[Genetic aspects of epilepsy: current knowledge and perspectives]. / Situation et perspectives de la génétique des épilepsies.

Rapidly advancing knowledge concerning the genetic aspects of epilepsy have led us to complete a recent article on the subject published in the journal. A contrasting picture is emerging, particularly between symptomatic and idiopathic epilepsy. For symptomatic epilepsy, divers gene products implicated in brain development and neuron survival have been identified. Inversely, for idiopathic epilepsy, the latest discoveries confirm their canalopathic nature. In addition, rapid progress in the field of mendelian inherited epilepsy has pointed out the lack of notable progress concerning common epilepsy with a complex hereditary pattern. These forms are one of the major challenges for genetic analysis of epilepsy.

Ion channel variation causes epilepsies.

The discovery of genetically transmissible form of epilepsy associated with a mutation in a gene that codes for a subunit of a ligand-gated channel shined a new light in this field of neurological diseases. Because this gene (CHRNA4) codes for a neuronal nicotinic acetylcholine receptor subunit, functional studies could be designed to evaluate the alterations caused by this mutation. Since this initial observation, five mutations were identified and determination of their functional properties initiated. These experiments were extended to pairwise expression of the control and mutated allele to mimic the heterozygote human genotype. The first common functional trait identified so far, in four of these mutants, is an increased sensitivity to the acetylcholine, suggesting that these mutations may cause a gain of function. An alternative possibility that cannot be excluded is that conditions in the brain are such that these higher responding receptors may be more prone to desensitization. The importance of ionic channels as cause of epilepsies was further demonstrated with the identification of the association between the benign neonatal epilepsy and mutations in genes coding for potassium channel subunits (KCNQ2, KCNQ3). Additional evidences were brought by the identification of mutations in voltage-dependent sodium channels (SCN1A, SCN1B) in a form of generalized epilepsy with febrile seizures.

Polymorphism analysis of JRK/JH8, the human homologue of mouse jerky, and description of a rare mutation in a case of CAE evolving to JME.

Disruption of the function of the mouse jerky gene by transgene insertion causes generalized recurrent seizures reminiscent of human idiopathic generalized epilepsy (IGE). A human homologue, JRK/JH8, has been cloned, which maps to 8q24, a chromosomal region associated with several forms of IGE. JRK/JH8 is, therefore, a candidate locus for at least some forms of IGE. We report corrected cDNA sequences and extended open reading frames for the mouse jerky and human JRK/JH8 genes, which add 48 amino acids to the N-terminus of the Jerky protein and which extends the region of homology with the N-terminal DNA-binding domain of the centromere-binding protein, CENP-B. Systematic sequencing of the coding region of the extended JRK/JH8 gene identified single nucleotide polymorphisms that define three haplotypes, which were used for association studies in patients with idiopathic generalized epilepsy. We report one subject with childhood absence epilepsy (CAE) that evolved to juvenile myoclonic epilepsy (JME) that has a unique de novo mutation that results in a non-conservative amino acid change at a potential protein glycosylation site. Familial analysis supports a causal role for this mutation in the disease.

[Recent insights about genetics of human idiopathic epilepsies and febrile seizures]. / Données récentes sur la génétique des épilepsies idiopathiques et des convulsions fébriles.

We present here recent insight into idiopathic epilepsies and febrile convulsions. For each case, main clinical features are presented, concomitantly with genetic advances (transmission, penetrance and expressivity, locus, gene, gene function, identified mutations).

Study of the voltage-gated sodium channel beta 1 subunit gene (SCN1B) in the benign familial infantile convulsions syndrome (BFIC).

