Exploration of clinical and genetic findings in Ataxia-Telangiectasia (AT) patients from the Indian subcontinent.

BACKGROUND: Ataxia-Telangiectasia (AT) is a rare autosomal recessive neurodegenerative disorder. It is caused by mutations in the Ataxia-Telangiectasia mutated (ATM) gene, which codes for protein ATM serine/threonine kinase. OBJECTIVE: We aim to describe the clinical and radiological findings in children and adolescents of 20 molecularly confirmed cases of AT. We aim to correlate these findings with the genotype identified among them. METHODS: This retrospective study included 20 patients diagnosed clinically and genetically with AT over 10 years. The clinical, radiological and laboratory data were extracted from the hospital's electronic medical records. Molecular testing was done using next generation sequencing and Sanger sequencing. In silico predictions were performed for the variants identified by applying Cryp-Skip, Splice site prediction by Neural Network, Mutation Taster and Hope prediction tool. RESULTS: Consanguinity was documented in nearly half of the patients. Telangiectasia was absent in 10%. Microcephaly was seen in 40% cases. The incidence of malignancy in our study population was low. Molecular testing done in the 18 families (20 patients) identified 23 variants of which ten were novel. Biallelic homozygous variants were noted in 13 families and compound heterozygous in 5 families. Out of the 13 families who were homozygous, 8 families (61.5%) (9 patients) have history of consanguinity. In silico prediction of novel missense variants, NM_000051.4 (ATM_v201): c.2702T > C showed disruption of the α-helix of ATM protein and NM_000051.4 (ATM_v201): c.6679C > G is expected to disturb the rigidity of protein structure in the FAT domain. The four novel splice site variants and two intronic variants result in exon skipping as predicted by Cryp-Skip. CONCLUSIONS: AT should be confirmed by molecular testing in young-onset cerebellar ataxia, even without telangiectasia. Awareness of this rare disease will facilitate study of larger cohorts from Indian population to characterize variants and determine its prevalence in this population.

Association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with vitamin B12 deficiency and adverse perinatal outcomes among pregnant women of rural South India - a cross sectional longitudinal study.

OBJECTIVES: To determine the occurrence of MTHFR gene polymorphisms and to study their association with vitamin B12 deficiency and adverse perinatal outcomes among a cohort of pregnant women from Kaniyambadi block, Tamil Nadu. METHODS: 120 consecutive pregnant women who were ≤20 weeks of gestational age from the 82 villages of Kaniyambadi block were recruited. Genomic DNA was isolated from the peripheral blood. PCR amplification was done followed by Sangers sequencing. Maternal and neonatal outcomes were extracted. Data was entered and analysed. RESULTS: Our study found the occurrence of c.1298A>C variant in homozygous state in 14.2% and c.677C>T heterozygous state in 15%. Sanger sequencing of exon 7 identified another pathogenic variant c.1262G>T in heterozygous state in two of them. Both the mothers who harboured that variant had preterm delivery and one of them gave birth to a low-birth-weight neonate. In the entire cohort, 5% of the mothers had abortion, 4.2% of them had preterm delivery and 8.8% of the neonates had low birth weight. Presence of c.1298A>C or c.677C>T variants were associated with vitamin B12 deficiency [Pearson Chi squared value (χ2)=7.9 and 7.6 respectively; p=0.02]. Heterozygous pathogenic variant c.1262G>T was associated with both adverse maternal [χ2=11.5; p=0.001] and neonatal [χ2=18.3; p=0.009] outcomes. CONCLUSIONS: MTHFR gene polymorphisms could be associated with several adverse perinatal outcomes and vitamin B12 deficiency. Further larger studies are needed to prove the pathogenicity of c.1262G>T variant on pregnancy.

Clinicogenetic Profile, Treatment Modalities, and Mortality Predictors of Gaucher Disease: A 15-Year Retrospective Study.

