Vitamin B12 deficiency-induced megaloblastic anemia in a pediatric patient with autism spectrum disorder with a chronically unbalanced diet.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a lack of behavioral flexibility and stereotyped language. Food selectivity is common among children with ASD because of their persnickety nature. A prolonged unbalanced diet results in an increased risk of several diseases, such as iron deficiency anemia, scurvy, rickets, dry eye, and Wernicke encephalopathy. However, no cases of megaloblastic anemia have been reported to date. We report the case of an 11-year-old boy with ASD who developed megaloblastic anemia due to vitamin B12 deficiency. He had a prolonged history of selective eating for more than 10 years. His nutritional status on admission was poor, and he had low weight and short stature. His food selectivity was so strong that intervention to expand diet variety was unsuccessful. A developmental-behavioral pediatrician found that the patient had visual dominance and could take some medications when suffering from a minor illness. Nutritional supplements were selected after consultation with a nutritionist. Although compulsory treatment was necessary during the acute phase, the therapy was continued at home. With multidisciplinary intervention tailored to the patient and his parents' characteristics, his nutritional status improved in a few months.

Interneuron dysfunction in epilepsy: An experimental approach using immature brain insults to induce neuronal migration disorders.

The main elements of the microcircuits in the cerebral cortex are excitatory glutamatergic pyramidal cells and inhibitory γ-aminobutyric acid (GABA) interneurons. Hypofunction/degeneration of GABAergic interneurons has been hypothesized to be a key to the neural circuit dysfunction that underlies epileptogenesis and the development of recurrent spontaneous seizures. Using two experimental animal models of neuronal migration disorders, this review reports that the insults to the immature developing brain causes interneurons to fail to undergo normal processes such as production, migration, and organization. These results represent critical evidence that supports a link between interneuron dysfunction and epilepsy.

Dietary supplementation with partially hydrolyzed guar gum helps improve constipation and gut dysbiosis symptoms and behavioral irritability in children with autism spectrum disorder.

Prebiotic dietary water-soluble fiber obtained from partially hydrolyzed guar gum was added to diets of children with autism spectrum disorders who presented constipation symptoms. Supplementation with partially hydrolyzed guar gum altered gut microbiota and significantly increased the frequency of defecation per week and altered the gut microbiota. In addition, supplementation with partially hydrolyzed guar gum significantly (p<0.05) decreased and tended to decrease (p = 0.07) the concentrations of serum interleukin-1ß and tumor necrosis factor-α, respectively. More importantly, supplementation with partially hydrolyzed guar gum significantly ameliorated behavioral irritability as per the Aberrant Behavior Checklist, Japanese Version. The present study demonstrated that supplementation with partially hydrolyzed guar gum to diets of constipated autism spectrum disorders children helped improve constipation and gut dysbiosis symptoms, which in turn helped attenuate the level of serum inflammation cytokines and behavioral irritability.

X-linked Charcot-Marie-Tooth disease type 5 with recurrent weakness after febrile illness.

X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is an X-linked disorder characterized by early-onset sensorineural hearing impairment, peripheral neuropathy, and progressive optic atrophy. It is caused by a loss-of-function mutation in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes isoform I of phosphoribosyl pyrophosphate synthetase (PRS-I). A decreased activity leads to nonsyndromic sensorineural deafness (DFN2), CMTX5, and Arts syndrome depending upon residual PRS-I activity. Clinical and neurophysiological features of pediatric CMTX5 are poorly defined. We report two male siblings with peripheral neuropathy and prelingual sensorineural hearing loss who carried a novel c.319A>G (p.Ile107Val) PRPS1 missense mutation. They exhibited recurrent episodes of transient proximal muscle weakness, showing Gowers' sign and waddling gait after suffering from febrile illness. This transient weakness has not been previously reported in CMTX5. A patient with Arts syndrome was reported to have transient proximal weakness after febrile illness. The transient weakness presenting in both CMTX5 and Arts syndrome suggests an overlap of signs and a continuous spectrum of PRS-I hypoactivity disease. Children presenting with transient neurological signs should be evaluated for peripheral neuropathy and consider genetic analysis for PRPS1.

