Megumi Takemoto

Genetic susceptibility to simple febrile seizures: Interleukin-1β promoter polymorphisms are associated with sporadic cases

Febrile seizures (FSs) are the commonest form of convulsions. A genetic predisposition to FSs is known, based on family studies, twin studies, and complex segregation analysis. Simple FSs may be more homogenous in their clinical manifestations, and show better agreement with the multifactorial inheritance theory than the complex type. Interleukin-1 (IL-1) beta is one of the pro-inflammatory cytokines that are postulated to be involved in the development of FSs. To determine whether or not function-related polymorphisms of the IL-1beta (IL1B) gene are associated with susceptibility to simple FSs, the genotypes for two biallelic polymorphisms in the promoter region at positions -31 and -511 of the IL1B gene were determined by means of PCR-restriction fragment length polymorphism in 229 FS patients (108 sporadic and 60 familial simple FS, and 61 complex FS patients) and 158 controls. IL1B -31C/T, a TATA box polymorphism, has been found to be in complete linkage disequilibrium with the IL1B -511C/T polymorphism. Sporadic simple FS patients exhibited significantly higher frequencies of IL1B -31C/-511T alleles and homozygotes than controls (uncorrected p = 0.0094 and 0.0029, corrected p = 0.038 and 0.035, respectively), while no differences were observed in patients with all or familial simple FSs versus controls. There were no significant differences in the frequencies of -31C/T and -511C/T in the IL-1beta promoter gene between complex FS patients and controls. The present study suggests that the IL-1beta gene contributes to a genetic susceptibility to the development of simple FSs of sporadic occurrence.

Functional MxA promoter polymorphism associated with subacute sclerosing panencephalitis

Background: The antivirally active MxA protein is induced by interferon (IFN) α/β and inhibits the replication of single-stranded RNA viruses including measles virus (MV). The authors investigated whether the MxA gene contributed to the development of subacute sclerosing panencephalitis (SSPE) in Japanese individuals. Methods: Single-nucleotide polymorphisms (SNP) in the promoter region of the MxA gene were screened, association studies were performed between two SNP and SSPE, and then a functional difference in the promoter activities of the two SNP was investigated by a dual luciferase reporter assay. Results: Four SNP were found (−88 G/T, −123 C/A, −200 T/C, and −213 G/T), and SSPE patients exhibited a higher frequency of both the −88T allele and the −88TT genotype than controls (p = 0.040 and 0.003). The IFN-induced up-regulation of the MxA promoter activity of the sequence with −88T was found to be significantly higher than that with G. Conclusions: MxA promoter −88 G/T SNP may confer host genetic susceptibility to SSPE in Japanese individuals. The finding that homozygotes of the MxA −88T allele with a high MxA-producing capability were more frequently seen in SSPE patients suggests that the MxA protein promotes the establishment of persistent MV infection of neural cells.

Association of toll-like receptor 3 gene polymorphism with subacute sclerosing panencephalitis

Innate immunity plays an important role in measles virus (MV) infection. MV-derived double-stranded RNA is recognized by toll-like receptor 3 (TLR3), retinoic acid-inducible protein I (RIG-I) and melanoma differentiation—associated gene 5 (MDA5). We investigated whether genes encoding these molecules contributed to the development of subacute sclerosing panencephalitis (SSPE) in Japanese individuals. Four single nucleotide polymorphisms (SNPs) of the three genes (TLR3 rs3775291:Leu412Phe, RIG1 rs277729 and rs9695310, and MDA5 rs4664463) were assessed in 40 SSPE patients and 84 controls. Because the TLR3 SNP showed a positive association with SSPE, three additional SNPs were subjected to haplotype analysis. The frequency of 412Phe allele of TLR3 rs3775291 in SSPE patients was significantly higher than that in controls (P=.03). In haplotype analysis of four SNPs in the TLR3 gene, the frequency of −7C/IVS3 +71C/Phe412/c.1377C haplotype was significantly increased in SSPE patients (P=.006, odds ration [OR]: 2.2). TLR3 gene may confer host genetic susceptibility to SSPE in Japanese individuals.

Diagnostic usefulness of diffusion-weighted magnetic resonance imaging in influenza-associated acute encephalopathy or encephalitis

A magnetic resonance imaging (MRI) study was performed for a 20-month-old girl with an influenza type A infection who presented acute encephalopathy. Conventional MRI performed 8 days after the onset of encephalopathy, including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery imaging, revealed only vague lesions in the right frontal, temporal, and parietal lobes. In contrast, diffusion-weighted imaging (DWI) then demonstrated the lesions much more intensively. On the 26th day, the lesions previously observed on DWI had become less discernible. The hyperintensity observed on DWI might reflect cytotoxic edema. Thus, DWI may be useful for evaluation of acute influenzal encephalopathy/encephalitis.

