Detection of copy number variations in epilepsy using exome data.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

MRI-based radiologic scoring system for extent of brain injury in children with hemiplegia.

BACKGROUND AND PURPOSE: Brain MR imaging is recommended in children with cerebral palsy. Descriptions of MR imaging findings lack uniformity, due to the absence of a validated quantitative approach. We developed a quantitative scoring method for brain injury based on anatomic MR imaging and examined the reliability and validity in correlation to motor function in children with hemiplegia. MATERIALS AND METHODS: Twenty-seven children with hemiplegia underwent MR imaging (T1, T2-weighted sequences, DTI) and motor assessment (Manual Ability Classification System, Gross Motor Functional Classification System, Assisting Hand Assessment, Jebsen Taylor Test of Hand Function, and Children's Hand Experience Questionnaire). A scoring system devised in our center was applied to all scans. Radiologic score covered 4 domains: number of affected lobes, volume and type of white matter injury, extent of gray matter damage, and major white matter tract injury. Inter- and intrarater reliability was evaluated and the relationship between radiologic score and motor assessments determined. RESULTS: Mean total radiologic score was 11.3 ± 4.5 (range 4-18). Good inter- (ρ = 0.909, P < .001) and intrarater (ρ = 0.926, P = < .001) reliability was demonstrated. Radiologic score correlated significantly with manual ability classification systems (ρ = 0.708, P < .001), and with motor assessments (assisting hand assessment [ρ = -0.753, P < .001]; Jebsen Taylor test of hand function [ρ = 0. 766, P < .001]; children's hand experience questionnaire [ρ = -0. 716, P < .001]), as well as with DTI parameters. CONCLUSIONS: We present a novel MR imaging-based scoring system that demonstrated high inter- and intrarater reliability and significant associations with manual ability classification systems and motor evaluations. This score provides a standardized radiologic assessment of brain injury extent in hemiplegic patients with predominantly unilateral injury, allowing comparison between groups, and providing an additional tool for counseling families.

Gender differences in emotional and behavioral disorders and service use among adolescent smokers: a nationwide Israeli study.

Marked gender differences have been identified in cigarette smoking. In this study, we aimed to identify the gender-specific emotional and behavioral disorders among adolescent smokers and their consequent utilization of mental health services. We performed a nationwide survey study of an Israeli representative sample of 906 adolescents and their mothers. Mental disorders were assessed using the Development and Well-Being Assessment (DAWBA) Inventory. Levels of emotional and behavioral difficulties were evaluated using the Strengths and Difficulties Questionnaire (SDQ). Mental health services use and smoking habits were also assessed. Among non-smoker adolescents there were significant gender differences in almost all SDQ scales: emotional problems, pro-social, hyperactivity/inattention and conduct problems, whereas in the smoker group there was a difference only in the SDQ emotional problems scale (both self- and maternal-rated, P<0.001 and P=0.002, respectively). Only marginal difference was noted between males and females in help-seeking for emotional or behavioral problems. Over 50% of both male and female smokers in the study had untreated mental disorders (non-significant gender difference). The well-established gender differences in psychiatric symptomatology narrowed markedly in adolescent smokers; the typical gender difference in disruptive behaviors was lost in the adolescent smoking population. The implications of these findings are particularly relevant to developing more effective gender-specific programs to prevent youth smoking, to facilitate quitting and prepare primary care practitioners to identify mental disorders and behavioral problems in adolescents with a smoking history.

Auditory system dysfunction due to infantile thiamine deficiency: long-term auditory sequelae.

Eleven infants who were fed a thiamine-deficient formula for a mean of 3 months were evaluated for immediate and long-term auditory abnormalities. At presentation, 8 infants had auditory neuropathy spectrum disorder (ANSD), which resolved with supplementary thiamine in 5 children, was permanent in 2 children, and deteriorated in 1 patient who died at the age of 7 years. An additional patient had an auditory pattern corresponding to that of auditory neuropathy of brain stem origin. The 2 remaining patients had unilateral cochlear hearing loss. Six to 8 years later, all patients with transient ANSD had normal audiograms, 2 patients had unilateral cochlear hearing loss, and the rest had neural hearing loss. All survivors had a language developmental delay and impaired speech intelligibility of varying degrees, especially in the presence of background noise. Thiamine is crucial for normal auditory development and function, and its deficiency may be considered an acquired metabolic cause of ANSD in infants.

Rate of readmission and mortality risks of schizophrenia patients who were discharged against medical advice.

