Craniofacial and dental characteristics of three Japanese individuals with genetically diagnosed SATB2-associated syndrome.

Craniofacial defects are one of the most frequent phenotypes in syndromic diseases. More than 30% of syndromic diseases are associated with craniofacial defects, which are important for the precise diagnosis of systemic diseases. Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is a rare syndromic disease associated with a wide variety of phenotypes, including intellectual disability and craniofacial defects. Among them, dental anomalies are the most frequently observed phenotype and thus becomes an important diagnostic criterion for SAS. In this report, we demonstrate three Japanese cases of genetically diagnosed SAS with detailed craniofacial phenotypes. The cases showed multiple dental problems, which have been previously reported to be linked to SAS, including abnormal crown morphologies and pulp stones. One case showed a characteristic enamel pearl at the root furcation. These phenotypes add new insights for differentiating SAS from other disorders.

Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Novel compound heterozygous EPG5 mutations consisted with a missense mutation and a microduplication in the exon 1 region identified in a Japanese patient with Vici syndrome.

Vici syndrome is a rare, autosomal recessive, multisystem disorder, characterized by agenesis of the corpus callosum, cataracts, psychomotor delay, cardiomyopathy, hypopigmentation, and recurrent infections. Mutations in the ectopic P-granules autophagy protein 5 homolog gene (EPG5), which encodes a key autophagy regulator, are responsible for this syndrome. A 3-year-old Japanese girl manifesting similar symptoms to those found in patients with Vici syndrome showed intractable diarrhea, rather than immunodeficiency. Whole exome sequencing identified only a heterozygous variant in EPG5, NM_020964.2(EPG5):c.3389A > C (p.His1130Pro), which was inherited from her mother. Sequencing analyses of the EPG5 messenger RNA showed only an altered nucleotide "C" at position, c.3389, indicating decreased expression of the wild-type allele. Microarray-based comparative genomic hybridization revealed a de novo microduplication in the exon 1 region. Large exon deletions and duplications of EPG5 have never been reported so far. This was considered the cause of the decreased expression of the wild-type allele. In conclusion, we successfully identified novel compound heterozygous mutations in EPG5 in a patient who was clinically considered to have Vici syndrome.

Clinical manifestations of Xq28 functional disomy involving MECP2 in one female and two male patients.

Subtelomeric imbalances are a frequent cause of cytogenetic abnormalities in patients with unexplained intellectual disability. Functional disomy of Xq28 involving the methyl-CpG-binding protein 2 gene (MECP2) has been observed mostly in subtelomeric duplications. We identified three patients with functional disomy of Xq28. A female patient showed an unbalanced translocation between 12q24.33 and Xq28. Two male patients showed an unbalanced translocation between Xq27.1- Yq11.22 and a recombinant X-chromosome containing duplicated material from Xq27.1 on Xp telomere, respectively. All three patients exhibited severe developmental delay, hypotonia, seizures, and distinctive facial features, including flat nasal bridge and hypertelorism. Additionally, brain magnetic resonance imaging (MRI) showed characteristic findings in each patient, including frontal dominant brain atrophy and hypoplasia of the corpus callosum, which are common findings in patients with functional disomies of Xq28 and interstitial duplications of Xq28, including MECP2. Brain MRI revealed a cystic lesion in the periventricular white matter in a patient, similar to our previous experience in patients with MECP2 duplication syndrome. Thus, white matter abnormalities may frequently be seen in cases of patients with additional MECP2 copies. © 2013 Wiley Periodicals, Inc.

[Pre-evening meal administration of tacrolimus improved refractory ocular symptoms in two young children with latent general myasthenia gravis].

