Itpr1 regulates the formation of anterior eye segment tissues derived from neural crest cells.

Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3'-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1, encoding a 218amino acid isoform. This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after completion of AES formation. Our analyses revealed that the 218-amino acid isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is also possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris.

Epigenetic aging in Williams syndrome.

BACKGROUND: Williams syndrome (WS) is a rare genetic disorder caused by a microdeletion at the 7q11.23 region and is characterized by diverse symptoms encompassing physical and cognitive features. WS was reported to be associated to altered DNA methylation (DNAm) patterns. However, due to the limited information from long-term studies, it remains unclear whether WS accelerates aging. Genome-wide DNAm profiles can serve as "epigenetic clocks" to help estimate biological aging along with age-related markers, such as plasma proteins and telomere length. METHODS: We investigated GrimAge, DNAm-based telomere length (DNAmTL), and other epigenetic clocks in blood samples of 32 patients with WS and 32 healthy controls. RESULTS: We observed a significant acceleration in GrimAge, DNAmTL, and other epigenetic clocks in patients with WS as compared with those of controls. In addition, several GrimAge components, such as adrenomedullin, growth differentiation factor-15, leptin and plasminogen activator inhibitor-1, were altered in patients with WS. CONCLUSIONS: This study provides novel evidence supporting the hypothesis that WS may be associated to accelerated biological aging. A better understanding of the overall underlying biological effects of WS can provide new foundations for improved patient care; thus, long-term follow-up studies are still warranted.

De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

OBJECTIVE: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. METHODS: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. RESULTS: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. CONCLUSION: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

Integrative network analysis reveals biological pathways associated with Williams syndrome.

BACKGROUND: Williams syndrome (WS) is a neurodevelopmental disorder that has been attributed to heterozygous deletions in chromosome 7q11.23 and exhibits a variety of physical, cognitive, and behavioral features. However, the genetic basis of this phenotypic variability is unclear. In this study, we identified genetic clues underlying these complex phenotypes. METHODS: Neurobehavioral function was assessed in WS patients and healthy controls. Total RNA was extracted from peripheral blood and subjected to microarray analysis, RNA-sequencing, and qRT-PCR. Weighted gene co-expression network analysis was performed to identify specific alterations related to intermediate disease phenotypes. To functionally interpret each WS-related module, gene ontology and disease-related gene enrichment were examined. We also investigated the micro (mi)RNA expression profiles and miRNA co-expression networks to better explain the regulation of the transcriptome in WS. RESULTS: Our analysis identified four significant co-expression modules related to intermediate WS phenotypes. Notably, the three upregulated WS-related modules were composed exclusively of genes located outside the 7q11.23 region. They were significantly enriched in genes related to B-cell activation, RNA processing, and RNA transport. BCL11A, which is known for its association with speech disorders and intellectual disabilities, was identified as one of the hub genes in the top WS-related module. Finally, these key upregulated mRNA co-expression modules appear to be inversely correlated with a specific downregulated WS-related miRNA co-expression module. CONCLUSIONS: Dysregulation of the mRNA/miRNA network involving genes outside of the 7q11.23 region is likely related to the complex phenotypes observed in WS patients.

[A case of West syndrome with a deletion at chromosome 2q24.3-q31.3].

A male infant suffered from partial seizures at four months of age, and developed West syndrome at eight months of age. ACTH therapy was effective for the West syndrome. However, partial seizures recurred at 14 months of age, which could not be sufficiently controlled with an anti-epileptic drug. A characteristic facial appearance, great toe abnormalities, and developmental retardation were noted. An interstitial deletion of 2q was detected by chromosomal G-banding and array comparative genomic hybridization (CGH) confirmed the deletion as arr 2q24.3q31.3 (166,303,447-180,982.972) ×1 (build19). He presented with clinical findings similar to those of the recently defined 2q31.1 deletion syndrome. The deletion extended to the SCN1A gene, a gene responsible for Dravet syndrome, mapped to the 2q24.3 region. No deletion was noted in the adjacent SCN2A gene. Thus, for interstitial deletions, detailed breakpoints should be identified by array CGH. The frequency of epilepsy varies with deletion ranges in the 2q24-q31 region, suggesting that deletions in the SCN1A gene deletion, as well as in the 2q31.1 region, are involved in the development of West syndrome.

