Hilary A. Phillips

Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel ß1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant ß1 subunit with a brain Na+-channel ß subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.

Sodium-channel defects in benign familial neonatal-infantile seizures

Ion-channel gene defects are associated with a range of paroxysmal disorders, including several monogenic epilepsy syndromes. Two autosomal dominant disorders present in the first year of life: benign familial neonatal seizures, which is associated with potassium-channel gene defects; and benign familial infantile seizures, for which no genes have been identified. Here, we describe a clinically intermediate variant, benign familial neonatal-infantile seizures, with mutations in the sodium-channel subunit gene SCN2A. This clinico-molecular correlation defines a new benign familial epilepsy syndrome beginning in early infancy, an age at which seizure disorders frequently have a sombre prognosis.

CHRNB2 Is the Second Acetylcholine Receptor Subunit Associated with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE.

Autosomal Dominant Nocturnal Frontal-Lobe Epilepsy: Genetic Heterogeneity and Evidence for a Second Locus at 15q24

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4). An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13.2. Seven additional sporadic cases showed no evidence of defective CHRNA4. One of the families showed evidence of linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster (maximum LOD score of 3.01 with D15S152). Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE. The CHRNA4 gene and the two known CHRNA4 mutations are responsible for only a minority of ADNFLE. Although the ADNFLE phenotype is clinically homogeneous, there appear to be a variety of molecular defects responsible for this disorder, which will provide a challenge to the understanding of the basic mechanism of epileptogenesis.

How mutations in the nAChRs can cause ADNFLE epilepsy.

Summary:  Purpose: The linkage between autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and neuronal nicotinic acetylcholine receptor has been strongly reinforced by the report of five distinct mutations in the two genes coding for the major brain α4β2 nicotinic acetylcholine (ACh) receptors. As a first step toward understanding the basic mechanisms underlying this genetically transmissible neurologic disorder, we examined the similarities and differences of the functional properties displayed by naturally occurring mutant forms of this ligand‐gated channel.

A de novo mutation in sporadic nocturnal frontal lobe epilepsy.

Autosomal dominant nocturnal frontal lobe epilepsy is sometimes due to mutations in CHRNA4. The commoner presentation of sporadic nocturnal frontal lobe epilepsy has not been associated with genetic defects. A 30‐year‐old woman diagnosed as having sporadic nocturnal frontal lobe epilepsy was found to have a de novo Ser252Leu CHRNA4 mutation. A pattern is emerging of site‐specific mutation within the second transmembrane domain of CHRNA4 in association with autosomal dominant nocturnal frontal lobe epilepsy and sporadic nocturnal frontal lobe epilepsy in families with different ethnic backgrounds. Ann Neurol 2000;48:264–267

Genetic variation of CACNA1H in idiopathic generalized epilepsy

In a recent report, Chen and colleagues described 12 putative mutations in the T-type calcium channel gene CACNA1H in 14 of 118 patients with childhood absence epilepsy (CAE), and concluded that missense mutations in this gene may predispose to CAE. To investigate variation of CACNA1H in our patient population, we screened exons 9 to 11, in which 75% of the putative mutations described by Chen and colleagues are located, in 192 patients (134 unrelated) with idiopathic generalized epilepsies or generalized epilepsy with febrile seizures plus. This group included 34 CAE and 15 juvenile absence epilepsy patients. The study was approved by the ethics committees of the Women’s and Children’s Hospital and Austin Health. Informed consent was obtained from participants. DNA was amplified by polymerase chain reaction and screened for variation by single-stranded conformation analysis. Sequencing was performed using ABI BigDye v3.0 on the ABI 3700 instrument. Ninety-six control samples were screened for variants identified in patients. When a variant was present in a patient and not in controls, available members of the patient’s family were tested for the variant. Four variants were present only in patients. These were c.1438G3A (A480T); c.1853C3T (P618L); c.18571858del (V621fsX654), and c.2264G3A (G755D). The inheritance of these changes in the families is shown in the Figure. None of these variants was found in CAE or juvenile absence epilepsy patients. None of the four variants segregate with a specific epilepsy phenotype in each family, nor is their presence associated with any one phenotype. There are two instances in which siblings with the same phenotype are discordant for a variant, and all four variants are present in unaffected individuals. Our failure to replicate the findings of Chen and colleagues in absence phenotypes in our patient population suggests that the significance of CACNA1H variants in the cause of human epilepsy remains unclear. Moreover, functional data are required for all CACNA1H variants before their role in epilepsy is established. Generalized epilepsies are likely to be polygenic in origin, with variations in multiple ion-channel subunits or other genes interacting to cause epileptogenesis. For example, a mutation of GABRG2 has been found previously in three members of Family E and it is probable that several genes

Gene Localization for an Autosomal Dominant Familial Periodic Fever to 12p13

We report gene localization in a family with a benign autosomal dominant familial periodic fever (FPF) syndrome characterized by recurrent fever associated with abdominal pain. The clinical features are similar to the disorder previously described as familial Hibernian fever, and they differ from familial Mediterranean fever (FMF) in that FPF episodes usually do not respond to colchicine and FPF is not associated with amyloidosis. Frequent recombination with the marker D16S2622, <1 Mb from FMF, at 16p13.3, excluded allelism between these clinically similar conditions. Subsequently, a semiautomated genome search detected linkage of FMF to a cluster of markers at 12p13, with a multipoint LOD score of 6.14 at D12S356. If penetrance of 90% is assumed, the FPF gene maps to a 19-cM interval between D12S314 and D12S364; however, if complete penetrance is assumed, then FPF maps to a 9-cM region between D12S314 and D12S1695. This interval includes the dentatorubropallidoluysian atrophy locus, which, with FPF, gave a maximum two-point LOD score of 3.7 at a recombination fraction of 0. This is the first of the periodic-fever genes, other than FMF, to be mapped. Positional candidate genes may now be selected for mutation analysis to determine the molecular basis for FPF. Together with the recent identification of the defective gene in FMF, identification of a gene for FPF might provide new insights into the regulation of inflammatory responses.

LGI1 mutations in temporal lobe epilepsies

Background and Objectives: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. Methods: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4. Results: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T→G; C42G) and 8 (c.1418C→T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. Conclusion: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12.

Summary:  Background: Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant syndrome characterized by partial seizures originating from different brain regions in different family members in the absence of detectable structural abnormalities. A gene for FPEVF was mapped to chromosome 22q12 in two distantly related French‐Canadian families.