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.

Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities.

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

Randomized controlled trial on effectiveness of mHealth (mobile/smartphone) based Preterm Home Care Program on developmental outcomes of preterms: Study protocol.

AIM: To describe a randomized controlled trial protocol designed to evaluate the effectiveness of mobile health based Preterm Home Care Program (mHealthPHCP) known as "NeoRaksha" mobile health application in improving parent-infant-interaction, growth and development of preterms. DESIGN: A prospective, randomized controlled clinical trial. The protocol is approved and funded by Department of Biotechnology, Government of India on 2 August 2016. METHODS: A total of 300 preterm-mother dyads admitted to neonatal intensive care unit of a tertiary care hospital will be recruited and randomized to intervention and control group. The intervention group would receive mobile health based Preterm Home Care Program and the control group would receive standard preterm care. Intervention group will be followed up at home by community health workers known as Accredited Social Health Activist who will be trained in using the NeoRaksha mobile health application. Preterms outcomes will be assessed during follow-up at hospital. DISCUSSION: Supporting continuity of preterm care is vital as parents and preterms experience transition from Neonatal Intensive Care unit to their home. Empowering mothers and community health workers by integrating mobile technology into health care can help promote healthy preterms, enhance development outcomes and follow-up, which in turn can reduce the mortalities, morbidities, and disabilities associated with prematurity. IMPACT: The results of this study could open up new horizons in integrating hospital and home based preterm care through technology, which paves way to scale up the model across the countries.

Metabolic Evaluation in Children aged 3 months to 2 years with Global Developmental Delay.

OBJECTIVES: To study the clinical profile and role of metabolic evaluation in children aged 3 mo to 2 y with global developmental delay (GDD) of unclear etiology. METHODS: In this prospective study, demographic and clinical data along with first line metabolic test results [blood glucose, arterial blood sample analysis, renal function tests, uric acid, serum electrolytes, liver function tests (LFTs), plasma ammonia, arterial blood lactate and pyruvate, urine ketone/ reducing substances] were documented and analyzed. Tandem Mass Spectroscopy (TMS) and Gas Chromatography and Mass Spectrometry (GC-MS) data were also analysed. RESULTS: Of 101 eligible children, 48 were excluded. Among 53 children included in the study, 32 (60.3%) were less than 1 y and 21 (39.7%) were more than 1 y. Four major developmental domains were almost equally affected in 16 (30.1%), three domains in 4 (7.5%) and two domains in 33 (62.4%) children. Fourteen (26.4%) children were found to have a probable metabolic disorder based on initial tests- 10 mitochondrial disorders, 3 organic-acidemias and 1 fatty-acid-oxidation defect. Further, on TMS and GC-MS tests, 11 (20.7%) had a metabolic disorder- 7 mitochondriopathies, 2 methylmalonic-aciduria, 1 each with glutaric-acidemia and ethylmalonic-aciduria. CONCLUSIONS: Among children with GDD of unclear etiology, metabolic errors constitute a small proportion of etiology. In this group early metabolic tests could identify potentially treatable conditions.

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.

Renal subcapsular abscess.

An 18-day-old neonate presented with fever and abdominal distension. Renal subcapsular abscess was diagnosed with sonography and CT scan. Percutaneous drainage resulted in aspiration of 20 mL of pus, which grew Staphylococcus aureus.

Comparative Efficacy and Safety of Caffeine and Aminophylline for Apnea of Prematurity in Preterm (≤34 weeks) Neonates: A Randomized Controlled Trial.

OBJECTIVE: To compare the efficacy and safety of standard doses of Caffeine and Aminophylline for Apnea of prematurity. STUDY DESIGN: Randomized controlled trial. SETTING: Tertiary-care referral centre and a teaching institution in Southern India. Trial was conducted from February 2012 to January 2015. PARTICIPANTS: 240 preterm (≤34 wk) neonates with apnea of prematurity. INTERVENTIONS: Neonates randomized into two groups: Caffeine group received loading dose of caffeine citrate (20 mg/kg) followed by 5 mg/kg/day maintenance dose every 24 hour. Aminophylline group received loading dose of Aminophylline - 5 mg/kg and maintenance dose of 1.5 mg/kg 8-hourly. OUTCOME MEASURES: Difference in apneic spells, associated respiratory morbidity, and acute adverse events were assessed. Association of efficacy with therapeutic drug levels was also evaluated. RESULTS: Infants on aminophylline experienced less apnea spells in 4-7 days of therapy (P=0.03). Mean apnea rate and isolated desaturations were similar in 1-3, 4-7 and 8-14 days of therapy. No difference was noted in duration of Neonatal Intensive Care Unit stay and hospital stay. Mean heart rate was significantly high in Aminophylline group (P<0.001). Risk of developing tachycardia was less (RR 0.30; 95% CI range 0.15 to 0.60; P<0.001) in Caffeine- over Aminophylline-treated infants. CONCLUSION: Aminophylline is as effective as caffeine for prevention of apneic spells in preterm neonates; however, dosage optimization needs to be done to reduce toxicity.

