川田 雅子

ムコ多糖症II型はライソゾーム酵素であるイズロン酸-2-スルファターゼの欠損によって発症するX染色体潜性遺伝形式の先天性代謝異常症である。グリコサミノグリカンが全身臓器に蓄積し、呼吸機能低下、肝脾腫、心弁膜症、関節拘縮、骨格異常などを呈する。2007年10月に酵素補充療法が国内で承認された。本研究では酵素補充療法を10年以上継続しているムコ多糖症II型3症例(治療開始時、成人2例、小児1例)の治療経過を後方視的に検討した。治療開始後、呼吸機能は軽度改善し、骨格異常を来した成人例においても呼吸機能及び運動機能の改善に有用だった。肝腫大は治療開始後1年以内に正常化し、維持された。治療に伴う重大な副作用はなく、長期治療の安全性が示された。(著者抄録)

Significance: It has been reported that children with attention-deficit hyperactivity disorder (ADHD) have impairment in the recognition of angry but not of happy facial expressions, and they show atypical cortical activation patterns in response to facial expressions. However, little is known about neural mechanisms underlying the impaired recognition of facial expressions in school-aged children with ADHD and the effects of acute medication on their processing of facial expressions. Aim: We aimed to investigate the possibility that acute administration of methylphenidate (MPH) affects processing of facial expressions in ADHD children. Approach: We measured the hemodynamic changes in the bilateral temporo-occipital areas of ADHD children observing the happy and angry facial expressions before and 1.5 h after MPH or placebo administration in a randomized, double-blind, placebo-controlled, crossover design study. Results: We found that, regardless of medication, happy expressions induced increased oxyhemoglobin (oxy-Hb) responses in the right inferior occipital region but not in the superior temporal region. For angry expressions, oxy-Hb responses increased after MPH administration, but not after placebo administration, in the left inferior occipital area, whereas there was no significant activation before MPH administration. Conclusions: Our results suggest that (1) ADHD children consistently recruit the right inferior occipital regions to process happy expressions and (2) MPH administration to ADHD children enhances cortical activation in the left inferior occipital regions when they process angry expressions.

Connectivity between brain regions has been redefined beyond a stationary state. Even when a person is in a resting state, brain connectivity dynamically shifts. However, shifted brain connectivity under externally evoked stimulus is still little understood. The current study, therefore, focuses on task-based dynamic functional-connectivity (FC) analysis of brain signals measured by functional near-infrared spectroscopy (fNIRS). We hypothesize that a stimulus may influence not only brain connectivity but also the occurrence probabilities of task-related and task-irrelevant connectivity states. fNIRS measurement (of the prefrontal-to-inferior parietal lobes) was conducted on 21 typically developing (TD) and 21 age-matched attention-deficit/hyperactivity disorder (ADHD) children performing an inhibitory control task, namely, the Go/No-Go (GNG) task. It has been reported that ADHD children lack inhibitory control; differences between TD and ADHD children in terms of task-based dynamic FC were also evaluated. Four connectivity states were found to occur during the temporal task course. Two dominant connectivity states (states 1 and 2) are characterized by strong connectivities within the frontoparietal network (occurrence probabilities of 40%-56% and 26%-29%), and presumptively interpreted as task-related states. A connectivity state (state 3) shows strong connectivities in the bilateral medial frontal-to-parietal cortices (occurrence probability of 7-15%). The strong connectivities were found at the overlapped regions related the default mode network (DMN). Another connectivity state (state 4) visualizes strong connectivities in all measured regions (occurrence probability of 10%-16%). A global effect coming from cerebral vascular may highly influence this connectivity state. During the GNG stimulus interval, the ADHD children tended to show decreased occurrence probability of the dominant connectivity state and increased occurrence probability of other connectivity states (states 3 and 4). Bringing a new perspective to explain neuropathophysiology, these findings suggest atypical dynamic network recruitment to accommodate task demands in ADHD children.

Connectivity impairment has frequently been associated with the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Although the connectivity of the resting state has mainly been studied, we expect the transition between baseline and task may also be impaired in ADHD children. Twenty-three typically developing (i.e., control) and 36 disordered (ADHD and autism-comorbid ADHD) children were subjected to connectivity analysis. Specifically, they performed an attention task, visual oddball, while their brains were measured by functional near-infrared spectroscopy. The results of the measurements revealed three key findings. First, the control group maintained attentive connectivity, even in the baseline interval. Meanwhile, the disordered group showed enhanced bilateral intra- and interhemispheric connectivities while performing the task. However, right intrahemispheric connectivity was found to be weaker than those for the control group. Second, connectivity and activation characteristics might not be positively correlated with each other. In our previous results, disordered children lacked activation in the right middle frontal gyrus. However, within region connectivity of the right middle frontal gyrus was relatively strong in the baseline interval and significantly increased in the task interval. Third, the connectivity-based biomarker performed better than the activation-based biomarker in terms of screening. Activation and connectivity features were independently optimized and cross validated to obtain the best performing threshold-based classifier. The effectiveness of connectivity features, which brought significantly higher training accuracy than the optimum activation features, was confirmed (88% versus 76%). The optimum screening features were characterized by two trends: (1) strong connectivities of right frontal, left frontal, and left parietal lobes and (2) weak connectivities of left frontal, left parietal, and right parietal lobes in the control group. We conclude that the attentive task-based connectivity effectively shows the difference between control and disordered children and may represent pathological characteristics to be feasibly implemented as a supporting tool for clinical screening.

