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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Principles and mechanisms of neurobehavioral teratogenesis are used to show commonalities between manifestations of abnormal development consequent to genetic abnormality or teratogenic exposure. A comparison and contrast of both the neuropathological and neuropsychological characteristics of children with early embryonic exposure to isotretinoin (Accutane) or with selected mental retardation syndromes is presented. Putative mechanisms of retinoid teratogenesis through the disruption of normal retinoid-triggered embryogenesis and the alteration of homeobox gene expression are discussed. Interference with homeobox gene expression as an avenue to the perturbation of early developmental processes and the production of hindbrain and craniofacial abnormalities is then proposed as a common basis for the translation and expression of several genetic mental retardation syndromes. Finally, dose-response effects and other modulators of vulnerability to abnormal development are used to provide a conceptual framework for the understanding of variability in the expression of genetically caused abnormalities.
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PMID:Similarities in genetic mental retardation and neuroteratogenic syndromes. 898

We describe two brothers aged 8 and 10 affected by severe bilateral schizencephaly, carrying an identical point mutation of the homeobox gene EMX2. Both children had severe neurologic deficits and mental retardation, although they differed in the anatomic extent of the brain malformation and in the severity of the clinical picture. The present findings, together with the reported cases of schizencephaly associated with EMX2 mutations, support the hypothesis that, at least in some cases, schizencephalies are determined by deleterious mutations of this homeobox gene. The different morphoclinical pictures suggest that, besides the EMX2 mutation, other factors are relevant in determining the severity of the brain malformation and clinical picture.
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PMID:Familial schizencephaly associated with EMX2 mutation. 915 81

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.
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PMID:Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. 1188 67

Investigation of a critical region for an X-linked mental retardation (XLMR) locus led us to identify a novel Aristaless related homeobox gene (ARX ). Inherited and de novo ARX mutations, including missense mutations and in frame duplications/insertions leading to expansions of polyalanine tracts in ARX, were found in nine familial and one sporadic case of MR. In contrast to other genes involved in XLMR, ARX expression is specific to the telencephalon and ventral thalamus. Notably there is an absence of expression in the cerebellum throughout development and also in adult. The absence of detectable brain malformations in patients suggests that ARX may have an essential role, in mature neurons, required for the development of cognitive abilities.
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PMID:ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. 1197 79

The novel Aristaless related homeobox gene, ARX, is widely expressed in the brain and is thought to play a key role in the regulation of brain development. Neurological phenotypes caused by ARX mutations have recently started to unfold. We describe a 72 year old man with X-linked mental retardation due to a 24 bp duplication mutation in exon 2 of the ARX gene. Cerebral MRI showed bilateral cystic-like cavities in both the cerebral and cerebellar hemispheres. No retraction or expansion in neighbouring parenchyma was observed, there was no history of acute neurological impairment, and no risk factors for cerebrovascular disease were found. The lesions appeared to be congenital and represented benign developmental cysts, possibly caused by the ARX mutation.
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PMID:Brain cysts associated with mutation in the Aristaless related homeobox gene, ARX. 1264 86

X-linked West syndrome, also called "X-linked infantile spasms" (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation. Recently, we have shown that the majority of the X-linked families with infantile spasms carry mutations in the aristaless-related homeobox gene (ARX), which maps to the Xp21.3-p22.1 interval, and that the clinical picture in these patients can vary from mild mental retardation to severe ISSX with additional neurological abnormalities. Here, we report a study of two severely affected female patients with apparently de novo balanced X;autosome translocations, both disrupting the serine-threonine kinase 9 (STK9) gene, which maps distal to ARX in the Xp22.3 region. We show that STK9 is subject to X-inactivation in normal female somatic cells and is functionally absent in the two patients, because of preferential inactivation of the normal X. Disruption of the same gene in two unrelated patients who have identical phenotypes (consisting of early-onset severe infantile spasms, profound global developmental arrest, hypsarrhythmia, and severe mental retardation) strongly suggests that lack of functional STK9 protein causes severe ISSX and that STK9 is a second X-chromosomal locus for this disorder.
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PMID:Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. 1273 70

