Indira Gandhi Institute of Child Health

Objective Recently, a mitochondrial encephalopathy due to biallelic HPDL variants was described, associated with a broad range of clinical manifestations ranging from severe, infantile‐onset neurodegeneration to adolescence‐onset hereditary spastic paraplegia. HPDL converts 4‐hydroxyphenylpyruvate acid (4‐HPPA) into 4‐hydroxymandelate (4‐HMA), necessary for the synthesis of the mitochondrial electron transporter CoQ10. This suggests a possible bypass of the metabolic block by 4‐HMA treatment; however, genotype–phenotype correlations are lacking. Methods We established an HPDL Patient Registry to prepare for a future clinical trial. Here we report the clinical features of 13 enrolled participants and compare them with 86 previously reported patients. We establish three major clinical classes: severe, intermediate, and mild, presenting onset in early infancy, childhood, and adolescence, respectively. The biallelic genotypes were classified into truncating/truncating, truncating/missense, and missense/missense variants, mapped onto the predicted 3D protein structure, and correlated with severity. Results Patients with biallelic truncating variants presented with severe phenotypes and earlier ages of onset. Missense variants were often associated with milder phenotypes, except those with variants predominantly located in or near the VOC2 domain containing iron‐binding sites or the C‐terminus, which had more severe phenotypes. In addition, p.Met1? variants were also correlated with more severe phenotypes. Interpretation This study demonstrates the correlation of age of onset and disease severity with genotype for HPDL‐related conditions. Patients with truncating variants and specific missense variants correlated with severe, early‐onset features, whereas the presence of at least one missense variant located outside of the iron‐binding sites correlated with milder presentations. Trial Registration Clinicaltrials.gov HPDL registry: https://clinicaltrials.gov/study/NCT05848271

Nutritional deficiency-associated morbidity is still widespread in India and occurs due to various factors like lifestyle, diet and social and cultural issues. Here, we report a teenager who presented with symptoms and signs of vitamin B 12 deficiency in association with a rare underlying metabolic disorder. A teenager in his early adolescence presented with acute febrile illness with clinical signs of hypopigmented hair, knuckle hyperpigmentation, dystonia and spasticity. Neuroimaging showed bilateral putamen signal changes and batwing sign features with a deranged metabolic profile (elevated serum homocysteine with low serum vitamin B 12 , free carnitine and acylcarnitine). Further, exome sequencing identified a novel, likely pathogenic frameshift deletion, c.1021delA, with the change of amino acid from threonine to leucine at position 341 with the introduction of stop codon after 16 amino acids with subsequent protein truncation, in the GCDH gene. Thus, we started the patient on parental cobalamin therapy with a glutaric aciduria type-1 specific diet. On follow-up, the child showed significant improvement, with a decrease in hyperpigmentation and dystonia.

With sophisticated technological improvements, genetic testing has become easily available. Different genetic conditions can coexist in a single individual, and it is important to identify them to manage the child confidently and effectively and to prognosticate. Here, we present a 9-year-old male child, with predominant motor delay with regression of attained motor milestones. Facial dysmorphism with strabismus, multiple café-au-lait macules with axillary freckles, flat foot with wasting and kyphoscoliosis were noted. Neurological examination revealed decreased tone, distal power of 2/5 and sluggish deep tendon reflexes, while other systems were normal. The magnetic resonance imaging brain, orbits and spine was normal. Nerve conduction studies (NCS) revealed demyelinating polyneuropathy. Genetic analysis revealed NF1 and SH3TC2 genes causing NF-1 with Charcot-Marie-Tooth type 4C with phenotypic correlation. To conclude, a thorough clinical examination, NCS and exome sequencing were used to definitively diagnose two distinct disorders in a single child after a clinical diagnosis of NF1 with coexisting peripheral neuropathy created a diagnostic conundrum.

Objective Definitive guidance regarding the duration of antibiotics for neonatal sepsis is lacking. We hypothesised that a 7-day antibiotic course is non-inferior to a 14-day course for treating culture-proven sepsis. Design Randomised, controlled, non-inferiority trial with masked outcome assessment in eight centres in a low and middle-income country. Patients Neonates with a birth weight (BW) ≥1000 g and blood culture-proven sepsis were randomised on day 7 of sensitive antibiotic therapy provided sepsis had clinically remitted. Exclusions: Staphylococcus aureus or fungal sepsis, and infections requiring prolonged antibiotics. We planned to enrol 350 per group, assuming 10% rate of primary outcome, +7% non-inferiority margin, one-sided 5% alpha, 90% power, 10% loss to follow-up. Intervention 7 days (no further treatment); comparison: 14 days (7 days postrandomisation). Outcomes Primary: relapse (definite or probable) within day 21 postantibiotic completion. Secondary outcomes: composite of mortality or definite/probable/secondary sepsis and duration of hospitalisation. One interim analysis (per protocol (PP)) was planned. Results 126 and 135 subjects were recruited in 7-day and 14-day groups, respectively, with mean (SD) birth weight (BW) 2250.9 (741.1) and 2187.8 (718.8) g. The trial was terminated early, based on interim PP analysis. 2/125 and 6/130 subjects had the primary outcome in 7-day and 14-day groups, respectively (risk difference (RD)=−3.0% (99.5% CI −9.2%, +3.1%), below non-inferiority margin). The composite secondary outcome also favoured the 7-day regimen (RD: −3.7% (99.5% CI −12.4% to +5.1%)). Duration of hospitalisation was shorter in 7-day group (median difference: −4 days (95% CI −5 to –3)). Conclusions A 7-day course of antibiotics may be non-inferior to a 14-day course for uncomplicated bacterial neonatal sepsis. Trial registration number NCT03280147 .

