Child Neurodevelopment After Multidomain Interventions From Preconception Through Early Childhood: The WINGS Randomized Clinical Trial.

Importance: Multidomain interventions in pregnancy and early childhood have improved child neurodevelopment, but little is known about the effects of additional preconception interventions. Objective: To evaluate the effect of a multifaceted approach including health; nutrition; water, sanitation, and hygiene (WASH); and psychosocial support interventions delivered during the preconception period and/or during pregnancy and early childhood on child neurodevelopment. Design, Setting, and Participants: In this randomized trial involving low- and middle-income neighborhoods in Delhi, India, 13 500 participants were assigned to preconception interventions or routine care for the primary outcome of preterm births and childhood growth. Participants who became pregnant were randomized to pregnancy and early childhood interventions or routine care. Neurodevelopmental assessments, the trial's secondary outcome reported herein, were conducted in a subsample of children at age 24 months, including 509 with preconception, pregnancy, and early childhood interventions; 473 with preconception interventions alone; 380 with pregnancy and early childhood interventions alone; and 350 with routine care. This study was conducted from November 1, 2000, through February 25, 2022. Interventions: Health, nutrition, psychosocial care and support, and WASH interventions delivered during preconception, pregnancy, and early childhood periods. Main Outcomes and Measures: Cognitive, motor, language, and socioemotional performance at age 24 months, assessed using the Bayley Scales of Infant and Toddler Development 3 tool. Results: The mean age of participants at enrollment was 23.8 years (SD, 3.0 years). Compared with the controls at age 24 months, children in the preconception intervention groups had higher cognitive scores (mean difference [MD], 1.16; 98.3% CI, 0.18-2.13) but had similar language, motor, and socioemotional scores as controls. Those receiving pregnancy and early childhood interventions had higher cognitive (MD, 1.48; 98.3% CI, 0.49-2.46), language (MD, 2.29; 98.3% CI, 1.07-3.50), motor (MD, 1.53; 98.3% CI, 0.65-2.42), and socioemotional scores (MD, 4.15; 98.3% CI, 2.18-6.13) than did controls. The pregnancy and early childhood group also had lower incidence rate ratios (RRs) of moderate to severe delay in cognitive (incidence RR, 0.62; 98.3% CI, 0.40-0.96), language (incidence RR, 0.73; 98.3% CI, 0.57-0.93), and socioemotional (incidence RR, 0.49; 98.3% CI, 0.24-0.97) development than did those in the control group. Children in the preconception, pregnancy, and early childhood intervention group had higher cognitive (MD, 2.60; 98.3% CI, 1.08-4.12), language (MD, 3.46; 98.3% CI, 1.65-5.27), motor (MD, 2.31; 98.3% CI, 0.93-3.69), and socioemotional (MD, 5.55; 98.3% CI, 2.66-8.43) scores than did those in the control group. Conclusions and Relevance: Multidomain interventions during preconception, pregnancy and early childhood led to modest improvements in child neurodevelopment at 24 months. Such interventions for enhancing children's development warrant further evaluation. Trial Registration: Clinical Trials Registry-India CTRI/2017/06/008908.

The spectrum of neurological manifestations and genotype-phenotype correlation in Indian children with Gaucher disease.

