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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. [ABSTRACT FROM AUTHOR]

Byline: A. Nalini, N. Devaraddi, N. Gayathri, Chandrajit. Prasad, V. Preethish-Kumar, K. Polavarapu, S. Shantanu We report the clinical, radiological, biochemical, muscle histology, and electron microscopic features of two members [...]

Byline: M. Manjunath, P. Kiran, V. Preethish-Kumar, A. Nalini, Ravinder. Singh, N. Gayathri Background: Multiplex ligation-dependant probe amplification (MLPA) is a highly sensitive and rapid alternative to multiplex polymerase chain [...]

Objective: Immunocharacterization of congenital muscular dystrophy (CMD) to determine the frequency of various subtypes in a large Indian Cohort. Materials and Methods: This retrospective (2014-2017) study was carried on muscle biopsies of clinically suspected cases of CMD with histological evidence of dystrophy/myopathic features. Immunohistochemistry (IHC) to antibodies against laminin (α2, α5,β1,γ1), Collagen-VI (A1,2,3), and Western blot (WB) for α-dystroglycan and POMT1 was performed. Results: The study included 57 cases, of which 15 cases (26.3%) had mean age at presentation of 3.5 years, M: F = 1.5:1, elevated creatinine kinase (CK) (mean 1657 U/L), global developmental delay, multiple contractures, abnormal facies, white matter hyperintensities and showed laminin-α2 deficiency (Merosin deficient CMD). In addition, secondary reduction in laminin-β1, over-expression of laminin-α5, and preserved laminin-γ1 was noted. Ullrich CMD constituted 11/57 cases (19.2%) with mean age at presentation of 5.3 years, M: F = 1.2:1 and normal CK. They presented with proximal muscle weakness, soft velvety palms and soles, contractures, and joint hyperextensibility. Collagen-VI (A1,2,3) showed either complete (n = 3) or sarcolemmal specific (n = 8) loss of staining. Out of the remaining 31 cases, WB for α-dystroglycan was performed in 17 cases which showed deficiency in seven (12.3%). Three of these in addition revealed secondary partial loss of laminin-α2. WB for POMT1 showed deficiency in a single case clinically diagnosed Walker–Warburg syndrome, who presented with seizures and classical features of pachygyria, lissencephaly, and cerebellar cyst on MRI. Twenty-four cases (42.2%) remained uncharacterized and need genetic evaluation. Conclusion: The study helped in characterizing 57.8% of the proband. Immunotyping helps to direct mutational analysis for targeted genes and offers a potential route for prenatal diagnosis.

Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8 years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction  ORAI-1 is a plasma membrane calcium release-activated calcium channel that plays a crucial role in the excitation-contraction of skeletal muscles. Loss-of-function mutations of ORAI-1 cause severe combined immunodeficiency, nonprogressive muscle hypotonia, and anhidrotic ectodermal dysplasia. Autosomal dominant gain-of-function mutation causes Stormorken's syndrome, which includes tubular aggregate myopathy along with bleeding diathesis. Methods  This is a description of a genetically confirmed case of ORAI-1-associated myopathy with clinical, histopathological, and imaging characteristics and a detailed literature review. Results  We report an 18-year-old woman who presented with 2-and-a-half year history of slowly progressive proximal lower limb weakness and ophthalmoparesis. Her serum creatine kinase levels were normal. Magnetic resonance imaging of the muscle showed predominant fatty infiltration of the glutei and quadriceps femoris. Histopathological analysis of muscle biopsy was suggestive of congenital fiber-type disproportion (CFTD). Clinical exome sequencing showed novel homozygous nonsense pathogenic variant NC_000012.12 (NM_032790.3): c.205G > T (p.Glu69Ter) in ORAI-1 gene. Conclusion  This report expands the phenotypic spectrum of ORAI-1-related myopathy to include congenital myopathy-CFTD with ophthalmoparesis, a novel manifestation., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background and Objectives: Cardiovascular magnetic resonance imaging (CMRI) is the noninvasive technique of choice for early detection of cardiac involvement in Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), but is seldom used in routine clinical practice in the Indian context. We sought to determine the prevalence of CMRI abnormalities in patients with DMD and BMD and to compare the CMRI parameters with the phenotypic and genotypic characteristics., Methods: A prospective, observational study was conducted on patients genetically diagnosed with DMD and BMD who could complete CMRI between March 2020 and March 2022. Abnormal CMRI was the presence of any late gadolinium enhancement (LGE) that signifies myocardial fibrosis (LGE positivity), regional wall motion abnormality, or reduced left ventricular ejection fraction (LVEF <55%)., Results: A total of 46 patients were included: 38 patients with DMD and eight with BMD. Cardiac abnormality was seen in 23 (50%) patients. LGE was more common than impaired LVEF in DMD (16, 42.1%), while impaired LVEF was more common in BMD (5, 62.5%). LGE was most frequently found in lateral wall (18/19) followed by inferior (6/19), septal (5/19), anterior (2/19), and apex (1/19). Among the various clinicodemographic parameters, only age ( r = 0.495, P = 0.002) and disease duration ( r = 0.407, P = 0.011) were found to significantly correlate with LGE in patients with DMD. No association was found between the various CMRI parameters and the genotype., Conclusions: The current study highlights the differences in myocardial fibrosis and LV dysfunction between DMD and BMD, along with other CMRI parameters. Notably, a genotype-CMRI correlation was not found in the current cohort, which needs to be further explored., (Copyright © 2024 Copyright: © 2024 Annals of Indian Academy of Neurology.)

