Disease relevance of ARX

• 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 [1].
• Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy [2].
• These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations [3].
• 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 [4].
• ARX mutation in a boy with transsphenoidal encephalocele and hypopituitarism [5].
• Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome [6].

Psychiatry related information on ARX

• At least fifty-nine mutations have been described in the ARX gene in seven X-chromosome linked disorders involving mental retardation [7].
• There is a significant difference between the ARX-extracted AEP and the traditional MTA-extracted AEP, in terms of response time [8].

High impact information on ARX

• We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR) [9].
• Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein [2].
• In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation [2].
• Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans [10].
• The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX) [11].

Chemical compound and disease context of ARX

• Recently, polyalanine (polyA) tract expansions in the Aristaless-related homeobox (ARX) protein have been identified in a subset of patients with infantile spasms and mental retardation [12].
• Mutations in the non-ion channel genes, leucine-rich, glioma inactivated 1 gene and Aristaless related homeobox gene, have emerged as important causes of their specific syndromes, with mutations in the latter gene frequently underlying X-linked mental retardation with epilepsy [13].

Biological context of ARX

• The ARX gene is emerging as one of the more important disease-causing genes on the X chromosome and ought to be considered for routine screening [7].
• Our data suggest expansions in one of the ARX polyA tracts results in nuclear protein aggregation and an increase in cell death; likely underlying the pathogenesis of the associated infantile spasms and mental retardation [12].
• Mutations of ARX are associated with a wide range of phenotypes; functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms [14].
• We also mapped the murine Arx gene to the mouse genome using a mouse/hamster radiation hybrid panel and showed that Arx and ARX are orthologues [15].
• The authors assessed ARX as a candidate gene for XLAG in a genetic analysis of neuronal migration disorders and found two different point mutations in two XLAG pedigrees affecting the homeodomain of the protein, confirming that ARX is a causative gene for XLAG [16].

Anatomical context of ARX

• The Aristaless-related homeobox gene, ARX, is an important transcription factor with a crucial role in forebrain, pancreas and testes development [7].
• In contrast to other genes involved in XLMR, ARX expression is specific to the telencephalon and ventral thalamus [17].
• X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene [18].
• Mutations of the ARX gene controlling the development of GABAergic interneurons exhibit pleiotropic effects including lissencephaly with a strong genotype-phenotype correlation [19].
• The expression pattern suggests that ARX is involved in the differentiation and maintenance of specific neuronal cell types in the human central nervous system [15].

Associations of ARX with chemical compounds

• Cerebral state index during propofol anesthesia: a comparison with the bispectral index and the A-line ARX index [20].
• With the prediction probability statistic during remifentanil washout, SVDEN = 0.79, spectral entropy = 0.81, A-Line ARX AEP index = 0.63, and BIS = 0.58 [21].
• A comparison of bispectral index and ARX-derived auditory evoked potential index in measuring the clinical interaction between ketamine and propofol anaesthesia [22].
• The A-line ARX index decreased at 2% sevoflurane compared with 0.5%, while the bispectral index remained unchanged [23].
• Propofol ensures a more stable A-line ARX index than thiopental during intubation [24].

Other interactions of ARX

• 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 [1].
• X-linked West syndrome, also called "X-linked infantile spasms" (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation [1].
• Both LIS1 and DCX participate in the development of GABAergic interneurons as well as pyramidal neurons, while ARX participates only in that of interneurons [19].
• 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 [25].
• X-linked mental retardation and epilepsy: pathogenetic significance of ARX mutations [26].

Analytical, diagnostic and therapeutic context of ARX

• Northern blot analysis showed that a 3.3kb human ARX transcript was expressed at high levels in fetal brain [15].
• We examined the correlation between 1) the clinically assessed state of consciousness, 2) implicit and explicit memory (by use of word pairs), and 3) various measures of EEG and AEP-bispectral index (BIS), A-Line ARX AEP index, spectral entropy, and entropy of the singular value decomposition (SVDEN; a measure of the complexity of the EEG) [21].
• Attenuation of the A-line ARX-index (AAI) for mid-latency auditory evoked potentials (MLAEP) during general anesthesia was profound [27].
• The A-line ARX index, but not the bispectral index, increased significantly by laryngeal mask airway insertion and skin incision [23].
• The hypothesis of the present study was that since the ARX-model extracts the AEP faster than the MTA-model, the former should be able to detect changes during the brief, intense stimulus of endotracheal intubation [8].

References