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Chronic progressive external ophthalmoplegia (CPEO) is symptom complex with progressive ptosis and restricted ocular motility without diplopia. MYH2 myopathy is rare disorder presenting with CPEO and muscle weakness. We report two Indian patients of MYH2 myopathy with unique features. Patient-1 presented with early adult-onset esophageal reflux followed, proximal lower limb weakness, proptosis, CPEO without ptosis. He had elevated creatine kinase along with characteristic muscle MRI findings of prominent semitendinosus and medial gastrocnemius involvement. Patient -2 presented with early adult onset CPEO without limb weakness. His creatine kinase was normal. Both the patients had novel MYH2 mutations: a homozygous 5’splice variation in intron 4 (c.348 + 2dup) in patient 1 and homozygous single base pair deletion in exon 32 (p. Ala1480ProfsTer11) in patient 2. Unique features noted include adult onset, isolated CPEO, proptosis, esophageal reflux disease and absence of skeletal abnormalities. MYH2 myopathy has to be considered in adult patients with CPEO.

Background: The phenotypic spectrum of Fukutin-related protein (FKRP) mutations is highly variable and comprises of limb girdle muscular dystrophy (LGMD) R9 (previously LGMD 2I) and FKRP related congenital muscular dystrophies. Objective: To identify the distinct genotype phenotype pattern in Indian patients with FKRP gene mutations. Methods: We retrospectively reviewed the case files of patients with muscular dystrophy having a genetically confirmed FKRP mutation. All patients had undergone genetic testing using next-generation sequencing. Results: Our patients included five males and four females presenting between 1.5 years and seven years of age (median age - 3 years). The initial symptom was a delayed acquisition of gross motor developmental milestones in seven patients and recurrent falls and poor sucking in one patient each. Two patients had a language delay, with both having abnormalities on the brain MRI. Macroglossia, scapular winging, and facial weakness were noted in one, three and four patients respectively. Calf muscle hypertrophy was seen in eight patients and ankle contractures in six. At the last follow-up, three patients had lost ambulation (median age - 7 years; range 6.5–9 years) and three patients had not attained independent ambulation. Creatine kinase levels ranged between 2793 and 32,396 U/L (mean 12,120 U/L). A common mutation - c.1343C>T was noted in 5 patients in our cohort. Additionally, four novel mutations were identified. Overall, six patients had an LGMD R9 phenotype, and three had a congenital muscular dystrophy phenotype. Conclusion: Patients with FKRP mutations can have varied presentations. A Duchenne-like phenotype was the most commonly encountered pattern in our cohort, with c.1343C>T being the most common mutation

The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the α, β, γ, and δ proteins which stabilizes the sarcolemma of muscle cells. The clinical phenotype is characterized by progressive proximal muscle weakness with childhood onset. Muscle biopsy findings are diagnostic in confirming dystrophic changes and deficiency of one or more sarcoglycan proteins. In this study, we summarized 1,046 LGMD patients for which a precise diagnosis was identified using targeted sequencing. The most frequent phenotypes identified in the patients are LGMDR1 (19.7%), LGMDR4 (19.0%), LGMDR2 (17.5%), and MMD1 (14.5%). Among the reported genes, each of CAPN3, SGCB, and DYSF variants was reported in more than 10% of our study cohort. The most common variant SGCB p.Thr182Pro was identified in 146 (12.5%) of the LGMD patients, and in 97.9% of these patients, the variant was found to be homozygous. To understand the genetic structure of the patients carrying SGCB p.Thr182Pro, we genotyped 68 LGMD patients using a whole genome microarray. Analysis of the array data identified a large ~1 Mb region of homozygosity (ROH) (chr4:51817441-528499552) suggestive of a shared genomic region overlapping the recurrent missense variant and shared across all 68 patients. Haplotype analysis identified 133 marker haplotypes that were present in ~85.3% of the probands as a double allele and absent in all random controls. We also identified 5 markers (rs1910739, rs6852236, rs13122418, rs13353646, and rs6554360) which were present in a significantly higher proportion in the patients compared to random control set ( n = 128 ) and the population database. Of note, admixture analysis was suggestive of greater proportion of West Eurasian/European ancestry as compared to random controls. Haplotype analysis and frequency in the population database indicate a probable event of founder effect. Further systematic study is needed to identify the communities and regions where the SGCB p.Thr182Pro variant is observed in higher proportions. After identifying these communities and//or region, a screening program is needed to identify carriers and provide them counselling.