Increased oxidative stress in patients with severe disability: Association with nutrition.

BACKGROUND: Previous studies have described a role of oxidative stress in the pathogenesis of various pediatric disorders, but investigation into oxidative stress status in patients with severe disability remains limited. The aim of the present study was therefore to clarify the oxidative stress status in patients with severe disability, focusing specifically on intake of three major nutrients and micronutrients with antioxidant activities. METHODS: Thirty-one patients with severe disability (mean age, 14.1 ± 7.8 years) were enrolled. Three in vivo biomarkers, plasma biological antioxidant potential (BAP), plasma reactive oxygen metabolite-derived compounds (d-ROM), and urinary 8-hydroxydeoxyguanosine (8-OHdG), were determined for evaluating oxidative status. The dietary intake of three major nutrients and various micronutrients was estimated from dietary records over a 3 day period. RESULTS: In patients with severe disability, BAP was significantly lower and d-ROM and 8-OHdG significantly higher than in historical controls. Among these markers, a significant positive correlation was found in BAP versus d-ROM and d-ROM versus 8-OHdG. On multiple regression analysis, a significant inverse association between 8-OHdG and carotenoid intake was seen. CONCLUSION: The oxidative/antioxidative balance shifts towards oxidative status dominance in patients with severe disability. More research is needed on nutritional intake of antioxidative nutrients to determine whether they can be used to reduce oxidative stress.

[A clinical study on high-dose erythropoietin therapy for acute encephalopathy or encephalitis].

OBJECTIVE: We performed high-dose erythropoietin therapy (hEPO) for acute encephalopathy or encephalitis (AE), and evaluated its safety and efficacy. METHODS: We performed hEPO in AE patients with widespread lesions demonstrated by diffusion-weighted imaging, and prospectively investigated changes in hemoglobin levels, adverse events, changes in images, and developmental quotients. RESULTS: All four patients showed neither an increase in the hemoglobin level nor adverse event possibly related to hEPO. One patient with acute encephalitis showed resolution of the lesion and normal developmental quotient. Two patients who had acute encephalopathy with febrile convulsive status epilepticus showed mild cerebral atrophy in the recovery phase;one had a normal developmental quotient. The patient with acute necrotizing encephalopathy including a brainstem lesion avoided acute-phase death. CONCLUSION: Two patients showed no sequelae despite images indicating widespread abnormality. hEPO could be performed safely in patients with AE, however further trials are necessary concerning its efficacy.

Epileptic encephalopathy with continuous spikes and waves in the occipito-temporal region during slow-wave sleep in two patients with acquired Kanji dysgraphia.

We encountered two patients with acquired Kanji dysgraphia in whom continuous spikes and waves, dominant in the occipito-temporal region, were recorded during slow-wave sleep. Electrical status epileptics during sleep (ESES) was demonstrated on overnight electroencephalography, and dipoles clustered in and around the posterior inferior temporal cortex on magnetoencephalography. Functional neuroimaging suggested dysfunction in the left posterior temporal lobe, including the posterior inferior temporal cortex. The patients had normal intelligence with no problems in reading and writing Kana, as well as copying, reading aloud, and identifying Kanjis, but showed Kanji dysgraphia (morphological, phonemic, and semantic error) accompanied by impaired visual processing. ESES was resolved by sodium valproate, clonazepam, and acetazolamide in Patient 1, and by adrenocorticotropic hormone, sodium valproate, and clorazepate in Patient 2. The present cases had the unique cognitive dysfunction of Kanji dysgraphia, which is distinct from that of Landau-Kleffner syndrome and continuous spikes and waves during slow-wave sleep. However, the present cases also share common features with these two encephalopathies in terms of the clinical course, pathophysiology, neuroimaging, and response to steroids and antiepileptic drugs. In the context of the Japanese language, acquired Kanji dysgraphia may occur due to electrical dysfunction of left posterior inferior temporal cortex in patients with ESES.

Comparison of the Sensory Profile Among Autistic Individuals and Individuals with Williams Syndrome.