We report two patients with latent general myasthenia gravis (MG) with refractory ocular symptoms who were successfully treated with pre-evening meal administration of tacrolimus. Patient 1 was a 4-year-old girl with persistent ocular symptoms despite high-dose steroid therapy and thymectomy. Oral tacrolimus was initiated at the age of 3 years, which was resulted in complete resolution of symptoms. After one year, hemilateral ptosis recurred. The plasma consentration of tacrolimus was very low, probably due to sudden weight gain. Increasing the dose and a change from post- to pre-evening meal administration of tacrolimus enabled maintenance of its concentration and complete control of ocular symptoms. Patient 2 was a 2-year-old boy whose symptoms were refractory to steroid therapy after his first relapse. Since post-meal administration of tacrolimus provided partial benefit, the closing schedule was changed to pre-evening meal administration, with good results. Neither patient had adverse effects of tacrolimus. It is difficult to maintain an effective tacrolimus concentration in children due to marked growth and rapid metabolic rates. Pre-evening meal administration of tacrolimus is an easy, safe and useful method of treatment in MG young children.

Secular trends in early motor development between 1980 and 2010 in Japan.

OBJECTIVE: Recent changes in birth characteristics in Japan may have a potential influence on children's developments. Therefore, we investigated secular trends in gross motor milestones. DESIGN: Data were collected from an official Japanese nationwide serial cross-sectional survey conducted every 10 years since 1960. 22 320 participants aged 2-18 months were identified from the four surveys from 1980 to 2010. OUTCOMES: We assessed whether or not a child achieved four gross motor milestones including rolling over (rolling), sitting without support (sitting), standing with support (standing) and walking alone (walking). The target age was defined as the age when the attainment rate ranged from >5% to >95% of the total. Multivariate logistic regression models were fitted. RESULTS: The final cohort included 20 570 children. The target ages were determined as follows: 3-6 months for rolling; 5-9 months for sitting; 6-11 months for standing; and 9-15 months for walking. The attainment rates of sitting, standing and walking in 1990 were higher than those in 2010, even after adjusting for child characteristics (sitting: adjusted OR (aOR)=2.07 (95% CI 1.62 to 2.65); standing: aOR=1.63 (95% CI 1.32 to 2.02); and walking: aOR=1.61 (95% CI 1.34 to 1.95)). CONCLUSIONS: The proportion of children who attained three motor milestones (sitting, standing and walking) by set target ages decreased between 1990 and 2010. The contribution of birth characteristics including a decrease in gestational age and fetal growth, as well as changes in other child characteristics, failed to explain why this decrease occurred.

CDKL5 alterations lead to early epileptic encephalopathy in both genders.

PURPOSE: Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. METHODS: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. KEY FINDINGS: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. SIGNIFICANCE: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.

STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome--result of Japanese cohort study.

We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox-Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct-sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause.

Microdeletion in Xq28 with a polymorphic inversion in a patient with FLNA-associated progressive lung disease.

Lung phenotype was reported as a novel phenotype in patients with mutations in the filamin A gene (FLNA) in 2011. FLNA mutations can result in pulmonary hyperinflation during the neonatal period or early infancy with progressive respiratory failure, culminating in a diagnosis of FLNA-associated progressive lung disease, particularly if the patient has periventricular nodular heterotopia and cardiac complications, such as patent ductus arteriosus, atrial septal defect, and pulmonary hypertension. We report the first Japanese case of FLNA-associated progressive lung disease caused by a microdeletion in Xq28 encompassing the FLNA gene with a polymorphic inversion.

[Topics on Child Development in Pediatrics].

Over the past few decades, advances in neonatal medicine have increased survival rates among very-low-birth-weight (VLBW) babies. Despite improvements in short-term outcomes, there is increasing concern about the probability of mild cognitive dysfunction in this population. Our analysis of VLBW babies born in our hospital revealed that the incidence of mild developmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactive disorder (ADHD) at the age of 3 years is 7.2%, which is markedly higher than the 2.8% incidence of ASD in the general population. Because problems related to ASD or ADHD tend to become more prominent as children grow up, the ages at diagnosis of developmental disorders are generally 6 years or above. Thus, in our follow up study of VLBW babies at age 6, the incidence of these developmental disorders had risen to 30%. These patients are apparently obstinate and difficult to train, causing parental problems with child care. It is important to support these children and help them establish good relationships with their parents. Given these problems, it is necessary to follow up VLBW children in the longterm, at least until they are elementary school students.

Cerebral Palsy and Intellectual Disability in the Children of Women With Chronic Kidney Disease.