Obesity is a globally expanding silent epidemic having multiple risk factors and consequences associated with it. Genetic factors have been found to be playing undeniable roles in obesity. Intermingled relationship between epigenetics, metagenomics, and the environment influences obesity traits. High precision diagnostic tools have outlined many single nucleotide polymorphisms (SNPs), as well as many novel genes, that have been identified that create an obesogenic environment. Rare single-gene diseases can lead to early childhood obesity and less satiety. With almost 30% of the global population being under the grip of obesity, the coming days are alarming. This review summarizes the existing knowledge on the genetic causes of obesity including the epidemiology as well as the issues of concern and new additions to the list. Furthermore, we discuss the ways to enhance the healthcare outcome for patients of obesity through interdepartmental collaborations apart from pharmacological therapy that is still limited to a few drugs. The teamwork of geneticists, genetic counselors, physicians, bariatric surgeons, nurses, endocrinologists, and pharmacists may provide promising results in intervention.

Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544T>G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 5 polymorphic markers surrounding the c.544T>G mutation in the cases and related family members as well as 150 unrelated controls from general Indian populations using PLINK1.9. We identified haplotype H1= G, A, T, G, G, T at a significantly higher frequency in cases compared to related controls and general Indian population. Upon segregation analysis within the family pedigrees, H1 is observed to co-segregate with c.544T>G in a homozygous state in all the pedigrees of cases except one indicating a probable event of founder effect. Furthermore, Identical-by-descent and inbreeding coefficient analysis revealed relatedness among 33 new pairs of seemingly unrelated individuals from sarcoglycanopathy cohort and a higher proportion of homozygous markers, thereby indicating towards common ancestry. Since all these patients are from the south Indian region, we suggest this region to be a primary target of mutation screening in patients diagnosed with sarcoglycanopathy.

Purpose: Inhalation of crystalline silica-rich dust particles can result in the deadly occupational lung disorder called silicosis. The risk of contracting tuberculosis and the potential for lung cancer increase as a result of silicosis. This review article aims to bring to light the state of Silicosis and TB scenario in the world and India for evaluating hurdles in the present and future to achieve the elimination road map, and assess these conditions in the backdrop of the COVID-19 pandemic. Methods: A PubMed Central search was conducted using the keywords “silico-tuberculosis” and “prevalence” and the time period of the last 20 years, which yielded 15 studies, out of which only the following were found to be relevant in terms of exemplifying the prevalence of Silico-tuberculosis at various geographical locations around the world. Results: A patient with silicosis has a 2.8-2.9 times higher risk of developing pulmonary tuberculosis and 3.7 times that of extrapulmonary tuberculosis. Incidences of missed cases when tuberculosis was misdiagnosed with silicosis due to indifferent clinical manifestations of the two in the initial stages aren’t uncommon. The duration of exposure to silica and the severity of silicosis, have a direct relation with the propensity to develop tuberculosis. As per a study, an average gap of 7.6 years has been noticed in a South African population for Silico-tuberculosis to develop post silicosis. In a study done on mine workers at Jodhpur, Rajasthan, it was seen that there is no definitive relation between patient with silicosis and possibility of having Covid-19. Conclusions: This paper has focused on the coexistence of silicosis and tuberculosis. It has been seen that the risk of tuberculosis is highly increased with pre-existing silicosis. There is a big need for the integration of the Silicosis control programme with Tuberculosis elimination programme for the government. A few of the steps that can include assessing the workplaces, periodic monitoring of the workers’ health, active case surveillance, identification of hotspots, and introducing reforms to curb the spread of dust and particulate matter from industrialized areas be taken in this regard.

