A novel loss of function mutation in adaptor protein complex 4, subunit mu-1 causing autosomal recessive spastic paraplegia 50.

BACKGROUND: Spastic paraplegia 50 (SPG50) is a rare autosomal recessive inherited disorder characterized by spasticity, severe intellectual disability and delayed or absent speech. Loss-of-function pathogenic mutations in the AP4M1 gene cause SPG50. METHODS: In this study, we investigated the clinical and genetic characteristics of a consanguineous family with two male siblings who had infantile hypotonia that progressed to spasticity, paraplegia in one and quadriplegia in the other patient. In addition, the patients also exhibited neurodevelopmental phenotypes including severe intellectual disability, developmental delay, microcephaly and dysmorphism. RESULTS: In order to identify the genetic cause, we performed cytogenetics, whole-exome sequencing and Sanger sequencing. Whole-exome sequencing of the affected siblings and unaffected parents revealed a novel exonic frameshift insertion of eight nucleotides (c.341_342insTGAAGTGC) on exon 4 of the AP4M1 gene. CONCLUSION: Insertion of these eight nucleotides in the AP4M1 gene is predicted to result in a premature protein product of 132 amino acids. The truncated protein product lacks a signal binding domain which is essential for protein-protein interactions and the transport of cargo proteins to the membrane. Thus, the identified variant is pathogenic and our study expands the knowledge of clinical and genetic features of SPG50.

KIAA1109 gene mutation in surviving patients with Alkuraya-Kucinskas syndrome: a review of literature.

BACKGROUND: Alkuraya-Kucinskas syndrome is an autosomal recessive disorder characterized by brain abnormalities associated with cerebral parenchymal underdevelopment, arthrogryposis, club foot and global developmental delay. KIAA1109, a functionally uncharacterized gene is identified as the molecular cause for Alkuraya-Kucinskas syndrome. Most of the reported mutations in KIAA1109 gene result in premature termination of pregnancies or neonatal deaths while a few mutations have been reported in surviving patients with global developmental delay and intellectual disability. To our knowledge, only three surviving patients from two families have been reported with missense variants in KIAA1109. In this study, we describe four surviving patients from two related families (a multiplex family) with global developmental delay and mild to severe intellectual disability with no other systemic manifestations. There were no miscarriages or neonatal deaths reported in these families. METHODS: X-chromosome exome panel sequencing was carried out in one patient and whole exome sequencing was carried out on the remaining three affected individuals and the unaffected father of the index family. Data analysis was carried out followed by variant filtering and segregation analysis. Sanger sequencing was carried out to validate the segregation of mutation in all four affected siblings and unaffected parents from both families. RESULTS: A novel homozygous missense mutation in a conserved region of KIAA1109 protein was identified. Sanger sequencing confirmed the segregation of mutation in both families in an autosomal recessive fashion. CONCLUSION: Our study is the second study reporting a KIAA1109 variant in surviving patients with Alkuraya-Kucinskas syndrome. Our study expands the spectrum of phenotypic features and mutations associated with Alkuraya-Kucinskas syndrome.

Lived experiences of children and adolescents with obsessive-compulsive disorder: interpretative phenomenological analysis.

BACKGROUND: Childhood obsessive-compulsive disorder (OCD) is distinct from OCD in adults. It can be severely disabling and there is little qualitative research on OCD in children. The present study aims to explore the subjective experiences of diagnosis, treatment processes and meaning of recovery in children and adolescents suffering from OCD and provide a conceptual model of the illness. METHODS: It is a qualitative study of ten children and adolescents selected by purposive sampling. MINI KID 6.0, Children's Yale-Brown Obsessive-Compulsive Scale and Clinical Global Impression-Severity Scale were administered at the time of recruitment of subjects into the study. Interviews were conducted using an in-depth semi-structured interview guide and audio-recorded. The transcribed interviews were analyzed using Interpretative Phenomenological Analysis (IPA). The study sought to explore participants' sense-making of their world, their thoughts, feelings and perceptions through interpretative enquiry. The findings were confirmed by a process called investigator triangulation, member check and peer validation. RESULTS: IPA yielded five major themes-'illness perception changes over time', 'disclosure on a spectrum', 'cascading effects of OCD', 'treatment infuses hope and helps', and 'navigating through OCD'. A summary of these themes and their subthemes is presented as a conceptual model. The essence of this model is to show the inter-relationship between themes and provide a comprehensive understanding of the phenomenon of OCD. CONCLUSIONS: To the best of our knowledge, this is the first study to explore lived experiences of children and adolescents with OCD using interpretative phenomenological analysis (IPA). It was noted that perception of illness and treatment processes evolves over time, and recovery is viewed as a process. Future qualitative research can be carried out with a focus on 'therapist-related barriers' or 'student-teacher dyads' that can inform clinical practice and school policies respectively. Trial registration NIMH/DO/IEC (BEH. Sc. DIV)/2018, l1 April 2018.