BACKGROUND: This study examined the risk of adverse maternal and neonatal outcomes, especially cerebral palsy and intellectual disability, in pregnant women with and without chronic kidney disease and their children. METHOD: In total, 156 pregnancies involving 139 women with chronic kidney disease who were treated at our center between 2001 and 2010 were identified. We also selected 3067 women without chronic kidney disease who delivered their infants without suffering any medical complications during the same period as control groups. Long-term neonatal prognosis was assessed based on the frequencies of cerebral palsy and/or intellectual disability. RESULTS: The pregnant women had the following types of chronic kidney disease: immunoglobulin A nephropathy (n = 54), glomerulonephritis (n = 17), chronic renal failure (n = 16), nephrotic syndrome (n = 12), nephritis (n = 11), diabetic nephropathy (n = 10), congenital malformations and deformations (n = 10), purpura nephritis (n = 7), and others (n = 19). Of the children who were born to mothers with chronic kidney disease, one developed cerebral palsy, and another developed cerebral palsy with intellectual disability. Seven of the children who were born to mothers without chronic kidney disease developed cerebral palsy. The posterior probability of these conditions was 0.01900 and 0.002610 in the children born to mothers with and without chronic kidney disease, respectively. A primiparous mother (odds ratio [OR]: 4.07, 95% confidence interval [CI]): 2.78 to 5.95), preeclampsia (OR: 6.44, 95% CI: 3.92 to 10.59), grade 1 to 4 intraventricular hemorrhaging (OR: 7.71, 95% CI: 2.05 to 28.92), and an Apgar score of less than 7 at five minutes (OR: 0.51, 95% CI: 0.27 to 0.96) were found to influence the risk of cerebral palsy and/or intellectual disability in children born to women with chronic kidney disease. CONCLUSION: We found that the incidence of cerebral palsy and/or intellectual disability is 7.2-fold higher in children born to women with chronic kidney disease than in those born to women without chronic kidney disease.

Surveillance of group B streptococcal toxic shock-like syndrome in nonpregnant adults and characterization of the strains in Japan.

Nine group B streptococci (GBS) strains were isolated from five toxic shock-like syndrome cases of nonpregnant adults in Japan from 2001 to 2005. All of them were identified as Streptococcus agalactiae. The serotypes of these strains were Ib, III, V, and VII. Pulsed-field gel electrophoresis revealed that the patterns of the strains isolated from the different patients were variable. Antimicrobial susceptibility tests showed that all of the strains were susceptible to penicillin G, ampicillin, cefotaxime, clindamycin, and telithromycin. One strain showed intermediate resistance to erythromycin.

Molecular mechanisms of high level tetracycline-resistance in group A streptococcal isolates, T serotypes 4 and 11.

The molecular mechanism of high level tetracycline resistance in T serotypes 4 and 11 group A streptococcal (GAS) isolates was examined in 61 tetracycline-resistant isolates in Japan. PCR and sequencing analyses revealed that the T serotype/emm genotype, T4/4 isolates carried tet(O) genes, which were genetically homogenous. The T11/11 and T11/89 isolates carried different subtypes of tet(M) genes, which were present on transposons Tn916 and Tn1545, respectively. In addition, these T11 isolates may have obtained the tet(M) gene after the 1990s, because resistance to tetracycline in T11 isolates was rarely found before then. These results strongly suggested that the T4 and T11 GAS isolates acquired tetracycline-resistance via different molecular mechanisms.

Probability distributions of the electroencephalogram envelope of preterm infants.

OBJECTIVE: To determine the stationary characteristics of electroencephalogram (EEG) envelopes for prematurely born (preterm) infants and investigate the intrinsic characteristics of early brain development in preterm infants. METHODS: Twenty neurologically normal sets of EEGs recorded in infants with a post-conceptional age (PCA) range of 26-44 weeks (mean 37.5 ± 5.0 weeks) were analyzed. Hilbert transform was applied to extract the envelope. We determined the suitable probability distribution of the envelope and performed a statistical analysis. RESULTS: It was found that (i) the probability distributions for preterm EEG envelopes were best fitted by lognormal distributions at 38 weeks PCA or less, and by gamma distributions at 44 weeks PCA; (ii) the scale parameter of the lognormal distribution had positive correlations with PCA as well as a strong negative correlation with the percentage of low-voltage activity; (iii) the shape parameter of the lognormal distribution had significant positive correlations with PCA; (iv) the statistics of mode showed significant linear relationships with PCA, and, therefore, it was considered a useful index in PCA prediction. CONCLUSION: These statistics, including the scale parameter of the lognormal distribution and the skewness and mode derived from a suitable probability distribution, may be good indexes for estimating stationary nature in developing brain activity in preterm infants. SIGNIFICANCE: The stationary characteristics, such as discontinuity, asymmetry, and unimodality, of preterm EEGs are well indicated by the statistics estimated from the probability distribution of the preterm EEG envelopes.

