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The high incidence of acute encephalopathy in East Asia suggests the role of genetic factors in its pathogenesis. It has recently been reported that variations of the CPT II (carnitine palmitoyl transferase II) gene may be associated with fatal or severe cases of influenza-associated encephalopathy. In the present study, we examined the genotype of CPT II in cases of acute encephalopathy associated with various preceding infections. Twenty-nine Japanese patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) or acute necrotizing encephalopathy (ANE) were studied. The frequency of F352C of CPT II exon 4 was significantly higher in patients than in controls. All patients who had allele C in F352C had allele I in V368I and allele M in M647V (CIM haplotype), which reportedly decreases CPT II activity to one third of that with FIM or FVM haplotype. The frequency of CIM haplotype was significantly different between patients and controls, but not between AESD and ANE. Our results revealed that having at least one CIM allele is a risk factor for the onset of acute encephalopathy, regardless of its antecedent infections., (Copyright © 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: We retrospectively reviewed six patients with incontinentia pigmenti (IP) who had encephalopathic manifestations during early infancy., Methods: We enrolled six patients who met the following criteria from the mailing list of the Annual Zao Conference: (1) diagnosis of IP; (2) encephalopathic manifestations with reduced consciousness and clusters of seizures by 6 months of age; and (3) no evidence of central nervous system infection or metabolic derangement., Results: The onset of the encephalopathic events was within the first 2 months of life in all but one patient. All had clusters of focal clonic seizures. The duration of seizures was typically 5 min. The seizures ceased within 5 days in all patients. Various degrees of reduced consciousness were observed in association with the frequent seizures. Diffusion-weighted imaging during the acute phase showed reduced water diffusion in the subcortical white matter, corpus callosum, basal ganglia, thalami, and internal capsule in two patients. Scattered subcortical white matter lesions were observed on fluid-attenuated inversion-recovery images in two patients., Conclusions: The encephalopathic manifestations in patients with incontinentia pigmenti were characterized by seizure clusters and reduced consciousness, albeit of relatively short duration. Magnetic resonance imaging abnormalities were predominant in the subcortical areas in most patients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: To clarify the immune pathophysiology of West syndrome (WS)., Study Design: We measured peripheral blood lymphocyte subset and serum cytokine profiles in 76 WS patients and 26 age-matched controls. Adrenocorticotropic hormone (ACTH) is one of the most effective therapy for WS and presumably immune-modulating; therefore, we compared the measured parameters between before ACTH (pre-ACTH) WS patients and controls, between cryptogenic and symptomatic WS patients before ACTH (pre-ACTH), and between before (pre-ACTH) and after (post-ACTH) ACTH WS patients. The post-ACTH group included those who received the last ACTH dose within 1 month of sampling., Results: CD3+ CD25+, CD19+, and CD19+ CD95+ cells were found to be significantly lower in the pre-ACTH group than in the controls. Interleukin (IL)-1 receptor antagonist (RA), 5, 6, and 15; eotaxin; basic fibroblast growth factor (bFGF); and interferon gamma-inducible protein (IP)-10 levels were higher in pre-ACTH group than in the controls. No significant differences were found between the pre-ACTH cryptogenic and symptomatic groups. CD4+ cells, CD3+ cells, CD4+/8+ ratio, IL-1 beta, IL-12, and macrophage inflammatory protein (MIP)-1 beta were significantly higher in pre-ACTH group than in the post-ACTH group., Conclusions: Our study revealed immunological alterations in WS patients, and these responses were modified by ACTH therapy. Further study is needed to elucidate whether or how the immune system alteration is involved in the pathophysiology of WS., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Baraitser-Winter syndrome (BaWS) is characterized by iris coloboma, ptosis, hypertelorism, and mental retardation; it is a rare multiple congenital anomaly or a mental-retardation syndrome of unknown etiology. Patients suffering from this syndrome have been also found to show brain anomalies such as pachygyria, subcortical-band heterotopia (SBH), and hippocampal malformations; therefore, these anomalies have been included in the phenotypic spectrum of this syndrome. We report the case of a Japanese boy suffering from BaWS; the patient's brain magnetic resonance imaging scan revealed pachygyria, SBH, and periventricular heterotopia. However, the results of the genome-wide array comparative genomic hybridization did not reveal any chromosomal rearrangements., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

