内田 智子

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology.

OBJECTIVE: Guillain-Barré syndrome (GBS), Fisher syndrome (FS), and Bickerstaff brainstem encephalitis (BBE) are immune-mediated neuropathies presenting with symptoms such as weakness, ophthalmoplegia, ataxia, and consciousness disturbances. Although the epidemiology of GBS and BBE in patients of all ages has been reported, childhood data have not been well-investigated. We aimed to determine the clinical features, therapeutics, and prognoses of childhood GBS, FS, and BBE in Japan. METHODS: We sent questionnaires to 1068 pediatric neurologists in Japan from 2014 to 2016 to determine the number of children less than 15 years old with GBS, FS, or BBE and their age and sex. We subsequently performed a secondary survey to investigate the clinical features, laboratory data, treatment, and prognosis. RESULTS: Five-hundred thirty-eight pediatric neurology specialists (50.4%) responded to the first survey. The total number of children with GBS, FS, and BBE in Japan from 2014 to 2016 were 87, 10, and 6, respectively. GBS was classified as acute inflammatory demyelinating neuropathy (35.6%), acute motor axonal neuropathy (20.7%), or acute motor-sensory axonal neuropathy (10.3%), with a male-to-female ratio of 1.29:1.0 and a wide distribution of onset ages. The disease severities of GBS, FS, and BBE were variable, but all children could walk within one year. CONCLUSION: The prognoses of childhood GBS, FS, and BBE were generally favorable, as long as the patient was promptly treated with either intravenous immunoglobulin or plasma exchange.

Cardio-facio-cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4-year-old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3-year-old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left-hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2-elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co-occurrence of mitochondrial HMG-CoA synthase deficiency and HMG-CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia.

【目的】重症筋無力症(MG)や慢性炎症性脱髄性多発根ニューロパチー(CIDP)をはじめとする免疫性神経筋疾患の治療は長期にわたるため、小児では成長や発達に配慮したきめ細かな日常生活上の管理が必要である。しかし、その具体策についてはエビデンスが不明確であり、担当医は疑問を抱えながら診療している。診療の標準化を図る目的で、多施設の状況について調査し検討した。【方法】2017年2月、小児免疫性神経筋疾患研究会会員(研究時の会員82名67施設)に対し、アンケートを行い解析した。【結果】15施設から回答を得た。各施設で平均5.5(中央値4)名のMG患者と0.3名のCIDP患者を診療中であった。易感染性や消化性潰瘍、骨粗鬆症など副腎皮質ステロイド薬の副作用への対策や、予防接種基準、眼科診察などについて、施設間での相違が明らかとなった。特に、MGにおいて禁忌であるベンゾジアゼピン系薬剤の、けいれんや鎮静の際の使用については様々な対応が見られた。【結論】小児の免疫性神経筋疾患患者における日常生活管理の基準は施設ごとに異なっており、経験する患者数の少なさもその一因であると考えられた。この結果と各種ガイドラインおよび文献を参考に、小児の日常生活指導案をまとめた。これらをもとに多施設での経験を集積し、より有用な基準の策定が望まれる。(著者抄録)

BACKGROUND: Japanese encephalitis is a flavivirus that can cause pandemic encephalitis, and is prevalent in Southeast Asia and Australia. Brain images of patients with Japanese encephalitis are characterized by thalamic lesions, distinct from those seen in viral encephalopathies caused by the herpes simplex virus and West Nile virus. AIM: Herein, we describe for the first time a time-dependent magnetic resonance imaging pattern in Japanese encephalitis in a 10-month-old Japanese boy. CASE: The patient was a previously healthy 10-month-old Japanese boy, who exhibited acute-onset flaccid tetraplegia and loss of tendon reflexes. RESULTS: Brain MRI showed characteristic thalamic changes on diffusion weighted images from spotty to uniform and from the left to the right side, associated with low apparent diffusion coefficient maps. These images suggest that the Japanese encephalitis virus may first affect the unilateral thalamus, possibly expanding to the other side, with characteristic patterns changing from spotty to uniform in a manner consistent with the presentation of cytotoxic edema. CONCLUSION: This report first showed longitudinal magnetic resonance changes in Japanese encephalitis, which may help in accurate diagnosis and in discrimination from other etiologies.

Gorlin syndrome (GS) is a hereditary disorder with tumorigenicity, caused by constitutive hyperactivity of hedgehog signaling. Smoothened (SMO) antagonists have been effectively used in the clinical treatment of hedgehog signaling-related cancer. However, these treatments have led to problematic side effects, including severe adverse reactions and drug resistance from additional somatic mutations. We profiled microRNAs in GS fibroblasts to explore a novel therapeutic target for controlling hyper-activated hedgehog signaling. To identify GS-related microRNAs, we analyzed dermal fibroblasts from five patients with GS and three normal controls. We used microarray comparative genomic hybridization to screen 632 human microRNAs in GS fibroblasts. We identified 16 down- and 19 upregulated microRNAs with over twofold change in expression. We validated the increased expression of four microRNAs, confirming hsa-miR-196a-5p downregulation and hsa-miR-4485 upregulation using real-time PCR. Moreover, hsa-miR-196a-5p is complementary to sites in the 3' UTR of MAP3K1, which exhibits upregulated expression at mRNA and protein levels in GS fibroblasts. In addition, hedgehog signal induction with exogenous components decreased miR-196a-5p expression and increased map3k1 expression in a mouse mesenchymal cell line. Given that MAP3K1 has been reported to activate hedgehog signaling, hsa-miR-196a-5p may contribute to the positive feedback loop in this pathway.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates cortical excitability in a polarity-dependent manner. The diffuse nature of tDCS makes it difficult to investigate the optimal stimulation parameters for more effective and specific cognitive enhancement; to address this deficit, a more focalized stimulation technique, high-definition tDCS (HD-tDCS), has been developed. To date, only a few studies have examined the effects of HD-tDCS on cognitive functions; and none has investigated the effects of HD-tDCS on different sensory modalities of verbal working memory. Therefore, the present study compared the effects of prefrontal HD-tDCS on visual and auditory working memory tasks. Twenty healthy participants completed three sessions of each modality task, and additionally a sustained attention task. Anodal or sham HD-tDCS was administered to the dorsolateral prefrontal cortex (DLPFC) during the second session of the task in a parallel, single-blind design. Anodal stimulation to the DLPFC significantly enhanced the visual verbal working memory accuracy during and 20 min after the stimulation. In contrast, auditory verbal working memory performance was not modulated by anodal stimulation. Anodal stimulation to the DLPFC showed no effect on any other cognitive functions. The present study revealed the differential effects of HD-tDCS on two different modalities (visual vs. auditory) of working memory performance: important preliminary findings for the establishment of a more effective and specific use of tDCS.

【背景】食物アレルギー児の母親は負担を感じやすく日常生活の様々な因子が母親のQuality of life(QOL)に影響を及ぼす。しかし、我が国においては彼らのQOLに影響を与える因子についての検討は少ない。今回、食物アレルギー児の母親のQOLを評価し、影響を与える因子について検討を行った。【方法】県内4施設のアレルギー外来に通院中の食物アレルギー児131名の母親を対象とし、Cohenらの質問票を基に作成した日本語版質問票にてQOL評価と行うと共に患者背景を調査し、関連性について検討した。【結果】除去品目数が多いこと、通信販売を利用していること、家族歴を有することは母親のQOLを低くすることが明らかになった。【結語】食物アレルギー児の母親のよりよいQOLのためには除去を必要最小限にすること、代替食品についての情報提供を行うことが重要であると思われる。(著者抄録)