Burkholderia cepacia sepsis among neonates.

Burkholderia cepacia is a rare cause of sepsis in newborns and its transmission involves human contact with heavily contaminated medical devices and disinfectants. The authors aimed to determine epidemiology, clinical features, antibiotic sensitivity pattern, complications and outcome of blood culture proven B. cepacia infections in 12 neonates. All neonates were outborn, 5 preterm and 7 term. B. cepacia was isolated from blood in all and concurrently from CSF in three neonates. Lethargy and respiratory distress (41.7 %) were major presenting features. Five newborns (41.7 %) required mechanical ventilation for 3-7 d. Highest bacterial susceptibility was observed for meropenem (100 %), followed by cefoperazone-sulbactam, piperacillin-tazobactam, sulfamethoxazole-trimethoprim (all 83 %), ceftazidime (75 %) and ciprofloxacin (42 %). Piperacillin-tazobactam, ciprofloxacin and cotrimoxazole either singly or in combination led to complete recovery of 11 (91.7 %) newborns; one developed hydrocephalus. Eight of nine infants who completed 6 mo follow up were normal. Prompt recognition and appropriate antibiotic therapy for B. cepacia infection results in complete recovery in majority.

Antenatal bartter syndrome: a review.

Antenatal Bartter syndrome (ABS) is a rare autosomal recessive renal tubular disorder. The defective chloride transport in the loop of Henle leads to fetal polyuria resulting in severe hydramnios and premature delivery. Early onset, unexplained maternal polyhydramnios often challenges the treating obstetrician. Increasing polyhydramnios without apparent fetal or placental abnormalities should lead to the suspicion of this entity. Biochemical analysis of amniotic fluid is suggested as elevated chloride level is usually diagnostic. Awareness, early recognition, maternal treatment with indomethacin, and amniocentesis allow the pregnancy to continue. Affected neonates are usually born premature, have postnatal polyuria, vomiting, failure to thrive, hypercalciuria, and subsequently nephrocalcinosis. Hypokalemia, metabolic alkalosis, secondary hyperaldosteronism and hyperreninaemia are other characteristic features. Volume depletion due to excessive salt and water loss on long term stimulates renin-angiotensin-aldosterone system resulting in juxtaglomerular hyperplasia. Clinical features and electrolyte abnormalities may also depend on the subtype of the syndrome. Prenatal diagnosis and timely indomethacin administration prevent electrolyte imbalance, restitute normal growth, and improve activity. In this paper, authors present classification, pathophysiology, clinical manifestations, laboratory findings, complications, and prognosis of ABS.

Bacterial isolates of early-onset neonatal sepsis and their antibiotic susceptibility pattern between 1998 and 2004: an audit from a center in India.