Introduction: Amyotrophic lateral sclerosis (ALS) is characterized by motor, cognitive, and behavioral impairment. There is a paucity of evidence about the cognitive/behavioral features of ALS patients from India. We aimed to investigate the cognitive/behavioral profile of ALS spectrum disorders in the Indian context., Methods: Sixty patients with ALS spectrum and 40 age-, gender-, and education-matched healthy controls were recruited. The scales used were Addenbrooke's Cognitive Examination (ACE-III), Clinical Dementia Rating (CDR) scale, and Frontal Systems Behavior (FrSBe) Scale., Results: The mean age of the overall cohort was 55 years, and male-to-female ratio was 2.5:1. The mean duration of illness of the cohort was 16 months. Patients were classified as ALS with normal cognition (ALS-cn, n = 21), mild cognitive or behavioral deficits (ALS-ci/-bi, n = 28), and frontotemporal dementia (ALS-FTD, n = 11). ALS-cn had poorer scores compared to healthy controls in global cognition, memory, and language (p &lt; 0.05). ALS-ci/-bi performed poorer than healthy controls on all cognitive domains (p &lt; 0.05). ALS-FTD had poorer scores than healthy controls and ALS-cn on all cognitive domains (p &lt; 0.001). Behavioral assessment showed an increase in apathy among all subtypes. ALS-FTD showed significant worsening in disinhibition and executive function compared to ALS-cn and ALS-ci/-bi., Conclusion: Our findings suggest that there are key cognitive and behavior characteristics in Indian patients with ALS spectrum. This further strengthens the evidence of a cognitive continuum in ALS and FTD in a diverse context and highlights the importance of meticulous evaluation and correct diagnosis that would assist in better management., (© 2024 S. Karger AG, Basel.)

