ReviewA new paradigm for West syndrome based on molecular and cell biology
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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