Primary Ciliary Dyskinesia with Identical Genotype but Distinct Phenotypes in Two Siblings.

In this study, we report two cases of siblings diagnosed with primary ciliary dyskinesia (PCD) sharing an identical genotype yet exhibiting distinct phenotypes. A 13-year-old girl with acute pneumonia was admitted to our hospital. Chest and sinus radiography revealed situs inversus and bilateral maxillary sinusitis. Chest computed tomography revealed bronchiectasis. Her 6-year-old brother with acute bronchitis was admitted and was diagnosed with bronchial asthma due to recurrent wheezing. Unlike his sister, he did not have situs inversus. Both patients had a chronic wet cough and were diagnosed with bronchial asthma by their family doctor. The mean PCD rule (PICADAR) scores were 9 and 7, respectively. Genetic analysis confirmed the presence of the same homozygous mutation (c.546C > A,pTyr182Ter) in DNAI2. To date, there have been four reports of the same pathogenic variants but different PCD phenotypes. Pathological variants of DNAI2 cause the loss of the outer dynein arm, the absence of which results in a lack of primary ciliary movement involved in the left-right axis formation during the embryonic period. A lack of functional cilia results in randomized visceral asymmetry; hence, the same pathogenic variant may exhibit different phenotypes. PCD is often overlooked and is sometimes managed as bronchial asthma, as in these siblings. In our case, the PICADAR score was useful in predicting the clinical diagnosis of PCD.

Lipid Peroxidation via Regulating the Metabolism of Docosahexaenoic Acid and Arachidonic Acid in Autistic Behavioral Symptoms.

The association between the lipid peroxidation product malondialdehyde (MDA)-modified low-density lipoprotein (MDA-LDL) and the pathophysiology of autism spectrum disorder (ASD) is unclear. This association was studied in 17 children with ASD and seven age-matched controls regarding autistic behaviors. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC). To compensate for the small sample size, adaptive Lasso was used to increase the likelihood of accurate prediction, and a coefficient of variation was calculated for suitable variable selection. Plasma MDA-LDL levels were significantly increased, and plasma SOD levels were significantly decreased in addition to significantly increased plasma docosahexaenoic acid (DHA) levels and significantly decreased plasma arachidonic acid (ARA) levels in the 17 subjects with ASD as compared with those of the seven healthy controls. The total ABC scores were significantly higher in the ASD group than in the control group. The results of multiple linear regression and adaptive Lasso analyses revealed an association between increased plasma DHA levels and decreased plasma ARA levels, which were significantly associated with total ABC score and increased plasma MDA-LDL levels. Therefore, an imbalance between plasma DHA and ARA levels induces ferroptosis via lipid peroxidation. Decreased levels of α-linolenic acid and γ-linolenic acid may be connected to the total ABC scores with regard to lipid peroxidation.

Lipid Peroxidation of the Docosahexaenoic Acid/Arachidonic Acid Ratio Relating to the Social Behaviors of Individuals with Autism Spectrum Disorder: The Relationship with Ferroptosis.

Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder.

The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation-reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD.

Postinfectious Bronchiolitis Obliterans Misdiagnosed as Bronchial Asthma in a Pediatric Patient.

Bronchiolitis obliterans is a chronic obstructive respiratory disease involving stenosis or occlusion of the bronchioles and smaller airways. The prognosis of bronchiolitis obliterans is poor, and the patient might require home oxygen therapy and/or lung transplantation. Bronchiolitis obliterans has various etiologies; in children, the most common causes are infections by respiratory pathogens like adenoviruses. In such cases, the condition is termed as postinfectious bronchiolitis obliterans. A 7-year-old girl was diagnosed with bronchial asthma at the age of 1 year and was on a regimen of a leukotriene receptor antagonist and an inhaled corticosteroid. At 1 year of age, she was admitted to our hospital with a respiratory syncytial virus infection, and despite continued treatment with the above drugs, she required frequent readmissions. At the age of 7 years, she was diagnosed with postinfectious bronchiolitis obliterans based on the following findings: mosaic perfusion on high-resolution chest computed tomography and ventilation-perfusion mismatch on ventilation-perfusion scintigraphy. A lung biopsy was not performed due to its invasiveness. It has been suggested that appropriate treatment during the early stage improves the prognosis of bronchiolitis obliterans. This disease might be misdiagnosed as bronchial asthma because of the clinical similarities. In patients who do not respond to the treatment for bronchial asthma, pediatricians should consider other diseases with similar signs and symptoms, such as bronchiolitis obliterans, in the differential diagnosis.