We report sibling cases of aromatic L-amino acid decarboxylase (AADC) deficiency, which is a very rare congenital metabolic disorder. These patients were born to healthy and non-consanguineous parents, and presented oculogyric crises, paroxysmal dystonic attacks, and severe psychomotor retardation since early infancy. In cerebrospinal fluid the levels of homovanilic acid and 5-hydroxyindoleacetic acid were very low and the level of L-dopa was very high. The diagnosis was confirmed by the lack of AADC activity in plasma, and a point mutation in the AADC gene. MRI revealed a slightly small volume of the prefrontal areas and normal myelination in both patients. Positron emission tomography using 2-deoxy-2[(18)F] fluoro-D-glucose was performed in one patient, which revealed hypometabolism in the prefrontal cortex and bilateral basal ganglia with a little laterality. These findings suggested that the severe dystonic features were caused by abnormal function of bilateral basal ganglia and severe psychomotor retardation could be due to abnormalities in prefrontal cortical activity., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Osteoporosis-pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal-recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early-onset visual disturbance, with or without mental retardation. We undertook standard PCR-based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT-PCR from lymphocytic RNA demonstrated splice error resulting in 63-bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT-PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom- designed oligonucleotide tiling microarray analyses targeted to a 600-kb genome region harboring LRP5 and discovered a 7.2-kb microdeletion encompassing exons 22 and 23 of LRP5. We found various types of LRP5 mutations, including an exon-level deletion that is undetectable by standard PCR-based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations.

We report on a girl with early onset Huntington disease (HD). Her initial symptoms at 2 years of age included oral motor dysfunction and gait disturbance. Magnetic resonance imaging of the head revealed severe atrophy of both the vermis and the cerebellar cortex in addition to the common findings of basal ganglia including the caudate nuclei, putamen, and globus pallidus. Molecular analysis showed 160 CAG repeats in the HD gene. This mutation was inherited from her mother who was also affected, with a HD CAG expansion of 60 repeats. Cerebellar symptoms should be considered as a manifestation of early onset HD.

It is known that rotavirus gastroenteritis can accompany some neurological manifestations, including encephalitis/encephalopathy or seizures. However, the detailed pathogenesis involved has not been fully understood. To date, acute cerebellitis associated rotavirus gastroenteritis has not been previously reported, except for one case. Herein, we describe two cases of acute encephalitis/encephalopathy and concurrent cerebellitis, associated rotavirus gastroenteritis. Following vomiting and diarrhea, case 1 experienced convulsions and consciousness disturbance and case 2, transient loss of consciousness with eye deviation. After these symptoms subsided, cerebellar signs became evident and a brain MRI showed cerebellar involvement in both cases. Both cases showed speech disturbances, such as mutism, slow speech and dysarthria. In this report, we will discuss the possible pathogenesis of rotavirus associated acute encephalitis/encephalopathy and concurrent cerebellitis.

Acute cerebellar ataxia is usually a self-limited benign disease, which may develop in children after certain viral infections or vaccinations. There are several reports of acute cerebellar ataxia associated with autoantibodies. Glutamate receptor delta2, a member of the glutamate receptor family, is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions. To date anti-GluRdelta2 autoantibody was detected in a patient with chronic cerebellitis. Herein, an 18-month-old boy presented with cerebellar ataxia 9 days following a mild respiratory tract infection. Although cerebellar ataxia gradually improved, it worsened yet again following mumps and varicella virus infection. Cerebro-spinal fluid examination and magnetic resonance imaging of the brain demonstrated pleocytosis and meningeal enhancement, respectively. Furthermore, glutamate receptor delta2 autoantibody was detected in serum and cerebro-spinal fluid. Thus, we believe that the glutamate receptor delta2 autoantibody may play a role in cerebellar ataxia and consecutive cerebellitis.

We describe a 12-year-old girl, who had been medicated with theophylline for bronchial asthma and developed acute encephalopathy with refractory status epilepticus, showing bilateral mesial temporal and claustral lesions, which were evident on fluid-attenuated inversion recovery images, obtained with 1.5 T magnetic resonance imaging. To date, oxidative stress has been implicated in aging or various disorders, including inflammatory or degenerative neurological disorders. One of the oxidative stress markers, 8-hydroxydeoxyguanosine, was increased in our patient's cerebro-spinal fluid, plasma and urine. We speculate that augmented oxidative stress was associated with refractory status epilepticus in our patient, accompanying bilateral mesial temporal, claustral lesions and severe neuronal damage. Serial measurements of oxidative stress markers in acute encephalitis, encephalopathy, or status epilepticus could clarify the relationships between acute brain damage and free radicals.

