BACKGROUND:Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder associated with spinal motor neuron loss and characterized by generalized muscle weakness. Only a few reports exist on SMA epidemiology in Japan. Additionally, nusinersen recently became available as a treatment for this condition. We estimated the prevalence of each type of SMA on Shikoku, Japan's fourth-largest major island.METHODS:We sent a questionnaire to all 131 hospitals in Shikoku that have pediatrics or neurology departments from March to September 2019, asking whether each hospital had SMA patients at that time. If so, we sent a second questionnaire to obtain more detailed information on the clinical data and treatment of each patient.RESULTS:A total of 117 hospitals (89.3%) responded to our first questionnaire, and 21 SMA patients were reported, 16 of whom had homozygous deletion of SMN1. Of the 21, nine had SMA type 1, five were type 2, five were type 3, one was type 4, and one was unidentified. The estimated prevalence for all instances of SMA and 5q-SMA was 0.56 and 0.43 per 100,000 people, respectively. Thirteen patients had received nusinersen therapy. Its outcomes varied from no obvious effects and being unable to sit to being able to sit independently.CONCLUSION:Our data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by homozygous mutations in the SMN1 gene. SMA has long been known to be the most common genetic cause of infant mortality. However, there have been no reports on the epidemiology of infantile SMA (types 1 and 2) based on genetic testing in Japan. In this study, we estimated the incidence of infantile SMA on Shikoku Island, which is a main island of Japan and consists of four prefectures: Ehime, Kagawa, Tokushima and Kochi. Methods: A questionnaire was sent to 91 hospitals on Shikoku Island to investigate the number of SMA infants born from 2011 to 2015. A second questionnaire was then sent to confirm the diagnoses of SMA based on clinical and genetic features. Results: Responses were received from all of the hospitals, and four patients were diagnosed with infantile SMA among 147,950 live births. We estimated the incidence of infantile SMA patients as 2.7 per 100,000 live births (95% confidence interval, 0.1- 5.4). A comparison of the four prefectures indicated that the incidence of infantile SMA was significantly higher in Ehime Prefecture than in the other three prefectures; 5.6 per 100,000 live births (95% confidence interval, -0.7 to 11.9) in Ehime Prefecture and 1.1 per 100,000 live births (95% confidence interval, -1.0 to 3.1) in the other prefectures. Conclusion: We estimated the incidence of infantile SMA in an isolated area of Japan. For more precise determination of the incidence of infantile SMA, further studies that include neonatal screening will be needed. (C) 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

The cyclin-dependent kinase-like 5 gene (CDKL5) is recognized as one of the genes responsible for epileptic encephalopathy. We identified CDKL5 mutations in five Japanese patients (one male and four female) with epileptic encephalopathy. Although all mutations were of de novo origin, they were located in the same positions as previously reported pathogenic mutations. These recurrent occurrences of de novo mutations in the same loci may indicate hot spots of nucleotide alteration.

Background: Trichloroacetic acid (TCA) treatment of allergic rhinitis proved clinically satisfactory. In the present study, for the purpose of providing evidence to support the effectiveness of the treatment, we attempted to compare the number of infiltrating Th2 and Th1 cells in specimens obtained from the TCA-treated inferior turbinate mucosae group with the non-treated group. Methods: Specimens were obtained from 21 patients with house dust mite allergic rhinitis who underwent turbinectomy combined with surgery for a deviated septum after unilateral TCA application for relief from persistent nasal symptoms. In each specimen, Th2 and Th1 cells were identified using immunohistochemical staining, and their numbers were counted to obtain each cell count per unit specimen area (/mm 2 ). Results: In TCA-treated mucosae, the mean cell count of Th2 cells was 4.93 ± 2.83 cells/mm 2 , while that in non-treated mucosae was 40.87 ± 15.63. The mean Th1 cell count in TCA-treated mucosae was 45.34 ± 25.34 cells/mm 2 , while it was 124.32 ± 54.91 cells/mm 2 in non-treated mucosae. There was a statistically significant difference in the cell count between TCA-treated and non-treated specimens for both cell types. Conclusions: TCA application inhibited Th2 cell infiltration, implying that chemosurgery with TCA for allergic rhinitis treatment was clinically effective with good prognosis.

