Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations.
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PMID:Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. 1214 61

Two families, originally diagnosed as having nonsyndromic X-linked mental retardation (NSXLMR), were reviewed when it was shown that they had a 24-bp duplication (428-45 1dup(24bp)) in the ARX gene [Stromme et al., 2002: Nat Genet 30:441-445]. This same duplication had also been found in three other families: one with X-linked infantile spasms and hypsarrhythmia (X-linked West syndrome, MIM 308350) and two with XLMR and dystonic movements of the hands (Partington syndrome, MIM 309510). On review, manifestations of both West and Partington syndromes were found in some individuals from both families. In addition, it was found that one individual had autism and two had autistic behavior, one of whom had epilepsy. The degree of mental retardation ranged from mild to severe. A GCG trinucleotide expansion (GCG)10+7 and a deletion of 1,517 bp in the ARX gene have also been found in association with the West syndrome, and a missense mutation (1058C>T) in a family with a newly recognized form of myoclonic epilepsy, severe mental retardation, and spastic paraplegia [Scheffer et al., 2002: Neurology, in press]. Evidently all these disorders are expressions of mutations in the same gene. It remains to be seen what proportions of patients with infantile spasms, focal dystonia, autism, epilepsy, and nonsyndromic mental retardation are accounted for by mutations in the ARX gene.
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PMID:Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. 1237 46

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.
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PMID:Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. 1472 18

Three families with X-linked mental retardation caused by a 24 base-pair duplication in ARX[428-451dup(24 bp)] are reported. The clinical features in these and six other published families are reviewed. In general, the clinical picture is variable. Mental retardation ranges from mild to severe. Infantile spasms (West syndrome) occurred in 12.5% and other less severe forms of seizures in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and dysarthria in 54%. The focal dystonia, in association with mental retardation, may prove to be diagnostic of this mutation.
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PMID:Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. 1520 May 6

We screened 165 mentally retarded patients for ARX gene 428-451 base pair (bp) duplication. Eighteen individuals from five families were found to carry the duplication, and all had intellectual impairment. Twelve presented with focal hand dystonia, while six patients had EEG abnormalities including seizures. Other symptoms included speech difficulties (4/18), testis enlargement (4/18), lower limb spasticity or foot dystonia (4/18), and facial telangiectasia (3/18). These features confirm the pleiotropic effect of the duplication.
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PMID:Genotype-phenotype associations for ARX gene duplication in X-linked mental retardation. 1708 67

ARX (Aristaless-related homeobox gene) is located at Xp22. It contains 5 exons and encodes a 562-amino acid protein. The protein contains 4 polyalanine tracts, 3 of which are encoded in exon 2 and 1 in exon 4. Mutations in the ARX gene have been found in X-linked infantile spasms syndrome, Partington syndrome (mental retardation with dystonic movements of the hands), X-linked lissencephaly with abnormal genitalia, X-linked myoclonus epilepsy with spasticity and intellectual disability, and in nonsyndromic X-linked mental retardation. The most common mutation in ARX (seen in X-linked infantile spasms syndrome, Partington syndrome, and X-linked mental retardation) is a 24-bp duplication in exon 2 resulting in expansion of a polyalanine tract. Truncating mutations (deletions, frameshift, non-sense) have been found in X-linked lissencephaly with abnormal genitalia, as well as homeodomain missense mutations in X-linked myoclonus epilepsy with spasticity and intellectual disability. The authors report a novel 24-bp in-frame deletion within exon 2 of the ARX gene in a male child with X-linked mental retardation and review the spectrum of ARX mutations. This mutation results in a contraction of the second polyalanine repeat.
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PMID:A novel mutation of the ARX gene in a male with nonsyndromic mental retardation. 1764 Dec 62

