Co-morbidity in Attention-Deficit Hyperactivity Disorder: A Clinical Study from India.

OBJECTIVE: To assess the prevalence of neurodevelopmental and psychiatric co-morbidities in children and adolescents diagnosed with attention-deficit hyperactivity disorder at a tertiary care child and adolescent psychiatry centre. METHODS: A total of 63 children and adolescents who were diagnosed with attention-deficit hyperactivity disorder and fulfilled the inclusion criteria were comprehensively assessed for neurodevelopmental and psychiatric co-morbidities. The tools used included the Mini-International Neuropsychiatric Interview for Children and Adolescents, Attention Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS), Children's Global Assessment Scale, Clinical Global Impression Scale, Vineland Social Maturity Scale, and Childhood Autism Rating Scale. RESULTS: All except 1 subject had neurodevelopmental and / or psychiatric disorder co-morbid with attention-deficit hyperactivity disorder; 66.7% had both neurodevelopmental and psychiatric disorders. Specific learning disability was the most common co-existing neurodevelopmental disorder and oppositional defiant disorder was the most common psychiatric co-morbidity. The mean baseline ADHD-RS scores were significantly higher in the group with psychiatric co-morbidities, especially in the group with oppositional defiant disorder. CONCLUSION: Co-morbidity is present at a very high frequency in clinic-referred children diagnosed with attention-deficit hyperactivity disorder. Psychiatric co-morbidity, specifically oppositional defiant disorder, has an impact on the severity of attention-deficit hyperactivity disorder. Co-morbidity needs to be explicitly looked for during evaluation and managed appropriately.

Childhood autism spectrum disorders with and without epilepsy: clinical implications.

This prospective cross-sectional study compared 25 children with pervasive developmental disorder and epilepsy and 25 children having pervasive developmental disorder without epilepsy on pervasive developmental disorder scores, Childhood Autism Rating Scale scores, language disability, presence of regression, and epileptiform abnormalities. Epilepsy phenotype was also studied. Children with pervasive developmental disorder and epilepsy had higher pervasive developmental disorder scores (P = .001), higher Childhood Autism Rating Scale scores (P = .016), and lower social quotient (P = .09). More than 50% of children with pervasive developmental disorder and epilepsy and 12% of children having pervasive developmental disorder without epilepsy had epileptiform abnormalities in electroencephalography (EEG). Regression of milestones was significantly associated with epilepsy and epileptiform abnormalities. Children with pervasive developmental disorder and epilepsy might have a worse developmental trajectory requiring intensive management. A behavioral phenotype of autism may coexist often in children with epilepsy, EEG abnormalities, and regression. Seizures might be difficult to control in these children despite adequate compliance. Studies with larger sample size and longitudinal follow-up will provide better understanding.

Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations.

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.

Revised moment propagation method for scalar transport.

The moment propagation (MP) method was used to study the transport of a passive scalar by a turbulent fluid. Numerical results show that the MP method does not accurately capture the evolution of a scalar field at moderate Reynolds numbers. A theoretical analysis proves that the diffusivity derived from the MP model depends on fluid velocity, which limits the range of Péclet number. We describe an improved MP model (MP2) which eliminates the velocity-dependent diffusion, leading to more accurate predictions of scalar transport in high-velocity flows; at low velocities both methods give similar results. We test the model for a variety of simple flows and find that accurate results can be obtained at grid Péclet numbers in excess of 10.

Psychological problems and quality of life in children with thalassemia.

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.

Is bipolar II disorder misdiagnosed as major depressive disorder in children?

OBJECTIVES: To estimate the lifetime prevalence of bipolar II disorder in children and adolescents presenting with DSM-IV major depressive disorder (MDD). METHODS: Sixty-one consecutive subjects aged < or =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.

Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex.

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.

Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.

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.

A follow-up study of juvenile obsessive-compulsive disorder from India.

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.

A family study of juvenile obsessive-compulsive disorder.

OBJECTIVES: To determine whether juvenile obsessive-compulsive disorder (OCD) is familial and whether the rate of Tourette syndrome (TS) and tic disorders is higher among relatives of patients with OCD than among relatives of controls subjects. METHOD: We assessed first-degree relatives of 35 juvenile OCD probands (aged 16 years or less) and 34 matched, psychiatrically unaffected control subjects, using the Diagnostic Interview for Children and Adolescents-Revised (DICA-R) (unpublished), a Questionnaire for tic disorders, the Children's Version of Leyton's Obsessional Inventory (CV-LOI), and the Children's Version of the Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Similarly, we assessed adult relatives, using the Schedule for Clinical Assessment in Neuropsychiatry (SCAN), Leyton's Obsessional Inventory (LOI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and a Questionnaire for tic disorders. The diagnoses were determined by consensus, using DSM-III-R criteria. We calculated age-corrected morbid risk, using Weinberg's method. RESULTS: The morbid risk for OCD among the relatives of OCD probands was 4.96%, while none of the relatives of unaffected control subjects had OCD. We did not diagnose TS in any of the relatives of either OCD probands or control subjects. We diagnosed chronic motor tic disorders in only 1 of the relatives of OCD probands, while none of the relatives of control subjects had any tic disorder. CONCLUSION: Most juvenile cases of OCD are nonfamilial and unrelated to tic disorders, while only a few are familial. There is a need to re-examine the issue of familiality in cases of OCD, as well as its relation to TS, using larger community samples to better understand the hypotheses of familial transmission and comorbidity with tic disorders.

