Introduction A retrospective study in India had showed high rate of comorbid disruptive disorders in children with Attention deficit hyperactivity disorder, but not depression and anxiety disorders as opposed to western literature. Studies using structured assessment tools are lacking in Indian population and thus valid data on prevailing pattern of comorbidities in ADHD children is lacking. Aims To study the pattern of co-morbidities in Indian children & adolescents (subjects) with ADHD and to compare the degree of functional impairment between ADHD subjects with and without comorbidities. Methods 60 consecutive subjects aged 6 to 16 years diagnosed as ADHD based on DSM IV TR were recruited with informed consent, from a tertiary care centre during a period of 6 months. Kiddie-SADS - PL was applied to identify comorbidities in these subjects. Global functioning was assessed by Children Global Assessment scale (CGAS) in all these subjects. Results 55% of recruited subjects had comorbidity, the most highly prevalent lifetime disorder being Oppositional Defiant disorder (25%), followed by conduct disorder (13.3%), Bipolar affective disorder (13.3%), Major depressive disorder (10%), Communication disorder (10%), Substance use disorder (8.4%), Obsessive compulsive disorder (8.3%), Tic disorder (5.4%), Learning disorder (5%), Elimination disorder (3.3%), Social phobia (1.7%) and Separation anxiety disorder (1.7%). Subjects with comorbidities had poorer global functioning (41.58 ± 0.45) when compared to ADHD subjects without comorbidities (47.67 ± 8.57) (p = 0.018). Conclusions Our study points out that Comorbid disorders like anxiety disorders are not as low as projected by the earlier Indian studies.

Primary microcephaly is an autosomal recessive disorder characterized by smaller than normal brain size and mental retardation. It is genetically heterogeneous with seven loci: MCPH1-MCPH7. We have previously reported genetic analysis of 35 families, including the identification of the MCPH7 gene STIL. Of the 35 families, three families showed linkage to the MCPH2 locus. Recent whole-exome sequencing studies have shown that the WDR62 gene, located in the MCPH2 candidate region, is mutated in patients with severe brain malformations. We therefore sequenced the WDR62 gene in our MCPH2 families and identified two novel homozygous protein truncating mutations in two families. Affected individuals in the two families had pachygyria, microlissencephaly, band heterotopias, gyral thickening, and dysplastic cortex. Using immunofluorescence study, we showed that, as with other MCPH proteins, WDR62 localizes to centrosomes in A549, HepG2, and HaCaT cells. In addition, WDR62 was also localized to nucleoli. Bioinformatics analysis predicted two overlapping nuclear localization signals and multiple WD-40 repeats in WDR62. Two other groups have also recently identified WDR62 mutations in MCPH2 families. Our results therefore add further evidence that WDR62 is the MCPH2 gene. The present findings will be helpful in genetic diagnosis of patients linked to the MCPH2 locus.

Objective. The study is aimed to assess psychological problems and quality of life (QOL) in children with thalassemia.Methods. Thirty-nine children (8-16 yr) with transfusion dependent thalassemia attending day care services for blood transfusion were assessed for psychological problems using the Childhood Psychopathology Measurement Schedule and QOL was assessed using the EQ-5D.Results. Forty-four percent of the children had psychological problems and 74% had a poor QOL. Anxiety-related symptoms (67%), emotional problems, particularly depression (62%), and conduct problems (49%) were the main findings. The children were most likely to report impaired QOL due to severe difficulties in pain/discomfort (64%) dimension, followed by depression and mobility problems of equal severity (33%). The side effects of chelation were an independent predictor of psychological problems and impaired QOL. Also psychological problems were a significant predictor of impaired QOL.Conclusion. The recognition and management of the psychological problems that accompany chronic physical illnesses including thalassemia would optimize treatment outcomes and QOL.

Objectives: To estimate the lifetime prevalence of bipolar 11 disorder in children and adolescents presenting with DSM-IV major depressive disorder (MDD).Methods: Sixty-one consecutive subjects aged <= 18 years attending the outpatient services of the Child and Adolescent Psychiatric (CAP) services of the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India with a diagnosis of MDD were evaluated using the Missouri Assessment of Genetics Interview for children (MAGIC). Two psychiatrists, one of whom was a child psychiatrist diagnosed hypomania by consensus.Results: Twelve children had a past episode of hypomania (20%), which was hitherto undiagnosed clinically.Limitations: We recruited subjects from a psychiatric hospital, thus limiting the generalizability of the finding. Sample size was relatively small and assessments were cross-sectional.Conclusions: Our study shows that bipolar II disorder is often misdiagnosed as MDD in children. The study also highlights that the chance of diagnosing bipolarity is enhanced by using semi-structured interview in routine clinical practice. (c) 2006 Elsevier B.V All rights reserved.