BACKGROUND: Epidemiology and surveillance of neonatal sepsis helps in implementation of rational empirical antibiotic strategy. OBJECTIVE: To study the frequency of bacterial isolates of early onset neonatal sepsis (EONS) and their sensitivity pattern. METHODS: In this retrospective study, a case of EONS was defined as an infant who had clinical signs or born to mothers with potential risk factors for infection, in whom blood culture obtained within 72 hours of life, grew a bacterial pathogen. Blood culture sample included a single sample from peripheral vein or artery. Relevant data was obtained from the unit register or neonatal case records. RESULTS: Of 2182 neonates screened, there were 389 (17.8%) positive blood cultures. After excluding coagulase-negative Staphylococci (160), we identified 229 EONS cases. Preterm neonates were 40.6% and small for gestational age, 18.3%. Mean birth weight and male to female ratio were 2344.5 (696.9) g and 1.16:1 respectively. Gram negative species represented 90.8% of culture isolates. Pseudomonas (33.2%) and Klebsiella (31.4%) were common among them. Other pathogens included Acinetobacter (14.4%), Staphylococcus aureus (9.2%), E.coli (4.4%), Enterobacter (2.2%), Citrobacter (3.1%) and Enterococci (2.2%). In Gram negative group, best susceptibility was to Amikacin (74.5%), followed by other aminoglycosides, ciprofloxacin and cefotaxime. The susceptibility was remarkably low to ampicillin (8.4%). Gram positive group had susceptibility of 42.9% to erythromycin, 47.6% to ciprofloxacin and above 50% to aminoglycosides. Of all isolates, 83.8% were susceptible to either cefotaxime or amikacin CONCLUSION: Gram-negative species especially Pseudomonas and Klebsiella were the predominant causative organisms. Initial empirical choice of cefotaxime in combination with amikacin appeared to be rational choice for a given cohort.

Subdural effusion complicating neonatal meningitis: successful treatment with acetazolamide.

Postmeningitis subdural effusion is rare in neonates when compared to infants and children. For treatment, various modalities are described. Serial subdural punctures and surgical drain placement are advised for cases having a mass effect on imaging. We report a neonate with symptomatic postmeningitis subdural effusion, who failed to respond to serial subdural punctures, but subsequently managed successfully with acetazolamide. He had no recurrence further. His development was normal at 18 months of age.

Transcutaneous bilirubin in predicting hyperbilirubinemia in term neonates.

OBJECTIVE: To assess the utility of 24 and 48 hours transcutaneous bilirubin (TcB) index for predicting subsequent significant hyperbilirubinemia in healthy term neonates. METHODS: TcB indices were obtained for healthy, breastfed, term AGA newborns at 24 +/- 2, 48 +/- 2 and subsequently at intervals of 24 hours. Neonates with illness, on treatment and positive Direct Coomb's test were excluded. Serum bilirubin levels were obtained whenever indicated. Neonates having serum bilirubin > or = 17 mg/dL were considered as significant hyperbilirubinemia. The 24 and 48 hour TcB indices, as risk predictors for such hyperbilirubinemia were determined. RESULTS: Study included 461 healthy term neonates. The mean birth weight was 2949 (+/- 390) gm and mean gestation of 38.6 (+/- 1.1) weeks. Eight one (17.6%) had significant hyperbilirubinemia. Of 461, 135 (29.3%) had TcB index. CONCLUSION: The 24 and 48 hour TcB indices are predictive for subsequent significant hyperbilirubinemia and can guide clinician in early discharge of healthy term newborns.

Neonatal thrombocytopenia associated with maternal pregnancy induced hypertension.

OBJECTIVE: To evaluate the prevalence of thrombocytopenia in neonates born to mothers with pregnancy induced hypertension (PIH) and identify the associated material and neonatal characteristics. METHODS: In the current, prospective study, platelet counts were assessed serially. Maternal and neonatal characteristic were recorded in pre-designed proforma. Primary outcome measures were thrombocytopenia defined as platelet count of <150,000/mm(3) and severe thrombocytopenia if counts were <30,000/mm(3) or <50,000/mm(3) with bleeding. RESULTS: Of 97 neonates born to PIH mothers 35 (36.1%) had thrombocytopenia. In 20 (20.6%) thrombocytopenia was severe. Higher percentage of thrombocytopenia was associated with male gender (47.7%), low birth weight (71.4%) and prematurity (67.4%). Severe thrombocytopenia was significantly associated with low birth weight (OR: 4.58; 95% CI: 0.98-21.3; p<0.03) and prematurity (OR: 2.52; 95% CI: 0.87-7.24; p<0.05). Material parity, onset of PIH, and medications did not seem to be associated significantly. CONCLUSION: Premature and low birth weight neonates born to mothers with pregnancy induced hypertension would require scrutiny for thrombocytopenia during early neonatal period.

Glomerulocystic disease: a severe form in a monozygous twin.

One of monozygous twins presented with anuria from birth and was diagnosed on renal biopsy with glomerulocystic kidney disease. There was no associated congenital or hereditary disorder. The other twin was normal and ultrasonography of the renal tracts of both infants was normal. He was managed by peritoneal dialysis. As renal transplantation was not available, the parents discharged him without further treatment.