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.

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.

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.

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.

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.

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.

Risk factors of malnutrition in children with severe motor and intellectual disabilities.

BACKGROUND: Children with severe motor and intellectual disabilities (SMID) are at a high risk of malnutrition and often require tube feeding to maintain their nutritional status. However, determining their energy requirements is difficult since inadequate dietary intake, severe neurological impairment, respiratory assistance, and cognitive impairment are all factors that affect malnutrition in SMID. AIM: This study investigated the factors affecting malnutrition and identified problems affecting the nutritional status of children with SMID. METHODS: Forty-two children with SMID with oral motor dysfunction who were receiving home medical care at one of four hospitals were enrolled. Their nutritional status was assessed using a 3-day dietary record, anthropometric measurements, and laboratory tests. The clinical findings associated with malnutrition were compared, and a body mass index (BMI) z-score less than -2SD was defined as malnutrition. The relationship between BMI z-score and other potential predictors was also investigated. RESULTS: Thirty-three (79%) children received tube feeding, and 20 (48%) experienced malnutrition. The median age of the malnourished children was older than that of non-malnourished children. Respiratory assistance was significantly correlated with higher BMI z-score, independent of other potential confounders such as nutrition method, muscle tonus, and energy intake. Cholesterol levels were significantly higher in children receiving a standard infant formula beyond 3 years of age than in those who switched to enteral formula before 3 years of age. CONCLUSIONS: Malnutrition in children with SMID was mainly associated with age or respiratory condition. Energy requirements should be regularly re-evaluated with considering these factors.

Integrated DNA methylation analysis reveals a potential role for ANKRD30B in Williams syndrome.

Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.

Dysregulation of the oxytocin receptor gene in Williams syndrome.

Williams syndrome (WS) is caused by a microdeletion of chromosome 7q11.23, and is characterized by various physical and cognitive symptoms. In particular, WS is characterized by hypersocial (overfriendly) behavior; WS has gained attention as aspects of the WS phenotype contrast with those of autism spectrum disorder (ASD). The oxytocin receptor gene (OXTR) contributes to social phenotypes in relation to regulation of oxytocin (OXT) secretion. Additionally, mounting evidence has recently shown that DNA methylation of OXTR is associated with human social behavior. However, the role of OXTR in WS remains unclear. This study investigated the regulation of OXTR in WS. We examined the gene expression levels in blood from WS patients and controls, and then analyzed the methylation levels in two independent cohorts. We showed that OXTR was down-regulated and hypermethylated in WS patients compared to controls. Our findings may provide an insight into OXTR in mediating complex social phenotypes in WS.

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.

Williams-Beuren Syndrome as a Potential Risk Factor for Burkitt Lymphoma.

Williams-Beuren syndrome (WBS) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion on chromosome 7q11.23. Though at present there is a limited number of reports on WBS patients with tumors, most cases are related to blood cancer in children with WBS. We describe a case of Burkitt lymphoma in a 21-year-old man with WBS. In addition to providing a summary of published reports describing tumors observed in patients with WBS, we present a hypothesis about a possible mechanism of oncogenesis. In particular, we identified some significantly dysregulated cancer-related genes using blood samples from this patient at the age of 19 years (who have not yet developed Burkitt lymphoma). Our findings may provide a new perspective on the relation between WBS and Burkitt lymphoma.

[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.

A case of succinic semialdehyde dehydrogenase deficiency with status epilepticus and rapid regression.

BACKGROUND: Clinical phenotypic expression of SSADH deficiency is highly heterogeneous, and some infants may develop refractory secondary generalized seizures. PATIENT: A 9-month-old boy manifested partial seizures, developing severe status epilepticus, and conventional antiepileptic drugs were ineffective. Use of ketamine contributed to the control of status epilepticus, achieving a reduction in frequency of partial seizures, and improving EEG findings without apparent complications. Diffusion-weighted images showed hyperintensities in the bilateral basal ganglia and fornix, and multiple T2 hyperintensity lesions were detected. (123)I-iomazenil (IMZ) SPECT revealed a decrease in binding of (123)I-iomazenil predominantly in the left temporal region by the 18th day of hospitalization. However, repeated IMZ-SPECT on the 46th day of hospitalization demonstrated almost no accumulation across a broad region, sparing the left temporal region. The patient showed rapid regression, refractory myoclonus, and severe progressive brain atrophy. CONCLUSION: IMZ-SPECT findings demonstrated reduced benzodiazepine receptor binding and its dynamic changes in an SSADH-deficient patient. Considering the down regulation of the GABAA receptor, ketamine should be included in pharmacotherapeutic strategies for treatment of refractory status epilepticus in SSADH-deficient patients.

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.

Early Detection and Treatment of Neuroblastic Tumor with Opsoclonus-Myoclonus Syndrome Improve Neurological Outcome: A Review of Five Cases at a Single Institution in Japan.