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.

The relationship between mismatch negativity and arousal level. Can mismatch negativity be an index for evaluating the arousal level in infants?

BACKGROUND: Electrophysiological and behavioral studies have shown that stimulus relevance contributes to auditory processing in sleep and auditory stimuli changes the sleep stages. So we observed changes in auditory processing due to sleep stages by recording infant mismatch negativity (MMN) during different states and investigated the arousal mechanisms. METHODS: Auditory event-related potentials (ERPs) of 26 neonates were recorded using high-density EGI EEG system. Stimuli consisted of 1000 Hz tones with 90% probability as standard and 1200 Hz with 10% probability as deviant. Study 1 was designed for the confirmation of the recording of MMN from neonates and Study 2 for investigating whether an appropriate stimulus onset asynchrony (SOA) of the stimulus would induce a clear difference in the latency or amplitude. RESULTS: (Study 1) MMN were obtained from all subjects. No differences of the latencies, amplitudes and distribution due to arousal or sleep stage were observed. After the MMN response occurred, a prominent negativity like Nc was seen in response to deviant stimuli in active sleep and waking state. (Study 2) No distinct differences between the difference states were seen in any SOA. CONCLUSIONS: Only MMN did not characterize the arousal or sleep stage. But the modality of the auditory evoked potentials (AEPs) may differ according to the state, so further detailed investigation could enable the detection of the infants' state using the AEP.

Functional brain imaging using fMRI and optical topography in infancy.

We performed functional magnetic resonance imaging and optical topography over the visual cortex of subjects during sedation with pentobarbital, and 8-Hz flickering light was intermittently projected onto their eyelids. Two age groups were analyzed: infants <60 days old and those >60 days old (corrected for gestational age at birth). The stimulus-related signal change was positive in the lateral geniculate nucleus regardless of the infant's age, but it reversed in the primary visual cortex from positive in the infants less than 60 days old to negative in the infants more than 60 days old (Experiment 1). We also investigated spontaneous changes in the cerebral oxygenation state of neonates and infants aged 1 month during quiet sleeping by using a form of multi-channel near-infrared spectroscopy: non-invasive optical topography. Spatially synchronized oscillations of changes in the concentration of oxy-hemoglobin (oxy-Hb) and deoxy-Hb were observed throughout the occipital cortex in neonates but not in the infants aged 1 month. Time series analysis based on the theory of non-linear oscillations showed that the mean periods of the oscillation for each infant ranged from 11 to 18s. The phase lag of oxy-Hb relative to deoxy-Hb was stable at about 3 pi/4 in neonates but in the infant aged 1 month, time lag was unstable. These findings may be due to rapid synaptogenesis in early life.

Hemodynamic responses to visual stimulation in occipital and frontal cortex of newborn infants: a near-infrared optical topography study.

A near-infrared optical topography (OT) was used to reveal spatio-temporal changes in the cerebral oxygenation of newborn infants in response to brief visual stimulation. Newborn infants were presented 3-s stroboscopic light flashing at 14 Hz during spontaneous sleep. Event-related changes in oxy- and deoxyhemoglobin ([oxy-Hb] and [deoxy-Hb]) were observed over the occipital and frontal cortex. The visual stimulus produced statistically significant increases in oxyhemoglobin not only in the occipital cortex but also in the prefrontal cortex. These results suggest that the cerebrovascular coupling is already functioning in newborn's brain. The prefrontal activation implies that it may contribute to early processing of sensory signals.