Benign familial infantile convulsions (BFIC) is a rare autosomal dominant epilepsy syndrome. This syndrome has been recently described in Italian and French pedigrees. Patients present with partial, then generalized seizures, with onset at age three months. The seizures usually spontaneously cease after one year without treatment, leaving no neurological abnormalities. We have mapped BFIC to chromosome 19q in five Italian pedigrees. The sodium channel beta1 subunit gene (SCN1B) maps to this candidate region and has been shown to be involved in one Australian pedigree with generalized epilepsy and febrile seizures "plus" (GEFS +). In this family, a missense mutation in SCN1B cosegregates with the GEFS+ phenotype. BFIC and GEFS+ have clinical features in common, therefore SCN1B is a candidate gene for BFIC. We studied SCN1B exons 1, 2, 3, 4, and 5, using four SSCP methods in 10 Caucasian BFIC probands of Western Europe. We found no exon variants. One variant was identified in intron 5 (IVS5-10C>G), which did not segregate with BFIC and was observed in 9.2% controls. A second variant in intron 5 was identified (IVS5+30G>A). It was rare, as not observed in controls, but not segregating with the BFIC phenotype.

Coexistence of dominant and recessive familial amyotrophic lateral sclerosis with the D90A Cu,Zn superoxide dismutase mutation within the same country.

The Cu,Zn superoxide dismutase (Cu,Zn SOD) mutations described in amyotrophic lateral sclerosis (ALS) have, for the most part, a dominant influence. However, while a few cases with a heterozygous D90A mutation have been described in different countries, D90A has been recently proven to be recessively inherited with a common founder effect in Scandinavia. We screened French ALS families for Cu,Zn SOD mutations. The presence of the D90A allele was found in two index-cases, and their families were subsequently studied. In the first family the ALS patients were homozygotes for D90A, while in the second, all ALS patients were heterozygotes. In both families the disease was found to initially involve the lower limbs with slower progression than in sporadic cases, and frequent atypical signs such as paresthesia and urgency of micturition. We determined the D90A allele frequency in controls (n = 200) and sporadic ALS patients (n = 408). No D90A allele was found. This is the first report of coexistence of dominant and recessive families with the D90A Cu,Zn SOD mutation within the same country.

Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33.

We report the identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+). Six family members manifested isolated typical febrile seizures (FS), and five had typical FS associated with generalized epilepsy (FS+, generalized tonic/clonic seizures). Afebrile seizures occurred from childhood until the teenage years. The maximum two-point LOD score was 3.99 for markers D2S294 and D2S2314. Flanking markers place the GEFS+ locus between D2S141 and D2S116, with multipoint analysis favoring the 13-cM interval spanned by D2S294 and D2S364. This locus is the second GEFS+ locus to be reported, which suggests that this syndrome is genetically heterogeneous.

Genetics of familial ALS and consequences for diagnosis. French ALS Research Group.

Familial amyotrophic lateral sclerosis (fALS) is a well-recognised condition that accounts for almost 10% of all cases of ALS. Most cases are now known to be transmitted by an autosomal dominant trait. When fALS is compared clinically to sporadic ALS, 20% of cases manifest atypical features such as pain, paraesthesia or urgency micturition. Moreover, a disease duration of over 10 years, with very slow progression, appears to occur almost exclusively in cases of fALS. Studies of superoxide dismutase (SOD1) mutations in fALS have shown that the disease may be multidegenerative, with oculomotor or cerebellar involvement. Molecular genetics has also demonstrated that not all SOD1 mutations have a dominant influence, and the detailed description of the Scandinavian D90A homozygous mutation is very informative in this regard. Misdiagnosis of fALS can be attributed to one of the following situations: (i) atypical phenotype ALS with a multidegenerative profile; (ii) unusually long lasting ALS with mild motor neuron involvement; (iii) significant clinical heterogeneity between affected family members; (iv) low reliability of family history; (v) existence of an unknown or unexpected mode of transmission; and (vi) other multidegenerative disorders with motor neuron involvement. Pedigrees and fALS cases corresponding to these situations are presented.

Identification of six novel SOD1 gene mutations in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SOD1 mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.

Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease.