PURPOSE: With the current study, we aimed to reveal the similarities and differences in sensory profiles between Williams syndrome (WS) and autism spectrum disorder. METHODS: Using the sensory profile questionnaire completed by the caregivers, we analyzed the WS (n = 60, 3.4-19.8 years) and autistic (n = 39, 4.2-14.0 years) groups. RESULTS: The Severity Analysis revealed a significant group difference in Sensory Sensitivity but not in Low Registration, Sensation Seeking, and Sensation Avoiding subscales. Age can modulate the subscale scores differently across groups. For Sensation Seeking, the scores of both groups decreased with development. However, the scores of Sensory Sensitivity decreased with age in the autistic group but not in the WS group. Sensation Avoiding scores increased with development in the WS group but not in the autistic group. No significant developmental changes were observed in Low Registration. CONCLUSION: This study highlights the cross-syndrome similarities and differences in sensory profiles and developmental changes in autistic individuals and individuals with WS.

[Clinical study of patients undergoing paperless electroencephalography in emergency room].

Fifty-eight patients who visited the emergency room of our center with febrile convulsions and impaired consciousness, and underwent paperless electroencephalography soon after arrival. They consisted of 25 male and 33 female children, ranging in age from 5 months to 15 years and 4 months, with a mean age of 4 years and 10 months. The final diagnoses were poor responsiveness associated with fever and febrile delirium in 5 patients, febrile convulsions in 26, encephalitis/encephalopathy in 24, convulsions associated with mild gastroenteritis in 2, and aseptic meningitis in 1. The appearance of spindle wave within 24 hours after admission was considered to be a favorable prognostic factor, whereas generalized high-amplitude delta waves without fast-wave components and dysrhythmic flat basic waves were considered poor prognostic factors. We conclude that bed-side paperless electroencephalography is useful for the evaluation of changes in the brain function and course of treatment.

[Usefulness of 123I-iomazenil SPECT in pediatric patients with neurological disease].

This study examined the usefulness of 123I-iomazenil SPECT (IMZ-SPECT), a type of brain scintigram that focuses on the central benzodiazepine receptor in order to determine its distribution and the function of inhibitory neurons. IMZ-SPECT has been used for the detection of epileptogenic foci, especially when surgical intervention is considered. Interictal study by IMZ-SPECT is widely available at numerous institutions and its usefulness has been confirmed in patients with not only focal cortical dysplasia and hippocampal sclerosis, but also tuberous sclerosis and neuronal migration disorders, even when magnetic resonance image fails to demonstrate any abnormal findings. When interpreting scintigrams, the developmental dynamic change of the central benzodiazepine receptor in childhood and the duration of the benzodiazepine exposure period should be taken into consideration. It is expected that IMZ-SPECT will be used in various neurological disorders other than epilepsy in the future allow medical services to be provided based on findings in the inhibitory synaptic system obtained with IMZ-SPECT.

Comparison of the Social Responsiveness Scale-2 among Individuals with Autism Spectrum Disorder and Williams Syndrome in Japan.

This study examined the similarities/differences between the social phenotypes of Williams syndrome (WS) and autism spectrum disorder (ASD). As cultural norms may affect symptom evaluation, this study administered the Social Responsiveness Scale-2 to Japanese individuals with WS (n = 78, 4.4-44.0 years) and ASD (n = 75, 4.7-55.4 years). The scores for Social Motivation and Social Communication were significantly more severe in the ASD than WS group. Overall, the similarities and differences between the social phenotypes of the syndromes were consistent with the findings of a recent study conducted in the UK, except for the social awareness subscale score. This highlights the importance of cross-cultural investigations of WS and ASD.

Progressive leukoencephalopathy with intracranial calcification, congenital deafness, and developmental deterioration.

We report on a 12-year-old male with a unique cerebral white matter disease. His initial symptoms were congenital hearing loss and multiple intracranial calcifications on head CT. He developed severe intellectual disability and epilepsy. MRI showed signal abnormalities in the posterior limbs of the internal capsules, thalami, and cerebral white matter. The abnormalities were progressive over time. The neuropathology revealed diffuse and severe disruption of myelin and axons of the cerebral white matter and cerebrospinal tracts. We performed various metabolic examinations, detailed pathological investigations and genetic analyses, but could not identify the cause. To our knowledge his clinical course has not been described in the literature.

