Identification and molecular characterization of two novel chromosomal deletions associated with autism.

Autism is a childhood-onset neurodevelopmental disorder with a strong genetic basis in its etiology. Conventional karyotype analysis has revealed that chromosomal structural aberrations such as translocation, inversion, deletion, and duplication play a role in causing autism spectrum disorders (ASD). In addition, recent array-based comparative genomic hybridization (array CGH) studies discovered that submicroscopic deletion and duplication of DNA segments also contributed significantly to the genetic etiology of ASD. Together, these studies indicate that genomic rearrangement is an important genetic mechanism of ASD. Using karyotyping analysis and array CGH technology, we identified a subtelomeric deletion of approximately 6.8 Mb at 4q35.1-35.2 and a terminal deletion of approximately 2.4 Mb at 8p23.2-pter in two autistic boys, respectively. These two deletions were further validated using fluorescent in situ hybridization and real-time quantitative polymerase chain reaction, and their breakpoints were delineated using high-resolution array CGH. The 4q deletion is a rare de novo mutation, while the transmission of 8p deletion is unknown, because the father of the patient was unavailable for study. These two deletions are rare mutations and were not found in the additional 282 patients with ASD and in the 300 control subjects in our population. The identification of these two chromosomal deletions contribute to our understanding of the genetic basis of ASD, and the haploinsufficiency of several genes located at the deleted regions of chromosome 8p and 4q may contribute to the clinical phenotypes of autism.

Influences of biological risk at birth and temperament on development at toddler and preschool ages.

PURPOSES: This study aimed at investigating: (1) the effects of temperament and biological risk at birth on various developmental domains at toddler and preschool ages; (2) the interaction effects of the biological risk and temperament on development. Participants One hundred and ten full-term and 98 preterm children without significant physical or developmental disabilities and consisting of various biological risks were examined at toddler age (18-36 months) and preschool age (51-67 months). METHODS: The Neonatal Medical Index was used to classify the biological risk level. Parental reports on the Chinese Toddler Temperament Scale at toddler age were collected and the temperament (easy, intermediate and difficult) of each child was assigned according to local norm. The Comprehensive Developmental Inventory for Infants and Toddlers was used for assessing child development at toddler and preschool ages. Other family variables were also collected as possible confounders for child development. Two-way ancova was conducted to analyse the predictability of biological risk and temperament, by controlling the potential family variables on child development. RESULTS: At toddler age, higher biological risk had significant adverse effects on both the Perceptual-motor developmental quotients (DQs) (F(1,201)= 19.4, P < 0.001) and Social-adaptive DQs (F(2,200)= 22.5, P < 0.001), while easy temperament had positive effects only on the Social-adaptive DQs (F(2,200)= 7.7, P < 0.01). At preschool age, none of the two factors had effects on DQs of the Comprehensive Developmental Inventory for Infants and Toddlers. There were no significant interactions between biological risk and temperament on DQs at both ages. CONCLUSION: The biological risk and temperament affected child development at toddler age but not at preschool age. No interaction of biological risk and temperament effects on the child development at toddler age existed. The effects of biological risk and temperament on child development were temporary for the children with relatively low biological risk.

Rates and patterns of comorbidity of adolescent behavioral syndromes as reported by parents and teachers in a Taiwanese nonreferred sample.

OBJECTIVE: To evaluate the rates and patterns of comorbidity between behavioral syndromes in adolescents as reported by parents and teachers. Whether the patterns of comorbidity were "epiphenomenal" was also assessed. METHOD: Parents of 854 randomly selected students (response rate = 88%) in Taipei in 1996 completed the Child Behavior Checklist; among them, 240 also were randomly selected to have the Teacher's Report Form completed by their teachers. In addition to bidirectional comorbidity rates, odds ratios with and without other comorbid pairs controlled for were estimated via multiple logistic regressions. RESULTS: High comorbidity rates between behavioral syndromes were found in adolescents as reported both by parents and teachers except for that of Somatic Complaints with other syndromes. When other comorbidity pairs were controlled for, the comorbidity rates between Anxious/Depressed with externalizing syndromes turned out to be epiphenomenal, whereas those between externalizing syndromes remained high for both informants' reports. Attention Problems also remained significantly comorbid with other syndromes in the multiple logistic regressions except for that of Aggressive Behavior in the Teacher's Report Form sample. CONCLUSION: High comorbidity rates between adolescent behavioral syndromes exist in both parents' and teachers' reports, and it is important to control for the epiphenomenal condition when assessing such comorbidity rates.