A complex pathogenesis involving several physiological systems is theorized to underline the development of depressive disorders. Depression is accompanied by circadian regulation disruption and interaction with the functioning of both central and peripheral oscillators. Many aspects of melatonin function unite these systems. The use of drugs for circadian rhythm disorders could inspire a potential treatment strategy for depression. Melatonin plays an essential role in the regulation of circadian rhythms. It exerts effect by activating two types of melatonin receptors, type 1A (MT1) and 1B (MT2). These are G-protein-coupled receptors, predominantly located in the central nervous system. MT1/MT2 agonists could be a useful treatment approach according to all three prevalent theories of the pathogenesis of depression involving either monoamines, synaptic remodeling, or immune/inflammatory events. MT1/MT2 receptors can be a potential target for novel antidepressants with impact on concentrations of neurotrophins or neurotransmitters, and reducing levels of pro-inflammatory cytokines. There is an interesting cross-talk mediated via the physical association of melatonin and serotonin receptors into functional heteromers. The antidepressive and neurogenetic effects of MT1/MT2 agonists can also be caused by the inhibition of the acid sphingomyelinase, leading to reduced ceramide, or increasing monoamine oxidase A levels in the hippocampus. Compounds targeting MT1 and MT2 receptors could have potential for new anti-depressants that may improve the quality of therapeutic interventions in treating depression and relieving symptoms. In particular, a combined effect on MT1 and/or MT2 receptors and neurotransmitter systems may be useful, since the normalization of the circadian rhythm through the melatonergic system will probably contribute to improved treatment. In this review, we discuss melatonergic receptors as a potential additional target for novel drugs for depression.

Background and Objectives: Thymic pathology is common in Myasthenia Gravis(MG) and plays a crucial role in its pathogenesis and clinical outcome. This study aims to discuss the clinicohistopathological spectrum of thymic lesions in MG. Methods: In this retrospective study, MG patients who underwent thymectomy from 2011 to 2020 were included. Clinical, radiological, serological, and histopathological details are described. Results: Of 83 patients(F = 45; M = 38), 7(8%) had ocular myasthenia, and the remaining 76(92%) had the generalized form. At onset, the median age was 36 years(M = 44; F = 31). AChR antibody was positive in 71/79 patients. RNST showed decrement response in 68/78 patients. The histopathological study demonstrated thymoma in 44(53%), thymic hyperplasias [32(38%)], involuted thymus [5(6%)], thymic cyst (1) and thymic lipoma (1). WHO grading of thymoma: B2- 48%, AB-18%, B-18%, B3-14%, A-2.3%. In these, capsular infiltration was noted in 11/44, 9 had focal and 2 had diffuse infiltration. Active germinal centers were present in 20/32 patients with thymic hyperplasia and 4/44 with thymoma. Thymomas were predominant in males and thymic hyperplasia in females. The age of onset and antibody positivity rate was higher in thymoma patients. Conclusion: In our cohort, there is a female preponderance. Thymoma was the commonest pathology followed by hyperplasia. We observed earlier onset of myasthenia in females. AChR antibody positivity rate was more frequent in thymomas. This study indicates that clinico-radiological evaluation adequately supported by serology and histopathology can effectively recognize the type of thymic pathology that can guide these patients’ treatment planning, management, prognosis and follow-up.

Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 309548, Funder: Lily Mae Foundation; doi: https://doi.org/10.13039/100012336, Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.

Background and Purpose: Mutations in the GMPPB gene affect glycosylation of α-dystroglycan, leading to varied clinical phenotypes. We attempted to delineate the muscle MR imaging spectrum of GMPPB-related Congenital Myasthenic syndrome (CMS) in a single-center cohort study. Objective: To identify the distinct patterns of muscle involvement in GMPPB gene mutations. Methods: We analyzed the muscle MR images of 7 genetically proven cases of GMPPB dystroglycanopathy belonging to three families and studied the potential qualitative imaging pattern to aid in clinico -radiological diagnosis in neuromuscular practice. All individuals underwent muscle MRI (T1, T2, STIR/PD Fat sat. sequences in 1.5 T machine) of the lower limbs. Qualitative assessment and scoring were done for muscle changes using Mercuri staging for fibro-fatty replacement on T1 sequence and Borsato score for myoedema on STIR sequence. Results: All patients were of South Indian origin and presented as slowly progressive childhood to adult-onset fatigable limb-girdle muscle weakness, elevated creatine kinase level, and positive decrement response in proximal muscles. Muscle biopsy revealed features of dystrophy. All patients demonstrated identical homozygous mutation c.1000G > A in the GMPPB gene. MRI demonstrated early and severe involvement of paraspinal muscles, gluteus minimus, and relatively less severe involvement of the short head of the biceps femoris. A distinct proximo-distal gradient of affliction was identified in the glutei, vasti, tibialis anterior and peronei. Also, a postero-anterior gradient was observed in the gracilis muscle. Conclusion: Hitherto unreported, the distinctive MR imaging pattern described here, coupled with relatively slowly progressive symptoms of fatigable limb-girdle weakness, would facilitate an early diagnosis of the milder form of GMPPB- dystroglycanopathy associated with homozygous GMPPB gene mutation.