Introduction   VMA21 -related myopathy is one of the rare forms of slowly progressive myopathy observed in males. Till now, there have been only a handful of reports, mainly from Europe and America, and two reports from India. Method  Here, we describe a case of genetically confirmed VMA21 -associated myopathy with clinical, histopathological, and imaging features with a list of known VMA21 mutations. Results  A 29-year-old man had the onset of symptoms at 18 years of age with features of proximal lower limb weakness. Muscle magnetic resonance imaging showed the preferential involvement of vasti and adductor magnus. A biopsy of the left quadriceps femoris showed features of autophagic vacuolar myopathy with vacuoles containing granular eosinophilic materials. In targeted next-generation sequencing, hemizygous mutation in the 3' splice site of intron 2 of the VMA21 gene (c.164-7 T > A) was identified and confirmed the diagnosis of X-linked myopathy with excessive autophagy. Conclusion  This report expands the phenotypic and genotypic profile of VMA21 -related myopathy, with a yet unreported mutation in India., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Hirayama disease (HD) is a cervical compressive myelopathy. Anterior cervical discectomy and fusion (ACDF) is identified as the best surgical approach. We evaluated surgical outcomes and factors influencing ACDF in HD., Methods: Between 2015 and 2019, 126 patients with HD underwent ACDF. Contrast magnetic resonance imaging of the cervical spine in full flexion was performed. Clinical examination and preoperative/postoperative assessment of hand function using Fugl-Meyer assessment, Jebsen-Taylor hand function test, and handheld dynamometry were performed at 3-monthly intervals for 1 year. Surgical outcomes were assessed as per the Odom criteria and Hirayama outcome questionnaire., Results: Age at onset and duration of illness were 12-31 years (mean, 18 ± 2.7) and 1-96 months (32.7 ± 24.4), respectively. All patients had progressive weakness and wasting of the affected limb. Cord atrophy was seen in 97.1%, with epidural detachment and engorgement of the posterior epidural venous plexus in all. All patients underwent ACDF. Of these patients, 54% had an excellent/good outcome and 39% had a satisfactory outcome as per the Odom scale at last follow-up (mean, 44.9 ± 16.5 months) after surgery. Handheld dynamometry showed improvement from preoperative values to 1 year follow-up. Duration of illness and age at onset had a negative correlation and the preoperative Fugl-Meyer score had a positive correlation with improvement., Conclusions: ACDF resulted in remarkable improvement or stabilization in neurologic deficits in many patients with HD. Because motor disability ensues over time, early surgical intervention during the progressive phase is advocated., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Congenital myasthenic syndromes (CMS) are a rare group of inherited disorders caused by gene defects associated with the neuromuscular junction and potentially treatable with commonly available medications such as acetylcholinesterase inhibitors and β2 adrenergic receptor agonists. In this study, we identified and genetically characterized the largest cohort of CMS patients from India to date. Genetic testing of clinically suspected patients evaluated in a South Indian hospital during the period 2014-19 was carried out by standard diagnostic gene panel testing or using a two-step method that included hotspot screening followed by whole-exome sequencing. In total, 156 genetically diagnosed patients (141 families) were characterized and the mutational spectrum and genotype-phenotype correlation described. Overall, 87 males and 69 females were evaluated, with the age of onset ranging from congenital to fourth decade (mean 6.6 ± 9.8 years). The mean age at diagnosis was 19 ± 12.8 (1-56 years), with a mean diagnostic delay of 12.5 ± 9.9 (0-49 years). Disease-causing variants in 17 CMS-associated genes were identified in 132 families (93.6%), while in nine families (6.4%), variants in genes not associated with CMS were found. Overall, postsynaptic defects were most common (62.4%), followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%). Other genes found to cause neuromuscular junction defects (DES, TEFM) in our cohort accounted for 2.8%. Among the individual CMS genes, the most commonly affected gene was CHRNE (39.4%), followed by DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%) and COLQ (4.5%). We identified 22 recurrent variants in this study, out of which eight were found to be geographically specific to the Indian subcontinent. Apart from the known common CHRNE variants p.E443Kfs*64 (11.4%) and DOK7 p.A378Sfs*30 (9.3%), we identified seven novel recurrent variants specific to this cohort, including DPAGT1 p.T380I and DES c.1023+5G>A, for which founder haplotypes are suspected. This study highlights the geographic differences in the frequencies of various causative CMS genes and underlines the increasing significance of glycosylation genes (DPAGT1, GFPT1 and GMPPB) as a cause of neuromuscular junction defects. Myopathy and muscular dystrophy genes such as GMPPB and DES, presenting as gradually progressive limb girdle CMS, expand the phenotypic spectrum. The novel genes MACF1 and TEFM identified in this cohort add to the expanding list of genes with new mechanisms causing neuromuscular junction defects., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy., Methods: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records., Results: All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene., Discussion: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients., Competing Interests: HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). AT has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 779257 (Solve-RD). All other authors report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: GNE myopathy is a rare slowly progressive adult-onset distal myopathy with autosomal recessive inheritance. It has distinctive features of quadriceps sparing with preferential anterior tibial involvement. Most patients eventually become wheelchair bound by 10-20 years after onset. This study analyzes the phenotype-genotype characteristics and disease progression in a large cohort of GNEM patients from India., Materials and Methods: Retrospective observational study on GNEM from a quaternary neurology referral hospital in southern India. Data was collected from clinical phenotyping, serum creatine kinase levels, muscle biopsy histopathology, genetic analysis and functional assessment scales - IBMFRS and MDFRS., Results: 157 patients were included with mean age at onset and diagnosis: 26.5±6.2 years and 32.8±7.8 years, respectively. M:F ratio was 25 : 13. Most common presenting symptom: foot drop (46.5%) and limb girdle weakness (19.1%). Wasting and weakness of small muscles of hand and finger flexors seen in 66.2% and as an initial symptoms in 5.2%. Though tibialis anterior involvement was most common (89.2%), early quadriceps weakness was noted in 3.2% and Beevor's sign in 59.2%. Rimmed vacuoles were present in 75% of patients with muscle biopsy. Most common variant was the Indian Founder variant identified in 129 patients (c.2179 G>A, p.Val727Met - 82.2%) and most common zygosity being compound heterozygous state (n = 115, 87.5%). Biallelic kinase domain variations predisposed to a more severe phenotype. Wheelchair bound state noted in 8.9% with a mean age and duration of 32.0±7.1 and 6.3±4.9 years respectively, earlier than previous studies on other ethnic groups., Conclusion: This is the largest GNEM cohort reported from South Asia. The p.Val727Met variant in compound heterozygous state is noted in majority (82.2%) of the cases. Observed relationships between genotype and clinical parameters shows that severity of the disease might be attributable to specific GNE genotype and thus could aid in predicting the disease progression.

