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.

[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.

[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.

[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.

[Effects of a rich emotionally-satisfying childbirth experience of mothers on their later parental attitudes and behavior in school-age children].

This study examined the effects of a rich, emotionally-satisfying childbirth experience (CBE) of mothers on the behavior of school-age children using longitudinal data measured from immediately to 7 years and 6 months after birth. The results of structural equation modeling revealed the following: 1) giving birth in a midwifery center enhances emotional satisfaction with CBE, 2) a rich CBE of mothers was associated with parental warmth, 3) parental warmth during early childhood increased prosocial behavior and reduced behavioral problems in school-age children, and 4) temperamentally difficulty in early childhood were linked to later behavioral problems in school-age children. Thus, a rich CBE and parental warmth were suggested to be factors contributing to the good behavior of school-age children.

[Effectiveness of social skills training for children with developmental disorders: behavioral analysis using a two-dimensional motion capture system].

The current study sought to develop a new behavioral analysis methods to evaluate the effects of social skills training (SST). SST is known to be an effective method to improve the social skills of children with behavioral problems. However, current evaluation methods involve behavioral rating scales that are heavily dependent on evaluators' particular experiences they have had. To quantitatively examine the behavioral effects of SST, we examined subjects' head-movements related to social behavior, using a two-dimensional motion capture system (Kissei Comtec, Japan). Four children (three male, one female, 7-8 years of age) with pervasive developmental disorder (PDD) or attention deficit/hyperactivity disorder (AD/HD) participated in 16 sessions of SST. Before and after SST, head-coordinates on a two-dimensional plane were calculated using their behavior during a pair task, measured by four digital cameras. After SST, the number of communication behaviors was increased compared to before SST. In addition, children looked longer at another child within 30 degrees of the central visual field. Time-series analysis of the visual field during the detection of another child revealed significant auto-correlation from about -1.12 second. before to the beginning of communication behavior (p<0.05). The results suggested that our method can provide a quantitative index of characteristics related to skilled social behaviors. We conclude that a two-dimensional motion capture system would be useful for visualization of the interventional effects of SST, which would supplement assessments by the conventional observational strategies.

Effect of corpus callosotomy on attention deficit and behavioral problems in pediatric patients with intractable epilepsy.

To evaluate the effect of corpus callosotomy (CC) on attention deficit and behavioral problems in pediatric patients with intractable epilepsy, we retrospectively investigated sequential patients who had undergone CC to control seizures. Between August 2005 and April 2010, a total of 15 patients aged between 3.1 and 17.9 years underwent CC at our institute. All the patients experienced either drop attacks or head nodding, which were considered to be therapeutic targets of CC. A standardized instrument, the Child Behavior Checklist (CBCL), was used to assess behavioral and emotional problems before and after surgery. On postoperative EEGs, 8 (53%) showed improvement and 7 (47%) showed no change in epileptiform discharges. The Attention Problems scale and total score on the CBCL significantly improved in patients whose postoperative EEGs showed improvement. In addition to amelioration of target seizures, CC can improve attention impairments in association with improvement in the postoperative EEG.

[Developmental changes of rapid automatized naming and Hiragana reading of Japanese in elementary-school children].

Two hundred and seven Japanese elementary school children aged from 6 (Grade 1) to 12 (Grade 6) years old were tested for their abilities to name numbers and pictured objects along with reading Hiragana characters and words. These children all showed typical development and their classroom teachers judged that they were not having any problems with reading or writing. The children were randomly divided into two groups, the first group was assigned to two naming tasks;the rapid automatized naming (RAN) of "numbers" and "pictured objects," the second group was assigned to two rapid alternative stimulus (RAS) naming tasks using numbers and pictured objects. All children were asked to perform two reading tasks that were written in Hiragana script: single mora reading task and four syllable word reading task. The total articulation time for naming and reading and performance in terms of accuracy were measured for each task. Developmental changes in these variables were evaluated. The articulation time was significantly longer for the first graders, and it gradually shortened as they moved through to the upper grades in all tasks. The articulation time reached a plateau in the 5th grade for the number naming, while gradual change continued after drastic change in the lower grades for the pictured object naming. The articulation times for the single mora reading and RAN of numbers correlated strongly. The articulation time for the RAS naming was significantly longer compared to that for the RAN, though there were very few errors. The RAS naming showed the highest correlation with the four syllable word reading. This study demonstrated that the performance in rapid automatized naming of numbers and pictures were closely related with performance on reading tasks. Thus Japanese children with reading disorders such as developmental dyslexia should also be evaluated for rapid automatized naming.