Four patients with encephalitis/encephalopathy and parenchymal lesions accompanying reversible splenial lesions were retrospectively evaluated. In 3 patients, reversible lesions with transiently reduced diffusion were seen in the splenium and symmetrically in the peripheral frontoparietal white matter, clinical signs and symptoms were mild, and recovery was complete. These and previous observations suggest a less severe course and outcome for patients with reversible lesions isolated to the splenium or to the splenium and peripheral frontoparietal white matter.

Purpose: We tested the hypothesis that Sotos syndrome (SoS) due to the common deletion is a contiguous gene syndrome incorporating plasma coagulation factor twelve (FXII) deficiency. The relationship between FXII activity and the genotype at a functional polymorphism of the FXII gene was investigated., Methods: A total of 21 patients including those with the common deletion, smaller deletions, and point mutations, and four control individuals were analyzed. We examined FXII activity in patients and controls, and analyzed their FXII 46C/T genotype using direct DNA sequencing., Results: Among 10 common deletion patients, seven patients had lower FXII activity with the 46T allele of the FXII gene, whereas three patients had normal FXII activity with the 46C allele. Two patients with smaller deletions, whose FXII gene is not deleted had low FXII activity, but one patient with a smaller deletion had normal FXII. Four point mutation patients and controls all had FXII activities within the normal range., Conclusion: FXII activity in SoS patients with the common deletion is predominantly determined by the functional polymorphism of the remaining hemizygous FXII allele. Thus, Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.

This report describes a patient with Costello syndrome associated with moyamoya-like vasculopathy. His clinical findings were sparse, thin, and light-colored hair, bilateral ptosis, low-set ears, depressed nasal bridge, bulbous nose, short neck, loose pigmented skin with deep palmar and plantar creases, bilateral cryptorchidism, and delays in growth and development. Brain magnetic resonance imaging and cerebral angiography revealed moyamoya-like vasculopathy. A skin biopsy from the extensor surface of the right thigh revealed shortening and rupture of elastic fibers. Electron microscopy indicated reduced depositions of elastin. Formation of a stable elastic fiber system may be impaired in patients with Costello syndrome, and brain magnetic resonance imaging and magnetic resonance angiography would be recommended for these patients.

We report on a family with dominantly inherited asymptomatic Alexander's disease due to a novel Glial fibrillary acidic protein (GFAP) mutation. The proband, a 16-month-old boy, presented with megalocephaly and brain magnetic resonance imaging (MRI) showing the typical findings of Alexander's disease. Molecular analysis showed that he was a heterozygote of the L331P mutation of GFAP. His mother and sister, without megalocephaly or other neurological abnormalities, were also heterozygotes of the mutation and their brain magnetic resonance imaging showed mild changes in the caudates and deep frontal white matters. These results suggest the existence of a forme fruste of Alexander's disease. The L331P mutation may be associated with the mild phenotype of Alexander's disease. To elucidate the genotype-phenotype correlation in Alexander's disease, molecular diagnosis and MRI examination are required for many patients and their families.

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion, This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias., (Copyright 2003 Wiley-Liss, Inc.)

Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically.

We describe a 5-year-old boy and a 33-year-old woman with spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form (spondyloepimetaphyseal dysplasia with multiple dislocations) (MIM 6003546), and two 12-year-old girls with the disorder who were previously reported as examples of a variant of sponatrime dysplasia. Their clinical manifestations included midface hypoplasia, micromelic short stature, and generalized joint laxity that caused multiple joint problems, including thoracolumbar scoliosis, hip subluxation, progressive genu valgum with knee and patellar subluxation, elbow subluxation, and malalignment of the wrist. Laryngotracheomalacia was present in two individuals, and myopathy was noted in one. The radiological findings in the four individuals included mild platyspondyly most conspicuous in infancy, narrow interpediculate distances of the lumbar spine evident in infancy, retarded epiphyseal ossification that evolved to epiphyseal dysplasia and later to degenerative joint disease, metaphyseal irregularities and striations present in early childhood, and leptodactylic appearance (slender short tubular bones) of the hand., (Copyright 2002 Wiley-Liss, Inc.)