Attention deficit/hyperactivity disorder (ADHD) has been frequently reported as co-occurring with autism spectrum disorder (ASD). However, ASD-comorbid ADHD is difficult to diagnose since clinically significant symptoms are similar in both disorders. Therefore, we propose a classification method of differentially recognizing the ASD-comorbid condition in ADHD children. The classification method was investigated based on functional brain imaging measured by near-infrared spectroscopy (NIRS) during a go/no-go task. Optimization and cross-validation of the classification method was carried out in medicated-naïve and methylphenidate (MPH) administered ADHD and ASD-comorbid ADHD children (randomized, double-blind, placebo-controlled, and crossover design) to select robust parameters and cut-off thresholds. The parameters could be defined as either single or averaged multi-channel task-evoked activations under an administration condition (i.e., pre-medication, post-MPH, and post-placebo). The ADHD children were distinguished by significantly high MPH-evoked activation in the right hemisphere near the midline vertex. The ASD-comorbid ADHD children tended to have low activation responses in all regions. High specificity (86 ± 4.1%; mean ± SD), sensitivity (93 ± 7.3%), and accuracy (82 ± 1.6%) were obtained using the activation of oxygenated-hemoglobin concentration change in right middle frontal, angular, and precentral gyri under MPH medication. Therefore, the significantly differing MPH-evoked responses are potentially effective features and as supporting differential diagnostic tools.

Functional near-infrared spectroscopy (fNIRS) signals are prone to problems caused by motion artifacts and physiological noises. These noises unfortunately reduce the fNIRS sensitivity in detecting the evoked brain activation while increasing the risk of statistical error. In fNIRS measurements, the repetitive resting-stimulus cycle (so-called block-design analysis) is commonly adapted to increase the sample number. However, these blocks are often affected by noises. Therefore, we developed an adaptive algorithm to identify, reject, and select the noise-free and/or least noisy blocks in accordance with the preset acceptance rate. The main features of this algorithm are personalized evaluation for individual data and controlled rejection to maintain the sample number. Three typical noise criteria (sudden amplitude change, shifted baseline, and minimum intertrial correlation) were adopted. Depending on the quality of the dataset used, the algorithm may require some or all noise criteria with distinct parameters. Aiming for real applications in a pediatric study, we applied this algorithm to fNIRS datasets obtained from attention deficit/hyperactivity disorder (ADHD) children as had been studied previously. These datasets were divided for training and validation purposes. A validation process was done to examine the feasibility of the algorithm regardless of the types of datasets, including those obtained under sample population (ADHD or typical developing children), intervention (nonmedication and drug/placebo administration), and measurement (task paradigm) conditions. The algorithm was optimized so as to enhance reproducibility of previous inferences. The optimum algorithm design involved all criteria ordered sequentially (0.047 mM mm of amplitude change, 0.029    mM    mm / s of baseline slope, and 0.6 × interquartile range of outlier threshold for each criterion, respectively) and presented complete reproducibility in both training and validation datasets. Compared to the visual-based rejection as done in the previous studies, the algorithm achieved 71.8% rejection accuracy. This suggests that the algorithm has robustness and potential to substitute for visual artifact-detection.

Perampanel (PER) is a novel class of anti-epileptic drug and a noncompetitive inhibitor of the AMPA receptor. Some reports have described the efficacy and side-effects of PER in Japan. We prescribed PER to 33 refractory epilepsy patients, including some with intellectual disabilities and/or an age under 12 years. A "Good response" was defined as more than 50% seizure reduction, and we investigated the responder rates for focal seizure (Fs) and generalized tonic clonic seizure (GTCS). The effective rate for Fs and GTCS were both 50%, and the overall seizure rate was 52%. The efficacy in patients &lt 12 years of age was similar to those &gt 12 years of age. Although there were no significant differences in the responder rates among the concomitant antiepileptic drugs (AEDs), two patients who received KBr combination treatment showed a good response. The responder rates with CYP3A4-inducing AEDs such as CBZ and PHT tended to be low (30% and 18%, respectively). Adverse events occurred in 55% of patients, including emotional and behavioral abnormalities in 30%, somnolence in 18%, and dizziness in 15%. We should therefore closely monitor young patients and those with intellectual disabilities, as emotional and behavioral abnormalities tend to occur with the administration of PER.

Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0 MB to 43.8 MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia,,severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.