Gaucher disease (GD), one of the most frequent autosomal recessive lysosomal storage disorders, occurs due to bi-allelic pathogenic variants in the GBA1. Worldwide, the c.1448T>C (L483P) homozygous pathogenic variant is reported to be associated with neurological GD phenotype. Clinical distinction between GD1 and GD3 may be challenging due to subtle neurological features. Objective methods to evaluate neurological signs and saccades may help in early diagnosis. This study was conducted to assess the neurological phenotype, and its severity using a modified severity scoring tool (mSST), and the genotype-phenotype correlation. A total of 45 children aged 2 years 6 months to 15 years with a confirmed enzymatic and molecular diagnosis of GD with or without therapy were recruited. mSST tool was used to assess the severity of the neurological phenotype. A digital eye movement tracker (View Point Tracker) was used to assess eye movements. Clinical and genetic findings were analyzed. Out of 45 patients, 39 (86.7%) had at least one neurological phenotype detected using the mSST tool, with impairment of cognitive function (68.8%, 31/45) being the commonest feature. Thirty-two of 45 (71%) were assessed for saccadic eye movements using the eye tracker. Of these, 62.5% (20/32) had absent saccades. Four children (8.9%, 4/32) without clinical oculomotor apraxia had absent saccades on the viewpoint eye tracker. Overall, 77.7% (35/45), had homozygosity for c.1448T>C in GBA1 of which 91.4% (32/35) had neurological manifestations. Other alleles associated with neurological phenotype included c.1603C>T(p.R535C), c.1184C>T (p.S395F), c.115+1G>A (g.4234G>A), c.260G>A (p.R87Q) and c.1352A>G (p.Y451C). To conclude, in India, the c.1448T>C pathogenic variant in GBA1 is the commonest  and is associated with neurological phenotype of GD. Therefore, every patient of GD should be assessed using the mSST scoring tool for an early pick up of neurological features. The routine use of a viewpoint eye tracker in children with GD would be useful for early recognition of saccadic abnormalities.

Neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia: Experience from a tertiary care center in India.

BACKGROUND: Data of neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL) is scarce from low middle-income countries (LMICs), and is influenced by biological and cultural variations. The objective of this study was to assess the prevalence and spectrum of neurocognitive deficits in a cohort of survivors from India. PROCEDURE: Seventy survivors of childhood ALL were evaluated for neurocognitive deficits by the Indian adaptation of Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IVINDIA ). The prevalence of neurocognitive deficits was calculated based on the full-scale intelligence quotient (FSIQ), and scores in discrete domains like verbal comprehension, perceptual reasoning, working memory, and processing speed were calculated and compared to demographics, treatment, and sociocultural factors. RESULTS: The mean (SD) current age and time since diagnosis was 10.5 (±3.2) years and 5 (±2.8) years, respectively. The mean FSIQ was 86.1 ± 20.5, with significant neurocognitive deficit (FSIQ <90) being prevalent in 50% (95% CI: 38%-62%) of the cohort. The proportion of survivors with deficits in individual domains of verbal comprehension, perceptual reasoning, working memory, and processing speed were 49%, 50%, 47%, and 44%, respectively. The odds of having neurocognitive deficits were higher when a child belonged to lower socioeconomic strata (OR 5.7, p = .004), parents with lower education attainment (OR 4.3, p = .041), and whose birth order was higher (OR 20.1, p = .005). Age at diagnosis/assessment, chemotherapy received, or dose of radiotherapy did not have a direct impact on neurocognition. CONCLUSIONS AND RELEVANCE: Rates of neurocognitive deficits are higher in survivors in LMICs, with socioeconomic variables contributing more than the direct neurotoxic effects of treatment.

Surgery for Drug-Resistant Epilepsy in Children.

BACKGROUND: Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials. METHODS: In this single-center trial, we randomly assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet-Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory. RESULTS: At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (P<0.001). Between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the score on the Hague Seizure Severity scale (difference, 19.4; 95% confidence interval [CI], 15.8 to 23.1; P<0.001), on the Child Behavior Checklist (difference, 13.1; 95% CI, 10.7 to 15.6; P<0.001), on the Pediatric Quality of Life Inventory (difference, 21.9; 95% CI, 16.4 to 27.6; P<0.001), and on the Vineland Social Maturity Scale (difference, 4.7; 95% CI, 0.4 to 9.1; P=0.03), but not on the Binet-Kamat intelligence quotient (difference, 2.5; 95% CI, -0.1 to 5.1; P=0.06). Serious adverse events occurred in 19 patients (33%) in the surgery group, including hemiparesis in 15 (26%). CONCLUSIONS: In this single-center trial, children and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection. (Funded by the Indian Council of Medical Research and others; Clinical Trial Registry-India number, CTRI/2010/091/000525 .).

Decoding of novel missense TSC2 gene variants using in-silico methods.