We report two brothers with microcephaly, cerebellar atrophy, and focal segmental glomerulosclerosis. The elderbrother showed nephrotic syndrome from 2 years of age and died of renal failure at 8 years of age. The younger brother showed mild proteinuria from 2 years of age, and his renal function was still preserved at 15 years of age. We propose that our patients may be affected with a mild form of Galloway-Mowat syndrome or another autosomal recessive syndrome with focal segmental glomerulosclerosis and central nervous system abnormalities.

We report a 19-month-old boy with Menkes' syndrome that was complicated by a progressive sliding hiatal hernia. He presented with convulsions, developmental delay, elongation and tortuosity of major cerebral arteries, and diverticulae of the bladder at 4 months of age. Based on the diagnosis of Menkes' syndrome, treatment with intravenous or subcutaneous copper-histidine administration was initiated at 6 months of age. At 13 months of age, he vomited frequently owing to sliding hiatal hernia, which progressed rapidly and required surgical treatment. Connective tissue abnormalities are characteristic complications of Menkes' syndrome. Sliding hiatal hernia is probably one of the connective tissue manifestations and should be carefully evaluated in patients with Menkes' syndrome demonstrating recurrent gastrointestinal and/or respiratory symptoms.

A Japanese boy developed febrile seizures and gait disturbance at 2 years of age and dysarthria a year later. He had generalized tonic-clonic seizures once or twice a year from the age of 4 years. Brain computed tomography (CT) showed symmetric low-density areas in the white matter of the frontal lobes. However, abnormal CT findings fluctuated occasionally, with no apparent change in clinical manifestations. Clinical evaluation at 9 years of age revealed hyper-reflexia, psychomotor retardation, megalencephaly, and slurred nasal speech. Magnetic resonance imaging showed white matter abnormalities, predominantly in the frontal lobes. He was a heterozygote of the Arg239Cys mutation of the glial fibrillary acidic protein gene and was diagnosed with Alexander's disease. Fluctuation of CT findings in white matter may reflect blood-brain barrier dysfunction in Alexander's disease.

We investigated the molecular basis of holoprosencephaly in a sporadic patient and identified a novel missense mutation in the signal sequence of the sonic hedgehog (Shh) gene. Magnetic resonance imaging of the head showed a lobar type of holoprosencephaly and partial agenesis of the anterior corpus callosum. He was treated for craniosynostosis at 7 months of age. All three exons of the Shh gene were amplified by polymerase chain reaction from genomic DNA of the patient and controls. Sequencing analysis of the polymerase chain reaction fragments, screened by single-strand conformation polymorphism analysis, revealed a heterozygous mutation of a T-to-C substitution at nucleotide position 50. This mutation predicted an amino acid replacement of leucine to proline at codon 17 located in the signal peptide of SHH protein. It probably disturbs the translocation of the protein into the endoplasmic reticulum and may lead to holoprosencephaly because of haploinsufficiency of Shh.

In vitro and in vivo antibacterial activities and pharmacokinetics of M14659 were investigated. In vitro activity of M14659 was superior to that of ceftazidime against Staphylococcus aureus. Against Gram-negative bacteria except Pseudomonas aeruginosa, its activity was almost equal to that of ceftazidime. M14659 was more active against P. aeruginosa including multi-drug resistant strains than cefsulodin, cefoperazone or ceftazidime. Affinities of M14659 for penicillin-binding proteins (PBPs) of Escherichia coli and P. aeruginosa were 2 to 14 times higher for PBP-1A and PBP-1B than found for ceftazidime, and almost the same for PBP-3. In vivo activity of M14659 against S. aureus was superior to that of cefamandole, cefotaxime or ceftazidime. Against Gram-negative bacteria including P. aeruginosa, M14659 was 2 to 220 times more active than cefotaxime or ceftazidime. Plasma half-life of M14659 in mice was about 3 times longer than that of ceftazidime. M14659 administered intravenously to mice was mainly excreted in urine without metabolism, and its recovery rate was almost equal to that of ceftazidime.