The telomeric copy (t) of the survival motor neuron (SMN) gene is homozygously deleted in more than 90% of patients with infantile motor neuron disease (MND). In the general population, no homozygous SMNt deletion has been found, whereas 5% of centromeric SMN (SMNc) deletions can be observed. Although SMNt deletions appear causal for infantile and at least some adult-onset spinal muscular atrophy (SMA) (type IV), the respective role of SMN deletions remains unclear in adult-onset MNDs. We studied SMN gene in three different groups of patients with adult-onset MNDs. In sporadic amyotrophic lateral sclerosis (ALS; n = 177) and familial ALS (n = 66), no SMNt deletion had been found, and the frequency of SMNc deletions was not increased. Conversely, among the 14 patients with sporadic pure lower MND (LMND), we found 2 patients with homozygous SMNt deletions (14%) and 5 patients with homozygous SMNc deletions (36%). These data suggest that (1) SMNt deletions do not account for the major part, if any, of adult-onset LMND cases; and (2) SMNc deletions act as a susceptibility factor for LMNDs in adults. The clinical and genetic heterogeneity of LMND cases, including SMA type IV, are yet to be unexplained. Further studies on large groups of adult-onset LMND patients are warranted to refine its nosology.

[Clinical study of familial forms of amyotrophic lateral sclerosis. Review of the literature]. / Etude clinique des formes familiales de sclérose latérale amyotrophique. Revue de la littérature.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving both upper and lower motor neurons. The disease is possibly due to several factors, including a genetic one. This is supported by the existence of 5 to 10 p. 100 familial cases. In these pedigrees, the transmission is autosomal dominant, with a high penetrance (> 90 p. 100). We studied the phenotypes of these familial cases, in reviewing the literature on familial ALS (FALS). It has been noted that FALS are heterogeneous, with different age of onset, site of onset and disease duration. Moreover, in FALS, onset is earlier than in the sporadic form (48 vs 60 years, as usually reported in the literature). We also frequently noted sensory disorders (20 p. 100), onset on the lower limbs (46 p. 100) and decreased or absent ankle-jerks (75 p. 100) in FALS patients.

Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disorder of unknown etiology. Recently, in Alzheimer's disease (AD) apolipoprotein E (APOE) alleles have been shown to play an important role in disease phenotype. To determine whether APOE have a similar influence in other neurodegenerative disorders, we studied APOE genotypes in 130 sporadic ALS patients, compared with controls. We also analyzed APOE genotypes regarding ALS clinical criteria. The frequency of APOE genotypes was not different between ALS and controls. However, subjects with the APOE2/E3 genotype showed a significantly longer duration of the disease: 51 months vs. 28.5 for APOE3/E3 and 27.5 for APOE3/E4 (p = 0.001 and p = 0.02, respectively). There was a significantly higher proportion of bulbar ALS patients in the APOE3/E4 group (72% of the cases), whereas 90% of patients in the APOE2/E3 group showed limb onset (p = 0.01). In the bulbar group, patients with APOE4 showed earlier onset of the disease: 60 vs. 66 years (mean age, p = 0.05). These results are consistent with a protective role of APOE2 and a deleterious role of APOE4 in ALS as already found for AD. This parallel supports the idea of a general role of APOE in neuronal degeneration or regeneration rather than a specific role in ALS or AD etiopathogenesis.

A nonsense mutation in the alpha4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions (EBNI)

Benign Familial Neonatal Convulsions (BFNC) is an epileptic disorder with an autosomal dominant mode of transmission. It has been shown that about 80% of BFNC pedigrees are linked to a genetic defect on chromosome 20q13.3. A candidate gene for the epilepsies, the gene coding for the alpha4 subunit of the nicotinic cholinergic receptor (CHRNA4), has previously been localized on chromosome 20. Here we report a single point mutation converting a serine codon to a stop codon in the exon 5 of CHRNA4, in one BFNC family. Identification of CHRNA4 as the defective gene in 20q-BFNC represents the first example of a human idiopathic epilepsy caused by a mutation directly affecting a neurotransmitter receptor in the central nervous system.