PURPOSE: To compare the readmission and the mortality rates of schizophrenia patients who were discharged against medical advice (AMA) and patients who were discharged by physician recommendation. METHODS: The records (1984-2005) of all consecutive admissions (n=12,937) of schizophrenia patients (n=8,052) were reviewed. Out of this group, 673 (8.3%) refused to remain in the hospital and signed a hospital form for discharge AMA. Their records were analyzed for rates of re-hospitalization and mortality at study closure. The records of AMA patients were compared to those of patients with regular discharge (n=1345). RESULTS: AMA patients were younger at admission (P<0.001), comprised more males (P<0.01), more were single (P<0.0001), and had a shorter duration of illness than the controls (P<0.05). A total of 49.9% of AMA events occurred within the first 2 weeks of hospitalization. The readmission rate was significantly higher for AMA patients than for the controls (P<0.001). The mortality rate as a result of suicide (P<0.0001) and accidents (P<0.05) was higher for AMA patients compared to controls. CONCLUSION: The schizophrenia patients discharged AMA have a higher readmission rate and a higher mortality rate due to suicide and accidents compared to non-AMA discharged patients. Patients with AMA discharge warrant special community surveillance to improve outcome.

Epilepsy in children with infantile thiamine deficiency.

OBJECTIVE: To report the follow-up findings of 7 children with severe epilepsy as a result of thiamine deficiency in infancy caused by a defective soy-based formula. METHODS: The medical records of 7 children aged 5-6 years with thiamine deficiency in infancy who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging results were recorded. The clinical course and present outcome of these children, now 5 years after exposure to thiamine deficiency, are described. RESULTS: All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six infants had an EEG recording at this stage and all showed slow background. Five of them had no epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1-9 months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7 patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have mental retardation and motor disabilities as well as symptoms of brainstem dysfunction. CONCLUSIONS: Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.

Verbal short-term memory span in children: long-term modality dependent effects of intrauterine growth restriction.

BACKGROUND: Recent reports showed that children born with intrauterine growth restriction (IUGR) are at greater risk of experiencing verbal short-term memory span (STM) deficits that may impede their learning capacities at school. It is still unknown whether these deficits are modality dependent. METHODS: This long-term, prospective design study examined modality-dependent verbal STM functions in children who were diagnosed at birth with IUGR (n = 138) and a control group (n = 64). Their STM skills were evaluated individually at 9 years of age with four conditions of the Visual-Aural Digit Span Test (VADS; Koppitz, 1981): auditory-oral, auditory-written, visuospatial-oral and visuospatial-written. Cognitive competence was evaluated with the short form of the Wechsler Intelligence Scales for Children--revised (WISC-R95; Wechsler, 1998). RESULTS: We found IUGR-related specific auditory-oral STM deficits (p < .036) in conjunction with two double dissociations: an auditory-visuospatial (p < .014) and an input-output processing distinction (p < .014). Cognitive competence had a significant effect on all four conditions; however, the effect of IUGR on the auditory-oral condition was not overridden by the effect of intelligence quotient (IQ). CONCLUSIONS: Intrauterine growth restriction affects global competence and inter-modality processing, as well as distinct auditory input processing related to verbal STM functions. The findings support a long-term relationship between prenatal aberrant head growth and auditory verbal STM deficits by the end of the first decade of life. Empirical, clinical and educational implications are presented.

Circulatory neurosteroid levels in underweight female adolescent anorexia nervosa inpatients and following weight restoration.

Nineteen female adolescent inpatients diagnosed with anorexia nervosa, restricting type (AN-R) and 16 non-eating disordered (ED) controls were assessed for plasma dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulphate (DHEA-S), and cortisol levels, and for eating-related and non-eating-related psychopathology. AN-R patients were assessed at admission, 1 month and 4 months following hospitalization. The non-ED controls were assessed once. No baseline between-group differences were found in plasma cortisol, DHEA, and DHEA-S levels, whereas the patient group had a significantly lower Cortisol/DHEA-S ratio and elevated scores on most psychopathological parameters. A significant increase was found in the body mass index of the AN-R patients at 4 months post-hospitalization, accompanied by a decrease in plasma cortisol levels and a trend towards decreased Cortisol/DHEA and Cortisol/DHEA-S ratios, whereas no change occurred in psychopathology. The difference in Cortisol/DHEA-S ratio between AN-R patients and non-ED controls, and the different patterns of change in cortisol vs. DHEA(-S) levels following weight restoration, may in part account for the feeding difficulties in AN, particularly during refeeding.