Introduction: Nuclear envelopathies occur due to structural and/or functional defects in various nuclear envelope proteins such as lamin A/C and lamin related proteins. This study is the first report on the phenotype-genotype patterns of nuclear envelopathy-related muscular dystrophies from India., Methods: In this retrospective study, we have described patients with genetically confirmed muscular dystrophy associated with nuclear envelopathy. Data on clinical, laboratory findings and muscle MRI were collected., Results: Sixteen patients were included with median age at onset of 3 years (range: 1 month - 17 years). Three genes were involved: LMNA (11, 68.75%), EMD (4, 25%) and SYNE1 (1, 6.25%). The 11 patients with LMNA variants were Congenital muscular dystrophy (MDCL)=4, Limb Girdle Muscular Dystrophy (LGMD1B)=4 and Emery-Dreifuss Muscular Dystrophy (EDMD2)=3. On muscle biopsy, one patient from each laminopathy phenotype (n = 3) revealed focal perivascular inflammatory infiltrate. Other notable features were ophthalmoparesis in one and facial weakness in one. None had cardiac involvement. Patients with EDMD1 had both upper (UL) and lower limb (LL) proximo-distal weakness. Cardiac rhythm disturbances such as sick sinus syndrome and atrial arrhythmias were noted in two patients with EDMD1. Only one patient with variant c.654&#95;658dup (EMD) lost ambulation in the 3rd decade, 18 years after disease onset. Two had finger contractures with EMD and SYNE1 variants respectively. All patients with LMNA and SYNE1 variants were ambulant at the time of evaluation. Mean duration of illness (years) was 11.6±13 (MDCL), 3.2±1.0 (EDMD2), 10.4±12.8 (LGMD1B), 11.8±8.4 (EDMD1) and 3 (EDMD4). One patient had a novel SYNE1 mutation (c.22472dupA, exon 123) and presented with UL phenotype and prominent finger and wrist contractures., Conclusion: The salient features included ophthalmoparesis and facial weakness in LMNA, prominent finger contractures in EMD and SYNE1 and upper limb phenotype with the novel pathogenic variant in SYNE1.