Duplications of the 2q33 region are rare; to date, only 13 patients have been reported to have this chromosomal abnormality. The reported duplications are of varying size, and the patients shared developmental delay and minor dysmorphic findings. In this study, we identified a duplication of 2q32.1–q33.3 in a patient with psychomotor developmental delay, epilepsy, and autistic behavior. The duplicated region of this patient was reciprocal to the 2q32–q33 deletion syndrome. Chromosomal microarray testing confirmed the 19.5 Mb of duplication that includes over 100 genes, some of which could have functional relevance to the neurological features of this patient. The SATB homeobox 2 gene (SATB2)—the primary gene responsible for the 2q32–q33 deletion syndrome—may be one of them, because of its expression in the cortical projection neurons of the developing brain. The duplication of the potassium channel tetramerisation domain‐containing 18 gene (KCTD18) and the ADAM metallopeptidase domain 23 gene (ADAM23) may also contribute to the phenotype. FISH analysis confirmed a tandem configuration of the duplicated segments. This result is in agreement with our previous study, in which we observed that duplicated segments as interstitial duplications are generally inserted in the tandem configuration. © 2013 Wiley Periodicals, Inc.

Abnormalities in the protocadherin 19 (PCDH19) gene cause early-onset epilepsy exclusively in females. We aimed to explore the genetic and clinical characteristics of PCDH19-related epilepsy by focusing on its early features and treatment efficacy. PCDH19 was analyzed in 159 Japanese female patients with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. We identified 17 patients with PCDH19 abnormalities: point mutations were observed in 14 patients and whole PCDH19 deletions were detected in 3 patients. One affected sister of a proband with a mild phenotype was also analyzed. The frequency of PCDH19 deletion among all probands identified in Japan was 12.5% (3/24, including 7 probands reported previously by us). Clinical features included early onset (mean age at onset, 8.6 months), recurrent clusters of brief seizures (17/18), fever sensitivity (18/18), tonic seizures (13/18, probably including focal tonic seizures), tonic-clonic seizures (8/18), focal seizures often with subsequent generalization (17/18), intellectual disabilities (15/18), and autistic traits (13/18). Three patients exhibited delay in motor milestones before seizure onset. In 16 patients, seizures appeared in clusters from the onset of the disease. Among 6 patients for whom detailed information at onset was available, 2 onset patterns were identified: a biphasic course of short seizure clusters (each within days) in 2 patients and a prolonged course of clusters (from weeks to a month) in 4 patients. In both cases, initial seizures started during fever and transiently disappeared with the decline of fever; however, afebrile clusters recurred. In the former patients, motor development was delayed before onset, and seizures appeared in strong clusters from the onset of the disease. In the latter patients, initial development was normal and initial seizures were mild, but were followed by strong clusters lasting several weeks, even without fever. Treatment using phenytoin, potassium bromide, and clobazam showed high efficacy. Although focal seizures were the main feature in PCDH19-epilepsy, the efficacy of carbamazepine was poor. This study highlighted the significance of PCDH19 deletion, a unique pattern of initial seizure clusters, and the efficacy of antiepileptic drugs. Our data will facilitate early diagnosis and development of a treatment strategy for better clinical management of patients with PCDH19-related epilepsy.

In patients with severe motor and intellectual disabilities (SMID), fatal esophageal hemorrhage including penetration of the descending aorta, has often been reported. We experienced 2 patients with severe scoliosis who developed esophageal hemorrhage during catheter placement in the esophagus. We compared chest CT images of these cases with those of 38 SMID patients in our hospital. As a result, a few patients showed esophagus bending to the left of the descending aorta while the vertebral body curved to the right and the mediastinum shifted to the left. It is suggested that there is a risk of esophageal hemorrhage caused by catheter stimulation, when a catheter is placed in the esophagus in such patients. It is therefore necessary to use the thinnest and softest catheter possible and to consider the indications for gastrostomy.

We recently encountered a 13-year-old girl who developed persistent cerebellar symptoms one month after mixed measles/rubella vaccination, making it difficult to distinguish this condition from conversion disorders. Severe truncal ataxia was the initial manifestation in this case. The patient had no abnormalities in objective tests but began to show extraordinary circadian variations in certain parameters. Her cerebellar symptoms were thus considered to possibly be associated with conversion disorders. Later, she tested positive for cerebrospinal fluid anti-glutamic acid receptor (GluR) delta2 antibody. The lymphocyte stimulation test yielded a positive reaction to GluRdelta2 antigen. In addition, in the chronic stage SPECT revealed reduced cerebellar blood flow. She was thus diagnosed as having persistent cerebellar ataxia due to autoimmune mechanisms and modification of cerebellar symptoms due to secondary conversion disorders. Our experience with this case suggests that checking cerebrospinal fluid for anti-GluRdelta2 antibody is possibly useful for distinguishing between conversion disorders and cerebellar ataxia due to autoimmune mechanisms.