Intellectual outcome of patients with congenital hypothyroidism detected by neonatal screening.

BACKGROUND AND PURPOSE: Mental retardation is a major sequela of delayed treatment for congenital hypothyroidism; congenital hypothyroidism can be treated early if detected with neonatal screening. We evaluated the intellectual outcomes of 62 patients with congenital hypothyroidism detected by neonatal screening at a major teaching hospital in northern Taiwan. The effects of thyroid pathology, age at the initiation of treatment, socioeconomic status, and severity of hypothyroidism on intellectual outcome were also analyzed. METHODS: All patients had euthyroid status at the time of intelligence testing. The Chinese Fourth Revision of the Binet-Simon Scales was used to evaluate the patients' intelligence between the ages of 3 and 6 years. RESULTS: The mean intelligence quotient (IQ) score was 102 +/- 18. Only four of the 62 patients were mentally retarded. Patients with lower initial serum thyroxine concentrations (T4; < 2 micrograms/dL) at the time of diagnosis of congenital hypothyroidism had significantly lower IQs (95 +/- 19, n = 26) than those with higher initial T4 concentrations (106 +/- 16, n = 36; p < 0.05). Patients with fewer than three ossification centers had lower IQs (91 +/- 20, n = 12) than those with three or more (104 +/- 17, n = 36; p < 0.05). Significantly lower IQs were also found in patients with a smaller femoral epiphysis area (< 0.1 cm2) (92 +/- 20, n = 15) than in those with larger epiphyses (106 +/- 15, n = 21; p < 0.05). The type of pathology (ectopia, athyrosis, dyshormonogenesis), age at the start of treatment (before or after 30 days of age), and socioeconomic status did not significantly affect the intellectual outcome. CONCLUSIONS: Our results indicate that intellectual outcome in Taiwanese patients with congenital hypothyroidism has been improved by neonatal screening and that the severity of hypothyroidism at diagnosis is the most important prognostic factor affecting intellectual outcome in these patients.

Competence and behavioral/emotional problems among Taiwanese adolescents as reported by parents and teachers.

OBJECTIVE: To investigate competence and behavioral/emotional problems among nonreferred adolescents in Taiwan, using a Chinese version of the Child Behavior Checklist (CBCL-C) and the Teacher's Report Form (TRF-C). The psychometric properties of these instruments and cross-cultural differences were also examined. METHOD: Parents of 854 junior high school students aged 12 to 16 years in Taipei, Taiwan, were asked to complete the CBCL-C. Among these students, 162 had their teachers' ratings of the TRF-C. RESULTS: The internal consistency and 1-month test-retest reliability were satisfactory for both the CBCL-C and TRF-C, which were moderately correlated. Both exploratory and confirmatory factor analysis provided some support for the validity of Achenbach's cross-informant model. Parents' reports showed that compared with their American counterparts, Taiwanese adolescents tended to have lower scores on most competence scales, higher scores on scales that reflect covert behavior problems, and lower scores on scales that reflect more overt behavior problems. However, teachers' reports showed no significant differences on most competence and behavior problem scales. CONCLUSION: The CBCL-C and TRF-C are useful tools for assessing the mental health status of Taiwanese adolescents. The cross-cultural differences in adolescent behavior problems are discussed.

Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: a case-control study.