Clinical profile of children and adolescents diagnosed with anorexia nervosa in Indian context.

OBJECTIVE: This study was conducted to assess the trends observed in the prevalence pattern, clinical presentation, psychosocial profile and treatment profile of anorexia nervosa in children and adolescents who presented to a tertiary care child and adolescent psychiatry centre over a period of ten years. METHODS: Case records of children and adolescents diagnosed with anorexia nervosa at the department of child and adolescent psychiatry from 1st April 2009-31 st March 2019 were obtained from the medical records department of the National Institute of Mental Health and Neurosciences (NIMHANS). Standardized data abstraction forms were developed and used for the purpose of this study. Pseudo-anonymization was done to ensure confidentiality and clinical characteristics of the sample were studied using frequency analysis and central tendencies. RESULTS: Prevalence of anorexia nervosa in a clinic-based population is estimated to be 0.07% over the 10-year period. The mean age at presentation was 13.96 years (SD-2.3) and the male to female ratio was 1:12. The majority (80.8%) were admitted and only one patient (3.8%) received treatment on an outpatient basis. Two or more psychosocial stressors were associated with the onset of illness in 88.5% (n = 23) of the patients and dysfunctional family dynamics was noted to be a significant issue in the majority of cases. All the patients received pharmacotherapy and CBT-based individual therapy. The overall outcome was favourable based on the CGI-I scores. CONCLUSIONS: Prevalence of anorexia nervosa in the clinic-based setting is rising in the Indian context. Sample characteristics are similar to those seen in the west. There is a huge demand-supply gap that calls for creating a service provider network to ensure community-based care.

Shukla-Vernon Syndrome: A Second Family with a Novel Variant in the BCORL1 Gene.

Shukla-Vernon syndrome (SHUVER) is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral anomalies, and dysmorphic features. Pathogenic variants in the BCORL1 gene have been identified as the molecular cause for this disorder. The BCORL1 gene encodes for BCL-6 corepressor-like protein 1, a transcriptional corepressor that is an integral component of protein complexes involved in transcription repression. In this study, we report an Indian family with two male siblings with features of Shukla-Vernon syndrome. The patients exhibited global developmental delay, intellectual disability, kyphosis, seizures, and dysmorphic features including bushy prominent eyebrows with synophrys, sharp beaked prominent nose, protuberant lower jaw, squint, and hypoplastic ears with fused ear lobes. No behavioral abnormalities were observed. Whole exome sequencing revealed a novel potentially pathogenic arginine to cysteine substitution (p.Arg1265Cys) in the BCORL1 protein. This is the second report of Shukla-Vernon syndrome with a novel missense variant in the BCORL1 gene. Our study confirms and expands the phenotypes and genotypes described previously for this syndrome and should aid in diagnosis and genetic counselling of patients and their families.

A Novel Missense Variant in PHF6 Gene Causing Börjeson-Forssman-Lehman Syndrome.

Börjeson-Forssman-Lehman Syndrome (BFLS) is a rare X-linked recessive syndrome characterized by intellectual disability, developmental delay, obesity, epilepsy, swelling of the subcutaneous tissues of the face, large but not deformed ears, hypogonadism, and gynecomastia. Pathogenic mutations in PHD finger protein 6 (PHF6) have been reported to cause BFLS. In this study, we describe two male siblings with mild intellectual disability, global developmental delay, short stature, microcephaly, and nyctalopia. Whole exome sequencing of the affected siblings and the parents identified a missense variant (c.413C > G) in the PHF6 gene, which leads to alteration of a serine residue at position 138 to cysteine. This mutation is located in a highly conserved region. Sanger sequencing confirmed the segregation of this mutation in the family in an X-linked recessive fashion. Multiple mass spectrometry-based proteomic studies have reported phosphorylation at serine 138 that describes the possible role of serine 138 in signaling. This novel variant in PHF6 gene helped in establishing a diagnosis of BFLS.