Genetic susceptibility to febrile seizures: Case-control association studies

OBJECTIVE A genetic predisposition to febrile seizures (FS) has long been recognized. The inheritance appears to be polygenic in small families or sporadic cases of FS encountered in daily clinical practice. To determine whether candidate genes are responsible for the susceptibility to FS, we have performed genetic association studies in FS patients and controls. METHODS The single-nucleotide polymorphisms (SNPs) of genes involved in immune response (interleukin (IL) 1B), endocannabinoid signaling (CNR1), acid-base balance (SLC4A3, SLC9A1, SLC9A3), gap junction channel (CX43), and GABA(A) receptor trafficking (PRIP1) were examined in 249 FS patients (186 simple and 63 complex FS) and 225 controls. RESULTS There were no significant differences in the allele frequencies of the SNPs between controls and all FS, simple FS, and complex FS patients. When the simple FS patients were divided into two groups according to either having (familial) or not having a family history of FS in close relatives (sporadic), there was a significant association between IL1B -511 SNP and sporadic simple FS (p=0.003). CONCLUSIONS These data suggest that cytokine genes may act as enhancers or attenuators of FS susceptibility. Genetic association study may be an effective approach to understanding the molecular basis of FS at least in a subgroup of patients.

Rubinstein-Taybi syndrome: a girl with a history of neuroblastoma and premature thelarche.

A 7-year-old girl with Rubinstein-Taybi syndrome (RTS) who had a history of neuroblastoma and premature thelarche is reported. The neuroblastoma was detected at age 6 months on a nation-wide neuroblastoma screening program, surgically removed, and took a favorable clinical course with minimal therapy. She developed isolated breasts at age 6 years, had normal plasma levels of estradiol, follicular-stimulating hormone (FSH), and luteinizing hormone (LH), and showed a FSH-predominant pattern on the LH-releasing hormone stimulation test. In view of these findings, she was diagnosed to have premature thelarche. Premature thelarche may not be uncommon in girls with RTS.

Founder effect of the C9 R95X mutation in Orientals.

A nonsense mutation at codon 95 (R95X) in the C9 gene is responsible for most Japanese C9 deficiency (C9D) cases, with a carrier frequency of 6.7%. Upon analysis of microsatellite markers and newly identified dinucleotide repeat number polymorphisms in the 3′ flanking region of the C9 gene, a founder effect was demonstrated for the R95X mutation of the C9 gene in Japanese. Screening for the R95X mutation in Korean and Chinese individuals showed that the R95X carrier frequencies in Koreans and Chinese were 2.0% and 1.0%, respectively. Although homozygotes for the R95X mutation were not found in Korea or China, the shared haplotype of the dinucleotide repeat number polymorphisms appeared to be associated with the R95X mutation in the heterozygotes in Korea and China. The founder effect found in East Asians (Japanese, Koreans and Chinese) but not in Caucasians, as well as the haplotype sharing in only a small chromosomal interval, suggested that the R95X mutation of C9 gene was ancient and had occurred after the divergence of East Asians and Caucasians, and before migration of the Yayoi people to Japan. Since the mortality of meningococcal infections in complement-deficient patients is lower than that in normal individuals, a founder effect and a selective advantage in isolation might be the main reasons for the high frequency of the R95X mutation in Japan.

An Infant with Precursor Natural Killer (NK) Cell Leukemia Successfully Treated with an Unrelated Cord Blood Transplantation

Here we report a case with precursor natural killer (NK) cell leukemia successfully treated with an unrelated cord blood transplantation. A 7-month-old Japanese boy was diagnosed to have NK cell leukemia based on the existence of abnormal cells in the bone marrow with the phenotype of CD3-/CD4 /CD7-/CD8-/CD167-CD33+/CD34-/CD56+/HLA-DR+NKBI+ CD94+. The leukemic cells showed few azurophilic granules in the cytoplasm and weak cytotoxic activity. Although he presented with a huge mass occupying the bilateral paranasal sinuses and hepatosplenomegaly, he achieved complete remission by the conventional chemotherapeutic regimen for acute myelogenous leukemia, followed by an unrelated cord blood transplantation. He has remained in complete remission for 14 months posttransplant. To our knowledge. this is the youngest reported case with precursor NK cell leukemia; cord blood transplantation may thus be the treatment of choice for this disease.

Association study of polymorphisms in SOCS family genes with type 1 diabetes mellitus

Suppressors of cytokine signalling (SOCS) proteins play important roles in the negative regulation of cytokine signal. We first searched for polymorphisms in SOCS‐1, SOCS‐3 and SOCS‐5 genes, and examined the association of the polymorphisms with type 1 diabetes (T1D). As a result, we did not find any significant associations between SOCS genes and T1D.

A novel R275X mutation of the SLC25A15 gene in a japanese patient with the HHH syndrome

The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (MIM 238970) is an autosomal recessive metabolic disorder caused by a deficiency of the mitochondrial ornithine transporter, one of the urea cycle components. Mutations in the SLC25A15 gene have been coupled to the HHH syndrome. We describe a Japanese female patient with the HHH syndrome due to a novel homozygous R275X SLC25A15 mutation and male sibling who presumably carried the same mutation. He exhibited slowly progressive deterioration with seizures, a gait disturbance due to polyneuropathy, episodic confusion, and died of acute encephalopathy at 34 years of age while the proband exhibited moderate mental retardation, seizures, mild spastic paraplegia, and deafness without neurological deterioration for more than 20 years. The clinical features of previously documented patients with the homozygous SLC25A15 mutation demonstrated that genotype did not simply correlate with clinical severity. The phenotypic variability might depend on other factors, such as dietary and other genetic ones.