OBJECTIVE: This study investigated the psychiatric comorbidity, personality traits and family history of adolescents with sleep terrors and/or sleepwalking. METHOD: Thirty students with sleep terrors and/or sleepwalking and 30 classroom controls were selected on the basis of a sleep habit questionnaire. After completing the Junior Eysenck Personality Inventory (JEPI), the 60 subjects were interviewed by the first author with the Chinese-version Kiddie-SADS-E (Schedule for Affective Disorders and Schizophrenia for Children--Epidemiology Version). All subjects and their parents were interviewed for the subjects' sleep habits, sleep disorders, and personality characteristics in the previous year. The case and the control groups were divided based on whether the sleep terrors and/or sleepwalking had occurred in the previous year. There were 21 case and 30 control subjects in the final data analysis. RESULTS: The case group had more psychiatric diagnoses and problems; there were statistically significant differences in overanxious disorder, panic disorder, simple phobia and suicidal thoughts between the two groups. The case group had more sleeptalking and nightmares during the previous year as well as more enuresis in earlier years. From their parents' perspective, the case group was more nervous and pessimistic. The results of the JEPI showed a high neuroticism score in the case group. There was an increased familial occurrence of these two sleep disorders. CONCLUSIONS: Adolescents with sleep terrors and sleepwalking were found to have an increased prevalence of other sleep disorders, neurotic traits, and psychiatric disorders and problems. Whereas sleep terrors and sleepwalking in childhood are related primarily to genetic and developmental factors, their persistence and, especially, their onset in adolescence may be related to psychological factors.

Intellectual outcomes of patients with congenital hypothyroidism not detected by neonatal screening.

Mental retardation is a major sequela of delayed treatment of congenital hypothyroidism. In this study, we investigated the intellectual outcomes of patients with congenital hypothyroidism diagnosed before a nationwide screening project started. Eighty-two patients had intelligence tests done while in the euthyroid state. Their mean intelligence quotient (IQ) was 78 +/- 21 (+/- SD) (n = 79). The mean verbal IQ was significantly higher than the mean full-scale IQ. The mean IQs of both ectopic thyroid (84 +/- 21, n = 28) and dyshormonogenic patients (85 +/- 14, n = 18) were significantly higher than that of patients with athyrosis (64 +/- 18, n = 19) (p < 0.05). Patients who were treated before 3 months of age had significantly higher mean IQs (90 +/- 16, n = 16) than those treated after 3 months (75 +/- 21, n = 63) (p < 0.01). Our results confirm that both patients with ectopic thyroids and those with dyshormonogenesis have better intellectual outcomes than athyrotic patients do, and that early treatment improves the intellectual outcome of patients with congenital hypothyroidism.

Long-term effect of increased lead absorption on intelligence of children.

The authors examined the reversibility of cognitive impairment caused by a mild increase in lead absorption among children. The results of our initial study revealed that air and soil outside a lead-recycling plant in Taiwan were seriously contaminated by lead, which was associated with lowered intelligence quotients of 32 children who attended a nearby kindergarten (i.e., kindergarten A). Thirty-five children-who were comparable with respect to age, sex, birth order, sibling number, and parental education level-from another kindergarten (i.e., kindergarten B) located 5 km from the plant were enrolled as the reference group. Following the initial study, kindergarten A school children moved 2 km from the lead-recycling plant. Twenty-eight children in each group were followed successfully 2.5 y later. Blood lead, intelligence quotient, and intelligence quotient-related factors were reassessed. The results showed that the average blood lead level of the exposed pupils dropped 6.9 microg/dl (standard deviation [SD] = 3.9 microg/dl) (p < .001), and the average intelligence quotient increased 11.7 points (SD = 13.2) (p < .01), compared with the results of the initial study. The average blood lead level of the reference group decreased by 1.7 microg/dl (SD = .1.3) (p < .001), whereas the average intelligence quotient increased by 4.2 points (SD = 13.8) (p = .115). There was a significant difference in intelligence quotients between the two groups during the initial study, but the difference subsequently disappeared during the follow up. The authors concluded that intelligence quotient impairment, caused by a mild subclinical elevation of blood lead (i.e., likely no more than 30 microg/dl) for a period of 1-3 y in 3- to 5-y-olds, is at least partially reversible.

Diagnosis of zygosity by questionnaire and polymarker polymerase chain reaction in young twins.