Purpose: Inferior turbinates chemosurgery with trichloroacetic acid (TCA) has been assessed histopathologically in allergic rhinitis by comparing bilateral inferior turbinates with both sides treated by turbinectomy and only the deviation-free side treated with TCA due to a deviated nasal septum.Because such deviation may influence comparison results, we assessed its influence on Th2 and Th1 cell infiltration of specimens. Subjects: Specimens were bilateral inferior turbinate membranes from 13 subjects with non treated HD allergy. Methods: The two types of cells were counted immunohistochemically per 1mm2 per specimen. Two-way analysis of variance used the deviation and cell type as primary factors. Results: The cell type, but not the deviation factor, was significant at p<0.01. Conclusion: The deviation factor was not related to Th2 or Th1 cell infiltration, but has not been accounted for conventional assessment. Our results confirmed that necessity of the deviation factor need not be considered in assessing TCA treatment efficacy.

In a one-year-plus follow-up study in 17 of 26 cases involving apparent liquid aspiration during videoendoscopic screening, subjects were instructed in swallowing using video images and in choosing food, utensils, and posture. The amount of sputum decreased in 10 case (59%), and sputum sticking in the throat disappeared in 4 (18%). Body weight also increased in 4 (24%). Choking coughs noted in 11 during initial videoendoscopy disappeared in 2 (18%). We thus, concluded that detecting dysphagia symptoms early and providing follow-up could help prevent aspiration pneumonia.

In screening tests for dysphagia conducted using videoendoscopy in 81 subjects over 75-years-old apparent liquid aspiration was found in 26 (32%). In 2 of these 26 saliva aspiration was observed. Logistic analysis of aspiration versus clinical symptoms, including endoscopic findings, showed a significant correlation between aspiration and longer time required for meals, bending forward during swallowing, choking during meals, hypoesthesia of the larynx, delayed swallowing reflex and difficulty in spitting. Results were considered clinically significant although they did not appear to fully agree with those of previous studies. The usefulness of videoendoscopy was confirmed.

The sympathetic nervous system regulates peripheral organs via the adrenal chromaffin cells containing adrenaline (A-cells) or noradrenaline (NA-cells) and the sympathetic ganglia. We examined the effect of intracerebroventricularly administered bombesin on neuronal activities of adrenal A-cells and NA-cells and several kinds of sympathetic ganglia (superior cervical, stellate and celiac ganglia) using c-Fos (a marker for neuronal activation), with regard to brain prostanoid, in anesthetized rats. Bombesin induced c-Fos in both adrenal A-cells and NA-cells, but not in any of the sympathetic ganglia. Central pretreatment with either indomethacin (a cyclooxygenase inhibitor) or furegrelate (a thromboxane A2 synthase inhibitor) abolished all bombesin-induced responses. These results suggest that bombesin centrally activates adrenal A-cells and NA-cells by brain thromboxane A2-mediated mechanisms in rats.

The sympathetic efferent pathway projects to the sympathetic ganglia and the adrenal medulla. In this study, we examined centrally administered corticotropin-releasing factor (CRF)-induced neuronal activation of noradrenergic postganglionic neurons in several kinds of the sympathetic ganglia (superior cervical, stellate and celiac ganglia) in anesthetized rats. CRF significantly increased c-Fos expression in the celiac and stellate ganglia, with more pronounced effect on the celiac ganglion. On the other hand, CRF had no effect on c-Fos expression in the superior cervical ganglion even at a higher dose. These results suggest that brain CRF selectively regulates neuronal activity of each sympathetic ganglion.