BACKGROUND Ultrasonography (USG) of the diaphragm is a promising alternative to pulmonary function tests (PFT) for assessing respiratory function in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). METHODS We studied 33 patients fulfilling Awaji criteria (definite = 14; probable = 12; possible = 7) and 33 age and gender-matched controls. Diaphragm thickness was measured using USG at the end of expiration (DTex) and end of inspiration (DTin). The thickness ratio (TR) was calculated as DTin/DTex. The mean age at onset and duration were 49.73 ± 12.7 years and 13.57 ± 9.7 months, respectively. Men = 25 (75.8%); Limb onset ALS/MND = 24 patients (72.7%); bulbar onset = 9 (27.3%). RESULTS Compared to controls, ALS/MND patients had reduced mean DTex (2.22 ± 0.29 mm vs. 2.02 ± 0.32 mm, p = .012) and DTin (4.0 ± 0.71 mm vs. 3.41 ± 0.38 mm, p

The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines.In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron ofA dominantly inherited deep intronic GAA repeat expansion in

Dysferlinopathies are a group of limb-girdle muscular dystrophies causing significant disability in the young population. There is a need for studies on large cohorts to describe the clinical, genotypic and natural history in our subcontinent. To describe and correlate the clinical, genetic profile and natural history of genetically confirmed dysferlinopathies. We analysed a retrospective cohort of patients with dysferlinopathy from a single quaternary care centre in India. A total of 124 patients with dysferlinopathy were included (40 females). Median age at onset and duration of illness were 21 years (range, 13-50) and 48 months (range, 8-288), respectively. The average follow-up period was 60 months (range, 12-288). Fifty-one percent had LGMD pattern of weakness at onset; 23.4% each had Miyoshi and proximo-distal type while isolated hyperCKemia was noted in 1.6%. About 60% were born to consanguineous parents and 26.6% had family history of similar illness. Twenty-three patients (18.6%) lost ambulation at follow-up; the median time to loss of independent ambulation was 120 months (range, 72-264). Single-nucleotide variants (SNVs) constituted 78.2% of patients; INDELs 14.5% and 7.3% had both SNVs and INDELs. Earlier age at onset was noted with SNVs. There was no correlation between the other clinical parameters and ambulatory status with the genotype. Thirty-seven (45.7%) novel pathogenic/likely pathogenic (P/LP) variants were identified out of a total of 81 variations. The c.3191G A variant was the most recurrent mutation. Our cohort constitutes a clinically and genetically heterogeneous group of dysferlinopathies. There is no significant correlation between the clinico-genetic profile and the ambulatory status.