BACKGROUND: Mutations in TSC1 or TSC2 gene cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the formation of non-malignant hamartomas in multiple vital organs. TSC1 and TSC2 gene products form TSC heterodimer that senses specific cell growth conditions to control mTORC1 signalling. METHODS: In the present study 98 TSC patients were tested for variants in TSC1 and TSC2 genes and 14 novel missense variations were identified. The pathogenecity of these novel variations was determined by applying different bioinformatics tools involving computer aided protein modeling. RESULTS: Protein modelling could be done only for ten variants which were within the functional part of the protein. Homology modeling is the most reliable method for structure prediction of a protein. Since no sequence homology structure was available for the tuberin protein, three dimensional structure was modeled by a combination of homology modeling and the predictive fold recognition and threading method using Phyre2 threading server. The best template structures for model building of the TSC1 interacting domain, tuberin domain and GAP domain are the crystal structures of clathrin adaptor core protein, Rap1GAP catalytic domain and Ser/Thr kinase Tor protein respectively. CONCLUSIONS: In this study, an attempt has been made to assess the impact of each novel missense variant based on their TSC1-TSC2 hydrophobic interactions and its effect on protein function.

Neurodevelopmental disorders in children aged 2-9 years: Population-based burden estimates across five regions in India.

BACKGROUND: Neurodevelopmental disorders (NDDs) compromise the development and attainment of full social and economic potential at individual, family, community, and country levels. Paucity of data on NDDs slows down policy and programmatic action in most developing countries despite perceived high burden. METHODS AND FINDINGS: We assessed 3,964 children (with almost equal number of boys and girls distributed in 2-<6 and 6-9 year age categories) identified from five geographically diverse populations in India using cluster sampling technique (probability proportionate to population size). These were from the North-Central, i.e., Palwal (N = 998; all rural, 16.4% non-Hindu, 25.3% from scheduled caste/tribe [SC-ST] [these are considered underserved communities who are eligible for affirmative action]); North, i.e., Kangra (N = 997; 91.6% rural, 3.7% non-Hindu, 25.3% SC-ST); East, i.e., Dhenkanal (N = 981; 89.8% rural, 1.2% non-Hindu, 38.0% SC-ST); South, i.e., Hyderabad (N = 495; all urban, 25.7% non-Hindu, 27.3% SC-ST) and West, i.e., North Goa (N = 493; 68.0% rural, 11.4% non-Hindu, 18.5% SC-ST). All children were assessed for vision impairment (VI), epilepsy (Epi), neuromotor impairments including cerebral palsy (NMI-CP), hearing impairment (HI), speech and language disorders, autism spectrum disorders (ASDs), and intellectual disability (ID). Furthermore, 6-9-year-old children were also assessed for attention deficit hyperactivity disorder (ADHD) and learning disorders (LDs). We standardized sample characteristics as per Census of India 2011 to arrive at district level and all-sites-pooled estimates. Site-specific prevalence of any of seven NDDs in 2-<6 year olds ranged from 2.9% (95% CI 1.6-5.5) to 18.7% (95% CI 14.7-23.6), and for any of nine NDDs in the 6-9-year-old children, from 6.5% (95% CI 4.6-9.1) to 18.5% (95% CI 15.3-22.3). Two or more NDDs were present in 0.4% (95% CI 0.1-1.7) to 4.3% (95% CI 2.2-8.2) in the younger age category and 0.7% (95% CI 0.2-2.0) to 5.3% (95% CI 3.3-8.2) in the older age category. All-site-pooled estimates for NDDs were 9.2% (95% CI 7.5-11.2) and 13.6% (95% CI 11.3-16.2) in children of 2-<6 and 6-9 year age categories, respectively, without significant difference according to gender, rural/urban residence, or religion; almost one-fifth of these children had more than one NDD. The pooled estimates for prevalence increased by up to three percentage points when these were adjusted for national rates of stunting or low birth weight (LBW). HI, ID, speech and language disorders, Epi, and LDs were the common NDDs across sites. Upon risk modelling, noninstitutional delivery, history of perinatal asphyxia, neonatal illness, postnatal neurological/brain infections, stunting, LBW/prematurity, and older age category (6-9 year) were significantly associated with NDDs. The study sample was underrepresentative of stunting and LBW and had a 15.6% refusal. These factors could be contributing to underestimation of the true NDD burden in our population. CONCLUSIONS: The study identifies NDDs in children aged 2-9 years as a significant public health burden for India. HI was higher than and ASD prevalence comparable to the published global literature. Most risk factors of NDDs were modifiable and amenable to public health interventions.