OBJECTIVE:To find the mutation and polymorphism spectrum of TSC1 and TSC2 genes in patients affected with tuberous sclerosis complex from the Indian population.MATERIAL AND METHODS:All coding exons and promoter regions of both TSC genes were screened for mutations and polymorphisms in 24 TSC families using polymerase chain reaction-single strand conformation polymorphism and DNA sequencing techniques.RESULTS:A single previously known mutation, c.2111_2112delAT was identified in the TSC1 gene. A total of 11 mutations were identified in the TSC2 gene. Of these, seven mutations, c.137_138delGA, c.2070delC, c.2087_2088insAA, c.3080T>C (p.L1027P), c.648+1G>A, c.3131+1G>A and c.5034C>G were novel. The remaining four mutations, c.4544_4547delACAA, c.1941_1942insT, c.1831C>T (p.R611W) and c.1832G>A (p.R611Q) had been reported previously in other populations. The novel mutation, c.137_138delGA was predicted to result in the production of a very small tuberin protein of 64 amino acids lacking all seven functional domains. In addition, we also detected three and 10 polymorphisms in the TSC1 and TSC2 genes respectively. DNA sequence analysis of promoter regions of both TSC genes in 24 families did not show any variation.CONCLUSIONS:This is the first molecular genetic study of TSC in an Indian population. A total of 12 mutations were detected in 24 Indian TSC families in TSC genes. All except one mutation were detected in the TSC2 gene. No variation was found in the promoter regions of either gene. As observed in the western and Japanese populations, the mutations were scattered across the TSC2 gene.

BACKGROUND & OBJECTIVE:There are limited data on child mental health needs in our country. Therefore, an epidemiological study to determine the prevalence rates of child and adolescent psychiatric disorders was initiated as a two-centre (Bangalore and Lucknow) study by the Indian Council of Medical Research. It also aimed to study the psychosocial correlates of the psychiatric disorders. We present here the findings of Bangalore Centre.METHODS:In Bangalore, 2064 children aged 0-16 yr, were selected by stratified random sampling from urban middle-class, urban slum and rural areas. The screening stage was followed by a detailed evaluation stage. The ICD-10 DCR criteria were used to reach a penta-axial diagnosis.RESULTS:The results indicated a prevalence rate of 12.5 per cent among children aged 0-16 yr. There were no significant differences among prevalence rates in urban middle class, slum and rural areas. The psychiatric morbidity among 0-3 yr old children was 13.8 per cent with the most common diagnoses being breath holding spells, pica, behaviour disorder NOS, expressive language disorder and mental retardation. The prevalence rate in the 4-16 yr old children was 12.0 per cent. Enuresis, specific phobia, hyperkinetic disorders, stuttering and oppositional defiant disorder were the most frequent diagnoses. When impairment associated with the disorder was assessed, significant disability was found in 5.3 per cent of the 4-16 yr group. Assessment of felt treatment needs indicated that only 37.5 per cent of the families perceived that their children had any problem. Physical abuse and parental mental disorder were significantly associated with psychiatric disorders.INTERPRETATION & CONCLUSION:Prevalence rates of psychiatric morbidity in 0-16 yr old children in India were found to be lower than Western figures. Middle class urban areas had highest and urban slum areas had lowest prevalence rates. The implications for clinical training, practice and policy initiatives are discussed.

Patients with primary microcephaly, an autosomal recessive trait, have mild to severe mental retardation without any other neurological deficits. It is a genetically heterogeneous disorder with six known loci: MCPH1 to MCPH6. Only the genes for MCPH1 and MCPH5 have been identified so far. We have ascertained nine consanguineous families with primary microcephaly from India. To establish linkage of these nine families to known MCPH loci, microsatellite markers were selected from the candidate regions of each of the six known MCPH loci and used to genotype the families. The results were suggestive of linkage of three families to the MCPH5 locus and one family to the MCPH2 locus. The remaining five families were not linked to any of the known loci. DNA-sequence analysis identified one known (Arg117X) and two novel (Trp1326X and Gln3060X) mutations in the three MCPH5-linked families in a homozygous state. Three novel normal population variants (i.e., c.7605G > A, c.4449G > A, and c.5961 A > G) were also detected in the ASPM gene.

