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This case–control study aimed to assess oxidative stress alterations in autism spectrum disorder (ASD). We used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a non-behavioural diagnostic tool for children with ASD. Serum samples of 39 children with ASD and 58 age-matched children with typical development were analysed. The ASD group showed decreased hydroxyl radical (·OH) and singlet oxygen scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against superoxide (O2·−) and alkoxyl radical (RO·) were increased in the ASD group suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of ·OH, O2·−, and RO· scavenging activities predicted ASD with high odds ratio (50.4), positive likelihood (12.6), and percentage of correct classification (87.0%). Our results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.

Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties in social communication and interaction, as well as repetitive and characteristic patterns of behaviour. Although the pathogenesis of autism spectrum disorder is unknown, being overweight or obesity during infancy and low weight at birth are known as risks, suggesting a metabolic aspect. In this study, we investigated adipose tissue development as a pathophysiological factor of autism spectrum disorder by examining the serum levels of adipokines and other metabolic markers in autism spectrum disorder children (n = 123) and typically developing children (n = 92) at 4–12 years of age. Among multiple measures exhibiting age-dependent trajectories, the leptin levels displayed different trajectory patterns between autism spectrum disorder and typically developing children, supporting an adipose tissue-dependent mechanism of autism spectrum disorder. Of particular interest, the levels of fatty acid binding protein 4 (FABP4) were significantly lower in autism spectrum disorder children than in typically developing subjects, at preschool age (4–6 years old: n = 21 for autism spectrum disorder and n = 26 for typically developing). The receiver operating characteristic curve analysis discriminated autism spectrum disorder children from typically developing children with a sensitivity of 94.4% and a specificity of 75.0%. We re-sequenced the exons of the FABP4 gene in a Japanese cohort comprising 659 autism spectrum disorder and 1000 control samples, and identified two rare functional variants in the autism spectrum disorder group. The Trp98Stop, one of the two variants, was transmitted to the proband from his mother with a history of depression. The disruption of the Fabp4 gene in mice evoked autism spectrum disorder-like behavioural phenotypes and increased spine density on apical dendrites of pyramidal neurons, which has been observed in the postmortem brains of autism spectrum disorder subjects. The Fabp4 knockout mice had an altered fatty acid composition in the cortex. Collectively, these results suggest that an ‘adipo-brain axis’ may underlie the pathophysiology of autism spectrum disorder, with FABP4 as a potential molecule for use as a biomarker., We discovered lower circulating fatty acid binding protein 4 (FABP4), mainly secreted by the adipose tissue, in children with autism spectrum disorder, and identified functional FABP4 variants in the autism spectrum disorder group. Furthermore, Fabp4 knock-out mice displayed autism spectrum disorder-relevant phenotypes. We propose that the ‘adipo-brain axis’ may underlie the pathophysiology of autism spectrum disorder., Graphical Abstract Graphical Abstract

Abnormalities of lipid metabolism contribute to ASD pathogenesis has been argued, but the mechanisms are not fully understood. We characterized the lipids metabolism in ASD children by lipidomics, and identified the dramatic alterations of 71 metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function. Identified fatty acids (FAs) indicated the correlations with clinical social interaction score of ASD diagnosis as well as lipoproteins-triglyceride concentrations in ASD. We also found the specific reduction of very-low-density lipoprotein (VLDL) in ASD, which showing correlations with a decrease of APOB concentrations in ASD. We further found a significant increase in APOJ known as a sensor for oxidative stress, demonstrating enhancing oxidative stress in ASD is due to VLDL-specific dyslipidemia. These results demonstrate the increases in FAs are due to VLDL-specific degradation, providing novel insights to uncover the mechanisms such as oxidative stress generations via mitochondrial dysfunction underlying ASD pathology. Funding Statement: This work was supported by the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.M.; the Grant-in-Aid for Scientific Research on Innovative Areas (#21200014) from MEXT to H.M.; SENSHIN Medical Research Foundation to H.M. and N.U.; Hamamatsu Foundation for Science and Technology Promotion to H.M.; the Grant-in-Aid for Early-Career Scientists (18K14814) from the Japan Society for the Promotion of Science (JSPS) to N.U.; Takeda Science Foundation to H.M. and N.U.; The Osaka Medical Research Foundation for Intractable Diseases to N.U.; Research Grant for Public Health Science to N.U.; Eli Lilly Japan Research Grant to N.U.; the Grant for Life Cycle Medicine from Faculty of Medical Sciences, University of Fukui to N.U. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures were approved by the Ethics Committee of the University of Fukui and the Hamamatsu University School of Medicine, and were conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare of Japan. All participants were given a complete description of the study and provided written informed consent from their parent and/or legal guardian before enrolled.

