Report of a novel recurrent homozygous variant c.620A>T in three unrelated families with thiamine metabolism dysfunction syndrome 5 and review of literature.

INTRODUCTION: Biallelic variants in thiamine pyrophosphokinase 1 ( TPK1 ) are known to cause thiamine metabolism dysfunction syndrome 5 (THMD5). This disorder is characterized by neuroregression, ataxia and dystonia with basal ganglia abnormalities on neuroimaging. To date, 27 families have been reported with THMD5 due to variants in TPK1 . METHODS: We ascertained three individuals from three unrelated families. Singleton exome sequencing was performed on all three individuals, followed by in silico mutagenesis of the mutant TPK protein. Additionally, we reviewed the genotypic and phenotypic information of 27 previously reported individuals with THMD5. RESULTS: Singleton exome sequencing revealed a novel homozygous variant c.620A>T p.(Asp207Val) in TPK1 (NM_022445.4) in all three individuals. In silico mutagenesis of the mutant protein revealed a decrease in protein stability and altered interactions with its neighboring residues compared to the wild-type protein. Thus, based on strikingly similar clinical and radiological findings compared to the previously reported individuals and with the support of in silico mutagenesis findings, the above-mentioned variant appears to be the probable cause for the condition observed in the affected individuals in this study. CONCLUSION: We report a novel homozygous variant in TPK1 , which appears to be recurrent among the Indian population.

Genetic Testing in Pediatric Epilepsy: Tools, Tips, and Navigating the Traps.

With the advent of high-throughput sequencing and computational methods, genetic testing has become an integral part of contemporary clinical practice, particularly in epilepsy. The toolbox for genetic testing has evolved from conventional chromosomal microarray and epilepsy gene panels to state-of-the-art sequencing techniques in the modern genomic era. Beyond its potential for therapeutic benefits through precision medicine, optimizing the choice of antiseizure medications, or exploring nonpharmacological therapeutic modalities, genetic testing carries substantial diagnostic, prognostic, and personal implications. Developmental and epileptic encephalopathies, the coexistence of neurodevelopmental comorbidities, early age of epilepsy onset, unexplained drug-refractory epilepsy, and positive family history have demonstrated the highest likelihood of yielding positive genetic test results. Given the diagnostic efficacy across different testing modalities, reducing costs of next-generation sequencing tests, and genetic diversity of epilepsies, exome sequencing or genome sequencing, where feasible and available, have been recommended as the first-tier test. Comprehensive clinical phenotyping at the outset, corroborative evidence from radiology and electrophysiology-based investigations, reverse phenotyping, and periodic reanalysis are some of the valuable strategies when faced with inconclusive test results. In this narrative review, the authors aim to simplify the approach to genetic testing in epilepsy by guiding on the selection of appropriate testing tools in the indicated clinical scenarios, addressing crucial aspects during pre- and post-test counseling sessions, adeptly navigating the traps posed by uncertain or negative genetic variants, and paving the way forward to the emerging testing modalities beyond DNA sequencing.

Applicability of the International League Against Epilepsy (ILAE) 2022 diagnostic criteria for epilepsy syndromes in children: A retrospective review of 1550 children with epilepsy.

OBJECTIVE: Recently, the ILAE Nosology and Definitions Task Force defined diagnostic criteria for epilepsy syndromes. There is paucity of data on the use of these new diagnostic criteria in children with epilepsy, and how these criteria may lead to changes from previous practice. METHODS: This was a retrospective chart review of data of children attending the epilepsy clinic in a tertiary care children's hospital from January 2011 to January 2023. The clinical details such as age at onset, types of seizures, co-morbidities, and results of EEG, MRI and genetic testing were reviewed. Epilepsy syndrome diagnosis was made as per the ILAE 2022 criteria, and compared with the previous syndrome diagnosis as per records. RESULTS: Data from 1550 children (63 % boys) with epilepsy were analysed, and 55.4 % children were classified to have epilepsy syndromes as per the new ILAE 2022 diagnostic criteria. Application of the new 2022 ILAE diagnostic criteria was associated with a change in name alone in 676 (77.8 %) children. Hundred (11.5 %) children were newly classified under an epilepsy syndrome who had previously remained unclassified. Eleven (1.3 %) children who were previously classified into an epilepsy syndrome could not be classified using the new diagnostic criteria. Eight (0.9 %) were shifted to a new syndromic category. Overall, change in diagnosis occurred in 13.7 (11.5 + 1.3 + 0.9)%. No change in epilepsy syndrome classification/nomenclature occurred in 74 (8.5 %) children. SIGNIFICANCE: The new diagnostic criteria led to an overall change in diagnosis in 13.7 % of children with epilepsy. These criteria will hopefully lead to uniformity in diagnosis of epilepsy syndromes across diverse settings.