Background We sought to determine the utility of PET-MRI in diagnosing Idiopathic Inflammatory Myositis (IIM), and look for association between FDG uptake and clinical, pathological and laboratory parameters. Methods A retrospective, observational study was conducted on IIM patients having positive serum autoantibodies and who underwent PET-MRI (3-Tesla SIEMENS Biograph MR scanner) between 2017 and 2021. Thirty patients who underwent PET-MRI to detect systemic metastasis without muscle involvement formed the control group. Results In the IIM cohort, female: male sex ratio was 1.73, mean age at diagnosis was 40.33 years, and the mean duration of illness was 7 months. 33.33% of patients had severe limb weakness. Mi2B (43.33%), Mi2A (43.33%), PL-7(10%), PL-12(6.67%), SRP (16.67%), Tif1gamma (3.33%), NxP2 (3.33%), Ro-52(40%), PM-Scl, U1-RNP, ANA (26.67%) were the serum autoantibodies identified. Using SUV max Ratio to quantify FDG uptake, PET-MRI showed a sensitivity of 100% with 93.3% specificity in diagnosing IIM.FDG uptake was maximum in proximal lower limb region followed by proximal upper limb. Multivariate regression analysis showed that the severity of muscle weakness, serum Mi2B antibody positivity and serum creatinine kinase levels had a significant positive correlation with FDG uptake (value of 0.005, 0.043, 0.042, respectively for whole-body FDG uptake). FDG uptake also showed good correlation with histopathological features and muscle MRI, but there was no significant association with treatment response. Three female patients in our cohort had primary malignancy involving the breast, uterus, and cervix. Conclusions PET-MRI is a promising diagnostic modality for IIM. PET-MRI reflects the severity of muscle inflammation, showing good association with various clinical/laboratory parameters, histopathology, and muscle MRI. Parameters associated with severe muscle inflammation in PET-MRI—clinical severity of muscle weakness, Mi2B positivity, and serum creatine kinase levels—may be used as clinical/laboratory markers of disease severity in IIM. PET-MRI has the added advantage of detection of systemic malignancy.

In 2016 NICE updated its guidance, extending the age to which early intervention in psychosis (EIP) services treat patients following their first episode of psychosis, to 65 years, from the previous cut-off of 35 years. The aim of this service evaluation was to identify differences in the demographic details, diagnoses, and treatments between patients below and above 35 years to identify any unmet needs in the latter age category.A total of 100 patients from the caseload were randomly selected, with 50 from each age group, to analyse in further detail. Descriptive statistics was predominantly used due to the relatively small sample size.The over 35 s were predominantly female (62%), whilst the under 35 s were predominantly male (66%). There was a statistically significantly higher rate of substance misuse in the under 35 s. Whilst schizophrenia was the most common diagnosis in both groups, higher rates of delusional disorders and psychosis NOS were observed in the over 35 s. In both age groups, a median of two different medications was used per patient. However, amongst the over 35 s there is less use of psychological therapy and of support, time and recovery workers (STR workers).There are distinct differences between the two age groups including demographic and diagnostic features. Being historically youth based, EIP services needs to ensure that treatments offered are tailored to meet the need of the older age demographic who have different needs.

The coronavirus disease pandemic has grown worldwide. As we understand the exact pathophysiology of the disease and how it affects the systems in the human body, we are in the process of discovering and repositioning drugs potentially effective in these regards. A few targets of these drugs are excessive inflammation following SARS-CoV-2 infection and sigma-1 receptor ER chaperone protein, which plays a role in replication. The recent discovery of antidepressants like fluvoxamine and clomipramine acting through these targets may provide a new ray of hope to decrease mortality and morbidity in severe COVID patients.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

Aims This study analyses the prevalence and antimicrobial resistance (AMR) of major diarrhoeagenic Escherichia coli (DEC) pathotypes detected in hospitalized diarrhoeal patients in Kolkata, India, during 2012–2019. Methods and Results A total of 8891 stool samples were collected from the Infectious Diseases Hospital, Kolkata and screened for the presence of enteric pathogens. Multiplex PCR identified the presence of DEC in 7.8% of the samples, in which ETEC was most common (47.7%) followed by EAEC (38.4%) and EPEC (13.9%). About 54% cases were due to sole DEC infections. Majority of the mixed DEC infections were caused by the Vibrio spp. (19.1%) followed by Rotavirus (14.1%) and Campylobacter spp. (8.4%). ETEC and EAEC were associated significantly with diarrhoea in children Conclusions These findings highlighted the high prevalence of MDR in major DEC pathotypes that could be considered as the leading aetiological bacterial agent responsible for diarrhoea and suggests a significant public health threat. Significance and Impact of the Study The results of this study can help to improve the understanding of the epidemiology of DEC infections in patients with diarrhoea. Monitoring of AMR surveillance needs special attention because the DEC isolates were highly resistant to commonly used antimicrobials in the treatment of diarrhoea.