Background Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. Methods An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. Findings Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. Interpretation Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. Funding This study was supported mainly by MEXT, Japan.

Objective Several studies have suggested that objective deficits in the processing of abstract information in conjunction with an enhanced ability to process concrete information is a definitive characteristic of autism spectrum disorder (ASD). However, this cognitive imbalance is not necessarily clear in high-functioning autistic individuals who do not display absolute differences relative to typically developing (TD) populations. Thus, the purpose of this study was to identify this cognitive tendency in high-functioning autistic individuals using intra-individual cognitive comparisons. Methods The reaction times (RTs) of TD children, children with ASD, and children with attention deficit hyperactivity disorder (AD/HD) (n = 17 in each group, mean age = 11.9 years, age range = 9.8–15.8 years) were compared using the Which/How-to-Apply Tools (W/HAT) test, which consists of tasks requiring the adaptive use of novel tools and familiar tools in atypical and typical situations. Differences in RTs between the atypical and typical trials ([A–T]) were used to assess intra-individual cognitive imbalances. Results As predicted, the [A–T] scores of the ASD group were significantly higher than those of the TD group even though the RTs in the atypical and typical trials did not differ. Additionally, the [A–T] values were significantly higher in the ASD group than in the AD/HD group, which indicates that the cognitive imbalance was specific to ASD individuals. No significant interaction was detected between the trial and subject group. Conclusions The findings of this study demonstrate that a cognitive imbalance in ASD individuals may enhance the current understanding of the pathophysiology of this disorder, which is found in a range of individuals, including those with obvious cortical dysfunction to those with only intra-individual imbalances.

We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy.

Brainstem reticular reflex myoclonus (BRRM) is characterized by sudden, generalized, shock-like movements that can be elicited by sensory stimulation. We present a boy, born after 35 weeks gestation, who was diagnosed with neonatal-onset BRRM. Within 1 hr of birth, the patient showed spasticity and generalized clonic movements of all limbs elicited with tactile stimulation anywhere on the body. Surface electromyography showed co-contraction of agonistic and antagonistic muscles, revealing that his generalized clonic movements were tremulous myoclonus in nature. Brain magnetic resonance imaging (MRI) at 21 hrs after birth disclosed high-intensity lesions in the Rolandic area, thalamus, basal ganglia, and brainstem, including the dorsal pons and medulla, the center of BRRM, in T1-weighted images. Follow-up MRI at 1 month revealed dramatic improvement in the pontine lesion. The patient showed gradual remission of the characteristic movements, which disappeared at 1 year of age, but the patient died unexpectedly at 1 year and 3 months. In conclusion, neonatal BRRM arises as a result of severe brainstem injury, and the associated lesions may only be seen temporarily on MRI taken soon after birth.

生下時体重1, 000g未満の超低出生体重児9名と正期産児7名の5歳時の言語能力を, 言語発達検査 (ITPA言語学習能力診断検査) と発話分析の2側面から明らかにするとともに, 発話の文法的複雑性が言語発達検査の成績とどのように関連するかについて検討を行った.発話分析については, 1) 遊具設定自由遊び場面と, 2) 連続絵説明課題において発話サンプルを収集し, MLU, および, 一発話あたりの平均自立語数を求めた.重文・複文構造が多く使われた連続絵説明課題における発話に対しては, T-unit (Hunt, 1965) を分析単位とした.分析の結果, 言語検査の成績, 発話の文法的複雑性ともに低出生体重児群では低い傾向がみられることが明らかになった.さらに, MLUなどの発話の文法的複雑性指標は言語検査に基づく言語発達段階と相関することが示された.これらのことから, 今回行ったような発話分析は言語能力の評価において有用であると考えられる.

To assess the efficacy of early intervention (EI) for very-low-birth-weight (VLBW) infants, we evaluated 62 2 year old children who were enrolled in an EI program and 48 control subjects aged 2 years. We determined the subjects' developmental quotients (DQ) and obtained information about the parents' evaluation of the children from a questionnaire sent to the parents. There was no significant difference in the DQ between the EI group and the control group. However, based on the responses to the questionnaire, subjects in the EI group showed slight, but statistically marginally significant, improvements in behavioral problems, especially a decrease in hyperkinesia, in adjusting to a circadian sleep cycle, and an improvement in language development, as compared with the control group (P