Interventions to Improve Medication Adherence in Children With Epilepsy: A Systematic Review.

Low medication adherence remains a major challenge in the treatment of epilepsy, particularly in children. In recent years, several approaches and interventions have been employed to promote medication adherence in children with epilepsy (CWE). In this study, we aimed to summarize the evidence on these interventions. In this systematic review, major medical electronic databases were searched for relevant literature from January 2005 till July 2023, including PsycINFO, Medline (via PubMed), Google Scholar, Taylor & Francis databases, and CENTRAL by the Cochrane Library. We planned to include observational studies (with a control arm) and clinical trials involving children/adolescents (<19 years) with epilepsy and/or their caregivers/families who underwent any intervention to improve adherence to anti-seizure medications. Out of 536 articles searched, eight (six randomized trials and two non-randomized intervention studies) were included in the systematic review. A total of 2,685 children/adolescents along with their caregivers participated in these studies. Six studies used educational and two used behavioral interventions to improve adherence to anti-seizure medications. Four studies showed variable levels of adherence improvement, ranging from 2-20% up to 73.9% post-intervention. To conclude, the findings suggest the potential for educational interventions to promote medication adherence in CWE. The class of evidence was II to III among the included studies, as per American Academy of Neurology guidelines.

Validation of the Hindi Versions of Three Autism Specific Screening Tools (M-CHAT-R/F, RBSK-ASQ and TABC) Widely Used in India in 16-30-Month-Old Children.

OBJECTIVE: To determine the diagnostic accuracy of MCHAT-R/F, RBSK-ASQ and TABC for screening children aged 16 to 30 months for autism spectrum disorder (ASD). METHOD: Children aged 16 to 30 months were recruited from the pediatrics department. Those with known neurodevelopmental disorders, disabilities, severe medical illnesses, unavailable mothers, or lack of maternal understanding of Hindi, were excluded. The three index tools were translated into Hindi; each tool was piloted on 25 mothers and modified accordingly. The researcher was trained in administration, scoring and interpretation of the three tools. After enrollment the index tools and Developmental Profile (DP-3) were administered to each participant. The reference tool was a comprehensive assessment by experts that included clinical evaluation, computation of DP-3 scores, and application of diagnostic criteria of ASD; the final diagnosis being ASD or Non-ASD. RESULTS: Sensitivity and specificity of M-CHAT-R/F were 95.2% and 94.4%, of RBSK-ASQ were 100% and 93.9%, and of TABC were 100% and 94.4%, respectively. Convergent validity was high (Spearman's correlation coefficient 0.98). Test-retest and inter-rater reliability of each tool was excellent (Intra-class correlation coefficient 1.00). CONCLUSION: All three tools had acceptable psychometric properties, high convergent validity and excellent test-retest and inter-rater reliability.

Genetic and phenotypic landscape of pediatric-onset epilepsy in 142 Indian families: Counseling and therapeutic implications.

The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.

The 2022 International League Against Epilepsy Classification and Definition of Childhood Epilepsy Syndromes: An Update for Pediatricians.

The 2017 classification of the epilepsies of International League Against Epilepsy (ILAE) defined three diagnostic levels, including seizure type, epilepsy type and epilepsy syndrome. Epilepsy syndromes have been recognized as distinct electroclinical entities well before the first ILAE classification of Epilepsies and Epilepsy Syndromes in 1985. A formally accepted classification of epilepsy syndromes was not available, and hence, the 2017-2021 Nosology and Definitions Task Force of ILAE was formulated. The ILAE position papers were published in 2022, which classified epilepsy syndromes into (1) syndromes with onset in neonates and infants (up to 2 years of age), (2) syndromes with onset in childhood, (3) syndromes that may begin at a variable age and (4) idiopathic generalized epilepsies. This classification recognized the concept of etiology-specific syndrome. These papers have addressed the specific clinical and laboratory features of epilepsy syndromes and specify the rationale for any significant changes in terminology or definition. This paper will review some pertinent changes and essential points relevant to pediatricians.