In the brain, corticotropin-releasing factor (CRF) has been shown to activate the sympatho-adrenomedullary outflow, but the central mechanisms of action are still not fully understood. Previously, we reported that inducible nitric oxide synthase (iNOS) is involved in central CRF-induced elevation of plasma catecholamines in rats. Nitric oxide is mainly synthesized by neuronal NOS (nNOS) and iNOS in many areas in the brain. Of these areas, the paraventricular hypothalamic nucleus (PVN) contains neurons projecting to the intermediolateral cell column (IML) of the spinal cord, thereby directly affecting the sympathetic activity. Therefore, in the present study, we investigated the effect of intracerebroventricularly (i.c.v.) administered CRF on plasma catecholamine levels and expression of NOS isozymes (iNOS and nNOS) and Fos (a marker for neuronal activation) in the spinally projecting PVN neurons, using rats microinjected with a monosynaptic retrograde tracer into the IML. CRF (1.5 nmol/animal, i.c.v.) effectively elevated plasma catecholamine levels. The spinally projecting neurons labeled with a tracer were detected in the dorsal cap, ventral part and posterior part of the PVN. CRF significantly increased the number of spinally projecting neurons triple-labeled with Fos and iNOS in all of these PVN subnuclei. On the other hand, CRF significantly increased the number of spinally projecting neurons triple-labeled with Fos and nNOS only in the ventral part of the PVN. These results suggest that in spinally projecting PVN neurons, iNOS mainly contributes to the centrally administered CRF-induced activation of the sympatho-adrenomedullary outflow in rats.

OBJECTIVE:To examine local inhibition of Th2 cell infiltration as the basis for demonstrating the superior clinical effect of trichloroacetic acid (TCA) treatment for allergic rhinitis. METHODS:Mirror-image sections of the inferior turbinate mucosae of both sides were obtained from 26 patients who underwent TCA treatment on one side because of the nasal anatomy status and who eventually underwent bilateral inferior turbinectomy because of failure of the TCA treatment. Th2 cell counts, defined as counts of cells positive for anti-CD4 antibody and anti-CKR4 antibody (double-positive cells) were obtained for comparison. The differences between the TCA-treated and non-TCA-treated mucosae were analyzed by Mann-Whitney's U test. RESULTS:Th2 cell infiltration was characteristically found just beneath the epithelium and in the periglandular areas. The mean count+/-standard deviation of Th2 cells was 4.96+/-2.72 cells/mm(2) in the TCA-treated mucosae and 12.03+/-7.19 cells/mm(2) in the non-treated mucosae, the difference being significant (p<0.01). CONCLUSION:TCA treatment induces inhibition of Th2 cell infiltration. This corroborates the suggestion that TCA treatment can inhibit local type I allergic reactions.

The adrenal glands and sympathetic celiac ganglia are innervated mainly by the greater splanchnic nerves, which contain preganglionic sympathetic nerves that originated from the thoracic spinal cord. The adrenal medulla has two separate populations of chromaffin cells, adrenaline-containing cells (A-cells) and noradrenaline-containing cells (NA-cells), which have been shown to be differentially innervated by separate groups of the preganglionic sympathetic neurons. The present study was designed to characterize the centrally activating mechanisms of the adrenal A-cells, NA-cells and celiac sympathetic ganglia with expression of cFos (a marker for neural excitation), in regard to the brain prostanoids, in anesthetized rats. Intracerebroventricularly (i.c.v.) administered corticotropin-releasing factor (CRF) induced cFos expression in the adrenal A-cells, but not NA-cells, and celiac ganglia. On the other hand, i.c.v. administered arginine–vasopressin (AVP) resulted in cFos induction in both A-cells and NA-cells in the adrenal medulla, but not in the celiac ganglia. Intracerebroventricular pretreatment with indomethacin (an inhibitor of cyclooxygenase) abolished the CRF- and AVP-induced cFos expression in all regions described above. On the other hand, intracerebroventricular pretreatment with furegrelate (an inhibitor of thromboxane A2 synthase) abolished the CRF-induced cFos expression in the adrenal A-cells, but not in the celiac ganglia, and also abolished the AVP-induced cFos expression in both A-cells and NA-cells in the adrenal medulla. These results suggest that centrally administered CRF activates adrenal A-cells and celiac sympathetic ganglia by brain thromboxane A2-mediated and other prostanoid than thromboxane A2 (probably prostaglandin E2)-mediated mechanisms, respectively. On the other hand, centrally administered AVP activates adrenal A-cells and NA-cells by brain thromboxane A2-mediated mechanisms in rats.