Interventions for Childhood Anxiety Disorders - What Works Best from a Child's Perspective: A Qualitative Study.

BACKGROUND: Anxiety spectrum disorders are the most prevalent psychopathology among children and adolescents. Qualitative research in childhood anxiety disorders can provide valuable insights regarding interventions. The objectives of this study were to examine the child's perspectives on the subjective experience of concerns, the impact of the symptoms on socioacademic functioning, and the process of recovery with interventions. METHODS: Children and adolescents aged 6-16 years, presenting with any subtype of anxiety spectrum disorder as per International Classification of Diseases and Related Health problems, 10th Revision (ICD-10) Diagnostic Criteria for Research, were included. Convenience sampling was used, and 30 children fulfilling inclusion and exclusion criteria were selected. An interview guide with simple questions to facilitate response was used, at the baseline and 12th week of follow-up, to generate a written narrative account of the experience of concerns, the impact of symptoms, and the treatment process. Children received treatment as usual, which included a workbook-based cognitive behavioral intervention. RESULTS: Content analysis was done using 30 baseline and 20 follow-up narratives. Clustering of themes were done. Themes related to the recovery process reflected perceived improvement in academic performance and competence, apart from the improvement in symptoms. There were more themes in favor of cognitive interventions. CONCLUSION: Children's narratives highlight the importance of cognitive interventions for anxiety disorders.

Early childhood network alterations in severe autism.

OBJECTIVE: To examine the differences in whole brain topology and connectivity in 17 children of the ages 3-8 years across severity of ASD, we performed resting state fMRI using a 3T MRI scanner and graph theoretical analysis of networks. METHOD: Patients were partitioned into two cohorts based on the severity of ASD, determined using the Childhood Autism Rating Scale (CARS) scores (Mild, 30-36; Severe, 37+). Standard preprocessing pipeline was used, followed by independent component analysis (ICA) to identify regions of interest (ROIs) to construct subject-specific Z-correlation matrices representing the whole brain network. Following which, graph theory measures were calculated in the range of sparsity 6%-35% and statistically analyzed, and corrected for significance (FDR corrected, p < 0.05). Regional clustering coefficient that revealed significant between-group (mild vs. severe) differences were correlated against clinical scores (CARS). RESULTS: Children with severe ASD revealed significantly increased clustering coefficient and small-worldness compared to those with mild or moderate ASD. Region of interest analysis revealed altered clustering in the Heschl's gyrus that significantly correlated with CARS scores. CONCLUSION: The findings from the current study provide early stage evidence of aberrant brain connectivity appearing in severe ASD, prior to the effect of environmental bias and pruning mechanisms. The clustering of the Heschl's gyrus correlated to the severity of ASD symptoms and agrees with current literature on ASD-associated cortical changes, reflecting early changes to language processing regions.

New initiatives: A psychiatric inpatient facility for older adolescents in India.

CONTEXT: Almost 1/5th of the adolescent population suffers from mental morbidity. In older adolescents, clinical challenges are accompanied by unique psychosocial and developmental needs. Recent legislations in India - the Mental Health Care Act, 2017 and the Juvenile Justice Act, 2015 - mandate specific arrangements and provisions for evaluation and treatment of children and adolescents. A separate inpatient Adolescent Psychiatry Center (APC) was started at National Institute of Mental Health and Neurosciences, Bangalore, in 2016. AIMS: (a) The aim of this study is to present the need for, development, infrastructure and workforce at APC; (b) to describe clinical profile of adolescents admitted to APC and (c) to identify clinical and psychosocial challenges in the management of older adolescents. SETTING AND DESIGN: The paper covers consecutive inpatient admissions over the first 7 months of APC. MATERIALS AND METHODS: Data were gathered from a review of hospital records, staff meetings, and case files. STATISTICAL ANALYSIS: Qualitative data, such as clinical management challenges, are summarized under major emergent themes. Quantitative data are summarized as means with standard deviations and frequencies with percentages. RESULTS: Males, from urban, nuclear family background constituted the majority admissions. Family stressors and risk behaviors were prevalent. Unique clinical challenges included - risk behaviors, issues related to autonomy, conflict with family and conflict with the legal system. CONCLUSIONS: Older adolescents need to be treated in an environment appropriate to their age and developmental stage. Restructuring of spaces, routines, and creative inputs to interventions strategies must be made for healing environments for youngsters. APC could be a model for the development of other similar centers.

