Stem cell transplantation for pediatric patients with adrenoleukodystrophy: A nationwide retrospective analysis in Japan.

BACKGROUND: Adrenoleukodystrophy (ALD) is an X-linked recessive disorder and 30-40% of patients develop progressive cerebral neurodegeneration. For symptomatic ALD patients, allogeneic stem cell transplantation (SCT) is considered the standard treatment modality to stabilize or prevent the progression of neurological symptoms. METHODS: We retrospectively analyzed the transplant outcomes of 99 pediatric patients with cerebral ALD in Japan. The conditioning regimens included Regimen A: fludarabine/melphalan/low-dose total body irradiation (TBI) with brain sparing (n = 39), Regimen B; busulfan/cyclophosphamide ± others (n = 23), Regimen C: melphalan/total lymphoid irradiation/thoracoabdominal irradiation ± anti-T lymphocyte globulin ± fludarabine (n = 27), and Regimen D: others (n = 10). RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 90.0% and 72.9%, respectively. The 5-year OS was 100.0% for Regimen A, 91.1% for Regimen B, 84.4% for Regimen C, and 67.5% for Regimen D (p = 0.028). The 5-year EFS was 78.3% for Regimen A, 78.0% for Regimen B, 70.4% for Regimen C, and 48.0% for Regimen D (p = 0.304). The OS marginally improved after 2007 compared with before 2006 (95.3% vs. 85.2%, p = 0.066), due to the improvement of cord blood transplantation (CBT) outcomes after 2007 compared with before 2006 (96.6% vs. 68.4%, p = 0.005). On magnetic resonance imaging of the brain, a reduced Loes score after SCT was only observed in one of the 15 bone marrow transplantation (BMT) patients, but in 5 of the 15 CBT patients (p = 0.173). CONCLUSIONS: Our study revealed that a reduced conditioning regimen with fludarabine/melphalan/low-dose TBI provides better outcomes, and the results of CBT significantly improved after 2007.

Osteoporosis pathology in people with severe motor and intellectual disability.

OBJECTIVES: We assessed the severity and pathology of osteoporosis in children and adults with severe motor and intellectual disabilities (SMID) by evaluating bone enzymes, by which we aimed to determine adequate treatment approaches for preventing fractures. METHODS: Ninety patients (44 men, 46 women; mean age, 34.5 years) underwent bone quality assessment. Quantitative ultrasonography (QUS) was used to measure the T-score and Z-score of the calcaneus, and blood tests were used to measure bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b levels as bone formation and resorption markers, as well as calcium, phosphorous, and parathyroid hormone levels as routine examination. RESULTS: Bone formation and resorption marker levels were within normal ranges in adults, although they were high during the growth period in children and adolescents and in elderly women. Patients receiving tube feeding showed a significantly lower Z-score than those without tube feeding. Tube feeding was a significant factor for the Z-score, whereas age, vitamin supplements, and anti-epileptic drugs were not. CONCLUSIONS: The severity of osteoporosis in SMID started during the growth period and seems to be caused by a lack of an effective increase in bone mineral density. Any treatment should be started during the growth period. More study about tube feeding is needed.

Elimination of amyloid precursor protein in senile plaques in the brain of a patient with Alzheimer-type dementia and Down syndrome.

The average lifespan of individuals with Down syndrome has approximately doubled over the past three decades to 55-60 years. To reveal the pathogenic process of Alzheimer-type dementia in individuals with Down syndrome, we immunohistochemically examined senile plaque formation in the cerebral cortex in the autopsy brain and compared findings with our previous studies. We described a 52-year-old female with Down syndrome who developed progressively more frequent myoclonus following cognitive decline and died at the age of 59 years. Her karyotype [46XX, inv(9)(p12q13), i(21)(q10)] included triplication of the gene for amyloid precursor protein and the Down syndrome critical region. On microscopy, very few gamma-aminobutyric acid-ergic (GABAergic) neurons, in the form of small granular cells, in the cortex and Purkinje cells in the cerebellum were visible. In our previous study, amyloid precursor protein immunoreactivity was first noted in senile plaques at the age of 32 years. In this patient, even though amyloid ß immunoreactivity was detected in the cores of senile plaques and diffuse plaques, amyloid precursor protein immunoreactivity was not noted in senile plaques in the frontal cortex. Amyloid precursor protein and its derivative amyloid-ß play an important role in the formation of senile plaques and the time course of immunoreactive expression may be related to the pathogenic process of Alzheimer-type dementia.

Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy.

OBJECTIVE: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. PATIENTS: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). RESULTS: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. CONCLUSION: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

Potential identification of vitamin B6 responsiveness in autism spectrum disorder utilizing phenotype variables and machine learning methods.

We investigated whether machine learning methods could potentially identify a subgroup of persons with autism spectrum disorder (ASD) who show vitamin B6 responsiveness by selected phenotype variables. We analyzed the existing data from our intervention study with 17 persons. First, we focused on signs and biomarkers that have been identified as candidates for vitamin B6 responsiveness indicators. Second, we conducted hypothesis testing among these selected variables and their combinations. Finally, we further investigated the results by conducting cluster analyses with two different algorithms, affinity propagation and k-medoids. Statistically significant variables for vitamin B6 responsiveness, including combination of hypersensitivity to sound and clumsiness, and plasma glutamine level, were included. As an a priori variable, the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores was also included. The affinity propagation analysis showed good classification of three potential vitamin B6-responsive persons with ASD. The k-medoids analysis also showed good classification. To our knowledge, this is the first study to attempt to identify subgroup of persons with ASD who show specific treatment responsiveness using selected phenotype variables. We applied machine learning methods to further investigate these variables' ability to identify this subgroup of ASD, even when only a small sample size was available.

[A case of prolonged paroxysmal sympathetic hyperactivity].

We report the case of a 4-year-old girl who presented with paroxysmal sympathetic hyperactivity (PSH), after developing severe hypoxic-ischemic-encephalopathy because of cardiopulmonary arrest. She showed dramatic paroxysmal sympathetic activity with dystonia. She was treated with wide variety of medications against PSH, which were found to be effective in previous studies. Among them, morphine, bromocriptine, propranolol, and clonidine were effective in reducing the frequency of her attacks while gabapentin, baclofen, dantrolene, and benzodiazepine were ineffective. Though the paroxysms decreased markedly after the treatment, they could not be completely controlled beyond 500 days. Following the treatment, levels of plasma catecholamines and their urinary metabolites decreased to normal during inter- paroxysms. However, once a paroxysm had recurred, these levels were again very high. This case study is considered significant for two rea- sons. One is that PSH among children have been rarely reported, and the other is that this case of prolonged PSH delineated the transition of plasma catecholamines during the treatment. The excitatory: inhibitory ratio (EIR) model proposed by Baguley was considered while dis- cussing drug sensitivity in this case. Accumulation of similar case studies will help establish more effective treatment strategies and elucidate the pathophysiology of PSH.

The Association between Children's Behavior and Parenting of Caregivers: A Longitudinal Study in Japan.

The purpose of this study was to elucidate the association between children's behavior (i.e., prosocial and problematic behavior) and the parenting style (i.e., laxness and overreactivity) of their caregivers by using longitudinal data in the Japanese population. These data were collected when the children were 7.5 and 9 years. We proposed three hypotheses: children's behavior at 7.5 years will predict their behavior at 9 years; children's behavior at 7.5 years will predict the parenting of their caregivers; and the parenting style of caregivers will affect their children's behavior at 9 years. We evaluated children's behavior and parenting behavior using a strength and difficulties questionnaire and a parenting scale. The hypotheses were tested using structural equation modeling (SEM). The results of the SEM showed that children's behavior at 7.5 years predicted their behavior at 9 years. Children's problematic behavior at 7.5 years triggered overreactive parenting in their caregivers at 9 years, which increased problematic behavior and decreased prosocial behavior in the children at 9 years. These findings indicate the association between children's behavior and the parenting style of caregivers in Japan.

Development and Evaluation of a Parenting Resilience Elements Questionnaire (PREQ) Measuring Resiliency in Rearing Children with Developmental Disorders.