To describe the effectiveness and tolerability of cannabidiol (CBD) in children with drug-resistant epilepsy (DRE). Records of children with DRE who received CBD for at least six months were reviewed. Reduction in seizure frequency [complete (> 90%), partial (30–90%), no response (< 30%)], parent reported adverse effects and discontinuation of CBD, if any, were noted. Records of 50 children with DRE (Lennox–Gastaut syndrome 32, Dravet syndrome 4, and Tuberous sclerosis complex 2), mean (SD) age 7.8 (4.3) years were reviewed. Complete, partial, and no response to CBD was seen in 10, 18 and 14 children; 8 became seizure-free. Eight children discontinued treatment due to lack of efficacy (n = 4), by increased adverse effects (n = 3) and aggravation of seizures (n = 1). Adverse effects were noted in 22 (44%), none required hospitalization. Cannabidiol is a useful and safe add-on drug in children with DRE.

Subacute sclerosing panencephalitis (SSPE) is an uncommon, progressive, and deadly brain condition that develops as a late consequence of a measles virus infection in otherwise healthy individuals, especially in children and young adults. Due to a decrease in vaccination adherence, which has been exacerbated by the COVID-19 pandemic, its frequency has increased in recent years. A 2-year-old male child, previously normal, presented with regression of attained milestones along with drop attacks, which eventually increased in frequency along with behavioural concerns. On retrospection, he had a history of self-limiting febrile exanthem with similar complaints in his mother. This child was diagnosed with SSPE and managed accordingly. To conclude, SSPE can present with a rapidly deteriorating course mimicking acute disseminated encephalomyelitis (ADEM). Myoclonic jerks with periodic complexes on EEG along with cerebrospinal fluid IgM for measles antibodies help to delineate from ADEM and avoid immunosuppression, which could be fatal.

Early diagnosis and intervention in children with autism spectrum disorder (ASD) is crucial. At present, diagnosis of ASD is primarily based on subjective tools. Identifying metabolic biomarkers will aid in early diagnosis of ASD complementing the assessment tools. The study aimed to conduct targeted metabolomic analysis and determine the plasma metabolites that can discriminate children with ASD from typically developing children (TD), and to determine the utility of machine learning in classifying ASD children based on the metabotypes. This was a multi-centric, analytical, case-control study conducted between April 2021–April 2023. Fasting plasma samples were obtained from seventy ASD and fifty-eight TD children, aged 2 to 12 years. Samples were quantitively analysed for 52 targeted metabolites (13 amino acids, 37 acylcarnitines, adenosine and 2-deoxyadenosine levels) using tandem mass spectrometry. An in-depth statistical analysis was performed. A total of 26 metabolites (11 amino acids, 14 acyl carnitines and adenosine) were found to be significantly (p < 0.005) different between ASD and TD children. Adenosine and amino acid levels were significantly decreased in ASD children. Among acyl carnitines, short- and long-chain acyl carnitine levels were significantly decreased, while medium-chain acyl carnitine levels were significantly increased in ASD children. Octenoylcarnitine-C8:1 (Cut-off value- 0.025 mmol/L, AUC- 0.683) and adenosine (Cut-off value- 0.025 mmol/L, AUC- 0.673) were found to predict children with ASD at a sensitivity of 55.7% and 57.1%, specificity of 79.3% and 72.4% respectively. Based on the metabolites, machine learning models like Support Vector Machine (SVM) and Random Forest (RF) were able to discriminate ASD from TD children with the classification accuracy score being highest in RF (79.487%, AUC- 0.800). Significant abnormalities in plasma metabolites were observed leading to disturbances in the Krebs cycle, urea cycle and fatty acid oxidation, suggesting mitochondrial dysfunction that may possibly contribute in the pathobiology of ASD. Octenoylcarnitine-C8:1 and Adenosine may serve as potential metabolic biomarkers for ASD.

Substance abuse is a rising concern world over and administering anesthesia to substance abusers has a variety of concerns and anesthetic implications. It is our humble attempt to describe anesthetic management for upper GI endoscopy after tactfully elicited history of substance abuse.