Electrophysiological evidence of cerebral dysfunction in childhood opsoclonus-myoclonus syndrome.

To address cerebral involvement in childhood opsoclonus-myoclonus syndrome (OMS), electrophysiological investigations including electroencephalograms and evoked potentials were performed in three children affected by nonparaneoplastic OMS. Most patients displayed abnormalities in visual- and somatosensory-evoked potentials, consisting of delayed latency or disorganization of cortical components. Symptoms of OMS have been attributed primarily to an abnormality in the cerebellum and its associated pathway. This theory was consistent with cerebellar lesions detected by neuroimaging. Electrophysiological evidence of cerebral dysfunction observed in this study, however, implies additional involvement of the cerebral cortex, which may contribute to the accompanying psychiatric and cognitive disorders.

[Relationship between clinical symptoms and Hiragana reading ability in children with difficulties in reading and writing:usefulness of a clinical-symptoms-checklist].

We investigated the clinical symptoms of children with developmental dyslexia (DD) and evaluated the relationship between these symptoms and their Hiragana reading abilities. In order to detect the clinical symptoms of DD, we newly developed a clinical-symptoms-checklist (CL), which consisted of a total of 30 yes/no questions regarding symptoms linked to reading (15 questions) and writing (15 questions). Subjects were 98 Japanese school grade (1 to 9) children, aged 6 to 15 years old, with normal intelligence confirmed by the Wechsler Intelligence Test for Children (WISC-Ill) and they were divided into 2 groups according to their diagnosis. Twenty four children diagnosed as developmental dyslexia consisted the DD group, and the remaining 74 children were grouped in the non-DD group. CL showed significant construct validity (p<0.05) and inner consistency (reading: a =0.82, writing: a =0.72) after deleting two questions from the originals. The number of questions checked in the CL reading subcategory significantly correlated with the Hiragana reading ability of articulation time in all Hiragana reading tasks (p<0.001). More severe clinical symptoms and lower reading ability were observed in the DD group compared to the non-DD group. Receiver Operating Characteristics (ROC) analysis indicated that these two groups could be discriminated by the CL and the results of the reading task, and both sensitivity and specificity rate were approximately 80%. It was suggested that 7 or more positive checks in the CL and 2 or more abnormal scores in the reading tasks might discriminate DD from other conditions which cause difficulties in reading and writing in Japanese children.

[Developmental changes in reading ability of Japanese elementary school children--analysis of 4 kana reading tasks].

Five hundred and twenty-eight Japanese elementary school children aged from 6 (Grade 1) to 12 (Grade 6) were tested for their abilities to read Hiragana characters, words, and short sentences. They were typically developing children whom the classroom teachers judged to have no problems with reading and writing in Japanese. Each child was asked to read four tasks which were written in Hiragana script: single mora reading task, four syllable non-word reading task, four syllable word reading task, and short sentence reading task. The total articulation time for reading and performance in terms of accuracy were measured for each task. Developmental changes in these variables were evaluated. The articulation time was significantly longer for the first graders, and it gradually shortened as they moved through to the upper grades in all tasks. The articulation time reached a plateau in the 4th grade for the four syllable word and short sentence reading tasks, while it did so for the single mora and four syllable non-word reading tasks in the 5th grade. The articulation times for the four syllable word and short sentence reading tasks correlated strongly. There were very few clear errors for all tasks, and the number of such errors significantly changed between the school grades only for the single mora and four syllable word reading tasks. It was noted that more than half of the children read the beginning portion of the word or phrase twice or more, in order to read it accurately, and developmental changes were also seen in this pattern of reading. This study revealed that the combination of these reading tasks may function as a screening test for reading disorders such as developmental dyslexia in children below the age of ten or eleven years old.