Does surgery help in reducing stigma associated with drug refractory epilepsy in children?

INTRODUCTION: Epilepsy has several comorbidities and associated stigma. Stigma associated with epilepsy is well known and prevalent worldwide. Surgical treatment is an established treatment for drug refractory epilepsy. Following surgery in children, it is possible that the stigma may reduce, but such an effect has not been studied earlier. MATERIALS AND METHODS: Analysis of prospectively collected data was performed for pediatric patients at a single tertiary center for treating epilepsy. Child stigma scale, as described by Austin et al., was used to evaluate stigma both pre- and postoperatively. Analysis was done using Paired t test. RESULTS: In this study, following surgery, there was significant reduction of stigma (P<0.001). This was proportional to the reduction in seizures, though there were 9 (30%) patients, who due to persistent neurodisability did not have any reduction of stigma despite having good seizure outcome. CONCLUSION: Surgery in drug-resistant epilepsy helps in reducing stigma. Seizure reduction is probably not the only factor responsible for a change in stigma outcome.

Late effects of treatment in survivors of childhood cancers: A single-centre experience.

BACKGROUND & OBJECTIVES: With improved survival of childhood cancer patients, the number of long-term cancer survivors is increasing. Some studies have assessed the long-term morbidity after childhood cancer treatment in the developing countries. This study was conducted to assess the spectrum of late effects of cancer treatment in paediatric cancer survivors. METHODS: Evaluation of the first 300 patients who completed five years of follow up in the after treatment completion clinic was done. Details of primary diagnosis, treatment received and current clinical status were noted. The spectrum of late effects was ascertained by appropriate investigations. RESULTS: Haematological malignancies comprised 25 per cent of total cases. Most common primary diagnosis comprised acute lymphoblastic leukaemia, retinoblastoma and Hodgkin's lymphoma. The median age at evaluation and follow up was 14 and 8.5 yr, respectively. Twenty three per cent (69) of the survivors had a minimal disability (growth retardation or underweight), 13 per cent (39) had moderate disabilities needing medical attention (hepatitis B surface antigen positive, myocardial dysfunction, azoospermia and hypothyroidism), while two per cent had major/life-threatening disabilities (mental retardation, liver disease and mortality). Eleven patients relapsed on follow up, of those five patients expired. Two second malignancies were recorded during the period of follow up. INTERPRETATION & CONCLUSIONS: Late effects were of concern; however, severe disability (Grade 3-5) was seen in only two per cent survivors. Lifelong follow up of childhood cancer survivors is required to assess cancer-related morbidity, occurrence of a secondary neoplasm, to facilitate timely diagnosis and to implement remedial or preventive interventions to optimize health outcomes. Awareness towards the existence of late effects of cancer therapy is required among parents, patients and health professionals.

Williams-Beuren Syndrome: Experience of 43 Patients and a Report of an Atypical Case from a Tertiary Care Center in India.

Williams-Beuren syndrome (WBS) or Williams syndrome (OMIM 194050) is a multisystem disorder manifested by neurodevelopmental delay and is caused by a hemizygous deletion of ∼ 1.5-1.8 Mb in the 7q11.23 region. Clinical features include cardiovascular anomalies (mainly supravalvular aortic stenosis), peripheral pulmonary stenosis, distinctive facies, intellectual disability (usually mild), unique personality characteristics, and growth and endocrine abnormalities. Clinical diagnostic criteria are available for WBS; however, the mainstay of diagnosis is the detection of the contiguous gene deletion. Although FISH remains the most widely used laboratory test, the diagnosis can also be established by means of qPCR, MLPA, microsatellite marker analysis, and chromosomal microarray (CMA). We evaluated the utility of MLPA to detect deletion/duplication in the 7q11.23 region in 43 patients suspected to have WBS using MLPA kits for microdeletion syndromes. A hemizygous deletion in the 7q11.23 region was found in 41 (95.3%) patients using MLPA. One patient had an atypical deletion detected by CMA. During the initial period of this study, the results of 12 patients tested by MLPA were also confirmed by FISH. Compared to FISH and CMA, MLPA is a cheaper, high-throughput, less labor-intensive and less time-consuming technique for the diagnosis of WBS. Although CMA is expensive and labor-intensive, its effectiveness is demonstrated to detect an atypical deletion and to delineate the breakpoints.