Variations in early gross motor milestones and in the age of walking in Japanese children.

BACKGROUND: Gross motor development is usually assessed in terms of age of achievement of motor milestones. Although there is generally an impression of faster development if the milestones are achieved at younger ages, no longitudinal studies have been done on the associations between the milestones, especially in Japan. As a part of the Japan Children's Study, the purpose of the present study was to determine whether the achievement of gross motor milestones in infancy is related with the age of walking. METHODS: This was a prospective cohort study of 290 healthy and term infants born in a district of Osaka City, Japan. Three milestones (rolling over, sitting, and crawling) were observed in the laboratory for infants aged at 4 and 9 months by a pediatrician and a developmental psychologist, and the age of walking was confirmed in questionnaires filled in by the parents at 18 and 27 months. RESULTS: Children who could roll over at 4 months, and sit and crawl at 9 months, walked earlier than children who could not roll over, sit and crawl, respectively. With regard to crawling, children who were creeping had a 1 month delay in walking, and those who could not move forward had a 2 month delay compared to typical crawlers. On multiple regression analysis these three milestones were positively associated with walking: rolling over (ß= 0.567), sitting (ß= 1.973) and crawling (ß= 1.473). CONCLUSION: The age and the patterns of sitting, crawling and rolling over were all related to the age of independent walking among Japanese infants. Consideration of milestone definition and variations is essential in medical check-up.

[Review of images in children with septo-optic dysplasia based on MRI and SPECT].

We reviewed MRI and SPECT images in 10 patients with septo-optic dysplasia (SOD). MRI was performed in all of them. Six of them had bilateral optic nerve atrophy and abnormality of midline brain structures (e. g., septum pellucidum, corpus callosum). Four cases had one-sided optic nerve atrophy. They have ipsilateral or bilateral cortical dysplasia. It may suggest that one of the pathogenesis of SOD is a disruption of the anterior cerebral artery at embryonic site. SPECT was performed in 3 patients with cortical dysplasia. At cortical dysplasia area, CBF-SPECT and IMZ-SPECT showed the same RI count as the normal cortex. This finding is compatible with the fact that few patients with SOD have epileptic seizures.

Thyroid function in patients with selenium deficiency exhibits high free T4 to T3 ratio.

Selenium, one of the essential trace minerals, is present in vivo in form of selenoproteins. Iodothyronine deiodinase, a selenoprotein, is involved in the activation and inactivation of thyroid hormone. Therefore, patients with selenium deficiency may present changes in thyroid hormone levels due to inhibition of T4 to T3 conversion; however, this assumption is still under debate. In the present study, we retrospectively investigated the thyroid function in 22 patients with selenium deficiency. Thyroid stimulating hormone (TSH) and free T4 (FT4) levels were increased in 3 (14%) and 5 (23%) patients, respectively, and free T3 (FT3) levels were decreased in 6 (27%) patients. The FT4/FT3 ratio was significantly higher in patients with selenium deficiency than that in the control group. There appeared to be a positive correlation between the decreased rate of selenium levels and FT4/FT3 ratio, thereby indicating that patients with severe selenium deficiency also exhibited abnormal thyroid hormone levels. Furthermore, when selenium was supplemented in seven patients with abnormal thyroid hormone levels, the TSH, FT4, and FT4/FT3 ratio were significantly decreased and FT3 levels were increased. Collectively, patients with selenium deficiency could present the characteristics of not only low FT3 but also high FT4 and FT4/FT3 ratio.

Early television exposure and children's behavioral and social outcomes at age 30 months.