India has the third-largest burden of human immunodeficiency virus (HIV) infection in the world. The coronavirus disease 2019 (COVID-19) pandemic has only exposed the cracks in the Indian healthcare infrastructure concerning HIV. The prevalence of HIV in India is more among the destitute or sections of society shrouded by years of social stigma such as prostitutes, truck drivers, transsexuals and intravenous drug users. National AIDS Control Organisation and The Joint United Nations Programme on HIV/AIDS (UNAIDS) organisation have many several efforts over the years to set up counselling and testing centres all over the country and spread awareness about HIV among the masses. COVID-19 pandemic has reversed years of progress made by the same. HIV patients are biologically more susceptible to COVID-19, and the lockdown has led to the loss of jobs, economic crises, shortage of drugs and necessities such as food and housing among this vulnerable population, which can result in lowered CD4-T cell counts in the coming months and make way for dangerous opportunistic infection outbreaks in this population increasing the overall HIV burden of India. This article explores how COVID-19 has impacted India's already existing HIV epidemic and tries to put forth recommendations based on the evidence found to be better prepared in treating the HIV-positive population in India in the face of another catastrophe like the COVID-19.

Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gln missense mutation, located in the N-terminal region of the protein. This mutation resides between a zinc-finger motif and a RBD domain, involved in binding rnd3, a RhoA effector protein. We conclude that based on the characteristic phenotype presented by the patient and the supportive genetic findings, the PLEKHG5 mutation is the causative variant.

BackgroundSarcoglycanopathies (SG) is the most frequent form of autosomal recessive limb-girdle muscular dystrophies (LGMD) leading to progressive muscle wasting and weakness, predominantly characterized by limb-girdle weakness. LGMDR4 is caused by mutations in SGCB encoding for the beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype cosegregating in 14 SG cases from 13 unrelated families with the likely pathogenic homozygous mutation c.544A>C (p.Thr182Pro) in SGCB.MethodsThe genotypes of five selected markers (rs10009426, rs6824707, rs2271046, rs35414474 and rs17611952) surrounding the c.544A>C (p.Thr182Pro) were extracted from the variant call format (VCF) generated from whole-exome sequencing (WES) of 14 cases and 14 related family members as controls. The linkage data file was constructed and linkage disequilibrium (LD) plots were generated using HaploView to visualize patterns of LD. Further, haplotype reconstructions based on the 6 markers were conducted using PLINK1.9. using the expectation-maximization (EM) algorithm, an iterative method to find maximum likelihood. Subsequently, the R programming language was used to determine and compare plots of the haplotype frequencies and percentages for both groups to infer the risk haplotypes.ResultsFour strong LD blocks were identified in control group: rs10009426 to rs6824707 (0.27□kb), rs6824707 to rs2271046 (41.6 kb), rs10009426 to rs2271046 (41.8 kb) and rs35414474 to rs17611952 (0.17 kb) which were absent in the case group. Similarly, a total of nine haplotypes were estimated in cases and controls of which haplotype H1= G, A, T, G, G, T showed significant statistical difference in the frequency between cases and controls. H1 is also observed to cosegregate with c.544A>C (p.Thr182Pro) in the pedigrees of all the cases.ConclusionThe identification of c.544A>C (p.Thr182Pro) mutation in 14 cases from India indicates a probable event of founder effect. Further, the H1 haplotype, cosegregating with this mutation, convincingly sheds light on the recent developments in population genetics allowing insights into demographic and population history. This haplotype can also be used as a genetic marker to screen individuals with genetic susceptibility as carriers and provide genetically informed risk stratification and management in the prevention of SG.

Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. Materials and methods: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. Results: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). Conclusion: We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).