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare leukoencephalopathy presenting in the infantile period and characterized by diffuse cerebral hypomyelination, and atrophy of the basal ganglia and cerebellum. As patients with H-ABC lack remarkable laboratory findings, the diagnosis is based on brain magnetic resonance imaging findings alone. Only eight cases have been reported in the literature, and thus the natural course and treatment of this disease are not fully understood. We report a 35-month-old boy with H-ABC who had hemidystonia, hypomyelination, and cerebellar ataxia. We diagnosed H-ABC after considering a thorough differential diagnosis, excluding other diseases involving hemidystonia, hypomyelination, and cerebellar ataxia. Furthermore, technetium-99m ethyl cysteinate dimmer-single-photon emission computerized tomography (Tc-ECD-SPECT) and positron emission tomography with fluorodeoxyglucose (18)F (FDG-PET) revealed decreased blood flow and glucose metabolism in the bilateral lenticular nucleus, thalamus, and cerebellum. A peroral levodopa preparation containing carbidopa (levodopa-carbidopa) was effective at ameliorating and stopping the progression of the patient's dystonia (final effective doses: levodopa, 200 mg/day and carbidopa, 20 mg/day). This is the first case report of a Japanese patient with H-ABC and treatment for this disease. Levodopa-carbidopa may be an effective treatment for H-ABC.

Satoyoshi syndrome is a very rare disease of unknown etiology, characterized by intermittent painful muscle spasms, alopecia, multiple epiphyseal changes, diarrhea and endocrine disorders. We administered intravenous gammaglobulin to a 7-year-old girl with Satoyoshi syndrome. Frequency of muscle spasms and the titers of antinuclear antibody and anti-DNA antibody decreased. This is the first report of gammaglobulin therapy of Satoyoshi syndrome. We suggest that this illness could be related to an autoimmune mechanism.

We reported the MRI findings and clinical course of two patients with ophthalmoplegic migraine. Both patients presented with unilateral oculomotor nerve palsy. Contrast enhanced MR imaging revealed unilateral enhancement and thickening of the oculomotor nerve in one patient. Prednisolone was effective in both patients, but only could transiently. On the other hand, cyproheptadine hydrochloride could completely prevent recurrent attacks of ophthalmoplegic migraine. Thus, MR imaging with of contrast enhancement is useful in the diagnosis of ophthalmoplegic migraine. Cyproheptadine hydrochloride is better than prednisolone to prevention recurrent attacks and to avoid adverse effects.

We described a child who developed paroxysmal abnormal eye movement. At the age of 12 months, she had a high fever and a febrile seizure. On the next day she showed tonic upward deviation of the eyes for 1 to 2 seconds, and downward saccades on attempted downward gaze. The upward deviation was repeated for a period of 2 to 3 hours, and disappeared during sleep. The administration of L-dopa was not effective. The symptoms subsided gradually over 10 months without other neurological impairment. She walked alone at 1 year and 6 months. At the beginning of her walking she showed truncal ataxia, but it gradually disappeared and her development was normal at the age of 2 years and 6 months. These abnormal eye movements and another symptoms were similar to paroxysmal tonic upgaze of childhood (PTU) that has been first described by Ouvrier and Billson (1988) as intermittent upward deviations of eyes. In Japan there was only one report of this syndrome with periventricular leukomalacia and hypomyelination.

West syndrome, although classified as a generalized epilepsy, is associated with localized cerebral lesions in some cases. However, similar localized cortical abnormalities usually can result in partial epilepsy, instead of West syndrome. We performed this study to determine the additional factors that result in West syndrome instead of partial epilepsy in patients with localized cerebral lesions. We reviewed the pathologic features, topographic localization, and side of unilaterally defined cerebral lesions in relation to the seizure types in 39 epileptic patients, including five patients who presented with West syndrome. The lesions of all five patients with West syndrome involved the temporal or occipital lobes (or both). Among the nine with an occipital lesion, four had West syndrome. In the 19 with a temporal lesion, three had West syndrome. However, in the 16 patients with a frontal lesion, none exhibited epileptic spasms. In four of the five with West syndrome the lesions were on the right side; 23 had lesions on the right, 16 had them on the left. Temporo-occipital lesions and lesions on the right were related to the genesis of West syndrome, which would be in close correlation with normal brain maturation.

The sucking behaviors of 15 low-risk full-term newborns were observed with ultrasonography and a special device directly measuring sucking pressure. In this study, the sequential changes in the movement of a tongue and other intra-oral structures and the sequential changes of the sucking pressure were successfully examined simultaneously. It was indicated that sucking pressure could be generated by sequential changes of an intra-oral volume caused by a peristalsis of the tongue in the sucking behavior.

