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For children with neurological disorders, we are often unable to identify any abnormalities during the examination based on the blood test, CT/MRI, EEG, EMG, etc. In such cases, it becomes necessary to check for congenital genetic anomalies, especially when two or more symptoms involving external malformation, organ malformation, and defect in eyesight or hearing ability are found. Under clinical settings, the G-banding stain is the first such test to be conducted. Although the cost is covered by insurance and the test can be used to examine all of the chromosomes, it is only capable of detecting comparatively large deletions and duplications. The FISH method, however, has far higher sensitivity compared to the G-banding in terms of identifying deletions and duplications. Unfortunately, since it utilizes specific DNA probes, it cannot be used without first specifying a particular target disease. Moreover, even if the correct target disease is chosen, this test consistently produces numerical abnormalities. Therefore, we may find it best to use the microarray-based comparative genomic hybridization （array CGH）. This test makes it possible to analyze an entire genome domain, and the sensitivity is much higher than that of G-banding. In recent years, a large number of microdeletions have been found by this method. However, this method is expensive because it is not covered by insurance, and structural anomalies without abnormalities in the copy number are also undetectable. In addition, although analyses using next-generation sequencers are becoming more widespread, this test is still performed in the laboratory. At present, various gene abnormalities are being identified in pediatric neurological disorders through the progress of gene-analysis technology. Therefore, our knowledge of the genetic diseases we analyze is increasing rapidly, and we frequently need to consult with genetic specialists. Unfortunately, since the types of examinations available in clinical settings are still somewhat restricted, we hope that the costs of a microarray analysis suitable for these types of genetic screening will soon be covered by insurance

Presenilin-2 Mutation Causes Early Amyloid Accumulation and Memory Impairment in a Transgenic Mouse Model of Alzheimer's Disease

In order to clarify the pathophysiological role of presenilin-2 (PS2) carrying the Volga German Kindred mutation (N141I) in a conventional mouse model of Alzheimer's disease (AD) expressing amyloid precursor protein (APP) with the Swedish mutation (Tg2576 line), we generated a double transgenic mouse (PS2Tg2576) by crossbreeding the PS2 mutant with Tg2576 mice. Here, we demonstrate that the PS2 mutation induced the early deposition of amyloid β-protein (Aβ) at 2-3 months of age and progressive accumulation at 4-5 months of age in the brains of the mutant mice. The PS2 mutation also accelerated learning and memory impairment associated with Aβ accumulation at 4-5 months of age in Tg2576 mice. These results suggest that the PS2 mutation causes early cerebral amyloid accumulation and memory dysfunction. PS2Tg2576 mice are a suitable mouse model for studying amyloid-lowering therapies

Dual phase regulation of experimental allergic encephalomyelitis by platelet-activating factor

Experimental allergic encephalomyelitis (EAE) serves as a model for multiple sclerosis and is considered to be a CD4+ Th1 cell–mediated autoimmune disease. To investigate the role of platelet-activating factor (PAF) in this disease, PAF receptor (PAFR) KO (PAFR-KO) and wild-type (WT) mice, on a C57BL/6 genetic background, were immunized with myelin oligodendrocyte glycoprotein 35–55. The levels of PAF production and PAFR mRNA expression in the spinal cord (SC) correlated with the EAE symptoms. PAFR-KO mice showed lower incidence and less severe symptoms in the chronic phase of EAE than WT mice. However, no difference was observed in T cell proliferation, Th1-cytokine production, or titer of IgG2a between both genotypes. Before onset, as revealed by microarray analysis, mRNAs of inflammatory mediators and their receptors—including IL-6 and CC chemokine receptor 2—were down-regulated in the SC of PAFR-KO mice compared with WT mice. Moreover, in the chronic phase, the severity of inflammation and demyelination in the SC was substantially reduced in PAFR-KO mice. PAFR-KO macrophages reduced phagocytic activity and subsequent production of TNF-α. These results suggest that PAF plays a dual role in EAE pathology in the induction and chronic phases through the T cell–independent pathways

Neuroradiological and neurofunctional examinations for the patients with 22q11.2 deletion