Psychological impact of the tsunami on children and adolescents from the andaman and nicobar islands.

OBJECTIVE: The aim of this article is to present the assessment of the presentation of symptoms and psychiatric morbidity of children and adolescents from the Andaman and Nicobar islands during the first 3 months following the December 2004 earthquake and tsunami. METHOD: According to predefined criteria, a primary survivor is one who was exposed directly to the earthquake and tsunami, a secondary survivor is one with close family and personal ties to primary survivors, and tertiary survivors are individuals from the communities beyond the impact area, a majority of which were exposed to the earthquake only. This study included 37 primary and secondary survivors (aged

Comparative study of psychiatric morbidity among the displaced and non-displaced populations in the Andaman and Nicobar Islands following the tsunami.

OBJECTIVE: The objective of this study was to compare the psychiatric morbidity between the displaced and non-displaced populations of the Andaman and Nicobar Islands during the first three months following the 2004 earthquake and tsunami. METHODS: The study was conducted at the 74 relief camps in the Andaman and Nicobar Islands. Port Blair had 12 camps, which provided shelter to 4,684 displaced survivors. There were 62 camps on Car-Nicobar Island, which provided shelter to approximately 8,100 survivors who continued to stay in their habitat (non-displaced population). The study sample included all of the survivors who sought mental health assistance inside the camp. A psychiatrist diagnosed the patients using the ICD-10 criteria. RESULTS: Psychiatric morbidity was 5.2% in the displaced population and 2.8% in the non-displaced population. The overall psychiatric morbidity was 3.7%. The displaced survivors had significantly higher psychiatric morbidity than did the non-displaced population. The disorders included panic disorder, anxiety disorders not otherwise specified, and somatic complaints. The existence of an adjustment disorder was significantly higher in the non-displaced survivors. Depression and post-traumatic stress disorder (PTSD) were distributed equally in both groups. CONCLUSIONS: Psychiatric morbidity was found to be highest in the displaced population. However, the incidence of depression and PTSD were distributed equally in both groups. Involvement of community leaders and survivors in shared decision-making processes and culturally acceptable interventions improved the community participation. Cohesive community, family systems, social support, altruistic behavior of the community leaders, and religious faith and spirituality were factors that helped survivors cope during the early phase of the disaster.

Immune aberrations in children with Autism Spectrum Disorder: a case-control study from a tertiary care neuropsychiatric hospital in India.

Multiple studies have identified the presence of peripheral immune aberrations in subjects with Autism Spectrum Disorder (ASD). However, comprehensive assessment of these peripheral immune aberrations, in the cellular and systemic compartments, in a single group of subjects with ASD is lacking. We assessed proportions of various subsets of immune cells in peripheral blood (T helper cells, T regulatory cells, B cells, monocytes, Natural Killer cells, dendritic cells) by multi-parametric flow cytometry in 50 children with ASD and compared it with thirty healthy controls matched for age, gender, socio-economic status and body mass index. There were no significant differences noted in the proportion of T regulatory cells, B cells, monocytes and Natural Killer cells, between ASD subjects and controls. On the contrary, the proportion of activated Th17 and myeloid dendritic cells were significantly higher in children with ASD. Based on these findings, group comparison of serum levels of Th17 cytokines (interleukin-6, interleukin-17A) was performed. Elevated serum levels of interleukin-6 and interleukin-17A in children with ASD corroborated our immunophenotyping findings. We did not find any significant differences among the pro-inflammatory (interleukin-1ß), Th1 (interferon-γ) and Th2 (interleukin-4) cytokines. This is the first evidence with concurrent findings from immunophenotyping and cytokine data demonstrating activation of the Th17 pathway in subjects with ASD. This finding assumes significance in the light of recent maternal immune activation mouse model study that has highlighted the role of Th17 pathway in the pathophysiology of ASD. Future longitudinal studies are needed to clarify the role of this dysregulated immune pathway in the development of ASD.

Adolescent-onset X-linked Adrenoleukodystrophy Presenting as Treatment-resistant Bipolar Disorder.

A small proportion of bipolar disorder of adolescent onset can be secondary to underlying neurological disorder (secondary mania). We report a case of treatment-resistant mania secondary to cerebral form of adrenoleukodystrophy of adolescent onset. This case demonstrates the need for clinicians to be alert to the possibility of rare neurological diseases that can present with psychiatric manifestations.