We developed a parenting resilience elements questionnaire (PREQ) measuring the degree to which mothers possess elements that aid in adapting to challenges and difficulties related to children with developmental disorders (DD). A total of 424 parents of children with DD were recruited from five medical institutes. Psychometric properties of PREQ were evaluated using data of 363 mothers of children with DD. Furthermore, multiple regression analysis was performed, predicting depressive symptoms and parenting behavior with PREQ subscales, a general health questionnaire, and the total difficulties score of a strength and difficulties questionnaire. Factor analysis revealed three reliable factors: "knowledge of the child's characteristics," "perceived social supports," and "positive perceptions of parenting." Moreover, multiple regression analysis showed that "knowledge of the child's characteristics" was associated with parenting behavior, whereas "perceived social supports" predicted depressive symptoms; "positive perceptions of parenting" influenced both parenting behavior and depressive symptoms. These findings indicated that the PREQ may be used as a scale measuring resiliency in mothers of children with DD and is useful for evaluating their parenting ability in clinical interventions.

Artificial oxygen carriers rescue placental hypoxia and improve fetal development in the rat pre-eclampsia model.

Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.

[Parenting resilience for rearing a child with autism spectrum disorder: a qualitative study].

OBJECTIVE: Resilience is defined as the dynamic process of positive adaptation despite the experience of adversity. The aims of this study were to apply the concept of resilience to the mothers of children with autism spectrum disorder (ASD), which we call "parenting resilience" for rearing a child with ASD, and to explain the construct of parenting resilience. METHODS: Interviews were conducted with 23 mothers of adults with ASD to collect data on rearing these children from infancy to adulthood. Data were analyzed using a modified grounded-theory approach. RESULTS: The analytic theme was the thought process from the problems associated with raising developmentally challenged children to the implementation of the appropriate coping method. We proposed a model comprising twelve concepts and five categories, i. e., "a sense of motherhood", "self-efficacy", "knowledge of the child's characteristics", "perceived social support", and "foresight". The model assumes that a sense of motherhood and self-efficacy motivate these mothers to cope with the problems associated with developmentally challenged children, and they derive the way of dealing with it from knowledge of the child's characteristics, perceived social support, and foresight. DISCUSSION: We suggest that the construct of parenting resilience for rearing a child with ASD is composed of the proposed categories and concepts.

Auditory agnosia as a clinical symptom of childhood adrenoleukodystrophy.

OBJECTIVE: To investigate detailed auditory features in patients with auditory impairment as the first clinical symptoms of childhood adrenoleukodystrophy (CSALD). SUBJECTS AND METHODS: Three patients who had hearing difficulty as the first clinical signs and/or symptoms of ALD. Precise examination of the clinical characteristics of hearing and auditory function was performed, including assessments of pure tone audiometry, verbal sound discrimination, otoacoustic emission (OAE), and auditory brainstem response (ABR), as well as an environmental sound discrimination test, a sound lateralization test, and a dichotic listening test (DLT). The auditory pathway was evaluated by MRI in each patient. RESULTS: Poor response to calling was detected in all patients. Two patients were not aware of their hearing difficulty, and had been diagnosed with normal hearing by otolaryngologists at first. Pure-tone audiometry disclosed normal hearing in all patients. All patients showed a normal wave V ABR threshold. Three patients showed obvious difficulty in discriminating verbal sounds, environmental sounds, and sound lateralization and strong left-ear suppression in a dichotic listening test. However, once they discriminated verbal sounds, they correctly understood the meaning. Two patients showed elongation of the I-V and III-V interwave intervals in ABR, but one showed no abnormality. MRIs of these three patients revealed signal changes in auditory radiation including in other subcortical areas. CONCLUSION: The hearing features of these subjects were diagnosed as auditory agnosia and not aphasia. It should be emphasized that when patients are suspected to have hearing impairment but have no abnormalities in pure tone audiometry and/or ABR, this should not be diagnosed immediately as psychogenic response or pathomimesis, but auditory agnosia must also be considered.

Epidemiological study of Landau-Kleffner syndrome (LKS) in Japan.