Since neuroradiological features of patients with 22q11.2 deletion syndrome are not well-understood, examinations using functional imaging were performed in this study. Brain magnetic resonance imaging(MRI) and 1H-magnetic resonance spectroscopy(MRS) were performed using a clinical 3-tesla MR imager in 4 patients with 22q11.2 deletion syndrome (2 boys and 2 girls; 2~6 years.) and 20 age- and sex-matched healthy control subjects. Furthermore, interictal 123I- iomazenil (IMZ) single photon emission computed tomography(SPECT) was examined in two of the four patients. Among 4 patients with 22q11.2 deletion syndrome, 2 patients showed polymicrogyria and 1 patient showed agyria. Those patients with brain malformations also showed abnormal brain artery and decreased accumulation of IMZ in 123I-IMZ SPECT. Although all 4 patients showed epileptic discharges in electroencephalogram(EEG), one patient with polymicrogyria had no seizure episode. Decreases in γ-aminobutyric acid(GABA) corresponding to the areas of polymicrogyria and/or epileptic discharges in EEG were shown in all patients except for the patient with agyria. Although consistent evidence was not seen in patients with 22q11.2 deletion syndrome in this study, brain malformations and disturbances of the GABAergic nervous system would be underlying mechanisms of the neurodevelopmental abnormalities in this syndrome

Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

Heart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced alpha-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention

A 16q22.2-q23.1 deletion identified in a male infant with West syndrome

In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10 months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient

Evaluation of the GABAergic nervous system in autistic brain : 123I-iomazenil SPECT study

Purpose: To evaluate the GABAA receptor in the autistic brain, we performed 123I-IMZ SPECT in patients with ASD. We compared 123I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings. Subjects and methods: The subjects consisted of 24 patients with ASD (mean age, 7.3±3.5years), including 9 with autistic disorder (mean age, 7.0±3.7years) and 15 with Asperger’s disorder (mean age, 7.5±3.2years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8±3.6years) without intellectual delay as a control group. For an objective evaluation of the 123I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically. Results In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of 123I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings. Conclusion The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of 123I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind)

Multi-delay arterial spin labeling brain magnetic resonance imaging study for pediatric autism

Introduction Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that can measure regional cerebral blood flow (rCBF) without radiation exposure. This study aimed to evaluate rCBF in individuals with autism and their age-matched controls, globally and regionally. Methods We performed ASL MRI (3T, pulsed-continuous ASL, 3 delayed ASL imaging sequences) for 33 patients with autism spectrum disorder (ASD) (average age: 7.3 years, range: 2-14 years). Nineteen children (average age: 8.6 years, range: 3-15 years) without ASD and intellectual delay were included as controls. Patients with morphological abnormalities detected on MRI were excluded. Objective analysis was performed with automatic region of interest analysis of the ASL results. The Mann-Whitney U test was used to compare the rCBF results between the groups. Results Compared to the controls, patients with ASD showed a statistically significant decrease in rCBF, respectively, in the insula [left, rCBF 51.8±9.5 mL/100 g/min (mean±SD) versus 59.9±9.8, p=0.0017; right, 51.2±10.1 versus 57.8±8.8, p=0.0354], superior parietal lobule (left, 44.6±8.4 versus 52.0±7.8, p=0.003), superior temporal gyrus (left, 50.0±8.6 versus 56.9±8.6, p=0.007; right, 49.5±8.4 versus 56.4±7.7, p=0.0058), and inferior frontal gyrus (left, 53.0±9.8 versus 59.3±9.9, p=0.0279), which are associated with the mirror neuron system. Conclusions We concluded that patients with ASD showed a statistically significant decline in CBF in regions associated with the mirror neuron system. The advantages of ASL MRI include low invasiveness (no radiation exposure) and short imaging time (approximately 5 min). Studies with larger sample sizes are required to establish the diagnostic value of ASL MRI for ASD

The treatment effect of endovascular therapy for chronic limb‐threatening ischemia with systemic sclerosis

Systemic sclerosis (SSc) is a collagen disease with immune abnormalities, vasculopathy, and fibrosis. Ca blockers and prostaglandins are used to treat peripheral circulatory disturbances. Chronic limb-threatening ischemia (CLTI) is a disease characterized by extremity ulcers, necrosis, and pain due to limb ischemia. Since only a few patients present with coexistence of CLTI and SSc, the treatment outcomes of revascularization in these cases are unknown. In this study, we evaluated the clinical characteristics and treatment outcomes of seven patients with CLTI and SSc, and 35 patients with uncomplicated CLTI who were hospitalized from 2012 to 2022. A higher proportion of patients with uncomplicated CLTI had diabetes and male. There were no significant differences in the age at which ischemic ulceration occurred, other comorbidities, or in treatments, including antimicrobial agents, revascularization and amputation, improvement of pain, and the survival time from ulcer onset between the two subgroups. EVT or amputation was performed in six or two of the seven patients with CLTI and SSc, respectively. Among those who underwent EVT, 33% (2/6) achieved epithelialization and 67% (4/6) experienced pain relief. These results suggest that the revascularization in cases with CLTI and SSc should consider factors such as infection and general condition, since revascularization improve the pain of these patients