Diagnostic and Statistical Manual of mental disorder-IV (DSM-IV) TR based INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD) is an established instrument for the diagnosis of ASD in Indian subcontinent and low-middle income countries (LMIC). The introduction of DSM-5 necessitated revision of existing INDT-ASD tool to incorporate the DSM-5 related changes. This study was undertaken to develop and validate the DSM-5 based All India Institute of Medical Sciences (AIIMS)-Modified-INDT-ASD Tool. The modifications were done using Delphi method and included: (a) rearrangement of questions from the previous tool; and (b) addition of new questions on sensory symptoms. The modified tool was validated against DSM-5 diagnostic criteria. In addition, receiver operating characteristic (ROC) curves were used to determine the cut-off for total score as compared to Childhood Autism Rating Scale (CARS) score to grade the severity of ASD. Two-hundred-twenty-five children (159 boys, median age = 47months) were enrolled. The modified tool demonstrated sensitivity of 98.4% and specificity of 91.7% to diagnose ASD. A score ≥14 on the tool was suggestive of severe ASD (CARS>36.5) with a sensitivity and specificity of 80% and 80.7% respectively [Area under the curve = 0.89]. AIIMS-Modified-INDT-ASD Tool is a simple and structured instrument based on DSM-5 criteria which can facilitate diagnosis of ASD with acceptable diagnostic accuracy.

Background POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. Methods Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. Results A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. Conclusions We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.

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GRIN2B is a gene encoding GluN2B subunit under the family of N-methyl D-aspartate (NMDA) receptors, which is responsible for neurogenesis and cognitive processes. The role of NMDA receptor antagonists like memantine is being explored for therapies in drug-resistant epilepsies. Here, we present a case of a 20-month-old boy who presented with refractory epileptic spasms. Upon failure of multiple antiepileptic drugs, he was started on oral memantine. There was a significant reduction in average seizure episodes by ∼80%. The use of memantine along with antiepileptic drug polytherapy has proved to be beneficial in our case. Our experience with memantine and favorable outcome opens up the scope of more research into the use of NMDA receptor antagonist as a drug option for refractory epilepsies with proven genetic mutation and hence improves the overall neurodevelopmental outcome and survival chance.

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