Objective: Data on outcome of juvenile onset bipolar disorder is limited. This study examined the course and outcome of bipolar disorder and assessed the rate and predictors of recovery and relapse in a sample of children and adolescents over a 4-5 year period.Method: Twenty-five consecutively ascertained subjects (9-16 years) with a diagnosis of mania (mean duration at intake of 4.6 +/- 3.9 weeks), were comprehensively assessed at baseline and at 6-month intervals using the Diagnostic Interview for Children and Adolescents (revised) (DICA-R), the Missouri Assessment for Genetic Interview in Children (MAGIC), the Young's Mania Rating Scale (YMRS) and the Children's Global Assessment (CGAS). The study phenotype required DSM-IV criteria of mania with elation and/or grandiosity as a criterion to distinguish them from those with attention deficit hyperactivity disorder. Subjects received the standard treatment as prescribed by their primary treating team.Results: During the course of the study period, all 25 subjects (100%) recovered from the index episode. The mean time to recovery was 44 +/- 46 days. The mean duration of follow-up was 51.6 +/- 4.1 months. Sixteen subjects (64%) relapsed after a mean period of 18 +/- 16.4 months. A majority of the relapses (72.4%) were while the subjects were on treatment.Conclusions: Acute juvenile onset mania has a high rate of recovery and low chronicity. The relapse rate was high and most of these occurred in the first 3 years despite aggressive prophylactic treatment. The effectiveness of currently used thymoleptics, in particular lithium, in the prophylaxis of juvenile bipolar disorder needs to be evaluated in controlled studies.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with loci on chromosome 9q34.12 (TSC1) and chromosome 16p13.3 (TSC2). Genes for both loci have been isolated and characterized. The promoters of both genes have not been characterized so far and little is known about the regulation of these genes. This study reports the characterization of the human TSC1 promoter region for the first time. We have identified a novel alternative isoform in the 5′ untranslated region (UTR) of the TSC1 gene transcript involving exon 1. Alternative isoforms in the 5′UTR of the mouse Tsc1 gene transcript involving exon 1 and exon 2 have also been identified. We have identified three upstream open reading frames (uORFs) in the 5′UTR of the TSC1/Tsc1 gene. A comparative study of the 5′UTR of TSC1/Tsc1 gene has revealed that there is a high degree of similarity not only in the sequence but also in the splicing pattern of both human and mouse TSC1 genes. We have used PCR methodology to isolate approximately 1.6 kb genomic DNA 5′ to the TSC1 cDNA. This sequence has directed a high level of expression of luciferase activity in both HeLa and HepG2 cells. Successive 5′ and 3′ deletion analysis has suggested that a ~587 bp region, from position +77 to −510 from the transcription start site (TSS), contains the promoter activity. Interestingly, this region contains no consensus TATA box or CAAT box. However, a 521-bp fragment surrounding the TSS exhibits the characteristics of a CpG island which overlaps with the promoter region. The identification of the TSC1 promoter region will help in designing a suitable strategy to identify mutations in this region in patients who do not show any mutations in the coding regions. It will also help to study the regulation of the TSC1 gene and its role in tumorigenesis.

Objective: To study the long‐term course and outcome of juvenile obsessive–compulsive disorder (OCD). Method: Two to 9‐year follow‐up of largely self‐referred, drug‐naïve subjects ( n = 58) by employing catch‐up longitudinal design. Results: The mean follow‐up period was 5 years. Nearly three‐fourth of the sample was adequately treated with medications. Only 21% of the subjects had clinical OCD at follow‐up and 48% were in true remission (no OCD and not on treatment). Earlier age‐at‐onset was associated with better course and outcome. Conclusion: Juvenile OCD has favorable outcome. Our findings are applicable to psychiatric hospital settings in India and perhaps to the general psychiatric settings in the Western countries. Whether the better outcome in this sample is the result of differing clinical characteristics or because of true cross‐cultural variation in the course needs further exploration. It is speculated that early onset OCD could be a subtype of juvenile OCD with better outcome.