A preliminary study of gut dysbiosis in children with food allergy.

Gut microbiota of food allergic children was analyzed by high throughput 16S rRNA gene sequencing. Signs of gut dysbiosis, which is likely associated with gut inflammation, was observed in children with food allergies. For example, decreased abundance of genus Akkermansia but increased abundance of Veillonella was found in children with food allergy in comparison with healthy control children.

A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders.

Fecal and blood samples of infants with autism spectrum disorders (ASD) and healthy infants were analyzed to investigate the association of altered gut microbiota and ASD development. 16S rRNA gene-based sequencing found that, unlike those of healthy infants, feces of ASD infants had significantly higher and lower abundance of genera Faecalibacterium and Blautia, respectively. Moreover, DNA microarray analysis of peripheral blood mononuclear cells (PBMC) detected more highly than low expressed genes in ASD infants than in healthy infants. Gene Ontology analysis revealed that differentially expressed genes between ASD and healthy infants were involved in interferon (IFN)-γ and type-I IFN signaling pathways. Finally, strong positive correlations between expression of IFN signaling-associated genes in PBMC and fecal abundance of Faecalibacterium were found. Our results strongly suggested that altered gut microbiota in infants resulted from ASD development and was associated with systemic immunity dysregulation, especially chronic inflammation.

Successful every-other-day liothyronine therapy for severe resistance to thyroid hormone beta with a novel THRB mutation; case report.

BACKGROUND: Resistance to thyroid hormone beta (RTHß) is a rare and usually dominantly inherited syndrome caused by mutations of the thyroid hormone receptor ß gene (THRB). In severe cases, it is rarely challenging to control manifestations using daily therapeutic replacement of thyroid hormone. CASE PRESENTATION: The present case study concerns an 8-year-old Japanese girl with a severe phenotype of RTH (TSH, fT3, and fT4 were 34.0 mU/L, >25.0 pg/mL and, >8.0 ng/dL, respectively), caused by a novel heterozygous frameshift mutation in exon 10 of the thyroid hormone receptor beta gene (THRB), c.1347-1357 del actcttccccc : p.E449DfsX11. RTH was detected at the neonatal screening program. At 4 years of age, the patient continued to suffer from mental retardation, hyperactivity, insomnia, and reduced resting energy expenditure (REE), despite daily thyroxine (L-T4) therapy. Every-other-day high-dose liothyronine (L-T3) therapy improved her symptoms and increased her REE, without thyrotoxicosis. CONCLUSION: In a case of severe RTH, every-other-day L-T3 administration enhanced REE and psychomotor development, without promoting symptoms of thyrotoxicosis. Every-other-day L-T3 administration may be an effective strategy for the treatment of severe RTH.

Seizure susceptibility due to antihistamines in febrile seizures.

The aim of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures. The study population comprised 14 patients with simple febrile seizures and 35 patients with complex febrile seizures. Detailed clinical manifestations were compared between patients with and without administration of antihistamine. The time from fever detection to the seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than that in nonantihistamine group. Interleukin-1beta is thought to be associated with causing febrile seizures via its dual role as a pyrogen and convulsant substance. Moreover, interleukin-1beta may activate the turnover of hypothalamic neural histamine. These considerations, along with the present results, suggest that the depletion of hypothalamic neuronal histamine induced by antihistamines may increase neuronal excitability, thereby increasing seizure susceptibility in patients with febrile seizures.

Experimental neuronal migration disorders following the administration of ibotenate in hamsters: the role of the subventricular zone in the development of cortical dysplasia.