Safety, Efficacy, and Tolerability of Modified Atkins Diet in Persons With Drug-Resistant Epilepsy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Modified Atkins diet (MAD) has emerged as an adjuvant therapy in drug-resistant epilepsy (DRE). Most studies are in children; there is limited evidence for DRE in adults. This study aimed to investigate whether MAD along with standard drug therapy (SDT) was indeed more effective than SDT alone in reducing seizure frequency and improving psychological outcomes at 6 months in adolescents and adults with DRE (nonsurgical). METHODS: A prospective randomized controlled trial was conducted at tertiary care referral center in India. Persons with DRE aged 10-55 years attending outpatient epilepsy clinics between August 2015 and April 2019, who had more than 2 seizures per month despite using at least 3 appropriate antiseizure medications (ASMs) at their maximum tolerated doses and had not been on any form of diet therapy for the past 1 year, were enrolled. Patients were assessed for the eligibility and randomly assigned to receive SDT plus MAD (intervention arm) or SDT alone (control arm). The primary outcome was >50% reduction in seizure frequency, and the secondary outcomes were quality of life (QOL), behavior, adverse events, and rate of withdrawal at 6 months. Intention-to-treat analysis was performed. RESULTS: A total of 243 patients were screened for eligibility; 160 patients (80 adults and 80 adolescents) were randomized to either the intervention or control arm. Demographic and clinical characteristics in both groups were comparable at baseline. At 6 months, >50% seizure reduction was seen in 26.2% in the intervention group vs 2.5% in the control group (95% CI 13.5-33.9; p < 0.001). Improvement in QOL was 52.1 ± 17.6 in the intervention group vs 42.5 ± 16.4 in the control group (mean difference, 9.6; 95% CI 4.3 to 14.9, p < 0.001). However, behavior scores could be performed in 49 patients, and improvement was seen in the intervention vs control group (65.6 ± 7.9 vs 71.4 ± 8.1, p = 0.015) at the end of the study. One patient had weight loss; 2 patients had diarrhea. DISCUSSION: The MAD group demonstrated improvement in all aspects (reduction in seizure frequency and behavioral problems) compared with the control group at the end of the study. MAD is an effective modality in controlling seizures; further research is required to assess its efficacy in terms of biomarkers along with descriptive metabolomics studies. TRIAL REGISTRATION INFORMATION: The clinical trial registry of India: CTRI/2015/07/006048. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the MAD increases the probability of seizure reduction in adolescents and adults with DRE.

Association of fetal ultrasound anthropometric parameters with neurodevelopmental outcomes at 24 months of age.

BACKGROUND: There is a paucity of studies which have examined associations between ultrasound based fetal anthropometric parameters and neurodevelopment in all infants. We examined the association between ultrasound based fetal anthropometric parameters and neurodevelopment in all infants through a secondary analysis of data collected in a large community based randomized controlled trial. METHODS: A total of 1465 mother-child dyads were included. Ultrasound based fetal anthropometric parameters which included the head circumference (HC), abdominal circumference (AC), femur length (FL), biparietal diameter (BPD) and transcerebellar diameter (TCD) were collected at 26-28 weeks of gestation and their association with neurodevelopment at 24 months of age was examined. RESULTS: Only the transcerebellar diameter z score was positively associated +0.54 units (95% CI: 0.15, 0.93) with motor composite score. When the neurodevelopment outcomes were analyzed as categorical, none of the fetal variables were associated with risk of moderate to severe neurodevelopment impairment. CONCLUSION: The findings suggest that transcerebellar diameter could be useful for early prediction of neurodevelopmental outcomes in childhood. CLINICAL TRIAL REGISTRATION: Clinical trial registration of Women and Infants Integrated Interventions for Growth Study Clinical Trial Registry-India, #CTRI/2017/06/008908; Registered on: 23/06/2017, (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19339&EncHid=&userName=society%20for%20applied%20studies).

