Summary of mutations reported in
1. Introduction
Three benign epilepsy syndromes with autosomal dominant inheritance are recognised in infancy. These are Benign Familial Neonatal Epilepsy (BFNE), Benign Familial Neonatal-Infantile Epilepsy (BFNIE) and Benign Familial Infantile Epilepsy (BFIE). These disorders were previously known as Benign Familial Neonatal Seizures, Benign Familial Neonatal-Infantile Seizures and Benign Familial Infantile Seizures, respectively (Berg et al., 2010). They were recently renamed by the International League Against Epilepsy Classification Committee. The three disorders differ in their average ages of onset but age of onset distributions overlap between the syndromes. Ages of onset vary within syndromes and within families affected with any of the syndromes.
BFNE patients have lateralised motor seizures with a mean age of onset of around 3 days of age and a mean age of seizure offset of 3 months of age. Subsequent neurological development usually proceeds normally. However, about 15% of patients have later seizures or epilepsy and occasional cases deteriorate into severe epileptic encephalopathies with intellectual disability (Dedek et al., 2003; Borgatti et al., 2004; Steinlein et al., 2007). The benign form of the disorder was originally described in an Austrian family by Rett and Teubel (1964). Since then numerous BFNE families have been described, many with potassium channel subunit mutations, to provide a well established range of presentations.
BFIE was originally described by Watanabe and colleagues in 1987, and is sometimes referred to as Watanabe syndrome. Watanabe observed that a subgroup of infants with generalised motor seizures had subsequent normal development and became seizure-free by 3 years of age. Similar families were subsequently described by Vigevano and colleagues (1992). Onset of seizures in BFIE occurs between 4 and 6 months of age with seizure offset generally occurring by 12 months of age. Seizures are generally not seen in later life. However, some cases develop paroxysmal dyskinesia or paroxysmal kinesigenic choreoathetosis in adolescence. This is known as infantile convulsions and choreoathetosis (ICCA) syndrome.
BFNIE patients have similar seizures to those seen in BFNE and BFIE, with the average age of onset intermediate between the other two. Although BFNIE differs from these disorders in the average age of seizure onset, the age of onset distribution which can range within a single family from 3 days up to 13 months of age (Herlenius et al., 2007), significantly overlaps with BFNE and BFIE. Seizure onset in BFNIE most commonly occurs at between 2 and 4 months of age. Clinically the condition was first described by Kaplan and Lacey (1983) and molecularly delineated two decades later (Heron et al., 2002).
The aim of this chapter is to describe the current state of knowledge of the molecular genetics underlying these disorders and the significance that this has for patient care.
2. The molecular genetics of benign familial neonatal epilepsy
Benign familial neonatal epilepsy is most commonly caused by mutations in two related voltage-gated potassium channel subunit genes,
2.1. BFNE caused by mutations in the potassium channel subunit KCNQ2
BFNE was originally mapped to the
In total, 85 mutations in
Approximately one-third of the mutations in
The published mutations in
Start Codon | 2 |
Missense | 28 |
Nonsense | 9 |
Frameshift | 21 |
In-frame deletion | 3 |
Splice site | 11 |
Large deletion or duplication | 10 |
Other | 1 |
2.2. BFNE caused by mutations in the potassium channel subunit KCNQ3
Following the linkage of BFNE to the
Only four mutations in
2.3. BFNE with other causes
Occasional cases of BFNE have been reported with causes other than mutations in
Mutations have also been reported that cause BFNE with co-morbidities (Dedek et al., 2001; Dedek et al., 2003; Borgatti et al. 2004; Schmitt et al., 2005; Stenlein et al., 2007). Recently a family with familial neonatal seizures and intellectual disability caused by a microduplication at chromosome 2q24.3 has been reported (Heron et al., 2010). The four affected members of this family all had neonatal seizures and some degree of intellectual disability ranging from borderline intelligence to an IQ score less than 40. A second patient with a similar microduplication has been described with seizures starting at 2-3 weeks of age and developmental delay (Raymond et al., 2011). This suggests that microduplications at chromosome 2q24.3, which contains a cluster of five voltage-gated sodium channel genes, could be a recurrent cause of neonatal seizures accompanied by intellectual disability. Such mutations can be easily detected and characterised using comparative genome hybridisation (CGH), therefore patients with neonatal seizures and intellectual disability should be tested for microduplications using this method. The pathogenic mechanism of these microduplications is hypothesised to be an increase in the expression of the duplicated sodium channel genes, in contrast to the haploinsufficiency cause by truncating or deletion mutations or the changes in function caused by missense mutations in
These reports suggest that not all cases of BFNE are caused by
3. The molecular genetics of benign familial neonatal-infantile epilepsy
Patients with benign familial neonatal-infantile epilepsy (BFNIE) have similar seizures to those seen in BFNE and BFIE. BFNIE differs from these disorders in the age of onset, which can range within a single family from 3 days up to 13 months of age (Herlenius et al., 2007), although seizure onset in BFNIE most commonly occurs at between 2 and 4 months. BFNIE was first described as a distinct clinical entity by Kaplan and Lacey in 1983. They described an American family with 12 affected individuals who had seizures with onset ranging from 3 days to 3½ months. All these individuals had subsequent normal development. Another family was subsequently described with seizure onset also occurring between 3 days and 3½ months of age (Lewis et al., 1996). Linkage to
3.1. Identification of mutations in the sodium channel subunit gene SCN2A
The mutations in
3.2. Clinical overlap between BFNE and BFNIE
There is considerable similarity in the phenotypes of BFNE caused by potassium channel mutations and BFNIE caused by
This clinical overlap means that determining the genetic defect is the only certain method to distinguish between BFNE and BFNIE. Making the distinction accurately is of clinical significance as 15% of patients with
4. The molecular genetics of benign familial infantile epilepsy