Comorbidity of mental retardation and affective disorders.

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.

Comorbidity in juvenile obsessive-compulsive disorder: a report from India.

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.

Family interview for stress and coping in mental retardation (fisc-mr) : a tool to study stress and coping in families of children with mental retardation.

Stress and coping in the families caring for their member with mental retardation has recently received worldwide research attention. There is no comprehensive instrument to study these issues in India. This study reports on development and standardization of a new instrument to fill this lacuna. Family Interview for Stress and Coping in Mental Retardation (FISC - MR), a semi-structured interview schedule, was developed as a part of two years prospective study of efficacy of brief family intervention for 157 children with mental retardation (funded by ICMR). The tool consists of 2 sections - one measuring stress (daily care, emotional, social and financial) and the other measuring mediators of stress or coping strategies (awareness, attitudes, expectations, rearing practices and social support). Results indicate moderate to high reliability (internal consistency, inter-rater reliability and test-retest reliability) and validity (factorial, criterion and construct) of the instrument. It is concluded that FISC -MR is a useful, reliable and valid instrument for both clinical and research purposes.

Triplet repeat polymorphism & fragile X syndrome in the Indian context.

Mental retardation due to fragile X syndrome is one of the genetic disorders caused by triplet repeat expansion. CGG repeat involved in this disease is known to exhibit polymorphism even among normal individuals. Here we describe the development of suitable probes for detection of polymorphism in CGG repeat at FMR1 locus as well as the diagnosis of fragile X syndrome. Using these methods polymorphism at the FMR1 locus has been examined in 161 individuals. Ninety eight patients with unclassified mental retardation were examined, of whom 7 were found to have the expanded (CGG) allele at the FMR1 locus. The hybridization pattern for two patients has been presented as representative data.

A prospective study of bipolar disorder in children and adolescents from India.

Bipolar disorder in adults is known to run an episodic course. However, little information exists on the long-term naturalistic course of bipolar disorder in juvenile populations. The present study was undertaken with the objectives of (i) documenting the rates of recovery and relapse, (ii) identifying the predictors of recovery and relapse and (iii) assessing the rates of comorbid conditions. A total of 30 subjects with onset of bipolar illness (according to DSM-III-R criteria) in childhood and adolescence were assessed systematically at baseline and 4 to 5 years later. All 30 subjects (100%) had recovered from their index episodes and none had exhibited chronicity. Twenty of the 30 subjects (67%) had relapsed, with most relapses occurring within 2 years of recovery from index episodes. No predictors of recovery and relapse could be identified. Conduct disorder was the only comorbid diagnosis in two subjects (7%). The main implication of our study, in view of the high rates of relapse in the crucial developmental phase of a young individual, is that long-term maintenance medication should be considered in juvenile bipolar patients, even if it is a first episode.

Clinical profile of mania in children and adolescents from the Indian subcontinent.

OBJECTIVES: To see whether classic DSM-III-R criteria for mania are applicable to Indian youngsters and to examine the clinical presentation of mania in an Indian child and adolescent psychiatric sample. METHOD: Fifty subjects with a diagnosis of functional psychosis as per the definition in ICD-9 were recruited from the population referred during the study period of approximately one year (n = 840) to the Child and Adolescent Psychiatry (CAP) clinic of the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, South India. The subjects were systematically evaluated using a standardized clinical interview and demographic questionnaire and were classified according to DSM-III-R. The subjects who satisfied DSM-III-R criteria for mania formed the sample for this study. RESULTS: Twenty-one subjects received a diagnosis of mania according to DSM-III-R. The most common symptoms of mania included pressure of speech, irritability, elation, distractibility, increased self-esteem, expansive mood, flight of ideas, and grandiose delusions. No subject had comorbid attention-deficit hyperactivity disorder (ADHD). Additionally, 13 (61%) of the 21 manic subjects had delusions and/or hallucinations. The other common symptoms included psychomotor agitation, reduced sleep, anger, temper tantrums, decreased concentration, disobedience, aggression, and hyperactivity. CONCLUSIONS: Mania was diagnosable in Indian children and adolescents using classic DSM-III-R criteria. The clinical profile appears to be generally similar to that seen in adults. ADHD is not a comorbid condition. The presence of aggressive or disruptive behaviours and hyperactivity in childhood- and adolescent-onset mania, however, could lead to a misdiagnosis of attention-deficit hyperactivity disorder/conduct disorder (ADHD/CD). Similarly, the presence of psychotic features could lead to a misdiagnosis of schizophrenia.