Short-term neurodevelopment and growth outcomes of very and moderate preterm Indian infants.

OBJECTIVE: To study the growth and neurodevelopmental outcome of very and moderate preterm infants (VMPT) compared to term appropriate-for-age (term AGA) infants at 18-months corrected age. METHODS: This prospective cohort study enrolled consecutively born 212 VMPT infants and 250 term AGA controls delivered during study period. OUTCOME MEASURES: Major neurodevelopmental impairment (NDI) defined as any one of cerebral palsy, motor (MoDQ) or mental developmental quotient (MoDQ) <70 on Developmental Assessment Scale for Indian infants, visual or hearing impairment, or epilepsy, and growth outcomes. RESULTS: Among 195 VMPT and 240 term AGA infants who completed follow-up, the frequency of major NDI was 12.8% and 2.5% respectively (RR 5.1; 95% CI [2.13-12.19]). Major NDI was higher among infants <28 weeks gestation (39%) and birthweight <1000 grams (27%). A quarter of VMPT infants exhibited wasting and 18% stunting than 7% each among controls. CONCLUSION: VMPT infants had a higher frequency of major NDI and growth failure at 18-months.

Association of Sleep Apnea With Development and Behavior in Down Syndrome: A Prospective Clinical and Polysomnographic Study.

BACKGROUND: The prevalence of sleep-disordered breathing is high in children with Down syndrome. Although the association between sleep-disordered breathing and developmental delay and behavioral abnormalities are proven among typically developing children, there are few such studies of children with Down syndrome. This study assesses the relationship between the severity of sleep apnea and development and behavioral abnormalities in individuals with Down syndrome. METHODS: In a cross-sectional prospective study, 53 children with Down syndrome were assessed for sleep-disordered breathing by overnight polysomnography. Behavior was assessed using Child Behavior Checklist (CBCL) and developmental quotient (DQ) using Developmental Profile 3. The association between various domains of behavior and development with the Apnea-Hypopnea Index (AHI) was assessed using Spearman rank correlation. Multiple linear regression assessed the independent effects of various factors on development and behavior. RESULTS: Of 53 subjects (three to 11.8 years), 51 (96%) were found to have obstructive sleep apnea (OSA). In both three to five year and six to 12 year age groups, there was a statistically significant positive correlation between the CBCL scores and the AHI (rho = 0.77 and 0.83, respectively). There was a statistically significant negative correlation between the DQ and the AHI (rho = -0.62). In multiple linear regression, AHI was the only independent variable that was associated with CBCL and DQ. CONCLUSIONS: This study provides robust evidence that OSA can negatively influence the development and behavior in children with Down syndrome as in typically developing children. Moreover, with increasing severity of OSA, children with Down syndrome have more behavioral abnormalities, especially attention deficit and hyperactivity, and also have poorer development scores.

A patient with POLA1 splice variant expands the yet evolving phenotype of Van Esch O'Driscoll syndrome.

Van Esch-O'Driscoll syndrome (VEODS) is a rare cause of syndromic X-linked intellectual disability characterised by short stature, microcephaly, variable degree of intellectual disability, and hypogonadotropic hypogonadism. To date, heterozygous hypomorphic variants in the gene encoding the DNA Polymerase α subunit, POLA1, have been observed in nine patients from five unrelated families with VEODS. We report a three-year-old child with VEODS having borderline intellectual disability due to a novel splice site variant causing exon 6 skipping and reduced POLA1 expression.

Development and Evaluation of a Working Memory Intervention Kit in Children with Epilepsy in Low-Resource Settings.