Neuropsychiatric Manifestations of Pediatric NMDA Receptor Autoimmune Encephalitis: A Case Series From a Tertiary Care Center in India.

OBJECTIVE: Although psychiatric manifestations are one of the most common presentations of pediatric N-methyl-D-aspartate receptor (NMDAR) encephalitis, there is a lack of studies that characterize psychiatric aspects of this disorder. This study was designed to address this gap. METHODS: Initial clinical presentations including psychiatric symptoms, treatment details, and outcome with respect to psychiatric symptoms were collected from medical case records of children aged less than 18 years with seropositive NMDAR encephalitis from a single tertiary care center (May 2010-November 2016). The Brief Psychiatric Rating Scale for Children (BPRS-C) was administered at the time of presentation and at follow-up. RESULTS: Clinical records from 16 girls and 5 boys of whom 12 were prepubertal (< 12 years) and 9 were postpubertal (≥ 12 years) were analyzed. All 21 children presented with psychiatric symptoms at initial presentation. In 10 children (47.6%), psychiatric symptom was the first symptom. Major psychiatric symptoms included inappropriate crying (most common, 66.7%, n = 14), social withdrawal (57.1%, n = 12), unprovoked anger outburst (47.6%, n = 10), unprovoked screaming behavior (38.1%, n = 8), and talking to self irrelevantly (42.9%, n = 9). In addition to psychiatric symptoms, at least 1 of the following was also seen in all children: speech disturbance (85.7%, n = 18), seizure (85.7%, n = 18), or movement disorder (76.2%, n = 16). Mood symptoms (85.7%, n = 18) were the most common psychopathology. A comorbid psychiatric diagnosis (ICD-10 criteria) was made in 11 children (52.4%); the most common was organic mood disorder (n = 6). The mean BPRS-C score at presentation in prepubertal children was higher than that of postpubertal children (21 vs 17). After immune modulation, clinical improvement was noted after a mean ± SD of 7.4 ± 4.8 months in all 20 children followed up. Three of the 4 children with residual psychiatric symptoms and persistent academic difficulties were prepubertal. CONCLUSIONS: Psychiatric manifestations that are usually mood related are quite common in pediatric NMDAR encephalitis. Prepubertal presentation of this disorder appears to be more severe and may lead to persistent psychiatric and cognitive symptoms.

Social experiential deprivation in autism spectrum disorders: A possible prognostic factor?

Autism spectrum disorders (ASD) are well known to be influenced by various environmental factors. Among these influencers, social experiential deprivation (SED) in infancy is one of them which is not well reported. We explored factors contributing to SED in 11 young children diagnosed to have ASD and compared them to 24 children without SED also having ASD. Intervention mainly addressing factors causing SED for 6 months demonstrated that children with SED had a better outcome at follow up. Could SED be a possible prognostic factor in children with ASD?

Profile of two hundred children with Autism Spectrum Disorder from a tertiary child and adolescent psychiatry centre.

BACKGROUND: There is a recent trend of increase in diagnosis of Autism Spectrum Disorder in India. Till date, there are few retrospective and prospective Indian studies with limited sample sizes ranging from 16 to 94 children. With this background, we planned a retrospective chart review of all new cases of Autism Spectrum Disorder for a period of 1 year in our tertiary care child psychiatry centre. METHODOLOGY: Objectives of this study were to compare the sociodemographic and clinical profile of children below and above 3 years of age and between those who were self-referred versus those referred by professionals. RESULTS: Out of a total of 1957 case records, 201 children (10.3%) were diagnosed with Autism Spectrum Disorder. Male to female ratio was 4:1.2. Mean age of consultation was significantly higher in males. Seventy six percent had a comorbid disorder with Intellectual disability, Attention Deficit Hyperactivity Disorder and Epilepsy being the most common comorbidities. Most caregivers (92.5%) recognized symptoms by 3 years of age. Presenting complaint of poor social response was more prevalent in children <3 years and co-morbidities in children above 3 years. Presenting complaint of speech delay was more common in children who were referred by professionals when compared with those who were self-referred. DISCUSSION: There is a need to sensitize parents and professionals for early intervention and to standardize protocols for assessment and intervention.

Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability.

Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next-generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.

Epidemiological study of child & adolescent psychiatric disorders in urban & rural areas of Bangalore, India.

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.