Prenatal diagnosis and management of intrauterine growth restriction: A long-term prospective study on outcome and maternal stress.

This study examines long-term effects of antenatal management of intrauterine growth restriction (IUGR) on developmental outcome and on maternal coping using a prospective cross-sectional design. Sixty-nine families were evaluated using psychological testing and risk questionnaires. The effects of timing of diagnosis (prenatal/perinatal) and of pregnancy management [induction of labor (IL)/conservative management (CM)/none, i.e., diagnosed-at-birth (DaB)] on maternal stress were tested at 6 years' postbirth. In general, prenatal management protocols of IUGR were efficient in preventing major disabilities; however, 49% of the variance in maternal stress at 6 years' postbirth could be attributed to the child's presenting behavior and to pregnancy management of IUGR condition. Mothers who received CM treatment reported being more stressed by their child's poor emotional adjustment (ps < .01-.002) and distractibility (p < .029), and to have more difficulty in accepting them (p < .01). Prenatal psychological consultation to better handle stress for parents whose fetus is diagnosed with IUGR is recommended, particularly when pregnancy is managed conservatively and familial-educational resources are low.

NQO2 gene is associated with clozapine-induced agranulocytosis.

Clozapine is a dibenzodiazepine neuroleptic with atypical pharmacological and clinical profiles. Treatment with this drug may be complicated with agranulocytosis (AGR). It is likely that defective oxidative mechanism may be the cause of AGR. A candidate gene, dihydronicotinamide riboside (NRH) quinone oxidoreductase 2 (NQO2), which is involved in detoxification of drugs, was selected. This gene has been mapped to the short arm of chromosome six. The gene was studied by single-strand conformation polymorphism analysis and direct sequencing in 98 schizophrenic patients that were treated with clozapine. Eighteen of these patients developed AGR. Ten polymorphisms in the coding regions, in intron 1, and in the promoter region were found, two of which were novel. Comparisons of the polymorphisms in the first intron in AGR patients and controls suggested that this site might be connected with AGR. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the level of NQO2 mRNA is low in AGR patients compared with the control group. Such a reduction in message suggests that the NQO2 gene may be involved in the development of clozapine-induced AGR.

Mianserin or placebo as adjuncts to typical antipsychotics in resistant schizophrenia.

The beneficial effect of atypical antipsychotic drugs (APDs) in treatment-resistant schizophrenia patients has been attributed, mostly, to their relatively high serotonergic (5-HT)2 to dopaminergic (D)2 receptor blockade ratio. We hypothesized that a combination of typical APDs (D2 antagonists) and mianserin, a potent 5-HT2 antagonist, might also exert superior efficacy in this population. Eighteen inpatients with treatment-resistant schizophrenia who had an acute psychotic exacerbation of the disorder received, in a double-blind design, 30 mg/day mianserin (n = 9) or placebo (n = 9) in conjunction with typical neuroleptics [haloperidol (n = 9) or perphenazine (n = 9)]. Clinical status was evaluated before, during, and at the end of 6 weeks of combined treatment with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms and Hamilton Rating Scale for Depression. The typical APD/mianserin group exhibited significantly greater improvement in total BPRS scores (17.6% versus 5.5%; P= 0.03) and a trend towards greater improvement in SAPS scores (35.3% versus 13.0%; P = 0.07). Our study indicates that patients with chronic treatment-resistant schizophrenia who have an acute psychotic exacerbation ('acute-on-chronic') may benefit from the addition of a potent 5-HT2 blocker, such as mianserin, to typical antipsychotics. Our findings may further emphasize the contribution of enhanced 5-HT2 blockade to the 'atypicality' of the atypical APDs and to their greater efficacy in alleviating symptoms of chronic treatment-resistant schizophrenia.

Blood pressure values in children with intrauterine growth retardation.

BACKGROUND: Low birth weight has been shown to be strongly related to hypertension in adult life. OBJECTIVES: To determine whether blood pressure is higher in children with intrauterine growth retardation than in control subjects. METHODS: Blood pressure was measured in 58 children aged 4-6 years with IUGR and in 58 age-matched controls. The control children, whose birth weight was appropriate for gestational age, were also matched for gestational age. RESULTS: The children with IUGR had significantly higher mean values of systolic (P < 0.05) and diastolic blood pressures (P < 0.05) and mean arterial pressure (P < 0.05). Significant differences in blood pressure values were found between preterm IUGR (n = 21) and preterm controls (P < 0.05). CONCLUSIONS: These data indicate that children with IUGR may be at higher risk of hypertension already in childhood.