INTRODUCTION: Opsoclonus-myoclonus syndrome (OMS) is a paraneoplastic neurological disorder associated with neuroblastic tumor (NT) in childhood. Half of patients have neurological sequelae after the neurological and oncological treatment. We reviewed the neurological and oncological outcomes of NT with OMS, and discussed whether the treatment of NT would contribute to improving the neurological prognosis. METHODS: We retrospectively assessed NT patients with OMS from January 2001 to December 2013 at a single institution in Japan. Demographic data, neurological and oncological status, histopathology, treatments, prognosis, and diagnosis and treatment timing were retrospectively reviewed from the records. The timings assessed were the interval between OMS onset and NT detection, initial NT therapy, and initial OMS therapy, the interval between NT therapy and OMS remission, and duration of OMS. RESULTS: A total of 73 patients with NT were treated during the study period, and 5 of 73 patients were diagnosed as having NT with OMS. The median age at onset of OMS was 22 months (range, 18-30 months). The median age at detection of NT was 29 months (range, 21-33 months). Three of five cases showed no uptake on meta-iodobenzylguanidine scintigraphy. The tumor histopathology was neuroblastoma in two patients, ganglioneuroblastoma in two patients, and ganglioneuroma in one patient. Primary resection was performed in three cases. All patients survived. Two of five cases presented with atypical neurological symptoms without opsoclonus. The initial neurological therapy was started within a mean of 20 days (range, 3-76 days) from the onset of OMS in all cases. Four patients received intravenous immunoglobulin, and one with persistent neurological problems received rituximab. Neurological symptoms resolved in three cases. The mean interval between the onset of OMS and the detection of NT in case without neurological sequelae was 57 days (range, 25-113 days), while in case with neurological sequelae it was 365 days (range, 271-458 days). The mean interval between onset of OMS and initial therapy for NT in case without neurological sequelae was 88 days (range, 47-145 days), while in case with neurological sequelae it was 389 days (range, 292-486 days). CONCLUSION: The interval between the onset of OMS and the detection and initial therapy of NT tended to be longer in patients with neurological sequelae than in those without neurological sequelae. This study suggested that early detection and treatment of NT with OMS might improve the neurological outcomes.

Influence of sleep-onset time on the development of 18-month-old infants: Japan Children's cohort study.

OBJECTIVE: We report here the influence of sleep patterns on the development of infants in Japan. A total of 479 infants were registered in two different Japanese cities. Direct neurological observations were performed by licensed pediatric neurologists. METHOD: We designed a prospective cohort study and identified the sleep factors of children showing atypical development. The Kinder Infant Developmental Scale (KIDS) was used to evaluate the infant developmental quotient (DQ); we also applied a neurobehavioral screening battery. Neurobehavioral observations in 18-month-old infants were designed to check all developmental categories within the three areas of motor function, language, and social function. Based on the observations, each infant was classified as having "atypical development" or "typical development". RESULT: We found that later sleep onset time (>22:00 h), and longer naps during the day each had significant positive correlations with atypical development patterns in 18-month-old infants. For each hour the infant sleep-onset time extended past 22:00 h, the infants showed worse neurodevelopmental outcomes, at an odds ratio increase of 2.944. CONCLUSION: Although our results may be confounded by sleep problems resulting from pre-existing developmental disabilities, we can safely conclude that appropriate sleeping habits are important for healthy development in 18-month-old infants.

[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.

Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications.

OBJECTIVE: Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. METHOD: In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. RESULTS: We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. CONCLUSION: The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.

Carnitine in severely disabled patients: relation to anthropometric, biochemical variables, and nutritional intake.

BACKGROUND: Carnitine plays a pivotal role in a variety of cellular functions. Carnitine deficiency often occurs in severely disabled patients, especially under valproic acid administration. However, the possible causative factors underlying carnitine deficiency have not been fully identified. The present study aimed at clarifying the association of various anthropometric and biochemical variables, including dietary intake of carnitine, with carnitine levels in severely disabled patients. METHODS: Twenty-six severely disabled patients (mean age: 14.1 years; s.d. 7.8) were enrolled. Plasma carnitine levels were evaluated by an enzyme cycling assay. Estimation of the dietary intake of carnitine was made based on dietary records over a 3-day period. RESULTS: Plasma total and free carnitine levels in patients were significantly lower than those in controls obtained from the previous report. However, the ratios of free carnitine to total carnitine did not change significantly. Free carnitine levels were well correlated with a nutritional intake of carnitine. Administration of not only valproic acid but also other anti-epileptic drugs was found to cause a significant decrease of free carnitine levels after adjusting the nutritional intake of carnitine. Among various anthropometric or biochemical variables, albumin and uric acid showed a significant correlation with free carnitine levels. CONCLUSIONS: Physicians should be aware of the fact that severely disabled patients are at risk for carnitine deficiency even in the absence of valproic acid administration, and pay more attention to the nutritional intake of carnitine.