OBJECTIVE: We aimed to determine the incidence and prevalence of LKS in Japanese children. METHODS: A questionnaire was sent to all 3004 Japanese hospitals that have a department of pediatrics. The questionnaire asked for the number of first-visit LKS patients and LKS patients who were followed up at or visited their clinic during the past one year Vital statistics of the same year (2008) published by Ministry of Health, Labor and Welfare, Japan were referenced to calculate the estimated incidence and prevalence of LKS among Japanese children. RESULTS: Chiefs of 1562 pediatric departments answered our inquiry (51.9% of returns). Six chiefs had one new LKS patient, aged 6-14 years. Thirty two patients with LKS were followed in the same period. The number of children with LKS less than 20 years of age who needed medical care was at least 23 and at most 31. Vital statistics of Japan 2009 revealed that the population of children aged 5-14 years was 11,861,464 and that aged 5-19 years was 18,007,968. DISCUSSION: The number of the first-visit LKS patients was 6 in a year. We estimated the incidence of LKS in the 5- to 14-years-old Japanese population as about 1 in 978,000. The number of LKS patients aged 5-19 was estimated to range from 44.2 to 59.6 among a population of 18,007,968. This means the prevalence of LKS under medical care is roughly one in 302,147-407,420 children aged 5-19. This study is the first epidemiological estimation of the incidence and prevalence of children with LKS in Japan or, for that matter, in any other area. CONCLUSION: (1) Incidence of children with LKS aged 5-14 years was about 1 in a million in Japan. (2) Prevalence of children with LKS aged 5-19 and under medical care was one in about 300,000-410,000 in Japan. (3) This study constitutes the first epidemiological estimation of LKS in Japan.

Neurobehavioral and hemodynamic evaluation of Stroop and reverse Stroop interference in children with attention-deficit/hyperactivity disorder.

Failure of executive function (EF) is a core symptom of attention-deficit/hyperactivity disorder (ADHD). However, various results have been reported and sufficient evidence is lacking. In the present study, we evaluated the characteristics of children with ADHD using the Stroop task (ST) and reverse Stroop task (RST) that reflects the inhibition function of EF. We compared children with ADHD, typically developing children (TDC), and children with autism spectrum disorder (ASD), which is more difficult to discriminate from ADHD. A total of 10 children diagnosed with ADHD, 15 TDC, and 11 children diagnosed with ASD, all matched by age, sex, language ability, and intelligence quotient, participated in this study. While each subject performed computer-based ST and RST with a touch panel, changes in oxygenated hemoglobin (oxy-Hb) were measured in the prefrontal cortex (PFC) by near-infrared spectroscopy (NIRS) to correlate test performance with neural activity. Behavioral performance significantly differed among 3 groups during RST but not during ST. The ADHD group showed greater color interference than the TDC group. In addition, there was a negative correlation between right lateral PFC (LPFC) activity and the severity of attention deficit. Children with ADHD exhibit several problems associated with inhibition of color, and this symptom is affected by low activities of the right LPFC. In addition, it is suggested that low hemodynamic activities in this area are correlated with ADHD.

Psychometric properties of Japanese version of the Swanson, Nolan, and Pelham, version-IV Scale-Teacher Form: a study of school children in community samples.

BACKGROUND: Psychometric properties of The Japanese version of Swanson, Nolan, and Pelham IV scale (SNAP-IV)-Teacher Form were examined in this study. METHOD: Community samples of 1296 children (Grade 1-9, boys 52.9%) were collected from public elementary/middle schools in suburban areas. Teachers rated their children's behavior using Japanese version of SNAP-IV-Teacher Form and Strength and Difficulties Questionnaire (SDQ). RESULTS: A three-factor structure model, which was equivalent with AD/HD symptoms subscales (inattention, hyperactivity/impulsivity) and oppositional-defiant disorder symptoms subscale was obtained and confirmed in an explorative/confirmative factorial analysis (Goodness-of-Fit Index=0.913, Comparative Fit Index=0.959, root mean square error of approximation=0.056). The current version of the SNAP-IV-Teacher Form demonstrated good test-retest reliability (intra-class correlation=0.752-0.822), high internal consistency (Cronbach's α=0.933-0.952), significant correlations with relevant subscales of Japanese version of SDQ, and typical effects of age and gender on those subscales. CONCLUSION: The current study indicates that the Japanese version of SNAP-IV-Teacher Form is a reliable and valid instrument for rating symptoms related to AD/HD and ODD.

