Background Limited evidence exists on perinatal transmission and outcomes of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in neonates. Objective To describe clinical outcomes and risk factors for transmission in neonates born to mothers with perinatal SARS-CoV-2 infection. Design Prospective cohort of suspected and confirmed SARS-CoV-2 infected neonates entered in National Neonatology Forum (NNF) of India registry. Subjects Neonates born to women with SARS-CoV-2 infection within two weeks before or two days after birth and neonates with SARS-CoV-2 infection. Outcomes Incidence and risk factors of perinatal transmission. Results Among 1713 neonates, SARS-CoV-2 infection status was available for 1330 intramural and 104 extramural neonates. SARS-CoV-2 positivity was reported in 144 intramural and 39 extramural neonates. Perinatal transmission occurred in 106 (8%) and horizontal transmission in 21 (1.5%) intramural neonates. Neonates roomed-in with mother had higher transmission risk (RR1.16, 95% CI 1.1 to 2.4; P =0.01). No association was noted with the mode of delivery or type of feeding. The majority of neonates positive for SARS-CoV2 were asymptomatic. Intramural SARS-CoV-2 positive neonates were more likely to be symptomatic (RR 5, 95%CI 3.3 to 7.7; P <0.0001) and need resuscitation (RR 2, 95%CI 1.0 to 3.9; P =0.05) compared to SARS-CoV-2 negative neonates. Amongst symptomatic neonates, most morbidities were related to prematurity and perinatal events. Conclusion Data from a large cohort suggests perinatal transmission of SARS-CoV-2 infection and increased morbidity in infected infants.
Background Hypermanganesemia with dystonia 1 and 2 (HMNDYT1 and 2) are rare, inherited disorders of manganese transport. Objectives We aimed to describe clinical, laboratory features, and outcomes among children with HMNDYT. Methods We conducted a retrospective multicenter study involving tertiary centers across India. We enrolled children between 1 month to 18 years of age with genetically confirmed/clinically probable HMNDYT. Clinical, laboratory profile, genetic testing, treatment details, and outcomes scored by treating physicians on a Likert scale were recorded. Results We enrolled 27 children (19 girls). Fourteen harbored SLC30A10 mutations; nine had SLC39A14 mutations. The SLC39A14 cohort had lower median age at onset (1.3 [interquartile range (IQR), 0.7–5.5] years) versus SLC30A10 cohort (2.0 [IQR, 1.5–5.1] years). The most frequent neurological features were dystonia (100%; n = 27), gait abnormality (77.7%; n = 21), falls (66.7%; n = 18), and parkinsonism (59.3%; n = 16). Median serum manganese (Mn) levels among SLC39A14 (44.9 [IQR, 27.3–147.7] mcg/L) cohort were higher than SLC30A10 (29.4 [17.1–42.0] mcg/L); median hemoglobin was higher in SLC30A10 (16.3 [IQR, 15.2–17.5] g/dL) versus SLC39A14 cohort (12.5 [8.8–13.2] g/dL). Hepatic involvement and polycythaemia were observed exclusively in SLC30A10 variants. A total of 26/27 children underwent chelation with disodium calcium edetate. Nine demonstrated some improvement, three stabilized, two had marked improvement, and one had normalization. Children with SLC39A14 mutations had poorer response. Two children died and nine were lost to follow‐up. Conclusions We found female predominance. Children with SLC39A14 mutations presented at younger age and responded less favorably to chelation compared to SLC30A10 mutations. There is emerging need to better define management strategies, especially in low resource settings.
Tay–Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay–Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (< 2% of total hexosaminidase activity for infantile patients) in leucocytes. The enzyme activity was assessed by using substrates 4-methylumbelliferyl-N-acetyl-β-d-glucosamine and 4-methylumbelliferyl-N-acetyl-β-d-glucosamine-6-sulfate for total-hexosaminidase and hexosaminidase-A respectively, and heat inactivation method for carrier detection. The exons and exon–intron boundaries of the HEXA gene were bi-directionally sequenced on an automated sequencer. ‘In silico’ analyses for novel mutations were carried out using SIFT, Polyphen2 and MutationT@ster software programs. The structural study was carried out by UCSF Chimera software using the crystallographic structure of β-hexosaminidase-A (PDB-ID: 2GJX) as the template. Our study identified four novel mutations in three cases. These include a compound heterozygous missense mutation c.524A>C (D175A) and c.805G>C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C>T (p.R178C), (ii) c.964G>T (p.D322Y), and (iii) c.1385A>T (p.E462V); two nonsense mutations (i) c.709C>T (p.Q237X) and (ii) c.1528C>T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay–Sachs disease with clustering of ~ 73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.
ObjectiveLiterature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce from developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children.MethodsBetween January 2021 and June 2022, this cross‐sectional, study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural‐genetic and structural‐metabolic etiology, were recruited and underwent detailed in‐person assessment for phenotypic characterisation. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analysed.ResultsOf 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant‐55.2%, recessive‐14.2%), while the rest had X‐linked inheritance. Underlying chromosomal disorders included trisomy 21 (n=14), Xq28 duplication (n=2), and others (n=3). Trisomy 21 (n=14), ALDH7A1(n=10), SCN2A (n=7), CDKL5 (n=6), ALG13 (n=5), KCNQ2 (n=4), STXBP1 (n=4), SCN1A (n=4), NTRK2 (n=4), and WWOX (n=4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre‐existing developmental delay (94.3%), early age at onset of ES (<6mo; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre‐existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy.SignificanceOur study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.
Charcot Marie Tooth (CMT) disease is a group of hereditary motor sensory neuropathies with significant genetic heterogeneity. This disorder has been scarcely reported in the Indian literature. Here, we report a case of the rare but relatively more severe autosomal recessive CMT type 4C disease with a few features that are distinct from its regular presentation. Our patient was proven to have one of the common mutations in the SH3TC2 gene, which has so far not been described in Indian patients.
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