Introduction

In 1991, Ptàcek et al. identified the cause of hyperkalemic periodic paralysis as a mutation of the gene of the SCN4A Na+ channel. The following years saw the publication of a series of papers by the same and other researchers, which confirmed and completed the finding by demonstrating that other conditions belonging to the same group of muscular diseases (myotonic/periodic paralyses) could be attributed to mutations of the genes coding Na+, Ca2+ or Cl- channel subunits (Ptàcek, 1998). Other ion channel gene mutations were subsequently identified as being involved in episodic ataxias (K+ and Ca2+ channels), hemiplegic migraine (Ca2+ channel), long-QT cardiac arrhythmias (K+ and Na+ channels), hyperekplexia (glycine receptor), and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (cholinergic receptor). All of these ‘channelopathies’ (Ptàcek, 1997), have the common characteristic of acute and transient presentation in subjects who otherwise seem to be perfectly normal, and this is also a common characteristic of idiopathic epilepsies due to alterations in neuronal excitability that cannot be attributed ‘to any underlying cause other than a possible hereditary predisposition’ (Commission, 1989). The aim of this chapter is to summarize some of the data suggesting that idiopathic epilepsies may be considered channelopathies.

Epileptogenic alterations in neuronal excitability

The excitability of neuronal cells depends on the movement of ions through specific cell membrane channels.

Introduction

The autosomal dominant cerebellar ataxias are a heterogeneous group of dominantly inherited disorders which have been divided into several types with different predominant clinical features. Collectively, these disorders are called the spinocerebellar ataxias (SCAs) and are known to be genetically heterogeneous. For example, clinically similar (or identical) SCA, characterized by ataxia, nystagmus, and long tract signs, can be caused by a number of different SCA genes. In addition to this heterogeneity, there is also prominent pleiotropy with a single gene giving rise to considerable variation in phenotypic expression. SCA7 stands out as a unique form given the dramatic additional feature of retinal degeneration (Gouw et al., 1994). A third group of the SCAs is characterized by a purely cerebellar syndrome. More recent genetic studies have defined numerous loci for the SCAs. Disease loci were assigned to chromosomes 6p (SCA1: Zoghbi et al., 1991), 12q (SCA2: Gispert et al., 1993), 14q (SCA3: Stevanin et al., 1994), 16q (SCA4: Gardner et al., 1994), 11cen (SCA5: Ranum et al., 1994), 19p (SCA6: Zhuchenko et al., 1997), 3p (SCA7: Gouw et al., 1995; Benomar et al., 1995), 10q24 (SCA8: Nikali et al., 1997), and 22q13 (SCA10: Zu et al., 1999).

An interesting feature of many of these diseases is the clinical phenomenon of anticipation, where disease severity often worsens on transmission of a disease allele through families. Individuals in subsequent generations are affected at earlier ages and with more severe disease. Among the spinocerebellar ataxias, this is most notable in SCA7 (Gouw et al., 1994, 1998).