Tuberous sclerosis complex (TSC) is an autosomal dominant neuro-cutaneous disorder with loci on chromosome 9q34.3 (TSC1) and chromosome 16p13.3 (TSC2). Genes for both loci have been isolated and characterized. Pathologically, tuberous sclerosis complex is a disorder of cell proliferation, differentiation and migration. Clinical symptoms of TSC include cortical tubers, subependymal nodules, mental retardation, seizures, autism, shagreen patches and angiofibromas on the skin, cardiac rhabdomyomas, retinal hamartomas, ungual and peringual fibromas, and cysts and angiomyolipomas in the kidneys. More than 350 mutations have been reported in both TSC genes in patients mainly from the western and Japanese populations. However, there is no report on the mutation analysis of TSC genes in patients from the Indian population. We report here the mutational analysis of the TSC2 gene in 23 TSC families from India. Using PCR-SSCP and DNA sequence analyses, we have screened all 41 exons and promoter region of the TSC2 gene in seven familial and 16 sporadic TSC cases. We have identified a total of 12 mutations representing 25% and 75% of familial and sporadic cases respectively. Of these, eight mutations are novel. Of 12 mutations, 3 are deletions, 2 are insertions, 4 are missense, 2 are splice site and 1 is a nonsense mutation. In addition, we have also detected nine single-nucleotide polymorphisms (SNPs) in the TSC2 gene. Of these three are novel SNPs. There was no correlation between the types of mutations (missense, nonsense, etc.) and the severity of the disease. The mutations were found to be distributed across the gene without any clustering, suggesting that mutation analysis requires scanning of the complete coding sequence of the TSC2 gene (This work was financially supported by a grant from DBT, New Delhi to AK and SCG and a CSIR JRF to MA)

Objective: Recent studies of patients with juvenile bipolar disorder report low rates of recovery and high rates of chronicity. However, we lack data on the short-term outcome. This study examines the pattern of recovery from the index episode in an aggressively treated juvenile sample.Method: We assessed 25 subjects (< 16 years) with a diagnosis of mania, using the Diagnostic Interview for Children and Adolescents-Revised) (DICA-R), Young Mania Rating Scale (YMRS), and Children's Global Assessment Scale (CGAS) at intake and at 3 and 6 months. We studied the time taken to recover from the index episode, the level of functioning, and the factors predicting them.Results: After 6 months, 24 (96%) subjects had recovered from the index manic episode. The median time to recovery was 27 days. Total episode length was significantly longer among those with previous affective episodes.Conclusions: The findings suggest that juvenile-onset mania has high rates of recovery and low rates of chronicity. These differences from the existing literature need further exploration.

In microcephaly (small head), the size of the head as measured by the occipito-frontal circumference of an affected individual is greater than three standard deviations below the population age-related mean. The cranial vault in a microcephaly patient is smaller than normal relative to the facial skeleton and the rest of the body. The small cranial capacity results from underlying hypoplasia of the cerebral cortex rather than abnormal development of the overlying skull and there is no major abnormality in cortical architecture (Jackson et al 1998; Mochida and Walsh 2001). Microcephaly is known to have a heterogeneous etiology with environmental and genetic causes. Among the environmental causes are intrauterine infections, drugs (alcohol) taken during pregnancy, prenatal radiation exposure, maternal phenylketonuria and birth asphyxia. All of these except birth asphyxia are known to be rare causes of microcephaly. The majority of microcephalic cases are caused by a variety of genetic mechanisms including cytogenetic abnormalities and single-gene disorders (Jackson et al 1998).

Affective disorders in all forms do occur in persons with mental retardation. The presence and degree of mental retardation modify manifestations of these disorders. Diagnosis is difficult because of the absence of classical manifestations and frequent occurrence of inter-episode behaviour disturbances. Response to treatment may not be as favourable as in their normal counterparts.

Objective: Using minimal exclusion criteria, to assess systematically the psychiatric comorbidity in children and adolescents with obsessive–compulsive disorder (OCD) and compare the findings with those of previous studies. Method: Fifty-four children and adolescents who satisfied DSM-III-R criteria for OCD were assessed using a structured interview schedule, the Children's version of the Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and the questionnaire for tic disorders. All 54 subjects were recruited from the Child and Adolescent Psychiatry (CAP) services of the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, South India. Diagnoses were determined consensually after a review of all the available data. Results: Comorbidity was found in 69% of the sample: 22% were diagnosed with disruptive disorders; 20% met criteria for mood disorders; 19% had anxiety disorders; and 17% had tic disorders. Only 1 subject had bipolar disorder, and none had psychosis. The rates for individual diagnoses—in particular, the rates for disruptive disorders, bipolar disorder, and psychosis—were considerably lower than those reported in previous studies. Conclusions: Patterns of comorbidity in this study differed from those previously reported. Novel patterns of comorbidity with disruptive disorders, bipolar disorder, and psychosis reported in a few recent studies were not replicated in this study. These differences are probably due to different ascertainment methods. Comorbidity needs to be assessed in large epidemiological samples before definite associations can be made between certain comorbid disorders and juvenile OCD.