DOI: 10.3390/genes12020234 -
Journal of Intellectual Disabilities :... Jun 2020
Topics: Humans; Intellectual Disability; Resilience, Psychological
PubMed: 32489151
DOI: 10.1177/1744629520926850 -
Journal of Neurology, Neurosurgery, and... Dec 2020
Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Delivery of Health Care; Epilepsy; Humans; Intellectual Disability; Neurodevelopmental Disorders; Professional Practice Gaps; Psychotic Disorders; Rare Diseases; State Medicine; United Kingdom
PubMed: 32928935
DOI: 10.1136/jnnp-2020-324660