Background: Congenital myopathies (CMs) are a diverse group of inherited muscle disorders with broad genotypic and phenotypic heterogeneity. While the literature on CM is available from European countries, comprehensive data from the Indian subcontinent is lacking., Objectives: This study aims to describe the clinical and histopathological characteristics of a cohort of genetically confirmed CMs from India and attempts to do phenotype-genotype correlation., Methods: A retrospective chart review of genetically confirmed CMs was evaluated between January 2016 and December 2020 at the neuromuscular clinic. The clinical, genetic, and follow-up data were recorded in a pre-structured proforma as per the medical records, and the data was analyzed., Results: A total of 31(M: F = 14 : 17) unrelated patients were included. The median age at onset and duration of illness are 2.0(IQR:1-8) years and 6.0(IQR:3-10) years respectively. Clinical features observed were proximodistal weakness (54.8%), facial weakness (64.5%), and myopathic facies (54.8%), followed by ptosis (33.3%), and ophthalmoplegia (19.4%). Muscle histopathology was available in 38.7% of patients, and centronuclear myopathy was the most common histopathology finding. The pathogenic genetic variants were identified in RYR1 (29.0%), DNM2 (19.4%), SELENON (12.9%), KBTBD13 (9.7%), NEB (6.5%), and MYPN (6.5%) genes. Novel mutations were observed in 30.3% of the cohort. Follow-up details were available in 77.4% of children, and the median duration of follow-up and age at last follow-up was 4.5 (Range 0.5-11) years and 13 (Range 3-35) years, respectively. The majority were ambulant with minimal assistance at the last follow-up. Mortality was noted in 8.3% due to respiratory failure in Centronuclear myopathy 1 and congenital myopathy 3 with rigid spines (SELENON)., Conclusion: This study highlights the various phenotypes and patterns of genetic mutations in a cohort of pediatric patients with congenital myopathy from India. Centronuclear myopathy was the most common histological classification and the mutations in RYR1 followed by DNM2 gene were the common pathogenic variants identified. The majority were independent in their activities of daily living during the last follow-up, highlighting the fact that the disease has slow progression irrespective of the genotype.

Background: DM1 is a multisystem disorder caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK. Neuropsychological consequences and sleep abnormalities are important associations in DM1., Objective: To describe the clinical phenotype, disease progression and characterize the sleep alterations and cognitive abnormalities in a sub-set of patients., Materials and Methods: A retrospective study on 120 genetically confirmed DM1 cases. Findings in neuropsychological assessment and multiple sleep questionnaires were compared with 14 age and sex matched healthy individuals. All 120 patients were contacted through letters/telephonic consultation/hospital visits to record their latest physical and functional disabilities., Results: The mean age at symptom onset was 23.1 ± 11.4 years, M: F = 3.8:1, mean duration of illness = 14.3 ± 9.5 years. Clinically 54.2% had adult onset form, juvenile = 27.5%, infantile = 10.8%, late adult onset = 7.5%. Paternal transmission occurred more frequently. The predominant initial symptoms were myotonia (37.5%), hand weakness (21.7%), lower limb weakness (23.3%) and bulbar (10%). Twenty patients completed sleep questionnaires (SQ). Abnormal scores were noted in Epworth sleepiness scale (55%); Pittsburgh sleep quality index (45%); Berlin SQ (30%); Rapid eye movement sleep Behaviour Disorder SQ (15%); Restless leg syndrome rating scale (10%). Neuropsychological assessment of 20 patients revealed frontal executive dysfunction, attention impairment and visuospatial dysfunction. Frontal lobe was most affected (72%) followed by parietal (16%) and temporal lobe (12%)., Conclusions: The current study provides a comprehensive account of the clinical characteristics in Indian patients with DM1. Hypersomnolence was most commonly seen. Excessive daytime sleepiness and Sleep disordered breathing were the most common sleep related abnormality. Cognitive impairment comprised predominantly of frontal lobe dysfunction., (Copyright © 2024 Copyright: © 2024 Neurology India, Neurological Society of India.)