The clinico-genetic architecture of sarcoglycanopathies in Indian patients is reported only as short series. In the present study, we aimed to investigate the clinical picture, genetic basis, and disease progression of patients genetically confirmed to have sarcoglycanopathy. Next-generation sequencing was performed in 68 probands with suspected sarcoglycanopathy. A total of 35 different variants were detected in the sarcoglycan genes in 68 probands (M = 37; age range, 5-50 years). Consanguinity was present in 44 families. Thirty-two variants are predicted to be pathogenic/likely pathogenic, among which 25 (78.13%) are reported, and 7 (21.87%) are novel. The clinical diagnosis was confirmed in a total of 64 (94.12%) probands with biallelic variations [SGCA(n=18); SGCB(n=34); SGCG(n=7); SGCD(n=5)]. The most common mutation was c.544A C (p.Thr182Pro) in SGCB, and detected in 20 patients (29.42%). The majority of pathogenic mutations are homozygous (n = 30; 93.75%). Variants in 4 cases are of uncertain significance. Thirty-three patients lost ambulation at a mean age of 15.12 ± 9.47 years, after 7.76 ± 5.95 years into the illness. Only 2 patients had cardiac symptoms, and one had respiratory muscle involvement. The results from this study suggest that mutations in SGCB are most common, followed by SGCA, SGCG, and SGCD. The novel variations identified in this study expand the mutational spectrum of sarcoglycanopathies. To the best of our knowledge, this is the first study from India to describe a large cohort of genetically confirmed patients with sarcoglycanopathy and report its disease progression.

BACKGROUND AND OBJECTIVES Muscle ultrasound (MUS) is an emerging noninvasive tool to identify fasciculations in amyotrophic lateral sclerosis (ALS). We assessed the utility of MUS in detecting fasciculations in suspected ALS patients. METHODS Thirty-three patients (25 men) with possible (n = 7), probable (n = 12), or definite ALS according to Awaji criteria were studied. Electromyography was done in biceps brachii, quadriceps, and thoracic paraspinal muscles and MUS in biceps, triceps, deltoid, abductor-digiti-minimi, quadriceps, hamstrings, tibialis anterior, thoracic paraspinal, and tongue muscles. RESULTS The age at onset and illness duration was 49.73 ± 12.7 years and 13.57 ± 9.7 months, respectively. Limb-onset = 24 patients (72.7%) and bulbar-onset = 9 (27.3%). Totally 561 muscles were examined by MUS. Fasciculations were detected in 84.3% of muscles, 98.4% with and 73% without clinical fasciculations (p

Cross-sectional area (CSA) is the most important parameter to study peripheral nerves by high-resolution ultrasonography. The aim was to acquire normative data of CSA of the main upper and lower limb nerves in the Indian population.CSA of nerves was determined in 100 healthy volunteers at 11 predetermined sites: median and ulnar at the wrist, mid-forearm, elbow; radial (spiral groove); tibial (popliteal fossa, medial malleolus); common peroneal (CPN, fibular head) and sural (lateral malleolus).The mean age of participants was 40.7 ± 13.0 years (range: 18-79). Fifty were40 years of age. The mean height, weight and BMI were 161.5 ± 8.3 centimeters (range: 145-179), 58.6 ± 10.1 kilograms (range: 32-90) and 22.4 ± 3.2 kilogram/square meter (range: 14.03-30.44), respectively. The median and ulnar nerve measurements were non-uniform throughout its course, and the CSA was largest at the elbow and ulnar groove, respectively. With advancing age, there was a significant difference for median and ulnar nerves at the wrist (medianIt is apt for every defined population to have its own set of normative data of CSA as it varies with ethnicity, age, and the built of individuals. We provide a valuable set of CSA data for nerves in the Indian population, which can be used for comparison while investigating peripheral nerve disorders.

Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing–based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G T (5' splice site); c.1123C T (p.Gln375Ter)] and one reported missense mutation, c.581G A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

Lipid storage myopathies (LSM) constitute an important group of treatable myopathies. Genetic testing is essential for confirming the diagnosis and also helps in explaining phenotypic heterogeneity. The objective of this study was to describe the clinical features and genetic spectrum of LSM seen in a quaternary referral center in India.Eleven cases of suspected LSM underwent clinical, biochemical, histopathological and genetic evaluation. Tandem Mass Spectrometry and clinical exome sequencing with Sanger validation were performed.All patients had exertion induced myalgia and either progressive or episodic limb girdle muscle weakness (LGMW). The age of onset ranged 10 to 31 years (mean- 21 ± 6.7y), age at presentation- 14 to 49 years (mean- 26.5 ± 9.5y). Mutations identified:This is the first report on the genetic spectrum of LSM from India. LSM should be considered in patients with exertion induced myalgias, LGMW, cranial nerve involvement or dropped head syndrome. Genetic testing is essential for identification of these treatable disorders.