The role of lipid peroxidation in individuals with autism spectrum disorders.

The role of malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidized LDL, in the pathophysiology of autism spectrum disorder (ASD) is unclear. We studied association between MDA-LDL and behavioral symptoms in 11 individuals with ASD and 7 age -matched normal controls. Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). Because small sample size in this study, three measures were conducted: first, employment of adaptive Lasso for enhancing the accuracy of prediction and interpretability; second, calculation of coefficient of variation for an appropriate selection of plasma variables; and third, selection of good candidates of plasma variables. Plasma levels of MDA-LDL, eicosapentaenoic acid, docosahexaenoic acid (DHA) and DHA/arachidonic acid ratios were significantly higher, while plasma superoxide dismutase (SOD) levels were significantly lower in the ASD group than in the control group. The total ABC scores were significantly higher in the ASD group than in the control group. Multiple linear regression analysis and the adaptive Lasso revealed association of increased plasma DHA levels with the ABC total scores and increased plasma MDA-LDL levels. Such association between DHA and plasma MDA-LDL levels may contribute to behavior in individuals with ASD.

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and ß-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations.

Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.

Gaming Disorders: Navigating the Fine Line between Entertainment and Addiction-Gaming History, Health Risks, Social Consequences, and Pathways to Prevention.

The number of people immersed in excessive gaming has increased in this age of rapid digitalization. The World Health Organization and American Psychiatric Association Organization recognize a gaming disorder as a condition that results in significant problems in daily life as a result of excessive gaming. Both organizations emphasize the similarities to behavioral addictions such as gambling. We examined the appropriate usage of video games from the perspectives of health and management in this study. For the general population, video games provide positive impacts such as stress alleviation and memory improvement. Game playing leads to a loss of time and money for the individual. It also has a negative impact on the individual's family and social life, evolving into a social problem. Gaming addiction is often accompanied by psychological disorders and other addictions, and long-term medical treatment, including approaches to the individual's psychological background and cognitive-behavioral therapy, is necessary. Therefore, the prevention of gaming disorder is essential. From a societal standpoint, action is required in three contexts: the government, game developers, and within the household as a whole. Simultaneously, the public needs to understand the positive potential of gaming, such as e-sports.

Pseudohypoparathyroidism type 1B with involuntary movements: a case report and literature review.

Pseudohypoparathyroidism (PHP) is a rare disorder characterized by convulsions, tetany, and sensory abnormalities caused by hypocalcemia due to parathyroid hormone (PTH) resistance. Only few patients present with involuntary movements. We report the case of a 7-yr-old girl with PHP and involuntary movements triggered by running. Initially, she was suspected of having paroxysmal kinesigenic dyskinesia and was treated with carbamazepine (CBZ). Involuntary movements were reduced. However, 2 months post-treatment, she experienced convulsions during a fever. Blood tests and brain computed tomography revealed hypocalcemia, hyperphosphatemia, elevated intact PTH, and calcifications in the frontal cortex and basal ganglia. The patient showed no features of Albright's hereditary osteodystrophy. The involuntary movements disappeared after the discontinuation of CBZ and initiation of calcium and active vitamin D preparations. Methylation-specific multiplex ligation-dependent probe amplification for the GNAS region and microsatellite analysis of chromosome 20 led to the diagnosis of PHP1B caused by epimutation. In 15 reported cases, with or without intracranial calcification, PHP-associated involuntary movements disappeared or became less severe with treatment for hypocalcemia; in eight of 11 cases, they were triggered by exercise or movement. PHP-associated hypocalcemia can trigger exercise-induced involuntary movements owing to lowered serum ionized calcium levels. In such patients, early blood tests are vital for the differential diagnosis of PHP.

