A potential role of fatty acid binding protein 4 in the pathophysiology of autism spectrum disorder.

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.

Simultaneous evaluation of antioxidative serum profiles facilitates the diagnostic screening of autism spectrum disorder in under-6-year-old children.

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.

VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction.

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.

Intra-individual cognitive imbalance in ASD between perceptual reasoning and ambiguity-solving related to tool use: Comparison among children exhibiting ASD, AD/HD, and typical development.

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=11.9years, age range=9.8-15.8years) 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.

A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy.

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.

Neonatal-onset brainstem reticular reflex myoclonus following a prenatal brain insult: generalized myoclonic jerk and a brainstem lesion.

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.

Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum.

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.

[Clinical approach to improve quality of life of disabled children: introductory remarks].

This symposium, discussed clinical approaches to improve the quality of life for severely disabled children including the management of feeding and breathing problems, school life and grief care. Pediatric neurologists should be health care professionals for them, consider improving their quality of life at both home and school, help them to decide which information from different professionals is appropriate. In order to improve their quality of life, feeding and breathing problems are often the most important. Furthermore, we have to promote discussion and co-operation with school teachers, especially about so-called medical care.

[MRI findings and effectiveness of cyproheptadine in two patients with ophthalmoplegic migraine].

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.

[Paroxysmal tonic upgaze of childhood].

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.