We developed a zygosity questionnaire for use in young twins and assessed its validity using the results of DNA diagnosis. The participants were divided into two groups: 105 pairs of adolescent twins (12-16 years old), 47 pairs of child twins (2-12 years old), and their respective parents. The DNA diagnosis of zygosity was made with polymarker polymerase chain reaction (PCR) amplification of five loci, using the AmpliType PM PCR Amplification and Typing Kit; this method has an accuracy rate of 99.0%. A parsimonious model for each sample was established using stepwise logistic regression analysis of the 20 items of the questionnaire. The total accuracy rate of the model was satisfactory for both parental reports (three items) and self-reports (three items) of adolescent twins (97.4 and 95.6%, respectively), while that for parental reports on child twins (two items) was less satisfactory (92.5%). For adolescent twins, if DNA diagnostic workups were limited to those with discordant reports either from themselves or from their parents, the accuracy rate increased to 100% for parental reports and 98% for self-reports.

Occupational and environmental lead poisoning: case study of a battery recycling smelter in Taiwan.

The rapid industrialization in Taiwan has caused both prosperity and environmental pollution. The purpose of this study is to demonstrate a case of both occupational and environmental lead poisoning. A patient of lead poisoning initiated a survey of the battery recycling factory, which revealed that 31 of 64 workers suffered from lead poisoning. Children who attended a nearby kindergarten showed a significant increase of blood lead up to 15-25 micrograms/dl and a mild but significant decrease of IQ (intelligent quotient, by Binet-Simon scale) if compared with children of a nonexposed but socioeconomically comparable kindergarten. Outdoor workers of the nearby forging factory also showed a significant increase of blood lead if compared with indoor workers or workers of another nonexposed forging factory 20 Km away. Air sampling showed an average of more than 10 micrograms/m3 in the kindergarten. Soil sampling and analysis also revealed 400 folds increase of lead content, which decreased if the sample was taken deep down to 15-30 cm or 350 meters away from the battery recycling smelter. Moreover, after children were moved away from the pollution source, follow-up examination performed 2.5 years later showed a significant decrease of blood lead and partial recovery of IQ among them.

The needs and popularization of psychotherapy in Taiwan.

A literature review, a population survey and analysis of hospital statistics were used to assess the needs and the popularity of psychotherapy in Taiwan. Three community epidemiological studies revealed very similar prevalence rates of minor mental disorders. The statistics of the Children's Mental Health Center revealed that intensive psychotherapy was not a popular treatment received by patients. The second cycle Taiwan Social Change Survey also showed a high rate of anxiety and depression in the community. It also revealed a low acceptance of psychotherapy for treatment of anxiety and depression provided by professionals. The discrepancy between the great potential needs for psychotherapy and the unpopularity of psychotherapy in practice was discussion. Methods to make psychotherapy more popular are also suggested.

Kleine-Levin syndrome in a boy with Prader-Willi syndrome.

A 9 1/2-year-old Taiwanese boy with Prader-Willi syndrome had the following characteristics: difficulties with sucking, feeding and hypotonia during infancy, a dysmorphic face (triangular mouth, high arched palate, almond-shaped eyes and large head circumference with a relatively narrow bifrontal diameter), borderline intelligence, hypogonadism, hyperphagia, skin picking and truncal obesity. The boy experienced two hypersomnia episodes, at age 8 and 9 years, with both episodes lasting for 10 days. During the two episodes, he was found to have an exacerbated case of hyperphagia, pica, poor emotional control, stereotyped speech and agitated behavior upon awakening. After each episode, the boy had complete remission. Our findings show that the two episodes are compatible with Kleine-Levin syndrome. The relationship between the two syndromes, the Prader-Willi syndrome and the Kleine-Levin syndrome, deserves further study.

Sleep problems of junior high school students in Taipei.