OBJECTIVES: In this pilot study, the authors developed and evaluated a working memory intervention (WMI) using a combination of mobile phone-based application and an activity booklet, among children with idiopathic generalized epilepsy. METHODS: Pre- and post-intervention cognitive evaluation at 8 wk included: subtests comprising working memory index from Wechsler Intelligence Scale-IV, color cancellation task for sustained attention, and parent's rating from the Conners' ADHD/DSM-IV Scales of the Conners' Rating Scales-Revised. RESULTS: Fourteen children completed the intervention; one was lost to follow-up. Significant improvement in most working memory parameters occurred at 8 wk: digit span [scaled scores: median 7 (IQR 4-9) to 12 (IQR 9-14.25); p = 0.001]; letter-number sequencing [scaled scores: median 9 (IQR 5-10) to 11.5 (IQR 6.75-13); p = 0.03]; WMI [median 14 (IQR 9-18) to 22 (IQR 16.75-27); p = 0.001] and sustained attention [time for cancellation test improved from 95 (72-117) to 85 (63-98) s; p = 0.001]. CONCLUSION: This indigenous WMI was feasible and efficacious in improving working memory deficits in CWE in low-resource settings.

Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population.

Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by formation of hamartomas and broad phenotypic spectrum including seizures, mental retardation, renal dysfunction, skin manifestations and brain tubers. It is inherited in an autosomal dominant pattern, caused due to mutation in either TSC1 or TSC2 genes. Seizures are one of the major presenting symptoms of TSC that helps in early diagnosis. The present study describes the mutation spectrum in TSC1 and TSC2 genes in TSC patients and their association with neurocognitive-behavioral phenotypes. Ninety-eight TSC patients were enrolled for TSC genetic testing after detailed clinical and neurobehavioral assessment. Large genomic rearrangement testing was performed by multiplex ligation-dependent probe amplification (MLPA) technique for all cases and Sanger sequencing was performed for MLPA negative cases. Large rearrangements were identified in approximately 1% in TSC1 and 14.3% in TSC2 genes. The present study observed the presence of duplications in two (2%) cases, both involving TSC2/PKD1 contiguous genes which to the best of our knowledge is reported for the first time. 8.1% of small variants were identified in the TSC1 gene and 85.7% in TSC2 gene, out of which 23 were novel variations and no variants were found in six (6.1%) cases. This study provides a representative picture of the distribution of variants in the TSC1 and TSC2 genes in Indian population along with the detailed assessment of neurological symptoms. This is the largest cohort study from India providing an overview of comprehensive clinical and molecular spectrum.

Aetiology of global developmental delay in young children: experience from a tertiary care centre in India.

BACKGROUND: Global developmental delay is a common reason for referral to a paediatrician. We examined the aetiological yield of an extensive diagnostic work-up in young children with developmental delay in a tertiary referral centre. METHODS: To assess the diagnostic possibilities, we systematically examined 100 consecutive children with global developmental delay (< 5 years of age) who visited the paediatric outpatient department over a period of 18 months. An association between the presence of features at initial contact and aetiology was analysed by the 2-tailed Fisher exact test and chi-square test. RESULTS: Of the 100 children, 65 were < 2 years of age (mean age 23.6 months) at presentation. The presence of birth asphyxia, sepsis, seizures, abnormal neurological findings, and dysmorphism were significant predictors of aetiology. Four diagnostic categories--chromosomal disorders including Down syndrome, hypoxic-ischaemic encephalopathy, multiple malformation syndromes and cerebral dysgenesis--were the most common causes of global development delay in 20%, 15%, 14% and 11%, respectively. Moderate delay was seen in 42%, severe in 33% and mild in 25% of the patients. The aetiological yield did not differ with the severity of global developmental delay. Additional investigations such as neuroimaging, cytogenetic analysis, metabolic tests and specific molecular tests contributed to a diagnosis in 73% of the children, while in 23% these were the sole means of arriving at a diagnosis. Neuroimaging for a specific indication was almost twice more likely to yield an aetiology when compared with neuroimaging performed as a screening tool (65% v. 35%; p = 0.003). CONCLUSION: The aetiological yield in this selected cohort with global developmental delay was 73%. A step-wise investigational approach is justified in all children with developmental delay, regardless of the severity of delay or the absence of findings on history and physical examination. This study is an attempt to formulate an investigative approach in a child with global developmental delay, especially in developing countries where advanced molecular and cytogenetic studies are not routinely available.

