The first genetically confirmed cohort of Facioscapulohumeral Muscular Dystrophy from Northern India.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of hereditary myopathy. Sixty per cent of the world's population lives in Asia, so a significant percentage of the world's FSHD participants is expected to live there. To date, most FSHD studies have involved individuals of European descent, yet small-scale studies of East-Asian populations suggest that the likelihood of developing FSHD may vary. Here, we present the first genetically confirmed FSHD cohort of Indian ancestry, which suggests a pathogenic FSHD1 allele size distribution intermediate between European and North-East Asian populations and more asymptomatic carriers of 4 unit and 5 unit FSHD1 alleles than observed in European populations. Our data provides important evidence of differences relevant to clinical diagnostics and underscores the need for global FSHD participation in research and trial-ready Indian FSHD cohorts.

Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy: Advancement and Challenges.

Facioscapulohumeral muscular dystrophy (FSHD) is the second most common muscular dystrophy in adults, and it is associated with local D4Z4 chromatin relaxation, mostly via the contraction of the D4Z4 macrosatellite repeat array on chromosome 4q35. In this study, we aimed to investigate the use of Optical Genome Mapping (OGM) as a diagnostic tool for testing FSHD cases from the UK and India and to compare OGM performance with that of traditional techniques such as linear gel (LGE) and Pulsed-field gel electrophoresis (PFGE) Southern blotting (SB). A total of 6 confirmed and 19 suspected FSHD samples were processed with LGE and PFGE, respectively. The same samples were run using a Saphyr Genome-Imaging Instrument (1-color), and the data were analysed using custom EnFocus FSHD analysis. OGM was able to confirm the diagnosis of FSHD1 in all FSHD1 cases positive for SB (n = 17), and D4Z4 sizing highly correlated with PFGE-SB (p < 0.001). OGM correctly identified cases with mosaicism for the repeat array contraction (n = 2) and with a duplication of the D4Z4 repeat array. OGM is a promising new technology able to unravel structural variants in the genome and seems to be a valid tool for diagnosing FSHD1.

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Impact of the COVID-19 Pandemic on the Frequency, Clinical Spectrum and Outcomes of Pediatric Guillain-Barré Syndrome in India: A Multicentric Ambispective Cohort Study.

Objective: To study impact of COVID-19 pandemic on frequency, clinical/electrophysiological profile and treatment outcomes in pediatric Guillain-Barré syndrome (GBS). Background: GBS is the most frequent cause of pediatric acute flaccid paralysis. The effect of the COVID-19 pandemic on pediatric GBS is unclear in the literature. Methods: We conducted an ambispective, multicentric, cohort study involving 12 of 27 centres in GBS Consortium, during two periods: pre-COVID-19 (March-August 2019) and during COVID-19 (March-August 2020). Children ≤12 years who satisfied National Institute of Neurological Diseases and Stroke criteria for GBS/variants were enrolled. Details pertaining to clinical/laboratory parameters, treatment and outcomes (modified Rankin Scale (mRS) at discharge, GBS Disability score at discharge and 3 months) were analysed. Results: We enrolled 33 children in 2019 and 10 in 2020. Children in 2020 were older (median 10.4 [interquartile range 6.75-11.25] years versus 5 (2.5-8.4) years; P = 0.022) and had more sensory symptoms (50% versus 18.2%; P = 0.043). The 2020 group had relatively favourable mRS at discharge (median 1 (1-3.5) versus 3 (2-4); P = 0.042) and GBS disability score at 3 months (median 0 (0-0.75) versus 2 (0-3); P = 0.009) compared to 2019. Multivariate analysis revealed bowel involvement (P = 0.000) and ventilatory support (P = 0.001) as independent predictors of disability. No child in 2020 had preceding/concurrent SARS-CoV2 infection. Conclusions: The COVID-19 pandemic led to a marked decline in pediatric GBS presenting to hospitals. Antecedent illnesses, clinical and electrophysiological profile of GBS remained largely unchanged from the pre-pandemic era.

Impact of COVID-19 on Guillain-Barre Syndrome in India: A Multicenter Ambispective Cohort Study.