De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.

The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

Neurologic Complications in Patients With Lymphoreticular Malignancy: A Descriptive Cohort Study.

OBJECTIVES: The objectives of this study were to study the spectrum of neurologic complications in children with lymphoreticular malignancy (acute lymphoblastic leukemia, Hodgkin, and non-Hodgkin lymphoma) at diagnosis and during treatment and to determine the etiology of these complications. MATERIALS AND METHODS: In this descriptive cohort study, conducted between November 2018 and March 2020, 204 children with a diagnosis of lymphoreticular malignancy were enrolled. The baseline investigations were done in all the cases. Those who developed neurological symptoms were evaluated with cerebrospinal fluid examination and radiologic and electrophysiologic studies as per indication and were managed according to standard management guidelines. RESULTS: Of the 204 patients, 30 (14.7%) developed neurological complications. The majority of these complications (n=20/30; 87%) occurred during the intensive chemotherapy period. Common complications included acute methotrexate neurotoxicity (n=7), vincristine-induced neurotoxicity (n=7), central nervous system (CNS) relapse (n=4), and posterior reversible encephalopathy syndrome (n=2). L-asparaginase-induced thrombosis (n=1), intramedullary compression syndrome (n=1), CNS infection (n=2), CNS hemophagocytic lymphohistiocytosis (n=1), and steroid-induced myopathy (n=1) were also observed. The complications resolved in 21/30 (70%) patients after receiving appropriate treatment while the neurological complication persisted in 2/30 (6.7%) patients. Three patients (10%) abandoned the treatment, and 4 (13.3%) patients expired. CONCLUSIONS: Neurologic complications in patients with lymphoreticular malignancy are quite variable, having common presenting symptoms but varying imaging abnormalities. By close follow-up and effective treatment, the morbidity and mortality of these complications can be minimized.

Childhood Neurological Disorders With Hyperhomocystinemia: A Case-Based Review.

Hyperhomocysteinemia is a rare neurometabolic syndrome with diverse manifestations in the pediatric age group, thereby posing a diagnostic challenge. Biochemical testing is imperative to guide plan of evaluation, which may include appropriate genetic testing, in inherited disorders. Through this case-based approach, we demonstrate the heterogeneity of clinical presentation, biochemical and genetic evaluation, and treatment strategies that may reverse this condition among children.

Genetics and SUDEP: Challenges and Future Directions.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related deaths in children and adults with epilepsy. The incidence of SUDEP in children and adults is equal, approximately 1.2 per 1000-person years. Although inroads have been made in our understanding of SUDEP, its pathophysiology remains unknown. The most important risk factor for SUDEP is the presence of tonic-clonic seizures. Recently there has been growing interest in the contribution of genetic risk factors to SUDEP deaths. Pathogenic variants in epilepsy-related and cardiac genes have been found in some cases of SUDEP post-mortem. Pleiotropy may occur in which a single gene when altered may cause multiple phenotypes (i.e., epilepsy and cardiac arrhythmia). Recently it has been shown that some developmental and epileptic encephalopathies (DEEs) may also be at heightened risk of SUDEP. In addition, polygenic risk has been postulated to effect SUDEP risk with current models evaluating the additive effect of variants in multiple genes. However, the mechanisms underpinning polygenic risk in SUDEP are likely more complex than this. Some preliminary studies also highlight the feasibility of detecting genetic variants in brain tissue post-mortem. Despite the advances in the field of SUDEP genetics, the use of molecular autopsy remains underutilized in SUDEP cases. Several challenges exist concerning genetic testing post-mortem in SUDEP cases, such as interpretation, cost of testing, and availability. In this focused review, we highlight the current landscape of genetic testing in SUDEP cases, its challenges, and future directions.