The Development and Validation of DSM 5-Based AIIMS-Modified INDT ADHD Tool for Diagnosis of ADHD: A Diagnostic Test Evaluation Study.

BACKGROUND: The current study was planned at a tertiary centre in northern India to develop and validate a Diagnostic and Statistical Manual-5 (DSM-5)-based diagnostic tool and design a severity score for attention deficit hyperactivity disorder (ADHD) in children aged 6-18 years. An existing DSM-IV-based tool, INDT (International Clinical Epidemiology Network [INCLEN] diagnostic tool) for ADHD has been modified and named All India Institute of Medical Sciences (AIIMS)-modified INDT ADHD tool. METHOD: The first phase was development of the tool and the second phase was validation of the same against the gold standard of diagnosis by the DSM-5. A severity score was developed for ADHD in concordance with the Conners rating scale. RESULTS: The tool was validated in 66 children with a sensitivity and specificity of 100 per cent and 90 per cent, respectively. A cut-off score of 12 was decided for labelling severity of ADHD, which corresponded to 63 in the Conners rating scale. CONCLUSION: This diagnostic tool for ADHD based on DSM-5 has acceptable psychometric properties. The severity score will be useful for prognostication, monitoring treatment response, and designing intervention trials.

Development, Cognition, Adaptive Function and Maladaptive Behavior in HIV-infected and HIV-exposed Uninfected Children Aged 2-9 Years.

OBJECTIVE: To compare development/cognition, adaptive function and maladaptive behavior of HIV-infected and HIV-exposed uninfected children between 2 to 9 years with HIV-uninfected controls. METHODS: This hospital-based cross-sectional study was conducted from November, 2013 to March, 2015. 50 seropositive HIV-infected, 25 HIV-exposed uninfected and 25 HIV-uninfected children between 2 to 9 years were administered Developmental Profile 3, Vineland Adaptive Behavior Scale 2, and Child Behavior Checklist for assessing development, adaptive function and maladaptive behaviour, respectively. Additional data were obtained by history, examination and review of records. RESULTS: Significant developmental/cognitive impairment was observed in 38 (76%), 16 (64%) and 6 (24%) HIV-infected, HIV-exposed uninfected, and HIV-uninfected children, respectively. Significant impairment in adaptive function was found in 12 (24%) and 2 (8%) HIV-infected and HIV-exposed uninfected children, respectively. Maladaptive behavior was not seen in any group. CONCLUSIONS: High magnitude of impaired development/cognition and adaptive function in HIV-exposed and HIV-infected children warrants assessment of these domains during follow-up of these children, and incorporation of interventions for these deficits in standard care for this group.

Hospital Based Psychosocial Support Program for Children with ALL and their Families: A Comprehensive Triad's Perspective.

OBJECTIVES: To elucidate potential target areas of intervention and mechanisms for implementation of intervention for children with cancer during the treatment phase. METHODS: Focused group discussion (FGDs) served as a primary source of providing phenomenal perspectives to explore the key objective. Eight focus groups of 45-60 min each were held with 5-9 members in each discussion. The participants were either patients, their caregivers or health care providers. The focus group audio recordings were professionally transcribed after all identifiers were removed. Employing a constructivist paradigm with a phenomenological approach, also known as emergent-systematic focus group design the study reported on families' experiences of childhood cancer as construction of objective reality. Investigator triangulation method was adopted to ensure trustworthiness. RESULTS: Using constant comparison analysis, multistage process analysis was done which resulted in 849 codes, 32 subthemes, 20 themes and 5 domains. A total of 64 participants participated: 4 FGDs with parents of children with ALL (n = 31); 1 FGD with professionals working in the field of cancer (n = 10) and 3 FGDs with children with ALL (n = 23). Participant's mean age at the time of study was 10 y (+3.3) for children; 37 y (+4.93) for caregivers and 35 y (+3.5) for professionals. The number of participants and their age range at study varied slightly between the eight focus groups. CONCLUSIONS: Caregivers presented care burden and compromised aspects of Quality of life (QOL). An effective and culturally sensitive psychosocial support for patients and their families during and post treatment, in addition to medical therapy, is strongly recommended.