The objective of this work was to study the relationship between daily sleep time and characteristics of students, e.g. grade level, gender, and academic program. A sleep habit questionnaire was designed to survey students at two junior high schools, one from northern Taipei and the other from southern Taipei. The impact of shortened duration of sleep on daily function was also evaluated. A total of 965 students and their parents were selected randomly in December 1993 for the questionnaire study. The response rate was 96.4% (930) for students and 88.6% (855) for parents. The self-reported daily sleep time of students declined, and daytime sleepiness and moodiness increased in the higher grades. The girls slept fewer hours than the boys and did not show an increase in daytime sleepiness. Those students not taking the senior high school joint entrance examination slept more hours at night and maintained more alertness in the daytime than those who were taking the examination. The more academic pressures that adolescents faced, the fewer hours they slept. Students not participating in the joint entrance examination seemed to show a healthier sleep pattern. Little sleep at night made the students feel sleepy in the daytime and tired, drowsy, moody and difficult at arising in the morning. The reason why girls slept less than boys needs further investigation.

[Play therapy for a child with separation anxiety disorder].

Separation anxiety disorder is characterized by severe and exceeding anxiety and fear when a child is facing separation with attachment objects. More over, it affected the child in language, emotional and social interest and development. These children usually brought to physician's attention due to refusal to go to school, social withdraw or multiple somatic complaints with attachment behavior wanted to be nearby or closed to the attachment objects. A child's early attachment relationship and previous separation experience play a major role in the formation of separation anxiety disorder. This report presents a psychoanalytically-oriented play therapy for a 2-year-8-month-old boy in 17 months period total of 54 sessions. According to the main themes in each session the process can be divided into 4 stages, namely establishing therapeutic relationship, expressing repressed emotions, management of transference, attachment and conflict in therapy, and self growth and termination. The formulation of this case and management were discussed.

Locomotor strategies before independent walking: prospective study of 50 mentally retarded children.

To investigate the association between pre-walking locomotor strategies and psychomotor developments in children with mental retardation (MR), 50 children with non-specific MR were included in this study. There were 29 boys and 21 girls, 96% of whom had moderate to severe MR. They were followed from 4-53 months to 25-99 months of age, and their follow-up periods ranged from 10 to 48 months (mean 30 months). According to the pre-walking locomotor strategies, these children were categorized into three groups: the crawling group (n = 34) who used crawling or creeping as their main locomotion pattern before independent walking; the shuffling group (n = 9) who used shuffling prior to independent walking; and the direct-walking group (n = 7) who did not have any other locomotor strategies except rolling. In almost all motor developmental milestones, children in the direct-walking group developed earlier than those in the crawling and shuffling groups. Children in the crawling group had more advanced developments than those in the shuffling group. The difference in the mean ratio developmental quotients of the Bayley Mental Scale among the three groups was not significant. The present study showed that crawling may not be a necessary prerequisite for early ambulation or better cognitive function in MR children.

Dentine lead and child intelligence in Taiwan.

It is well known that lead is a developmental neurotoxin, but, because many factors influence a child's development, a safe level of lead for children is still not clear. In this study, personal lead exposure was assessed. A total of 940 deciduous teeth--mostly incisors--was collected from 764 children in grades 1-3 who attended 7 primary schools. Two of the primary schools were near smelters, 4 were in Taipei City, and 1 was located in a coastal village. Teachers were provided with a questionnaire about classroom performance, and 97% completed and returned the questionnaire to the laboratory. Parents were given a questionnaire about family background, pregnancy, and health history (92% returned). Dentine lead levels of shed incisors for children in Taipei City were higher than levels reported in Boston, i.e., mean (standard deviation) of 4.4 (3.5) versus 3.3 (2.5) micrograms/g, respectively (p less than .001). The lead values were significantly higher in children who attended school near a smelter than in children who attended school in Taipei City: 6.3 (3.3) (p less than .001). The mean lead levels in children who attended school in a coastal village was 5.1 (2.8). The ranges for all schools overlapped, which indicated that there were multiple lead sources. Intelligence scores from Raven's Colored Progressive Matrices Test were negatively correlated with lead levels, especially among girls and among children whose parents had less education. We adjusted for other risk factors--most notably parental education, which correlates inversely with lead levels--and found that the role of the lead term was lowered but not eliminated.