Benign familial infantile epilepsy (BFIE) has a later average age of onset than BFNE and BFNIE (Berkovic et al., 2004). The disorder was originally described by Watanabe and colleagues (1987), who observed that a subgroup of infants with generalised motor seizures had subsequent normal development and later became seizure-free. Additional families were described by Vigevano and colleagues (1992) several years later. The disorder was demonstrated to be genetically distinct from BFNE in 1994 when Malafosse and colleagues excluded BFIE families from linkage to the BFNE region containing
A subset of BFIE patients also have paroxysmal movement disorders with onset in adolescence: either paroxysmal kinesogenic choreoathetosis or paroxysmal dyskinesia. The co-occurrence of these disorders is referred to as infantile convulsions and choreoathetosis (ICCA) syndrome. None of the genes associated with BFIE have been identified. The disorder has been mapped to loci on chromosomes 1, 16 and 19 (Guipponi et al., 1997; Szepetowski et al., 1997; Li et al., 2008b). A single family has been described with partial co-segregation of BFIE and familial hemiplegic migraine (FHM) and a mutation in
4.1. Rare BFIE loci
The first locus for BFIE was described in 1997. Five Italian families were mapped to a locus on chromosome 19q. The five families shared partial marker haplotypes for the region, possibly suggesting a founder effect – that is, that the five families were descended from a common ancestor and had the same mutation. No further families have been described which map to this locus and the mutation in the region has not been identified. Study of a further seven Italian BFIE families showed that they were not linked to the locus (Gennaro et al., 1999). This suggests that the putative mutation at the chromosome 19 locus is a rare cause of BFIE restricted to a localised geographic region. Indeed, given the possible founder effect in the five families originally linked to the locus, it may harbour a single BFIE founder mutation.
Another single BFIE family has been mapped to a locus on chromosome 1. This was a large Chinese family containing eight affected individuals. The family was mapped to a 12.4 centiMorgan region on chromosome 1p36.12-p35.1 (Li et al., 2008b) with a maximum LOD score of 3.14. Analysis of 45 candidate genes selected from the 315 genes in the region on the basis of function or neuronal expression did not identify any causative mutations in the family (Li et al., 2010).
4.2. BFIE associated with ATP1A2
A single family has been described in which BFIE partially co-segregates with familial hemiplegic migraine (FHM) (Vanmolkot et al., 2003). FHM has been associated with several genes, including
4.3. The chromosome 16p11.2-q12.1 BFIE locus
By far the most common locus for BFIE is located in the pericentromeric region of chromosome 16, between 16p11.2 and 16q12.1. This locus was originally described by Szepetowski and colleagues (1997), who mapped four French families with co-occurrence of BFIE and paroxysmal kinesigenic choreoathetosis (PKC) to the region. Numerous other families have subsequently been mapped to the region for similar conditions. Numerous additional smaller families are consistent with mapping to the region, showing no recombination, although they are of insufficient size to demonstrate linkage. Families mapping to the region include those with BFIE or PKC and PKD alone as well as those with both disorders (ICCA). The intervals for ICCA, BFIE and PKC/PKD from 13 published studies are shown in Figure 3. Two of these localisations (Valente et al., 2000; Callenbach et al., 2005) are small and do not overlap, suggesting that there may be more than one causative gene in the region. However, most of the localisations are large and span the centromere, a region of greatly reduced recombination on chromosome 16, especially in female meioses.
Despite the large number of families that have been mapped to the locus (approximately 50 have been described in the literature), no causative mutation has been identified at the chromosome 16 BFIE locus. A recent analysis of copy number variants in the region did not reveal any pathogenic copy number changes in the region, although low copy numbers of a particular variant were observed with increased frequency in a small cohort of BFIE patients (Roll et al., 2010). This suggests that the BFIE mutation on chromosome 16 has an unusual mechanism or is in an unannotated gene. Such unusual mutational mechanisms include: mutations in regulatory regions; balanced inversions; small copy number changes, which would not be detected by standard CGH arrays; and repeat expansions or contractions as in unstable triplet repeats.
The identification of the mutation in the chromosome 16 BFIE locus will potentially require the application of techniques for the detection of alterations in gene expression, analysis of the non-coding sequence or the identification of small copy number changes. These techniques have not traditionally been applied for mutation detection. However, they may be required for the identification of the mutation or mutations causing BFIE linked to the pericentromeric region of chromosome 16.
5. Conclusions
The molecular genetic basis of the benign epilepsies of infancy has not been fully determined. The molecular basis for BFIE remains elusive. However, striking progress has been made in determining the mutations underlying BFNE, of which around 90% are in the potassium channel subunit gene
Some cases of BFNE associated with developmental delay or intellectual disability are caused by duplications of chromosome 2q24.3. This region contains a cluster of voltage-gated sodium channels and the overexpression of these and perhaps other contiguous genes within the microduplication is hypothesised to cause the seizures and other phenotypes associated with the duplications. Only two cases with these duplications have been described so far, but it is likely that more will emerge with the increased routine application of array comparative genome hybridisation in cases that do not fit within conventional syndrome parameters.
Mutations in the voltage-gated sodium channel
Several loci have been mapped for BFIE, but no genes have been identified at any of these loci. The most important locus located in the pericentromeric region of chromosome 16 has been the focus of considerable research, but no causative gene has been identified as yet. The identification of the BFIE gene on chromosome 16 remains is a major challenge for completing the molecular picture for the benign epilepsies of infancy.
Acknowledgments
This work was supported by the National Health and Medical Research Council of Australia and SA Pathology.
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