We report clinical, cytogenetic, and molecular cytogenetic studies on four patients with subtle or submicroscopic 7q36 deletions either of de novo origin or resulting from a cryptic parental translocation. Fluorescence in situ hybridization (FISH) studies indicated that in all four patients, the Sonic Hedgehog gene (SHH) and the homeobox gene HLXB9, among others, are comprised in the deletions. Besides mental retardation and short stature, all patients showed only minimal manifestations of the holoprosencephaly (HPE) spectrum and only one displayed symptoms of the Currarino syndrome. Patient 1 had a de novo 7q36.1-qter deletion and showed microcephaly, ptosis, sacral agenesis, tethered cord, but no structural brain anomaly. Patient 2 had a submicroscopic de novo 7q36 deletion detected by FISH, and showed facial and cerebral microsigns of the HPE spectrum. Patient 3 had a 7q36 deletion found by subtelomere FISH testing that was the unbalanced product of a subtle maternal 7q;10q translocation. She presented facial and ocular microsigns, but no structural abnormality of the brain. Patient 4 showed no specific syndromal pattern and was found to have a cryptic unbalanced de novo translocation of the terminal parts of chromosomes 7q and 9p by subtelomere FISH. Patients 2, 3, and 4 represent the first report of a de novo submicroscopic 7q36 deletion, the second report of a familial subtle translocation of 7q36, and the first report of an unbalanced de novo submicroscopic translocation of 7q36, respectively. Our results stress the importance of 7q36 deletion studies by FISH in patients with microsigns of the HPE spectrum.
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PMID:Minimal clinical expression of the holoprosencephaly spectrum and of Currarino syndrome due to different cytogenetic rearrangements deleting the Sonic Hedgehog gene and the HLXB9 gene at 7q36.3. 1521 64

X-linked lissencephaly with abnormal genitalia is the first human disorder in which deficient tangential migration in the brain has been demonstrated. Male patients with X-linked lissencephaly with abnormal genitalia show intractable seizures, especially clonic convulsions or myoclonus from the first day of life, but neither infantile spasms nor hypsarrhythmia on electroencephalograms so far. Brain magnetic resonance imaging shows anterior pachygyria and posterior agyria with a mildly thick cortex, agenesis of the corpus callosum, and dysplastic basal ganglia. ARX, a paired-class homeobox gene with four polyalanine sequences, is a responsible gene for X-linked lissencephaly with abnormal genitalia. The brain of Arx knockout mice shows aberrant tangential migration and differentiation of gamma-aminobutyric acid (GABA)ergic interneurons. In human X-linked lissencephaly with abnormal genitalia, a neuropathologic study has suggested a loss of interneurons. Meanwhile, polyalanine expansion of ARX causes symptomatic or nonsymptomatic West's syndrome and nonsyndromic mental retardation. The striking epileptogenicity of X-linked lissencephaly with abnormal genitalia and West's syndrome associated with ARX mutations i s considered to be caused by a disorder of interneurons involving a tangentialmigration disorder. We propose "interneuronopathy" as a term for this.
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PMID:X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy". 1592 Dec 44

The ARX protein (encoded by the aristaless-related homeobox gene) is a member of the paired class of homeoproteins. More precisely, it is a member of the Aristaless subclass of proteins with a glutamine residue (Q) at the critical position 50 of the homeodomain (Q50). Through identification of diverse inherited or de novo mutations, genetic investigations of X-linked mental retardation conditions have demonstrated the implication of ARX in a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. These investigations have recently directed attention to the role of this gene in brain development. Analysis of its spatiotemporal localization profile have revealed expression mainly in telencephalic structures at all stages of development. Interestingly, in adult, ARX expression becomes restricted to a population of GABAergic neurons. Although the identification of the target genes regulated by ARX remains a crucial step to better understanding its role during brain development, studies of the role of ARX orthologs in different models have indicated that it is essential for important developmental processes such as proliferation, cell differentiation and neuronal migration.
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PMID:The role of ARX in cortical development. 1651 52

Aristaless-related homeobox gene (ARX) is an important paired-type homeobox gene involved in the development of human brain. The ARX gene mutations are a significant contributor to various forms of X-chromosome-linked mental retardation with and without additional features including epilepsy, lissencephaly with abnormal genitalia, hand dystonia or autism. Here we demonstrate that the human ARX protein is a potent transcriptional repressor, which binds to Groucho/transducin-like enhancer of split (TLE) co-factor proteins and the TLE1 in particular through its octapeptide (Engrailed homology repressor domain (eh-1) homology) domain. We show that the transcription repression activity of ARX is modulated by two strong repression domains, one located within the octapeptide domain and the second in the region of the polyalanine tract 4, and one activator domain, the aristaless domain. Importantly, we show that the transcription repression activity of ARX is affected by various naturally occurring mutations. The introduction of the c.98T>C (p.L33P) mutation results in the lack of binding to TLE1 protein and relaxed transcription repression. The introduction of the two most frequent ARX polyalanine tract expansion mutations increases the repression activity in a manner dependent on the number of extra alanines. Interestingly, deletions of alanine residues within polyalanine tracts 1 and 2 show low or no effect. In summary we demonstrate that the ARX protein is a strong transcription repressor, we identify novel ARX interacting proteins (TLE) and offer an explanation of a molecular pathogenesis of some ARX mutations, including the most frequent ARX mutations, the polyalanine tract expansion mutations, c.304ins(GCG)7 and c.428_451dup.
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PMID:Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor. 1733 56


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