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.

[Evaluation of preclinical onset in patients with the childhood form of cerebral adrenoleukodystrophy--usefulness of visual cognitive function and evoked potential tests].

We examined both visual evoked potential (VEP) and neuropsychological tests in 18 patients with X-linked adrenoleukodystrophy (ALD). Patients consisted of 10 boys with apparent lesions in the posterior white matter on MR imaging, 3 with lesions in the frontal white matter area and 5 that were neurologically asymptomatic with no apparent brain MRI abnormalities. Almost all patients with posterior WM lesion showed patterns of lower PIQ than VIQ on WISC-III and lower scores on scales for simultaneous processing than for sequential processing on Kaufman Assesment Battery for Children (K-ABC). Four of 5 asymptomatic patients showed PIQ/VIQ patterns similar to those in the posterior group. Patients with a difference more than 13 between PIQ and VIQ also showed poor results on Frostig developmental test of visual perception (DTVP). There was a prolongation of the peak latency of P100 on flash VEP in many patients with posterior whitematter lesions, however, asymptomatic patients did not show any abnormality of P100 latency but there was an increased amplitude of N75-P100 on flash and pattern reversal stimuli VEP. One patient with abnormally high VEP (31.4 microV; + 3.6 SD) gradually improved to the normal range (11.4 microV; 0SD) after hematopoietic stem cell transplantation. These cognitive and neurophysiological examinations could be useful in the detection of preclinical onset of childhood ALD before the appearance of MRI lesions on MRI.

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.

[Cerebral inhibitory functioning in patients with attention deficit/hyperactivity disorder. I. Analysis of non-target-P300 component in a visual oddball paradigm].

The present study was organized to evaluate the cerebral inhibitory function in children with developmental disorders such as attention deficit/hyperactivity disorder (AD/HD) and pervasive developmental disorder (PDD). Target and non-target-P300 event related potential (ERP) in response to stimuli of a visual oddball paradigm was analyzed. Ten children with AD/HD, 10 children with PDD and 10 healthy children were included in the study participants. Target-P300 component was observed in all subjects, which showed predominant amplitudes in Pz electrode. No significant differences were observed in amplitude and latency of target-P300 among three groups. In healthy children, Non-target-P300 component was observed mainly in Cz and Pz electrodes, while children with AD/HD had significantly reduced amplitudes of the component at Cz and children with PDD showed shorter latency at Oz. These results suggest that Non-target-P300 component in visual oddball paradigm possibly reflects the brain function associated with inhibitory processing and there is a relationship between the non-target-P300 potential abnormality and the AD/HD behavior.

Characteristic findings of auditory brainstem response and otoacoustic emission in the Bronx waltzer mouse.

Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were evaluated serially from 1 to 22 months in Bronx waltzer homozygotes (bv/bv), heterozygotes (+/bv) and control (+/+) mice, which were differentiated by means of PCR of marker DNA (D5Mit209). The wave IV threshold of the click-evoked ABR was higher than the DPOAE threshold with the DP growth method in each bv/bv, although the two thresholds were almost the same in the +/+ group. The DP value at 2f(1) - f(2) in the bv/bv showed an apparent decrease at 2 to 3 months of age with 80 dB SPL stimulation using f(2) frequency 7996 Hz and frequency ratio f(2)/f(1) = 1.22, compared to control or heterozygote mice. It was characteristic that the 2f(2) - f(1) DP signal-to-noise ratio (SNR) value was more preserved from 80 to 60 dB SPL than the 2f(1) - f(2) DP value at f(2) frequency 7996 Hz in most bv/bv, however, control mice showed almost the same levels of 2f(1) - f(2) and 2f(2) - f(1) SNR value at both f(2) frequencies of 6006 and 7996 Hz. The preservation of a substantial 2f(2) - f(1) DP suggested that it would be generated basal to the primary-tone place on the basilar membrane and there might be a reflection of the unique function of the remaining outer hair cells in the Bronx waltzer mice. These findings suggest that combination of ABR with DPOAE could offer useful information about differentiating the mechanism of hair cell dysfunction of the hereditary hearing impairment in the clinical fields.