The development of the human inferior collicular nucleus was studied on serial sections of the brains of 9 fetuses at 12-34 weeks of gestation and an adult of 63 years using an electronic planimeter with a computer. Morphometric analysis of the development of the inferior collicular nucleus showed that its development accelerates after 18 weeks of gestation in terms of the columnar volume and length, size of neurons and circularity ratio. Large-sized neurons 2-3 times the area of small-sized neurons appeared after 18 weeks of gestation. The ratio of large neurons to the total ranged between 3 and 6% in the inferior collicular nucleus. The development of the inferior collicular nucleus was similar to that of the ventral cochlear nucleus and the medial superior olivary nucleus.

ation of developmental delay. The family history was not contributory. The pregnancy was moderately complicated with toxemia. He was born by means of cesarean section at 41 weeks because of cloudy amniotic fluid and fetal arrhythmia without asphyxia. His birth weight was 2650 g. His arrhythmia and feeding difficulty continued for 2 months. His motor progression was slow and his neck was unstable at 5 months, at which time he was noted to have pes valgus and he was thus referred for physiotherapy. At 8 months and at 8 years, he was subjected to CT and MRI, which revealed abnormal density of the white matter in the occipito-parietal region. Many diagnostic methods were tried unsuccessfully. He visited our hospital at the age of 9 years, 5 months. At this age, his development was that of a 5-year-old boy. On examination, he was a well nourished, happy boy with a head circumference of 51.3 cm (1.0 u), external strabismus, pes valgus, hypotonia, normo-active and symmetric DTR exaggeration, and extensor plantar responses. There was no hepato-splenomegaly or cardiovascular abnormality. His facial appearance was peculiar. Ophthalmologic examination was normal. Laboratory studies of blood and urine for amino acids, organic acids, ammonia, lactate, pyruvate and lysosomal enzymes, and immunological and chromosomal analyses were normal. CSF analysis and EEG including the hyperventilation test, EMG, SEP, VEP and ABR were all normal. Cranial CT disclosed characteristic multiple spots at the basal ganglia with indefinite Wilms’ arterial rings. Another demonstrable finding was low periventricular density in the bilateral parieto-occipital regions. MRI demonstrated many small foci of CSF signals in all pulse sequences in the high-convexity gray matter extending into the centrum semiovale. MR angiography revealed a stenotic region in the C3-C4 portion of the bilateral internal carotid arteries and demonstrated moyamoya vascular changes. lz31MP-SPECT revealed a marked reduction in blood flow in the left hemisphere. MR angiography is a beneficial new technique for the diagnosis and evaluation of moyamoya disease, because it is a noninvasive method and does not require contrast materials.

The subjects were 98 children with an average age of 5.8 years. The frequent seizures were categorized into the following three modes: (1) seizures occur more than five times a day; (2) 1-4 seizures occur every day for one week or more; (3) 1-4 seizures a day occur weekly for one month or more. The incidence of each mode was as follows: (1) 15.3%; (2) 16.3%; (3) 17.3%; (1) + (2) 43.9%; etc. We observed frequently the cases of tonic-clonic seizures in mode (1), infantile spasms (IS) in mode (2), simple partial seizures (SPS) in mode (3), and minor seizures, IS, and Lennox-Gastaut syndrome (LGS) in mode (1) + (2). Abnormal CT findings were observed in 37.8%. Of all the patients, 33.7% indicated a developmental quotient (DQ) or intelligence quotient (IQ) above 80, and 31.6% showed a DQ or IQ under 30. Of 96 patients followed for the past one year or more, 32.3%, consisting mainly of the cases with absence seizures and IS, had been seizure-free for at least one year; 60.4% including the cases with LGS, SPS, etc., still had seizures.

Forty-six normal newborn infants were studied at the age of 6 to 7 days. Each infant was at first breast fed and at the next session was given a bottle feeding of the same amount of expressed breast milk on the same day. The neonatal behavior was assessed over two three-hour periods following each feeding, during which continuous polygraphic recordings and observations were made. Our study consisted of four steps: an expressed breast milk bottle feeding (step 1), an equal holding time period (step 2), an equal sucking time period (step 3), and an equal holding and sucking time period using two kinds of bottles (step 4). Infants who were breast fed had a longer period of quiet sleep and slow heart rate in active sleep compared with those who were bottle fed. In step 4, there were no significant differences in the amount of quiet sleep and low heart rate in active sleep between breast and bottle feeding. From our results, each component of breast feeding alone such as the breast milk itself, the holding time, or the time for sucking does not have any specific positive influence on neonatal behavior. Rather, the study suggests that the total mother-infant interaction during breast feeding results in positive influences on neonatal behavior.