Background: Electrocardiography (ECG) remains an excellent screening tool for cardiac assessment in Duchenne muscular dystrophy (DMD), but an accurate interpretation requires comparison with age-matched healthy controls., Objective: We examined various ECG parameters in children with DMD, in comparison with age-matched controls., Methods: Standard 12-lead ECG tracings of serial patients were screened for quality and selected. Controls were healthy, age-matched school-going children. Both quantitative and qualitative ECG parameters were analyzed., Results: After screening, ECGs from 252 patients with DMD (8.32 ± 3.12 years, 2-21 years) and ECGs from 151 age-matched healthy controls (9.72 ± 2.23, 4-19 years) were included. A significantly higher heart rate, shorter R-R interval, and taller R wave in V1 were seen across all age group of DMD in comparison to controls, with the difference increasing with age. While QT prolongation was seen in all age groups of DMD, QTc prolongation was seen only at 10 years or more. Incomplete right bundle branch block (RBBB) and pathological Q waves in inferolateral leads were exclusive in DMD, with the latter declining with age. Evidence for left ventricular (LV) pathology, such as tall R in V5/V6, increase in SV1 + RV6 height, and QRS complex duration, were seen only in the age group of 10 years or more., Conclusion: Stratification based on age and comparison with age-matched healthy subjects showed that several ECG parameters were influenced by age, and it also identified age-dependent evidence for LV pathology and QTc prolongation in DMD., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Annals of Indian Academy of Neurology.)

Objective: To develop individualised psychosocial intervention program for people with MND and their families in India., Methods: People with MND and healthcare staff were constructively involved in co-designing the intervention program in four phases adapted from the MRC framework: 1. A detailed need assessment phase where 30 participants shared their perceptions of psychosocial needs 2. Developing the intervention module (synthesis of narrative review, identified needs); 3. Feasibility testing of the intervention program among seven participants; 4. Feedback from participants on the feasibility (acceptance, practicality adaptation). The study adopted an exploratory research design., Results: Intervention program of nine sessions, addressing psychosocial challenges through the different stages of progression of the illness and ways to handle the challenges, specific to the low resource settings, was developed and was found to be feasible. People with MND and families who participated in the feasibility study shared the perceived benefit through feedback interviews., Conclusion: MND has changing needs and challenges. Intervention programme was found to be feasible to be implemented among larger group to establish efficacy.

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., (© 2023. The Author(s).)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 by, 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 and Objective: Duchenne muscular dystrophy (DMD) is a degenerative X-linked muscle disease. Death frequently results from complications in cardiopulmonary systems. Preclinical/early diagnosis of cardiac autonomic abnormalities may aid initiate cardioprotective therapy and enhance prognosis., Methods: A cross sectional, prospective study of 38 DMD boys compared with 37 age-matched healthy controls was conducted. Lead II electrocardiography and beat-to-beat blood pressure were recorded to assess heart rate variability (HRV), blood pressure variability (BPV), and baroreceptor sensitivity (BRS) in a standardized environment. Data were analysed and correlated with disease severity and genotype., Results: In the DMD group, the median age at assessment was 8 years [IQR 7-9 years], the median age at disease onset was 3 years [IQR, 2-6 years], and the mean duration of illness was 4 years [IQR, 2.5-5]. DNA sequencing showed deletions in 34/38 (89.5 %) and duplications in 4/38 (10.5%) patients. The median heart rate in DMD children was significantly higher [101.19 (Range, 94.71-108.49)] /min compared to controls [81 (Range, 76.2-92.76)] /min (p < 0.05). All the assessed HRV and BPV parameters were significantly impaired in DMD cases except for the coefficient of variance of systolic blood pressure. Further, BRS parameters were also significantly reduced in DMD, excluding alpha-LF. A positive correlation was found between alpha HF with age at onset and duration of illness., Conclusion: This study demonstrates a distinct early impairment of neuro-cardio-autonomic regulation in DMD. Simple yet effective non-invasive techniques such as HRV, BPV, and BRS may help identify cardiac dysfunction in a pre-clinical state, paving the way for early cardio-protective therapies and limiting disease progression in DMD patients.

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.