Introduction Diaper area dermatoses is an umbrella term used to describe various skin conditions that can occur in the diaper area which is a common dermatological problem in neonates and younger children. Diaper dermatoses (DD) can occur as a primary disorder or as a part of an underlying systemic disorder. Methods One hundred and thirty-five children below the age of 5 years with eruptions in the diaper area were enrolled in the study. A detailed history and physical and dermatological examination were done and recorded on a predesigned proforma. Tests to aid in the diagnosis such as Gram stain, Tzanck smear, KOH examination, culture sensitivity, biochemical and hematological investigations, and skin biopsy were done whenever necessary. Results The prevalence of DD was 3.4%. A total of 26 dermatoses were encountered. Infections were the most common dermatoses observed in 68.8% followed by diaper dermatitis (primary irritant contact dermatitis) in 14.1% of children. The rarer dermatoses seen in our study were napkin psoriasis, purpura fulminans secondary to rickettsial infection, perianal pseudoverrucous papules and nodules, and aplasia cutis. Conclusions Our study highlighted the various morphological presentation and etiological factors of DD. Infective disorders were the most common dermatoses presenting in the diaper area in the present study.

To describe the clinical, laboratory profile, and outcome of Indian children with pyridoxine-dependent epilepsy (PDE). Retrospective chart reviews of all children with a genetically confirmed diagnosis of PDE between April 2012 and March 2024 were included; clinical and laboratory data were analyzed. Twenty-two children (13 boys) were diagnosed with PDE and all presented with seizures and encephalopathy. Oculogyric crisis was observed in majority (n = 20, 91%) cases. Variants were identified in ALDH7A1 (17), PLPBP (4), and PNPO (1) genes in the current cohort. One child expired within 24 h of initiation of pyridoxine. Another child had refractory seizures, two had epileptic spasms and seven had provoked seizures. Autistic features were noted in two and attention deficit hyperactivity disorder (ADHD) in 15 children. Seizures, encephalopathy, and oculogyric crisis help are clinical cues to aid in early diagnosis of PDE. PDE may be associated with comorbidities like autism and ADHD.

To describe the planning and implementation of the neonatal palliative care (NPC) program in the neonatal intensive care unit (NICU) in a major referral hospital in western India. The authors describe the neonatal characteristics, components of NPC care delivered and outcomes, along with barriers and enablers of the program. This was a retrospective, single-center observational study conducted in a level IIIB NICU from December 2021 to December 2022. Two hundred and sixty-six neonates were enrolled and 65 (24.4%) received NPC, of which 33 (50.8%) were enrolled at admission and 32 (49.2%) were re-directed from critical care towards palliation. The median enrollment was at 2 d of life. The most common conditions for initiating palliative care were severe sepsis with multi-organ dysfunction, complex congenital heart diseases and severe hypoxic-ischemic encephalopathy. For minimizing pain, all received non-pharmacological measures, however 8 (12.31%) additionally received pharmacological agents. The majority received enteral feeding during palliation (66.15%), frequently with the mother’s milk (93.02%). Nearly three-fourths (76.92%) were ventilated, with 90% of them receiving invasive ventilation. Memorabilia including footprints, photographs or infant personalized items were accepted by 53 families (81.53%). One hundred and nineteen (44.74%) neonates died, and bereavement support was extended to 113 (95%) of them. Parallel care model integrating NPC in NICU settings is achievable in collaboration with pioneering centers. This model helps support a large number of neonates in high-burden NICUs ensuring early initiation of NPC.

Background: BVVLS (Brown-Vialetto-Van Laere syndrome), a rare genetic condition characterized by progressive neuropathy, is caused by defects in SLC52A2 and SLC52A3 genes coding for hRFVT-2 and hRFVT-3. Methods: Five BVVLS cases were screened for disease-causing variants using exome sequencing and their functional contributions were evaluated by in silico analysis, riboflavin transport assay and confocal imaging. Results: Probands enrolled in this study were presented with unusual phenotypes like syndactyly, polydactyly, pedal edema and chronic osteomyelitis.

Biallelic variants in DPH2 have recently been reported to cause the syndrome of developmental delay with short stature, dysmor-phic facial features, and sparse hair-2, also known as diphthamide deficiency syndrome-2. Here we report a child with a biallelic loss-of-function variant p.(Arg477*) in DPH2 with clinical features of developmental delay, failure to thrive, sparse hair, seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. The electroencephalogram was suggestive of modified hypsarrhythmia. The phenotype of the current case overlaps with the previous cases reported in the literature; however, seizures, behavioral issues, and neuroimaging abnormalities have not been reported to date. This is the third report from the world. The current report gives a detailed account of an Indian child with a DPH2-related disorder.

Acute intermittent porphyria (AIP) is a dominant mendelian disorder caused due to deficiency of the enzyme porphobilinogen deaminase. It classically presents with pain abdomen, hypertensive crisis, electrolyte imbalance, mostly hyponatremia, and neuropsychiatric involvement. We report a case of a 12-year-old boy with AIP who experienced an acute crisis and later developed altered sensorium and seizures. Upon evaluation, he was found to have severe hyponatremia, which was secondary to the syndrome of inappropriate antidiuretic hormone secretion. His condition was corrected with intravenous hypertonic saline, and his sodium levels normalized over 2–3 days. Despite the successful correction of sodium levels, he developed extrapyramidal symptoms a week later. Magnetic resonance imaging of the brain revealed extrapontine myelinolysis. He was treated with intravenous steroids, which led to significant improvement. At 1-month follow-up, there were no neurological deficits.