Brain Hypothermia Therapy and Targeted Temperature Management for Acute Encephalopathy in Children: Status and Prospects.

In adult intensive care, brain hypothermia therapy (BHT) was reported to be effective in neuroprotection after resuscitation and cardiac arrest. By contrast, in neonatal intensive care, the pathophysiology of brain damage caused by hypoxic-ischemic encephalopathy (HIE) is attributed to circulatory disturbances resulting from ischemia/reperfusion, for which neonatal brain cryotherapy is used. The International Liaison Committee on Resuscitation, 2010, recommends cerebral cryotherapy for HIE associated with severe neonatal pseudoparenchyma death. The usefulness of BHT for neuroprotection in infants and children, especially in pediatric acute encephalopathy, is expected. Theoretically, BHT could be useful in basic medical science and animal experiments. However, there are limitations in clinical planning for treating pediatric acute encephalopathy. No international collaborative study has been conducted, and no clinical evidence exists for neuroprotection using BHT. In this review, we will discuss the pathogenesis of neuronal damage in hypoxic and hypoperfused brains; the history of BHT, its effects, and mechanisms of action; the success of BHT; cooling and monitoring methods of BHT; adverse reactions to BHT; literature on BHT. We will review the latest literature on targeted temperature management, which is used for maintaining and controlling body temperature in adults in intensive care. Finally, we will discuss the development of BHT and targeted temperature management as treatments for pediatric acute encephalopathy.

Acute encephalopathy in children with Dravet syndrome.

PURPOSE: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome. METHODS: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms. KEY FINDINGS: There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8-184 months). All children had status epilepticus followed by coma as the initial manifestation. Two different distributions of brain lesions were observed on diffusion-weighted images during the acute phase: cerebral cortex-dominant lesions with or without deep gray matter involvement and subcortical-dominant lesions. Four children died; nine survived with severe sequelae, and two had moderate sequelae. SIGNIFICANCE: We must be aware that acute encephalopathy is an important complication in children with Dravet syndrome, and associated with fulminant clinical manifestations and a poor outcome.

A Comprehensive Review of Pediatric Acute Encephalopathy.

Acute encephalopathy typically affects previously healthy children and often results in death or severe neurological sequelae. Acute encephalopathy is a group of multiple syndromes characterized by various clinical symptoms, such as loss of consciousness, motor and sensory impairments, and status convulsions. However, there is not only localized encephalopathy but also progression from localized to secondary extensive encephalopathy and to encephalopathy, resulting in a heterogeneous clinical picture. Acute encephalopathy diagnosis has advanced over the years as a result of various causes such as infections, epilepsy, cerebrovascular disorders, electrolyte abnormalities, and medication use, and new types of acute encephalopathies have been identified. In recent years, various tools, including neuroradiological diagnosis, have been developed as methods for analyzing heterogeneous acute encephalopathy. Encephalopathy caused by genetic abnormalities such as CPT2 and SCN1A is also being studied. Researchers were able not only to classify acute encephalopathy from image diagnosis to typology by adjusting the diffusion-weighted imaging/ADC value in magnetic resonance imaging diffusion-weighted images but also fully comprehend the pathogenesis of vascular and cellular edema. Acute encephalopathy is known as a very devastating disease both medically and socially because there are many cases where lifesaving is sometimes difficult. The overall picture of childhood acute encephalopathy is becoming clearer with the emergence of the new acute encephalopathies. Treatment methods such as steroid pulse therapy, immunotherapy, brain hypothermia, and temperature control therapy have also advanced. Acute encephalopathy in children is the result of our predecessor's zealous pursuit of knowledge. It is reasonable to say that it is a field that has advanced dramatically over the years. We would like to provide a comprehensive review of a pediatric acute encephalopathy, highlighting advancements in diagnosis and treatment based on changing disease classification scenarios from the most recent clinical data.

Current Status of Internet Gaming Disorder (IGD) in Japan: New Lifestyle-Related Disease in Children and Adolescents.