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., (© 2022. The Author(s).)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Neurocognitive disabilities in Duchenne muscular dystrophy (DMD) children beginning in early childhood and distal DMD gene deletions involving disruption of Dp140 isoform are more likely to manifest significant neurocognitive impairments. MRI data analysis techniques like brain-network metrics can provide information on microstructural integrity and underlying pathophysiology., Methods: A prospective study on 95 participants [DMD = 57, and healthy controls (HC) = 38]. The muscular dystrophy functional rating scale (MDFRS) scores, neuropsychology batteries, and multiplex ligand-dependent probe amplification (MLPA) testing were used for clinical assessment, IQ estimation, and genotypic classification. Diffusion MRI and network-based statistics were used to analyze structural connectomes at various levels and correlate with clinical markers., Results: Motor and executive sub-networks were extracted and analyzed. Out of 57 DMD children, 23 belong to Dp140 + and 34 to Dp140- subgroup. Motor disabilities are pronounced in Dp140- subgroup as reflected by lower MDFRS scores. IQ parameters are significantly low in all-DMD cases; however, the Dp140- has specifically lowest scores. Significant differences were observed in global efficiency, transitivity, and characteristic path length between HC and DMD. Subgroup analysis demonstrates that the significance is mainly driven by participants with Dp140- than Dp140 + isoform. Finally, a random forest classifier model illustrated an accuracy of 79% between HC and DMD and 90% between DMD- subgroups., Conclusions: Current findings demonstrate structural network-based characterization of abnormalities in DMD, especially prominent in Dp140-. Our observations suggest that participants with Dp140 + have relatively intact connectivity while Dp140- show widespread connectivity alterations at global, nodal, and edge levels. This study provides valuable insights supporting the genotype-phenotype correlation of brain-behavior involvement in DMD children., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting cortical and spinal motor neurons. There is a lack of optimal biomarkers to diagnose and prognosticate the ALS patients. C-reactive protein (CRP), an inflammatory marker, has shown promising results in ALS patients., Materials and Methods: PubMed, Embase, and Google Scholar databases were searched from 2000 to June 1, 2021 for suitable studies showing the relationship between CRP and ALS. The concentration of CRP levels was assessed between ALS patients and controls. Further, end outcomes like ALS functional rating scale (ALSFRS-R), survival status, and mortality risks were assessed in relation to CRP levels., Results: Eleven studies including five case-control, five cohorts, and one randomized control study were assessed. There were 2785 ALS patients and 3446 healthy controls. A significant increment in CRP levels among ALS patients in comparison with healthy controls were seen in most of the studies. ALSFRS-R and disease progression were found to be significantly correlated with CRP levels. Overall accuracy of CRP in CSF was 62% described in a single study., Conclusion: Although CRP has shown promise as a prognostic biomarker, extensive cohort studies are required to assess its prognostic value and accuracy in diagnosing ALS taking into account the confounding factors., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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 < 0.001). Fasciculation detection rate (FDR) by MUS was significantly higher in muscles with wasting (95.6%) than without wasting (77.6%, p < 0.001). Compared with EMG, FDR was significantly higher with MUS in quadriceps (81.8% vs. 51.5%, p = 0.002) and thoracic paraspinal muscles (75.8% vs. 42.4%, p = 0.013). The proportion of patients with definite ALS increased from 42% by clinical examination to 70% after combining EMG and MUS findings., Conclusions: MUS is more sensitive in detecting fasciculations than electromyography (EMG) and provides a safer, faster, painless, and noninvasive alternative to EMG in detecting fasciculations in ALS., (© 2021 Wiley Periodicals LLC.)

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.

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 < .001). PFTs done in 31 patients showed restrictive abnormality in 80.6%. Significant positive correlation was seen between percentage of predicted forced vital capacity (FVC%) and DTin (p = .009) and TR (p = .037) but not with DTex (p = .852). No significant correlation was seen between diaphragmatic thickness and other PFT parameters or ALSFRS scores., Conclusion: The diaphragmatic thickness showed a significant decrease in ALS/MND as compared to controls. End-inspiratory diaphragmatic thickness and TR correlated well with %FVC. Thus, diaphragmatic USG could be a potential alternative to PFTs in assessing respiratory function in ALS/MND patients having the advantage of less patient participation and ease of performing in late stages of ALS/MND., (© 2021 Wiley Periodicals LLC.)

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&#95;1940del (p.Val646&#95;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).