Mutations in the ARX gene are responsible for a wide variety of mental retardation conditions including X-linked infantile spasms (ISSX) and generalized dystonia. However, electroclinical descriptions in patients with ISSX carrying ARX mutations are scarce. Here, we report on the electroclinical features of a 4-year-old boy with an expansion of the trinucleotide repeat in the ARX gene. Epilepsy started at 2 months of age with subclinical spasms that consisted of episodes of eye rolling combined with atypical hypsarrhythmia. Later, the condition evolved into severe mental retardation with polymorphic ictal episodes that consisted of nocturnal brief axial contractions followed by dyskinetic movement of all four limbs and diurnal clusters of chaotic movements combined with myoclonic jerks. EEG recording of these episodes lead to the diagnosis of non-ictal dyskinetic movements. This combination of early infantile spasms followed by a complex movement disorder contributes further to extent the pleiotropy of the ARX-linked "interneuronopathy" and should lead the clinician to ARX mutation screening.
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PMID:Combination of infantile spasms, non-epileptic seizures and complex movement disorder: a new case of ARX-related epilepsy. 1846 66

Pathogenic variations of the ARX (aristaless-related homeobox) gene are associated with marked phenotypic pleiotropy. These phenotypes are X-linked neurological disorders that include brain and genital malformation and non-malformation syndromes. Typically, malformation phenotypes result from pathogenic variations that are predicted to truncate the ARX protein, or alter residues in the highly conserved homeodomain. While non-malformation phenotypes tend to be caused by pathogenic variations that are predicted to expand the first two polyalanine tracts of ARX, or alter residues outside of the homeodomain. The most common pathogenic variation of the ARX gene is a duplication of 24 bp, c.429_452 dup, which leads to an expansion of the second polyalanine tract of the ARX protein from 12 to 20 alanine residues. This pathogenic variation is associated with both sporadic and familial nonsyndromic mental retardation. Syndromic manifestations include mental retardation with hand dystonia (Partington syndrome), infantile spasms (West syndrome) and/or other epileptic seizures. Here, we report on a novel pathogenic variant of a tandem 33 bp duplication that is predicted to result in an expansion of polyalanine tract 2 in two brothers with mental retardation, epilepsy, dystonia, and the novel feature of intermittent hyperventilation. This pathogenic variation is predicted to result in a "non-homogeneous" polyalanine tract expansion that is longer than predicted expansion caused by the common 24 bp duplication. The location of the novel 33 bp duplication in the same region as the common 24 bp duplication supports this region as the ARX variation "hot spot."
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PMID:Clinical study of two brothers with a novel 33 bp duplication in the ARX gene. 1950 62

Genetic investigations of X-linked mental retardation 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 or moderate forms of mental retardation without apparent brain abnormalities, but with associated features of dystonia and epilepsy. These investigations have in recent years directed attention to the role of this gene in brain development. Analysis of its spatio-temporal localization profile revealed expression in telencephalic structures at all stages of development, mainly restricted to populations of GABA-containing neurons. Furthermore, studies of the effects of ARX loss of function either in humans or in lines of mutant mice revealed varying defects, suggesting multiple roles of this gene during development. In particular, Arx has been shown to contribute to almost all fundamental processes of brain development: patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. In this review, we will present and discuss recent findings concerning the role of ARX in brain development and how this information will be useful to better understand the pathophysiological mechanisms of mental retardation and epilepsy associated with ARX mutations.
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PMID:Mutations in ARX Result in Several Defects Involving GABAergic Neurons. 2030 Feb 1

The ARX gene is involved in the development of GABAergic interneurons in the forebrain. Loss-of-function mutations, such as nonsense or frameshifts mutation, of ARX cause a group of brain malformations, such as hydranencephaly, lissencephaly, and agenesis of the corpus callosum, while expansion mutations of the polyalanine tracts of ARX, supposed to be gain-of-function mutations, result in a non-malformation group, such as non-syndromic mental retardation, mental retardation with dystonia, West syndrome, and Ohtahara syndrome. A variety of phenotypes caused by pleiotropic mutations of the ARX gene are considered to share a common pathological mechanism connected with the structural and functional disturbance of interneurons, designated as 'interneuronopathies'. We identified the second gene responsible for Ohtahara syndrome, STXBP1, which is essential for synaptic vesicle release. Molecular studies of the diseases will reveal the relationships between the structure and function of the brain. It is indispensable to clarify the etiology of hereditary diseases and identify new approaches to treatment.
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PMID:[Topics of brain malformation and epilepsy--age-dependent epileptic encephalopathies and interneuronopathies]. 2084 63


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