INTRODUCTION: Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder, in which biallelic pathogenic variants in the Glucosidase beta acid (GBA) gene result in defective functioning of glucosylceramidase that causes deposition of glucocerebroside in cells. GD has 3 major types namely, non-neuronopathic (type I), acute neuronopathic (type II), and chronic neuronopathic (type III). Definite treatment options are limited and expensive. They succumb early to the disease, if untreated. There is paucity of studies from the Indian subcontinent, which elicit the factors resulting in their premature mortality. MATERIALS AND METHODS: A retrospective study was carried out in a tertiary care setting of South India to assess the clinical profile, mutation spectrum, and various management strategies (only supportive therapy, enzyme replacement therapy [ERT], substrate reduction therapy [SRT] haematopoietic stem cell transplant [HSCT]), and mortality predictors of patients with GD from 2004 to 2019. A Kaplan-Meier survival curve was plotted. In silico predictions were performed for novel variants. RESULTS: There were 60 patients with all types of GD seen over the study period of 15 years. Their median age at diagnosis was 2 years. The median follow-up was for 5 years (interquartile range [IQR] = 2-8). The overall mortality rate was 35%; however, it was only 10% in those receiving definite treatment. Mortality was higher (47.5%) by more than 4 folds in those only on supportive therapy. The median survival from the time of diagnosis was 6.3 years (IQR = 3.5-10.8) in the definite treatment group and 3.5 years (IQR = 1-5) in those on supportive therapy. The Kaplan-Meier survival analysis showed significant (p value 0.001) mortality difference between these groups. The multiple logistic regression analysis found the neuronopathic type (OR = 5) and only supportive therapy (OR = 6.3) to be the independent risk factors for premature mortality. CONCLUSION: GD is a rare disease with a high mortality rate, if left untreated. ERT and SRT are the definitive treatments which increase the survival. In resource-limited settings like India, with higher prevalence of the neuronopathic type, HSCT may be a more suitable definitive treatment option, due to its one-time intervention and cost, assuming similar efficacy to ERT. However, the efficacy and safety of HSCT in GD needs to be established further by substantial patient numbers undergoing it.

Lessons from healthcare personnel screening and management during H1N1 pandemic in preparation for the impending COVID-19 pandemic in a tertiary care hospital in India.

BACKGROUND: In the wake of the COVID-19 pandemic caused by a novel corona virus, health care personnel are at increased risk of acquiring the infection. In preparation for the management of health care personnel that are likely to be infected, we looked in to the data collected during the Influenza pandemic in 2009, caused by a novel strain of H1N1 influenza called swine flu. The care of healthcare personnel in our institution, who had an acute febrile respiratory illness (AFRI) during that period was routed through a single channel using a uniform protocol. We retrospectively analysed the available data, during the initial four months of the pandemic, to draw lessons from it. OBJECTIVE: To study the prevalence, clinical profile and risk factors of swine flu among health care personnel during the pandemic of 2009 in a tertiary care hospital in South India. METHODOLOGY: This retrospective study enrolled all the health care personnel including students of a tertiary care institution in South India, who presented with an AFRI between June to August, the initial four months of the swine flu pandemic of 2009. The clinical profile and risk factors were extracted. The results of the RT PCR for swine flu was obtained. Prevalence in each demographic group was calculated and compared. Characteristics of those with swine flu were compared with those who turned negative for the swine flu. RESULTS: The prevalence of all AFRI and only swine flu among health care personnel during the study period was 18 per thousand and 8.7 per thousand respectively. Highest prevalence of swine flu was found among students and office staff. After adjusting for confounding factors, hyperthermia at presentation was significantly higher {OR = 1.97; 95% CI (1.01-3.76)} among those who tested positive for swine flu as compared with those with other AFRI's. Only 2.5% of the entire AFRI group required admission and there was no mortality. CONCLUSION: Health care personnel are at increased risk of acquiring infection. Our study demonstrated that students and office staff were the most susceptible. Unprotected exposure to unknown infectious patients and relatives is likely to have been an important factor. Though the mode of transmission is similar, compared to H1N1, COVID-19 is associated with different comorbidities and has significantly higher mortality. Therefore, in preparation for the COVID-19 pandemic, the personal protective equipment of the healthcare personnel need to be escalated.