Elsevier

Epilepsy Research

Volume 70, Supplement, August 2006, Pages 87-95
Epilepsy Research

Review
A new paradigm for West syndrome based on molecular and cell biology

https://doi.org/10.1016/j.eplepsyres.2006.02.008Get rights and content

Abstract

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.

Introduction

In 1841, Dr. W.J. West first reported a peculiar type of convulsion in his own son. The boy was healthy until four months of age, when clusters of head bobbing began. These progressed in frequency and severity, and his developmental progress was arrested. He exhibited significant mental retardation and died at 20 years of age; an autopsy revealed no cause of death (Lux, 2001). West syndrome is now recognized as an epileptic syndrome in infancy, which is characterized by brief tonic spasms, a peculiar set of electroencephalographic findings termed hypsarrhythmia, and arrest of psychomotor development (ILAE Task Force, 1989). West syndrome is the most common epileptic syndrome causing neurological impairment in childhood, while a significant number of patients with this syndrome exhibit normal development (Riikonen, 2001), indicating that developmental arrest is not obligatory for the diagnosis of West syndrome (Lux and Osborne, 2004). Although the term “infantile spasms” is synonymously and confusingly used for West syndrome, here the author uses the term “infantile spasms” to mean tonic epileptic seizures of brief duration seen in infants, and the term “West syndrome” as the clinical diagnosis made based on infantile spasms and hypsarrhythmia on the EEG (Fukuyama, 2001).

Many etiological factors for West syndrome including hereditary and non-hereditary conditions, such as neonatal asphyxia, meningoencephalitis, cerebral dysgenesis, and congenital metabolic disorders, have been reported, and this syndrome is now classified into two groups, symptomatic and cryptogenic. The symptomatic group is characterized by the previous existence of signs of brain damage (psychomotor retardation, neurological signs, radiological signs, or other types of seizures) or by a known etiology (ILAE Task Force, 1989). The cryptogenic group is characterized by lack of previous signs of brain damage and of known etiology. The percentage of patients in the cryptogenic group ranges between 9 and 30% (Matsumoto et al., 1981, Vigevano et al., 1993). On the other hand, an idiopathic group has been proposed, and West syndrome in patients in this group is presumed to have resulted from an age-related multifactorial genetic predisposition (ILAE Task Force, 1992). Familial recurrence of West syndrome without known etiology has been reported with uneven distribution to males indicating X-linked inheritance (Feinberg and Leahy, 1977, Dulac et al., 1993, Sugai et al., 2001). Recently, mutations of two genes, ARX and STK9, have been found in patients with X-linked familial West syndrome (Stromme et al., 2002b, Weaving et al., 2004). A polyalanine expansion mutation of the ARX gene has also been found in a patient with sporadic cryptogenic West syndrome (Kato et al., 2003). It is important to distinguish patients with a genetic predisposition from those in the cryptogenic group. In this review, the author summarizes and discusses the molecular and biological background of the hereditary form of West syndrome or infantile spasms based on the recent findings of genotype–phenotype analysis and for transgenic mice on the genes causing this syndrome, focusing on cryptogenic or idiopathic West syndrome and symptomatic West syndrome associated with brain malformations (Table 1).

Section snippets

ARX

ARX (aristaless related homeobox) is a paired class homeobox gene located on human chromosome Xp22.13 and consists of five exons encoding protein of 562 amino acids (Miura et al., 1997, Kitamura et al., 2002). The ARX protein has four polyalanine tracts in which 7–16 alanine residues are sequentially repeated (Fig. 1). Three of the four polyalanine tracts are encoded in exon 2, and the first and second polyalanine tracts are mutation hot spots causing mental retardation and epilepsy including

LIS1/DCX or classical lissencephaly

Classical lissencephaly (previously type I) is characterized by a smooth or nearly smooth cerebral surface with a spectrum of gyral malformations from complete agyria (grade 1) to regional pachygyria (grade 4), and merges with subcortical band heterotopia (SBH, grade 5 or 6) (Kato and Dobyns, 2003). The thickness of the cortex is 10–20 mm in cases of agyria or pachygyria. Three genes, LIS1, 14-3-3ɛ, and DCX, have been identified as responsible for classical lissencephaly in humans. Miller–Dieker

Acknowledgement

This work was supported in part by a grant from the Japan Epilepsy Research Foundation.

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