| A new paradigm for West syndrome based on molecular and cell biology. | |
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MedLine Citation:
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PMID: 16806828 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Symptomatic West syndrome has heterogeneous backgrounds. Recently, two novel genes, ARX and CDKL5, have been found to be responsible for cryptogenic West syndrome or infantile spasms. Both are located in the human chromosome Xp22 region and are mainly expressed and play roles in fetal brain. Moreover, several genes responsible for brain malformations including lissencephaly, which is frequently associated with West syndrome or infantile spasms, have been found, and the mechanisms responsible for the neural network disorders in these brain malformations are rapidly being determined. Findings of animal and in vitro studies and mutation analyses in humans are delineating the molecular and cellular basis of West syndrome. Mutations of the ARX gene controlling the development of GABAergic interneurons exhibit pleiotropic effects including lissencephaly with a strong genotype-phenotype correlation. An expansion mutation of the first polyalanine tract of ARX is more strongly related to infantile spasms than is that of the second polyalanine tract. Although the phenotype of CDKL5 mutation is similar to Rett syndrome caused by MECP2 mutation, the former is characterized by early-onset seizures and association with West syndrome. Lissencephaly caused by LIS1 or DCX mutation frequently results in West syndrome, while lissencephaly due to ARX mutation is associated with the most severe form of epilepsy but never results in West syndrome nor infantile spasms. Both LIS1 and DCX participate in the development of GABAergic interneurons as well as pyramidal neurons, while ARX participates only in that of interneurons. Individuals with lissencephaly due to ARX mutation lack non-pyramidal or GABAergic interneurons. ARX is crucial for the development of GABAergic interneuron, so abnormal interneurons in patients with ARX mutation are thought to be implicated in the pathological mechanism, even though brain MRI is normal. Abnormal interneurons appear to play an essential role in the pathogenesis of West syndrome or infantile spasms, which can be considered an interneuronopathy. |
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Authors:
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Mitsuhiro Kato |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review Date: 2006-06-23 |
Journal Detail:
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Title: Epilepsy research Volume: 70 Suppl 1 ISSN: 0920-1211 ISO Abbreviation: Epilepsy Res. Publication Date: 2006 Aug |
Date Detail:
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Created Date: 2006-08-16 Completed Date: 2006-10-26 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8703089 Medline TA: Epilepsy Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: S87-95 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. mkato@med.id.yamagata-u.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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1-Alkyl-2-acetylglycerophosphocholine Esterase Brain / abnormalities Homeodomain Proteins / genetics* Humans Infant Microtubule-Associated Proteins / genetics* Mutation Neuropeptides / genetics* Protein-Serine-Threonine Kinases / genetics* Spasms, Infantile / genetics*, pathology Transcription Factors / genetics* |
| Chemical | |
Reg. No./Substance:
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0/ARX protein, human; 0/Homeodomain Proteins; 0/Microtubule-Associated Proteins; 0/Neuropeptides; 0/Transcription Factors; 0/doublecortin protein; EC 2.7.1.37/CDKL5 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.1.1.47/1-Alkyl-2-acetylglycerophosphocholine Esterase; EC 3.1.1.47/PAFAH1B1 protein, human |
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