Abnormal brain MRI signal in 18q-syndrome not due to dysmyelination.

BACKGROUND: 18q-Syndrome is a chromosomal disorder exhibiting various symptoms arising from the central nervous system. Brain magnetic resonance imaging (MRI) of patients with this syndrome usually demonstrates abnormal white matter intensities. This is widely believed to be due to impaired myelin formation because this syndrome involves the deletion of the myelin basic protein (MBP) gene in 18q23. However, this hypothesis has not been confirmed by actual pathology because early death is unusual and autopsy rarely performed. PATIENT: A 6-year-old boy with ring chromosome 18 syndrome was examined by genetic analysis for the MBP gene, brain MRI, and autopsy. RESULTS: Haploinsufficiency of the MBP gene was confirmed. T(2)-weighted MRI revealed diffuse high intensities throughout the cerebral white matter. Pathological examination showed the cerebral white matter to be uniformly stained by Klüver-Barrera and MBP immunohistochemical staining. Oligodendrocytes were immunoreactive for proteolipid protein and ferritin but not MBP. Electron microscopy revealed clusters of axons wrapped in compact myelin sheaths with distinct major dense lines. Holzer and immunohistochemical staining for glial fibrillary acidic protein showed extensive staining of the white matter and an increased number of glial filaments. CONCLUSIONS: This pathological study demonstrated that in this disorder, the brain was well myelinated, contrary to established hypotheses about this disorder. The MRI signal abnormalities in 18q-syndrome could be attributed to gliosis and not to dysmyelination.

[A case of infantile epileptic apnea with congenital brain anomaly].

Two months-old girl with psychomotor retardation had aminophylline-resistant apnea attacks and was investigated by video-EEG recording. She had hypogenesis of cerebral cortex and cerebellum and complete agenesis of corpus callosum. Left hemispheric 2 Hz rhythmic delta wave burst originating from the posterior temporal area lasted about 20 seconds, and was followed by an apnea attack persisting for 30 seconds. During the apnea attack, the basic activity of EEG was suppressed. The diagnosis of epileptic apnea was made, and the attacks were controlled with valproate sodium. Reports of cases of brain anomaly presenting with epileptic apnea are rare and this interesting case provided a clue to the pathomechanism of this condition.

Failure to find causal mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene in Japanese febrile seizure patients.

Recently, mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene were identified in two families with generalized epilepsy with febrile seizures plus (GEFS+) and two families with childhood absence epilepsy (CAE) and febrile seizures (FS). We tested the hypothesis that genetic variations in the GABRG2 gene confer susceptibility to FS in the Japanese population. We performed a systematic search for mutations in 94 unrelated Japanese patients with FS and detected six variants (-158C>T, 315C>T, 588T>C, IVS5-55C>T, IVS7+20G>A, and IVS7-141T>A). No non-synonymous mutation was detected. We genotyped three exonic polymorphisms and performed a case control study and a transmission disequilibrium test using 55 independent complete trios with FS and 106 control subjects. None of these polymorphic alleles were significantly associated with FS. Our results indicate that genomic variations of GABRG2 are not likely to be substantially involved in the etiology of FS in the Japanese population.

Molecular genetics of febrile seizures.

Febrile seizures are the most common form of convulsion, occurring in 2-5% of infants in Europe and North America and in 6-9% in Japan. In large families, the febrile seizure (FS) susceptibility trait is inherited by the autosomal dominant pattern with reduced penetrance. Two putative FS loci, FEB1 (chromosome 8q13-q21) and FEB2 (chromosome 19p13.3) have been mapped. A clinical subset of FS, termed generalized epilepsy with febrile seizures plus (GEFS+), was reported. In GEFS+ families, a mutation in the voltage-gated sodium channel beta1 subunit gene (SCN1B) at chromosome 19q13.1 and two mutations of the same alpha1 subunit gene (SCN1A) at chromosome 2q24 were identified. These loci are linked to febrile convulsions in large families. We conducted a genome-wide linkage search for FS in one large family with subsequent linkage confirmation in 39 nuclear families using nonparametric allele-sharing methods, and found a new FS susceptibility locus, FEB4 (chromosome 5q14-q15). In contrast to the FEB1, FEB2, and GEFS+ genetic loci, linkage to FEB4 was suggested in nuclear FS families, indicating that FEB4 may be the most common linkage locus in FS families.

A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures.

A naturally occurring mutation of the mass1 (monogenic audiogenic seizure-susceptible) gene recently has been reported in the Frings mouse strain, which is prone to audiogenic seizures. The human orthologous gene, MASS1, was mapped to chromosome 5q14, for which we previously have reported significant evidence of linkage to febrile seizures (FEB4). We screened for MASS1 mutations in individuals from 48 families with familial febrile seizures and found 25 DNA alterations. None of nine missense polymorphic alleles was significantly associated with febrile seizures; however, a nonsense mutation (S2652X) causing a deletion of the C-terminal 126 amino acid residues was identified in one family with febrile and afebrile seizures. Our results suggest that a loss-of-function mutation in MASS1 might be responsible for the seizure phenotypes, though it is not likely that MASS1 contributed to the cause of febrile seizures in most of our families.

Failure to find evidence for association between voltage-gated sodium channel gene SCN2A variants and febrile seizures in humans.

The voltage-gated sodium channel type II alpha polypeptide gene (SCN2A) R188W mutation with channel dysfunction was recently identified in a patient with febrile and afebrile seizures. A possible association between SCN2A R19K polymorphism and febrile seizures (FS) associated with afebrile seizures including generalized epilepsy with febrile seizures plus (GEFS+) was also noted. We attempted to identify the R188W mutation and confirm association of the R19K polymorphism in 93 Japanese patients with FS, 35 Japanese patients with FS associated with afebrile seizures including GEFS+, and 100 control subjects. The R188W mutation was not found. There were no significant differences in genotype or allele frequencies of the R19K polymorphism between groups. Our study failed to provide evidence supporting a causal relation between the SCN2A mutation/polymorphism and FS or FS associated with afebrile seizures including GEFS+ in the Japanese population.

Human rights and Japanese bioethics: a report from Japan.

The main contentions of this paper are two fold. First, there is a more than century-old Japanese tradition of human rights based on a fusion of Western concepts of natural rights and a radical reinterpretation of Confucianism, the major proponent of which was the Japanese thinker Nakae Chomin. Secondly, this tradition, although a minority view, is crucial for remedying the serious defects in the present Japanese medical system. In the latter half of the nineteenth century, Nakae Chomin sought to reinterpret Chinese tradition, especially Confucianism, by injecting the concepts of popular sovereignty and democratic equality, drawn from Western sources. The resulting view maintained the Confucian commitment to a moral nexus for society, but replaced hierarchy with egalitarianism. The pressing need for such an approach to patients' rights in present-day Japan is illustrated by two recent cases: the photographing and commercial exploitation of patients' genitals without serious response by authorities, and the attempt by physicians to manipulate the time of death and, possibly, to improperly pressure family members in order to transplant organs from the brain-dead victim of a criminal assault. Such problems stem from hierarchy and paternalism, which seem to be a legacy of the rapid, state-sponsored introduction of Western medicine in the mid-nineteenth century, and in particular from the government's adoption of and support for German military medicine as a model for Japan.