Introduction/Aims: Studies conducted during the coronavirus disease 2019 (COVID-19) pandemic have reported varied data regarding the incidence of Guillain-Barre syndrome (GBS). The present study investigated demographic and clinical features, management, and outcomes of patients with GBS during a specified period of the COVID-19 pandemic, and compared these features to those of GBS in the previous year. Methods: A multicenter, ambispective cohort study including 26 centers across India was conducted. Data from a pre-COVID-19 period (March 1 to August 31, 2019) were collected retrospectively and collected ambispectively for a specified COVID-19 period (March 1 to August 31, 2020). The study was registered with the Clinical Trial Registry India (CTRI/2020/11/029143). Results: Data from 555 patients were included for analysis: pre-COVID-19 (n = 334) and COVID-19 (n = 221). Males were more commonly affected during both periods (male:female, 2:1). Gastroenteritis was the most frequent antecedent event in 2019 (17.4%), whereas fever was the most common event in 2020 (10.7%). Paraparesis (21.3% versus [vs.] 9.3%, P = 0.001) and sensory involvement (51.1% vs. 41.3%; P = 0.023) were more common during COVID-19 in 2020, whereas back pain (26.3% vs. 18.4%; P = 0.032) and bowel symptoms (20.7% vs. 13.7%; P = 0.024) were more frequent in the pre-COVID period. There was no difference in clinical outcomes between the two groups in terms of GBS disability score at discharge and 3 months after discharge. Independent predictors of disability in the pre-COVID period included areflexia/hyporeflexia, the requirementfor intubation, and time to bulbar weakness; in the COVID-19 period, independent predictors included time from onset to admission, intubation, and intubation requirement. The mortality rate was 2.3% during the entire study period (13/555 cases). Discussion: Results of this study revealed an overall reduction in the frequency of GBS during the pandemic. The lockdown likely reduced the risk for antecedent infections due to social distancing and improved hygiene, which may have resulted in the reduction of the frequency of GBS.

Prevalence of elevated liver enzymes and its relationship with type 2 diabetes mellitus in North Indian adults.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) also referred as metabolic as metabolic (dysfunction) associated fatty liver disease. Type 2 diabetes mellitus (T2DM) is a major cause in progression of NAFLD and non-alcoholic steatohepatitis (NASH). The aim of the present study is to assess the activity of liver enzymes in T2DM in North Indian population. METHOD: This was a cross-sectional descriptive study clinic-based study in patients with T2DM. A total of 612 participants (226 healthy controls and 386 T2DM) were recruited. Body mass index (BMI), activity of liver enzymes including alanine and aspartate aminotransferase (ALT, AST) along with alkaline phosphatase (ALP) was measured. Fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) along with total protein (TP) and albumin were also measured. Quantitative variables were expressed as mean ± SD, while qualitative variables as frequencies (%). Pearson/Spearman correlation test, unpaired t-test, Chi-squared test was used to assess the correlation, association and significant differences between study groups respectively. A P-value of < .05 was set as statistically significant. The Statistical Package for Social Sciences (SPSS) ® Statistics, version 23 (IBM SPSS Statistics, Armonk, NY) was used to for analysis of data. RESULTS: The study was conducted on 386 T2DM patients, and out of 386 patients, 139 (36.01%) were male (P < .000) and 247 (63.98%) were female. The mean age of the T2DM patients was 46.4 ± 13.6 years, while healthy individuals have mean age of 39.2 ± 12.0 years (P < .000). It was observed that the activity of AST in T2DM is comparable with the healthy persons (P = .060). While the level of ALT, total bilirubin and ALP in T2DM is significantly higher compared to healthy control (P < .000). On average, 62.53% of T2DM subjects and 32% of participants of healthy subjects had abnormal liver enzymes activity. CONCLUSION: The present study has revealed widely co-existent derangements in liver function tests (LFTs) in the diabetic population of North India. A detailed workup in such patients may be helpful in timely diagnosis and treatment. Moreover, early detection and management of abnormal liver parameters in T2DM would help minimize liver-related morbidity and mortality.

Methylglyoxal and soluble RAGE in type 2 diabetes mellitus: Association with oxidative stress.

PURPOSE: Methylglyoxal (MGO) and MGO related advance end product (AGE) are thought to contribute to the development of diabetes and its complications. The present study was intended to determine plasma MGO and sRAGE levels in T2DM patients and to assess the relationship between MGO and other parameters, such as sRAGE and oxidative markers. METHODS: The study was carried out in 100 control and T2DM subjects. Methylglyoxal, sRAGE, HbA1c, and other markers were measured by using a standard protocol and the relationship between variables was analyzed using Spearman's correlation analysis. RESULTS: Plasma MGO levels in patients with T2DM (221.1 ± 9.50 ng/mL) were significantly higher than in control subjects (121.1 ± 6.52 ng/mL, P < 0.001). The plasma level of MGO was positively correlated with glycosylated hemoglobin (HbA1c, r = 0.50, P < 0.001). Plasma soluble form of RAGE (sRAGE) was significantly decreased in T2DM subjects (5.3 ± 0.64 ng/mL) as compared to the control group (7.7 ± 0.86 ng/mL, p < 0.05). However, at increased level of glycation (HbA1c > 10%), the sRAGE level was 6.2 ± 0.42 ng/mL and was not statistically significant as compared to control healthy group (> 0.05). Moreover, we have not found any correlation between MGO and other markers (p > 0.05). CONCLUSIONS: The findings of the present study showed that increased plasma MGO level is significantly associated with the HbA1c levels in T2DM patients. Moreover, the study shows that plasma sRAGE level is significantly augmented at increased level of glycation (HbA1c > 10%) in T2DM patients.