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.
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.
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 (SODl) 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 Zn 2+ binding sites, a region where no previous SODl mutations have been found. Our data increase the number of different SODl mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.
RESUME: Identification de six nouvelles mutations dans le gene SODl de patients atteints de laSclerose Laterale Amyotrophique. La Sclerose Laterale Amyotrophique (SLA) est une maladie neurodegenerative caracterisee par la mort prematuree des motoneurones. Dans 10% des cas, la SLA est herediataire et caracterisee par une transmission autosomique dominante (SLAF). II a ete prouve que des mutations dans le gene codant pour la Cu/Zn superoxyde dismutase (SODl) sont responsables de 15% des cas de SLAF. L'analyse des regions condantes du gene SODl de 70 patients nonapparentes atteints de SLAF nous a permis de decouvrir 10 mutations dont six sont nouvelles. Fait inatendu, nous avons trouve la premiere mutation dans l'exon 3 qui code pour la majeure partie du site actif et des sites de fixation du Zn 2+ . De plus, nous avons identife une deuxieme mutation recessive. Cette etude porte le nombre de mutations SODl differentes a 55 impliquant 37 codons, une fraction significative de cette proteine relativement petite constitute de 154 acides amines.
Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter. We performed a haplotype study of ULD chromosomes (ULDc) with the repeat expansion. We included 48 West European Caucasian (WEC) and 47 North African (NA) ULDc. We analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3' UTR (A2575G). We observed a founder effect in most of the NA ULD patients, as 61.7% of the NA ULDc (29/47) shared the same haplotype, A1 (1-1-A-1-6-7), for markers D21S1885-D21S2040-A2575G-D21S1259-D21S1912-PFKL. Moreover, if we considered only the markers D21S1885, D21S2040, A2575G and D21S1259, 43 of the 47 NA ULDc shared the same alleles 1-1-A-1, haplotype A. As previously shown, the WEC ULDc were heterogeneous. However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%). Finally, as almost all NA patients, like Scandinavian patients, were of the haplotype A, we assumed that there was an ancient common founder effect in NA and Baltic ULD patients. We estimated that the putative most recent common ancestral ULD carrier with this haplotype A must have existed about 2,500 years ago (100-150 generations). Finally, this work provides evidence for the existence of only a small number of founder mutations in ULD.
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