[Relationship between magnocellular function and reading skills in children: a study using visual evoked potentials].

OBJECTIVE: Developmental dyslexia (DD) is a neurodevelopmental disorder that is characterized by difficulties with accurate and/or fluent word recognition and by poor spelling and decoding abilities. The magnocellular deficit theory is one of several hypotheses that have been proposed to explain the pathophysiology of DD. In this study, we investigated magnocellular system dysfunction in Japanese dyslexic children. METHODS: Subjects were 19 dyslexic children (DD group) and 19 aged-matched healthy children (TD group). They were aged between 7 and 16 years. Reversed patterns of black and white sinusoidal gratings generated at a low spatial frequency, high reversal frequency of 7.5 Hz, and low contrasts were used specifically to stimulate the magnocellular system. We recorded visual evoked potentials (VEP) from the occipital area and examined their relationship with reading and naming tasks, such as the time to read hiragana characters, rapid automatized naming of pictured objects, and phonological manipulation. RESULTS: Compared to the TD group, the DD group showed a significantly lower peak amplitude of VEPs through the complex demodulation method. Structural equation modeling showed that VEP peak amplitudes were related to the rapid automatized naming of pictured objects, and better rapid automatized naming resulted in higher reading skills. There was no correlation between VEP findings and the capacity for phonological manipulation. CONCLUSIONS: VEPs in response to the magnocellular system are useful for understanding the pathophysiology of DD. Single phonological deficit may not be sufficient to cause DD.

Increased prefrontal oxygenation related to distractor-resistant working memory in children with attention-deficit/hyperactivity disorder (ADHD).

This study aimed at investigating the effect of distraction on working memory and its underlying neural mechanisms in children with attention-deficit/hyperactivity disorder (ADHD). To this end, we studied hemodynamic activity in the prefrontal cortex using near-infrared spectroscopy while 16 children with ADHD and 10 typically developing (TD) children performed a working memory task. This task had two conditions: one involved a distraction during the memory delay interval, whereas the other had no systematic distraction. The ADHD patients showed significantly poorer behavioral performance compared with the TD group, particularly under the distraction. The ADHD group exhibited significantly higher level of prefrontal activation than did TD children. The activity level was positively correlated with the severity of ADHD symptoms. These results suggest that the impairment in the inhibition of distraction is responsible for the working memory deficits observed in ADHD children. Inefficient processing in the prefrontal cortex appears to underlie such deficits.

Facial identity recognition in children with autism spectrum disorders revealed by P300 analysis: a preliminary study.

BACKGROUND: To reveal the neural substrate of communication difficulties in children with autism spectrum disorders (ASDs), we investigated the P300 component of event-related potentials (ERPs) as represented by the average of electroencephalography findings time-locked to events and behavior. Because the P300 amplitude influences attentional resource allocation during discrimination, the component elicited during perception of known and unknown faces should indicate familiarity processing. METHODS AND RESULTS: Nine typically developing children (TD) and nine children with ASDs participated in this study (Experiment 1). The P300 amplitude in TD children was significantly larger during familiar face perception than during unfamiliar face perception (p<0.01). However, there was no evidence of familiarity effect in children with ASDs. In three children with ASDs, we also assessed the P300 amplitude during perception of a therapist's face one month before (baseline), a few days before and after social skills training (SST) sessions (Experiment 2). To evaluate the effect of familiarity on facial identity processing, we analyzed the therapist/unknown ratio of P300 amplitudes related to the face discrimination task as an index. The ratio was larger after SST sessions than before, but there was no difference in the ratio between baseline and before SST assessments. CONCLUSION: The P300 might be influenced by attentional resource allocation depending on the stage of learning face identification in children with ASDs. We speculate that this approach to evaluating brain responses during facial identity recognition could be used as a tool to clarify children's communication difficulties.