To examine the role of subventricular zone in cortical dysplasia, an experimental model was established using a neuronal tracing study. Ibotenate is a glutamate receptor agonist, and its intracerebral injection produces excitotoxic lesions mimicking microgyria and heterotopia. A total of 72 newborn hamsters were subjected. Biotinylated dextran amine was injected into the ganglionic eminence for the neuronal tracer. The cortical lesions and apoptotic cells were analyzed. In the microgyric cortex, terminal deoxynucleotidyl transferase-mediated 2' -deoxyuridine 5'-triphosphate-biotin end labeling-positive cells were increased and accumulated in the cortical folding. Biotinylated dextran amine-positive cells and fibers were derived from the dorsolateral subventricular zone and directed toward the cortical folding. In the heterotopic cortex, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate- biotin end labeling-positive cells were distributed around the heterotopia, but number of cells was not remarkable. Our findings suggest that the subventricular zone plays an important role in the formation of cortical dysplasia, especially in the microgyria, after excitatory neuronal injury.

Delayed myelination at the onset of cryptogenic West syndrome.

To evaluate the prognostic value of delayed myelination at the onset of cryptogenic West syndrome, the relationship between the seizure or developmental outcome and myelination was examined. Cranial magnetic resonance imaging studies were performed in nine cryptogenic cases. Infantile spasms were controlled in all patients, but three cases showed a mild developmental delay at 2 years after onset. Delayed myelination was observed in three cases (33.3%) on T(1)-weighted images and in two cases (22.2%) on T(2)-weighted images. In the present study, neither the seizure outcome nor developmental status was positively correlated with the existence of delayed myelination at the onset of cryptogenic West syndrome.

Enhanced capacity of epilepsy in brain malformation produced during early development.

This study investigates the clinical features of epilepsy in 20 patients with brain malformation. Epileptic seizures were recognized in 15 patients, 12 of whom had their first seizure by 1 year of age. Partial seizure was the initial seizure type in 10 patients. Epileptic seizures were controlled in only four patients. Patients with holoprosencephaly and lissencephaly had seizure onset by 3 months of age, resulting in the most severe neurologic outcome. Only two patients with porencephaly had epileptic seizures, and in one of those patients the seizures were well controlled. A wide variety of clinical features of epilepsy in patients with brain malformation was found. More immature anomalous brain lesions may be associated with an enhanced capacity of epilepsy and resultant refractory seizures.

Effect of additional auditory and visual stimuli on continuous performance test (noise-generated CPT) in AD/HD children -- usefulness of noise-generated CPT.

The continuous performance test (CPT) is designed to measure sustained attention quantitatively. Several CPTs are used clinically. We have made changes to the conventional type of visual CPT, by displaying auditory and visual noise along with target or non-target stimuli. By influencing the recognition of the subjects in this way, the changes were intended to increase the sensitivity of detection of inattention and impulsiveness, to make CPT more useful for diagnosis, and to examine the effect of noise on AD/HD children during CPT performance. Its usefulness for AD/HD diagnosis and the reaction of AD/HD children to noise were examined using newly developed computer software. Using this CPT analysis, a significant difference was observed in all measurements, except mean reaction time, between the control and AD/HD groups, showing that it was useful as a supplementary diagnostic method for AD/HD, and was more useful in the younger age group than in the older age group, as the same for conventional CPTs. As compared to no-noise sessions, commission and omission errors both increased significantly in auditory and visual noise sessions. Thus, analyzing the changes in measurements during noise sessions will improve the diagnosis of inattention and combined AD/HD subtypes. Furthermore, it was suggested that analysis of the effects of noise on AD/HD children will benefit their handling in an educational environment. Since omission errors were decreased in AD/HD children by noise during the CPT performance as compared to the control group, noise may induce attention in AD/HD children. The present study presents new findings on the responses to noise of AD/HD children during the CPT.

Experimental cortical dysplasia following ibotenate administration in hamsters: pathogenesis of microgyria and associated gray matter heterotopia.

The study presented here investigated the pathogenetic relationship among different types of neuronal migration disorders occurring simultaneously in the brain using an experimental model induced by ibotenate in hamsters. In the cerebral cortex, abnormal neuronal arrangement was induced 1 day after ibotenate injection. This brain lesion resulted in microgyria in the rostral portion, focal subcortical heterotopia in the mid-portion, and focal subependymal heterotopia in the caudal portion in the same specimen. Vimentin-immunoreactive radial glial fibers were lacking in the area of disorganized neuronal arrangement, but were detected around the microgyria and the intermediate zone surrounding focal subcortical heterotopia. The focal subependymal heterotopia did not include radial glial elements. Glial fibrillary acidic protein (GFAP)-positive glial reaction was weak in these cortical lesions. We suggest that the occurrence of each type of migration disorder depends on the depth of the cortical lesion, that is, the production of microgyria, focal subcortical heterotopia and focal subependymal heterotopia are closely related to the lesions including the cortical plate, subplate and ventricular zone, respectively.

