Shinichi Hirabayashi

Developmental perspective of sensory organization on postural control

The development of sensory organization on postural control was studied using computerized dynamic posturography. Generalized postural stability increased with age but had not reached the adult level at the age of 15 years. The significance of each sensory component for postural control was analysed. Somatosensory function developed early and became comparable with the adult level at the age of 3-4 years. The visual function followed and reached the adult level at the age of 15 years. The vestibular function developed later, showing a considerably lower level even at the age of 15 years. Girls were superior to boys with respect to the vestibular function at the age of 7-8 years. The implication of this sexual difference for some developmental disorders is discussed.

Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome

Objective: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). Methods: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. Results: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. Conclusions: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.

Phenotypic Spectrum of COL4A1 Mutations: Porencephaly to Schizencephaly

Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations.

The metaphor and sarcasm scenario test: a new instrument to help differentiate high functioning pervasive developmental disorder from attention deficit/hyperactivity disorder

It is sometimes difficult to discriminate high functioning pervasive developmental disorders (HFPDD) from attention deficit/hyperactivity disorders (AD/HD) in young children because of the behavioral similarities between the two. For adequate diagnosis, understanding fundamental differences in their social cognitive abilities might become significant. In order to detect the differences in social cognitive abilities between AD/HD and HFPDD, a new test, the Metaphor and Sarcasm Scenario Test (MSST) was developed. One hundred and ninety-nine normal school children (the control group), 29 AD/HD children and 54 HFPDD children were involved. The results showed that the inability to understand a sarcastic situation was specific to children with HFPDD, both children with AD/HD and HFPDD could not equally understand metaphor. The correlation between the comprehension of sarcasm and success in the theory of mind task was remarkably high but not for comprehension of metaphor. In conclusion, the MSST has the potential to discriminate HFPDD from AD/HD in young children.

Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene

Mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) have been identified in families with early-onset spinocerebellar ataxia type 29 (SCA29) and late-onset SCA15, but have not been found in sporadic infantile-onset cerebellar ataxia. We examined if mutations of ITPR1 are also involved in sporadic infantile-onset SCA. Sixty patients with childhood-onset cerebellar atrophy of unknown etiology and their families were examined by whole-exome sequencing. We found de novo heterozygous ITPR1 missense mutations in four unrelated patients with sporadic infantile-onset, nonprogressive cerebellar ataxia. Patients displayed nystagmus, tremor, and hypotonia from very early infancy. Nonprogressive ataxia, motor delay, and mild cognitive deficits were common clinical findings. Brain magnetic resonance imaging revealed slowly progressive cerebellar atrophy. ITPR1 missense mutations cause infantile-onset cerebellar ataxia. ITPR1-related SCA includes sporadic infantile-onset cerebellar ataxia as well as SCA15 and SCA29.

The reliability and validity of the Oppositional Defiant Behavior Inventory.

The aim of this study was to develop an evaluation scale for use as a supplementary tool for the diagnosis of oppositional defiant disorder (ODD). The subjects were 98 Japanese children (91 males and 7 females), aged 6–15 years, diagnosed with attention deficit/hyperactivity disorder (ADHD) or ODD. Internal consistency, test-retest reliability, concurrent validity and divergent validity of the oppositional defiant behavior inventory (ODBI), an evaluation scale of oppositional defiant tendency, were examined. Cronbach’s α coefficient of the ODBI was 0.925. The correlation coefficient between the test and the retest was 0.820 (p < 0.0001). Both the ODBI scores (test and retest) were correlated with the number of items that matched the ODD diagnostic criteria of DSM-IV (r = 0.660, 0.659, p < 0.001), and with the ODD-scale of Disruptive Behavior Disorders Rating Scale (r = 0.725, 0.654, p < 0.001). Compared with the ADHD group or controls, the ADHD and ODD group showed a significantly higher ODBI score at p < 0.0001. The concurrent use of this scale with clinical examination is expected to increase the accuracy of the diagnosis of ODD.

Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations.

Cerebellar atrophy is recognized in various types of childhood neurological disorders with clinical and genetic heterogeneity. Genetic analyses such as whole exome sequencing are useful for elucidating the genetic basis of these conditions. Pathological recessive mutations in Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase (SEPSECS) have been reported in a total of 11 patients with pontocerebellar hypoplasia type 2, progressive cerebellocerebral atrophy or progressive encephalopathy, yet detailed clinical features are limited to only four patients. We identified two new families with progressive cerebellar atrophy, and by whole exome sequencing detected biallelic SEPSECS mutations: c.356A>G (p.Asn119Ser) and c.77delG (p.Arg26Profs*42) in family 1, and c.356A>G (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2. Their development was slightly delayed regardless of normal brain magnetic resonance imaging (MRI) in infancy. The progression of clinical symptoms in these families is evidently slower than in previously reported cases, and the cerebellar atrophy milder by brain MRI, indicating that SEPSECS mutations are also involved in milder late-onset cerebellar atrophy.

A nationwide survey of pediatric acquired demyelinating syndromes in Japan

Objective: To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan. Methods: We conducted a nationwide survey and collected clinical data on children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007. Results: Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval [CI], 0.34–0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58–0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04–0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group. Conclusions: Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population.

A case of pyruvate dehydrogenase E1α subunit deficiency with antenatal brain dysgenesis demonstrated by prenatal sonography and magnetic resonance imaging

Prenatal depiction of brain dysgenesis in patients with pyruvate dehydrogenase complex (PDHc) deficiencies has been infrequently reported. As PDHc plays a critical role in the brain that obtains all of the energy from the aerobic oxidation of glucose, its deficiency is a severe inborn disorder of metabolism, which predominantly affects the nervous system. This report describes a case of PDHc deficiency with antenatal brain dysgenesis depicted in detail by fetal ultrasound and magnetic resonance imaging. This is the first case report clearly demonstrating the developing mechanism and time course of antenatal brain lesions in a patient with PDHc deficiency.

Establishing the cut‐off point for the Oppositional Defiant Behavior Inventory

Abstract  The purpose of the present paper was to make a detailed examination of the cut‐off point for the Oppositional Defiant Behavior Inventory (ODBI). The subjects were 56 untreated boys (age 6–15 years), who were diagnosed to have oppositional defiant disorder and who presented between December 2001 and March 2008. Controls were 690 boys with no history of contacting hospitals and no developmental or behavioral disorders at two elementary schools and two junior high schools in a city and its suburbs. It was shown that the level of opposition in boys could be evaluated regardless of the age groups by the ODBI, because there was no significant difference in the ODBI score for the one‐way analysis of variance. Based on the sensitivity (88.2%), specificity (90.0%), positive predictive value (75.0%) and negative predictive value (95.7%), a score of 20 points was thus established as a suitable cut‐off point to distinguish the children who are eligible for ODD diagnosis from those who are not.