A group of infant onset epilepsies manifest very frequent generalized tonic-clonic seizures (GTC) intractable to medical therapy, which may or may not be accompanied by minor seizures such as myoclonic seizures, absences and partial seizures. They include severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with GTC (ICEGTC). They are commonly associated with fever-sensitivity, family history of seizure disorders and developmental decline after seizure onset. Mutations of the neuronal voltage-gated sodium channel alpha subunit type 1 gene (SCN1A) were recently reported in SMEI patients. To clarify the genotypic differences in this group of epilepsies, we searched for SCN1A abnormalities in 25 patients with SMEI and 10 with ICEGTC, together with the family members of 15 patients. Frameshift mutations in SCN1A were observed in four patients, nonsense mutations in five patients, missense mutations in 21 patients, other mutations in two patients and no mutation in five patients. SMEI patients showed nonsense mutations, frameshifts, or missense mutations, while ICEGTC patients showed only missense mutations. Study of both parents of 11 patients revealed that the mutations in these patients were de novo. However, two mothers had the same missense mutations as their ICEGTC children, and they had generalized epilepsy with febrile seizures plus. Here we suggest that SMEI and ICEGTC represent a continuum with minor phenotypic and genotypic differences.

Acad. Sci. USA (97, 13913-13918; First Published November 28, 2000; 10.1073͞pnas.250478897), the authors note that the exponents of some entries in Table 1 were misprinted. The correct values appear below. www.pnas.org͞cgi͞doi͞10.1073͞pnas.191384698 STATISTICS, GENETICS. For the article ''Significance analysis of microarrays applied to the ionizing radiation response'' by Virginia Goss Tusher, Robert Tibshirani, and Gilbert Chu, which appeared in number 9, April 24, 2001, of Proc. Natl. Acad. Sci. USA (98, 5116-5121; First Published April 17, 2001; 10.1073͞pnas.091062498), the authors note the following: ''In our discussion of the pairwise fold change method on page 5118, we cited a paper by Ly et al., crediting them for the method. We did not mean to imply that it was deficient for the analysis of their experiments. In fact, Ly et al. incorporate (98,(6384)(6385)(6386)(6387)(6388)(6389), the authors wish to correct the position given for the amino acid that was mutated in the patient. The mutation ''R187W'' should be ''R188W. '' www.pnas.org͞cgi͞doi͞10.1073͞pnas.191390798 FEB2, 19p; FEB3, and FEB4,. A small population of individuals with FS has additional generalized epilepsy (1) or afebrile seizures. Genes for a ␤-subunit (␤1) and an ␣ I -subunit (Na v 1.1: SCN1A) (10) of the neuronal voltage-gated Na ϩ channel have been identified to be responsible for generalized epilepsy with febrile seizures plus (GEFSϩ) type 1 and 2, respectively (11, 12). However, a large number of patients with GEFSϩ still show no mutation for those genes. These, therefore, suggest that other genes might also be involved in GEFSϩ and FS associated with afebrile seizures. The chromosomal locus 2q24, in which GEFSϩ has been mapped, harbors not only Na v 1.1 but also other ␣-subunits including Na v 1.2 (SCN2A) (10,(13)(14)(15). Given that Na v 1.2 is also expressed in high levels in the central nervous system with a tissue-specific profile (16), Na v 1.2 is an intriguing candidate. In the present study, we report a mutation of Na v 1.2 found in a patient with FS and afebrile seizures. A channel harboring the mutation shows abnormal electrophysiological properties that may underlie the neuronal hyperexcitability that triggers seizure activity. Materials and MethodsPatients and Pedigrees. This study recruited nineteen unrelated Japanese families with members clinically diagnosed with GEFSϩ or febrile seizures associated with afebrile seizures. Each participating subject or a responsible adult signed an informed consent form approved by the Ethics Review Committee of Fukuoka University or similar committees of the participating institutions. The proband of family K1 is a 6-yr-old boy with normal development (Fig. 1A). He had the first febrile seizure (FS) at 8 months of age and suffered 17 episodes of FS thereafter at both high and low grade fever. The FS were generalized tonic or tonic-clonic convulsions with duration of 1-5 min per episode. Since 4 yr of age, he also has experienced brief afebrile atonic seizures 5 times. The...

Mutations in the neuronal voltage-gated sodium channel alpha-subunit type I gene (SCN1A) were found responsible for severe myoclonic epilepsy in infancy (SMEI). The authors describe novel mutations of SCN1A in Japanese patients with SMEI. They screened 12 unrelated patients and a pair of monozygotic twins and detected 10 mutations that lead to truncation of the protein.