Peters' anomaly with bilateral perisylvian polymicrogyria and abdominal calcification.

We report a neonatal case of Peters' anomaly with bilateral perisylvian polymicrogyria and abdominal calcification. The male infant was born after a normal labor. Bilateral central corneal opacities with iridocorneal strands indicated Peters' anomaly. The X-ray and abdominal computed tomography demonstrated multiple calcifications beneath the diaphragma around the liver and the spleen. TORCH serology was negative. Intracranial calcification was not detected. Brain magnetic resonance imaging demonstrated bilateral perisylvian polymicrogyria. Abdominal calcification was suspected to be related to vascular disruption. Bilateral perisylvian polymicrogyria has been thought to result from ischemic events such as intrauterine hypotension or vascular occlusions. Based on these considerations, we conclude that a vascular disruption sequence may an important pathogenetic mechanism of Peters' anomaly.

Radial and tangential neuronal migration disorder in ibotenate-induced cortical lesions in hamsters: immunohistochemical study of reelin, vimentin, and calretinin.

To investigate the mechanisms of radial and tangential neuronal migration disorders, immunohistochemical expressions of reelin, vimentin, and calretinin were examined in brain lesions induced by ibotenate (an agonist of the N-methyl-D-aspartate [NMDA] complex receptor) in hamsters. Thirty-four newborn hamsters were subjected to intracerebral injections of ibotenate, and 12 animals served as the control. These hamsters were examined at 1, 2, 3, 5, and 7 days after injections. The cortical lesions observed after ibotenate injections had a strong resemblance to the following neuronal migration disorders: (1) microgyria, (2) focal subcortical heterotopia, and (3) leptomeningeal glioneuronal heterotopia. In microgyria, the radial glial fibers were sparsely distributed, but in leptomeningeal glioneuronal heterotopia, vimentin-positive fibers extended into this abnormal neural tissue. Calretinin-immunoreactive neurons and fibers were present along the lesion forming the microgyria and abnormal neuronal arrangement. Focal subcortical heterotopia also included a small number of calretinin-expressing neurons originating from the subplate neuronal population. These results imply that the neuronal migration disorders produced by ibotenate show not only the migrational arrest of neurons but also interference from the termination of the migration process. We also suggest that the heterotopic neurons constituting the focal subcortical heterotopia originate in the lateral or medial ganglionic eminence of the ventral telencephalon, probably caused by the abnormal tangential neuronal migration.

High molecular weight microtubule-associated protein 2 over-expression in neuronal migration disorders caused by N-methyl-D-aspartate receptor activation in hamsters.

To evaluate the neuronal cytoarchitectural changes in neuronal migration disorders, the immunohistochemical expression of microtubule-associated proteins (MAPs) was analyzed using the experimental model induced by ibotenate in newborn hamsters. The cortical lesions observed after intracerebral ibotenate injections strongly resembled the following neuronal migration disorders: (1) microgyria; (2) focal subcortical heterotopia; (3) focal subependymal heterotopia; and (4) leptomeningeal glioneuronal heterotopia. Microgyria and leptomeningeal glioneuronal heterotopia had MAP2 (HM-2: high and low-molecular-weight forms of MAP2) immunoreactive dendritic processes or neuronal elements. The high molecular weight isoform of MAP2 (AP-20), which is more characteristic of mature neurons, showed enhanced expression in neurons of focal subcortical or subependymal heterotopia, although MAP1B (AA6: early form of MAP) immunoreactive elements were not detected in these heterotopic areas. We conclude that high molecular weight isoform of MAP2 is closely associated with cytoarchitectural repair and remodeling of neuronal processes, resulting in neuronal heterotopia after NMDA receptor activation.