BACKGROUND: Previous research has suggested that television (TV) viewing may be associated with increased behavioral and emotional problems in children. However, there are few prospective studies targeted for its association with outcomes of children under 3 years old. The purpose of this study was to exam the association between children's early TV exposure at ages 18 and 30 months and the behavioral and emotional outcomes at age 30 months. METHODS: We analyzed data collected prospectively in the Japan Children's Study. TV exposure was assessed by mothers' report at infant ages of 18 and 30 months. The outcomes were assessed using the Strengths and Difficulties Questionnaire (SDQ). Analysis of Covariance was used to estimate the effect of TV exposure on behavioral and emotional outcomes. RESULTS: The percentage of children who watched TV 4 hours or more per day was 29.4% at age 18 months, 24.5% at age 30 months, and 21% at both ages. Hyperactivity-inattention at age 30 months was positively associated with TV exposure at age 18 months, whereas prosocial behavior was negatively associated with hours of exposure even after adjustment. However, there were no significant differences in SDQ subscales according to daily hours of TV viewing at age 30 months. CONCLUSIONS: Daily TV exposure at age 18 months was associated with hyperactivity-inattention and prosocial behavior at age 30 months. However, the directly casual relation was not proved in the present study. Additional research considering the TV program content and exposure timing are needed to investigate the causal relation between TV viewing and behavioral outcome.

Comparison of factors contributing to developmental attainment of children between 9 and 18 months.

BACKGROUND: Little is known about how contributing factors of development change during early childhood in Japan. The aim of this study was to investigate the factors that contributed to the developmental attainment of children between 9 and 18 months of age using prospective longitudinal data from a developmental cohort study. METHODS: We used data from observations at 3 time points (at infant age of 4, 9 and 18 months) in the Japan Children's Study. Mothers were administered questionnaires that requested information about their child's perinatal outcomes, temperament, family structure, family income, parental education, parenting stress, and child-rearing environment at home. At 9 and 18 months, mothers completed the Kinder Infant Development Scale to evaluate their child's development. RESULTS: A total of 284 children were available for analysis. Female children and children having siblings had higher probability of attaining developmental norms at 18 months than male and only children. Birth weight, gestational age, and temperament were associated with development at 9 months, but the effects of gestational age and temperament on development disappeared at 18 months. Stimulation from the mother at 9 months was not only related to development at that age but also promoted development at 18 months. CONCLUSIONS: Our findings suggest that the role of family environmental factors such as early mother's stimulation and sibling's existence in development during early childhood might become more important as the child gets older.

Head growth evaluation in early childhood, from the Japan Children's Study.

BACKGROUND: Head circumference (HC) trajectories are held to reflect neurological development and the acquirement of intelligence. It is important to assess HC growth accurately because atypical HC growth is an indicator of various developmental disorders. HC growth is determined by both familial and physical factors but, hitherto, no one has considered both factors together. The aim of the present study was thus to investigate the relationship between HC, physical growth, and parental HC. METHODS: The study group in the Japan Children's Study consisted of 192 healthy full-term Japanese children. HC (maximum occiptofrontal circumference), height and bodyweight were measured at the ages of 4, 9 and 18 months. Multiple regression analysis were conducted predicting the HC from the body measurements and mid-parental HC (defined as the average of standardized paternal and maternal HC). RESULTS: Adjusted multiple R(2) were 0.336, 0.307 and 0.259, measured at the aforementioned three stages. Bodyweight and mid-parental HC predicted the HC on each occasion (P < 0.01). Bodyweight was more relevant than mid-parental HC. CONCLUSIONS: HC growth is influenced by physical growth and parental HC; therefore, it is important to consider both physical and familial factors. A formula is herein proposed to assess HC using bodyweight and mid-parental HC.

[Laterality of upper extremity movements in infancy: observations at 4 and 9 months of age].

This study investigated the process involved in the lateralization of movements during infancy by observing upper extremity movements in a laboratory setting. Reaching for flying rings, balls, mini toy cars, and small round cookies were observed and recorded by videotape at 4 and 9 months of age. The subjects were 202 infants who participated in Japan Children's Study, a cohort study on the development of sociability. Infants reached for objects significantly more frequently at 9 months (98%) than at 4 months (40%) (p<0.001). Though the lateral preference in reaching for balls at 4 months was ambiguous, reaching for toy cars was performed more frequently with the right hand at 9 months (50%) than with the left one (19%) (p<0.01). Lateralization of the upper extremity movements is thought to appear by 9 months.