Background and Purpose Pathogenic variants in the myopalladin gene (MYPN) are known to cause mildly progressive nemaline/cap myopathy. Only nine cases have been reported in the English literature. Methods A detailed evaluation was conducted of the clinical, muscle magnetic resonance imaging (MRI), and genetic findings of two unrelated adults with MYPN-related cap myopathy. Genetic analysis was performed using whole-exome sequencing. MRI was performed on a 1.5-T device in patient 1. Results Two unrelated adults born to consanguineous parents, a 28-year-old male and a 23-year-old female, were diagnosed with pathogenic variants in MYPN that cause cap myopathy. Both patients presented with early-onset, insidiously progressive, and minimally disabling proximodistal weakness with mild ptosis, facial weakness, and bulbar symptoms. Patient 1 had a prominent foot drop from the onset. Both patients were followed up at age 30 years, at which point serum creatine kinase concentrations were minimally elevated. There were no cardiac symptoms; electrocardiograms and two-dimensional echocardiograms were normal in both patients. Muscle MRI revealed preferential involvement of the glutei, posterior thigh muscles, and anterior leg muscles. Whole-exome sequencing revealed significant homozygous splice-site variants in both of the probands, affecting intron 10 of MYPN: c.1973+1G>C (patient 1) and c.1974-2A>C (patient 2). Conclusions This study elaborates on two patients with homozygous MYPN pathogenic variants, presenting as slowly progressive congenital myopathy. These patients are only the tenth and eleventh cases reported in the English literature, and the first from South Asia. The clinical phenotype reiterates the mild form of nemaline rod/cap myopathy. A comprehensive literature review is presented.

Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.

Sickle cell anemia is a complex pathophysiologic single gene defect genetic disorder with a wide spectrum in the severity of the disease. Decomposing stature into its major components is a useful strategy to assess antecedents of disease, morbidity, and death in adulthood. CORMIC INDEX is calculated as (Sitting Height / Height) × 100. Leg length relative to total body proportions is a good indicator of overall growth reserve capacity of a person or a group of people. Previous studies in sickle cell patients have shown evidence of growth failure and are associated with delayed puberty. There is no study correlating growth pattern in sickle cell disease patients with the CORMIC index, in our study we tried to do this. The main conclusion in which we arrived is that “there is no significant correlation between the severity of sickle cell anemia and cormic index”, however, sickle cell affects many growth parameters i.e. height, weight, and sitting height.

Background and purpose Pathogenic variants in the myopalladin gene (MYPN) are known to cause mildly progressive nemaline/cap myopathy. Only nine cases have been reported in the English literature. Methods A detailed evaluation was conducted of the clinical, muscle magnetic resonance imaging (MRI), and genetic findings of two unrelated adults with MYPN-related cap myopathy. Genetic analysis was performed using whole-exome sequencing. MRI was performed on a 1.5-T device in patient 1. Results Two unrelated adults born to consanguineous parents, a 28-year-old male and a 23-year-old female, were diagnosed with pathogenic variants in MYPN that cause cap myopathy. Both patients presented with early-onset, insidiously progressive, and minimally disabling proximodistal weakness with mild ptosis, facial weakness, and bulbar symptoms. Patient 1 had a prominent foot drop from the onset. Both patients were followed up at age 30 years, at which point serum creatine kinase concentrations were minimally elevated. There were no cardiac symptoms; electrocardiograms and two-dimensional echocardiograms were normal in both patients. Muscle MRI revealed preferential involvement of the glutei, posterior thigh muscles, and anterior leg muscles. Whole-exome sequencing revealed significant homozygous splice-site variants in both of the probands, affecting intron 10 of MYPN: c.1973+1G>C (patient 1) and c.1974-2A>C (patient 2). Conclusions This study elaborates on two patients with homozygous MYPN pathogenic variants, presenting as slowly progressive congenital myopathy. These patients are only the tenth and eleventh cases reported in the English literature, and the first from South Asia. The clinical phenotype reiterates the mild form of nemaline rod/cap myopathy. A comprehensive literature review is presented.