Stability of diagnosis: a 20-year retrospective cohort study of Israeli psychiatric adolescent inpatients.

Outcome according to diagnosis and stability of diagnosis were investigated in a follow-back study of 351 adolescents with various psychiatric disorders hospitalized in a closed psychiatric ward. The duration of follow-back was 15-19 years. All diagnoses were based on the ICD-9. Data were collected from the Health Ministry registry and, in the patients who could be located, by structured telephone interview. Special attention was directed at the diagnosis of transient adolescent psychosis (TAP) vs. schizophrenia and prognostic indicators of suicide. The results showed that the most stable diagnosis was anxiety disorder. The stability of the different diagnoses over time was greater between the second and last admission than between the first and last (for patients with three or more admissions). Number of hospitalizations correlated negatively with prognosis. TAP at second admission was an unstable diagnosis; 66% of these patients had a final diagnosis of schizophrenia. However, patients with a diagnosis of TAP at first admission had a higher predictive index score and a higher outcome score than schizophrenic patients. TAP appeared to be a valid diagnostic entity, distinguishable from schizophrenia in course, frequency of suicidal behaviour and social-occupational outcome. Suicide victims had a higher cumulative length of stay than age- and sex-matched non-suicidal patients. Fifty per cent of the suicide victims had a final diagnosis of schizophrenia, compared to 30 per cent for the whole sample. In conclusion, these findings indicate that TAP is associated with a relatively good prognosis and should probably be differentiated from schizophrenia. Further retrospective and prospective studies of adolescent psychiatric inpatients may help delineate the nature and course of psychosis and other psychopathology in this age group.

Abnormal thermoregulation in drug-free male schizophrenia patients.

Schizophrenia patients may develop various thermoregulatory disturbances. We hypothesized that a standardized exercise-heat tolerance test [two 50-min bouts of walking a motor-driven treadmill at 40 degrees C (relative humidity=40%)] would reveal abnormal thermoregulation in drug-free schizophrenia patients. Six drug-free schizophrenia outpatients and seven healthy comparison subjects participated in this study. The schizophrenia patients exhibited significantly higher baseline and exertion-related rectal temperature. The relevance of these findings to the pathophysiology of schizophrenia-related thermoregulatory disorders is as yet unclear.

Response of catatonia to risperidone: two case reports.

The present study describes two patients, both of Yemenite origin, with catatonic schizophrenia who responded to treatment with risperidone. One had a long history of psychiatric disorder, whereas the other was a first-episode, drug-naive patient. Our observation agrees with previous reports on the use of risperidone and other novel neuroleptic agents in the treatment of catatonia of different etiologies.

The effect of intrauterine growth restriction on the development and health of children.

The neurodevelopmental and cognitive outcome of long-term Intrauterine Growth Restriction (IUGR) has been followed up from pregnancy to school age at the Tel Aviv Child Development Centre.

Beneficial effect of the addition of the 5-HT 2A/2C and alpha2 antagonist mianserin to ongoing haloperidol treatment in drug-resistant chronically hospitalized schizophrenic patients.

Atypical neuroleptics that block serotonin 2A (5-HT 2A) and dopamine 2 (D2) receptors have been shown to possess efficacious antipsychotic activity. We assessed the efficacy of the addition of the 5-HT 2A/2C and alpha2 antagonist mianserin to ongoing haloperidol treatment in chronically hospitalized (> 10 years) drug-resistant schizophrenic patients (N = 12). The patients were assessed at baseline and every three months for one year with the Brief Psychiatric Rating Scale and the Clinical Global Impression. Results showed a significant (but < 10%) improvement in the core symptoms of schizophrenia; however, only the reduction (by 43%) in anxiety was clinically relevant (P < 0.0001). The beneficial effect of mianserin may be related to the combined blockade of 5-HT 2A and histamine (H1) receptors.

Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis.

Methylenetetrahydrofolate reductase deficiency is the most common inborn error of folate metabolism and should be suspected when homocystinuria is combined with hypomethioninemia. The main clinical findings are neurologic signs such as severe developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma. Most patients present in early life. The infantile form is severe, with rapid deterioration leading to death usually within 1 year. Treatment with betaine has been shown to be efficient in lowering homocysteine concentrations and returning methionine to normal, but the clinical response is variable. We report two brothers with methylenetetrahydrofolate reductase deficiency: the first was undiagnosed and died at 8 months of age from neurologic deterioration and apnea, while his brother, who was treated with betaine from the age of 4 months, is now 3 years old and has developmental delay.