The World Health Organization recognizes internet gaming disorder (IGD) as a disorder that causes problems in daily life as a result of excessive interest in online games. The causes of IGD have become more apparent in recent years. Because of prolonged exposure to games, the mechanisms controlling the reward system, such as the prefrontal cortex, limbic system, and amygdala of the cerebrum, do not function properly in IGD. This mechanism is similar to that of various behavioral addictions, such as gambling addiction. IGD is particularly risky in children and adolescents because it easily causes brain dysfunction, especially in the developing brain. IGD should be regarded as a new lifestyle-related disease in younger individuals, and lifestyle modifications, including counseling and family therapy, are critical for its management.

Increased cytokines/chemokines and hyponatremia as a possible cause of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with acute focal bacterial nephritis.

OBJECTIVE: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), the second most common encephalopathy syndrome in Japan, is most often associated with viral infection. Bacterial MERS has been rarely reported but is mostly associated with acute focal bacterial nephritis (AFBN) for an unknown reason. We examined cytokines and chemokines in four MERS patients with AFBN to determine if they play an important role in the pathogenesis. METHODS: We examined the clinical charts and MRI results in four MERS patients with AFBN, and measured 10 cytokines and chemokines in serum and cerebrospinal fluid in the acute phase. These were analyzed using the Mann-Whitney U test, compared with the control group (cases with a non-inflammatory neurological disease). Longitudinal changes in the serum cytokine and chemokine levels were evaluated in two patients. RESULTS: Hyponatremia was observed in all four patients with MERS associated with AFBN (128-134 mEq/L). CSF analysis revealed increased cytokines/chemokines associated with Th1 (CXCL10, TNF-α, IFN-γ), T reg (IL-10), Th17 (IL-6), and neutrophil (IL-8 and CXCL1). In serum, upregulation was observed in those associated with Th1 (CXCL10, TNF-α, IFN-γ), Th17 (IL-6), and inflammasome (IL-1ß). The increased serum cytokines/chemokines in the acute stage normalized within 2 weeks in patients 1 and 2, so examined, in accordance with their clinical improvement. CONCLUSION: Increased cytokines/chemokines and hyponatremia may be factors that explain why AFBN is likely to cause MERS.

Lipid Peroxidation With Implication of Organic Pollution in Autistic Behaviors.

Background Lipid metabolism has been associated with the development of autism. The omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) readily undergo lipid peroxidation and conversion to malondialdehyde (MDA). MDA-modified low-density lipoprotein (MDA-LDL) is a marker of lipid peroxidation. However, the association between PUFAs and MDA-LDL in the pathophysiology of autism spectrum disorder (ASD) is unclear. Materials and methods We studied the association between PUFAs and MDA-LDL in 16 individuals with ASD (mean age: 11.5 ± 5.7 years) and seven age- and sex-matched healthy controls (mean age: 10.0 ± 4.1 years). The Aberrant Behavior Checklist (ABC) was used to assess behavioral symptoms. We overcame the small sample size by using the adaptive LASSO for enhancing the accuracy of prediction and interpretability. We also estimated the coefficient of variation for an appropriate variable selection and compared additional prior studies to support the findings. Thus, we conducted a careful selection of appropriate candidates to account for confounding variables. Results The ASD group had significantly higher plasma MDA levels, eicosapentaenoic acid levels, and a higher ratio of plasma docosahexaenoic acid (DHA)/arachidonic acid (ARA) levels than the control group. Plasma levels of the omega-6 PUFA fraction, dihomo-γ-linolenic acid, and superoxide dismutase levels were significantly lower in the ASD group than in the control group. Total ABC scores were significantly higher in the ASD group than in the control group. Multiple linear regression and adaptive LASSO indicated that plasma DHA levels and plasma DHA/ARA ratios were significantly associated with total ABC scores and plasma levels of MDA-LDL. Conclusion Increased plasma levels of DHA and DHA/ARA ratio might be related to organic pollution. These neurobiological bases may induce neuronal deficiency associated with autistic behavioral symptoms in individuals with ASD.