Lampros Mavrommatis, Abdul Zaben, Urs Kindler, Marie-Cécile Kienitz, Julienne Dietz, Hyun-Woo Jeong, Pierre Böhme, Beate Brand-Saberi, Matthias Vorgerd, Holm Zaehres
Large numbers of Calpain 3 (CAPN3) mutations cause recessive forms of limb-girdle muscular dystrophy (LGMD2A/LGMDR1) with selective atrophy of the proximal limb muscles. We have generated induced pluripotent stem cells (iPSC) from a patient with two mutations in exon 3 and exon 4 at the calpain 3 locus (W130C, 550delA). Two different strategies to rescue these mutations are devised: (i) on the level of LGMD2A-iPSC, we combined CRISPR/Cas9 genome targeting with a FACS and Tet transactivator-based biallelic selection strategy, which resulted in a new functional chimeric exon 3-4 without the two CAPN3 mutations...
2023: Stem Cells International
Carla Bolano-Diaz, José Verdú-Díaz, Alejandro Gonzalez-Chamorro, Sam Fitzsimmons, Gopi Veeranki, Volker Straub, Jordi Diaz-Manera
The identification of disease-characteristic patterns of muscle fatty replacement in magnetic resonance imaging (MRI) is helpful for diagnosing neuromuscular diseases. In the Clinical Outcome Study of Dysferlinopathy, eight diagnostic rules were described based on MRI findings. Our aim is to confirm that they are useful to differentiate dysferlinopathy (DYSF) from other genetic muscle diseases (GMD). The rules were applied to 182 MRIs of dysferlinopathy patients and 1000 MRIs of patients with 10 other GMD. We calculated sensitivity (S), specificity (Sp), positive and negative predictive values (PPV/NPV) and accuracy (Ac) for each rule...
November 10, 2023: Neuromuscular Disorders: NMD
Feng Lin, Kang Yang, Xin Lin, Ming Jin, Long Chen, Fu-Ze Zheng, Liang-Liang Qiu, Zhi-Xian Ye, Hai-Zhu Chen, Min-Ting Lin, Ning Wang, Zhi-Qiang Wang
BACKGROUND: Limb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited diseases predominantly characterized by limb-girdle muscle weakness and dystrophic changes on histological analysis. The frequency of LGMD subtypes varies among regions in China and ethnic populations worldwide. Here, we analyzed the prevalence of LGMD subtypes, their corresponding clinical manifestations, and molecular data in a cohort of LGMD patients in Southeast China. METHODS: A total of 81 consecutive patients with clinically suspected LGMDs from 62 unrelated families across Southeast China were recruited for targeted next-generation sequencing and whole-exome sequencing from July 2017 to February 2020...
November 16, 2023: Orphanet Journal of Rare Diseases
Indar Kumar Sharawat, Aparna Ramachandran, Prateek Kumar Panda, Aman Elwadhi, Apurva Tomar
INTRODUCTION: There is no bedside clinical examination-based prediction score for Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in children with neuromuscular diseases (NMDs) presenting with proximal limb-girdle weakness. METHODS: We compared the details of 200 cases of lower motor neuron type of weakness and had some proximal limb-girdle muscle weakness and divided them into 2 groups: with/without a confirmed diagnosis of DMD/BMD. We determined the predictive factors associated with a diagnosis of DMD/BMD using multivariate binary logistic regression...
2023: Annals of Indian Academy of Neurology
Laura Pezzoni, Roberta Brusa, Teresa Difonzo, Francesca Magri, Daniele Velardo, Stefania Corti, Giacomo Pietro Comi, Maria Cristina Saetti
BACKGROUND: Distrophinopathies are a heterogeneous group of neuromuscular disorders due to mutations in the DMD gene. Different isoforms of dystrophin are also expressed in the cerebral cortex and Purkinje cells. Despite cognitive abnormalities in Duchenne muscular dystrophy subjects that have been described in the literature, little is known about a comprehensive cognitive profile in Becker muscular dystrophy patients. AIM: The aim of this study was to assess cognitive functioning in Becker muscular dystrophy patients by using an extensive neuropsychological battery...
November 15, 2023: Neurological Sciences
Jeremy Vidal, Eric A Fernandez, Martin Wohlwend, Pirkka-Pekka Laurila, Andrea Lopez-Mejia, Julien Ochala, Alexander J Lobrinus, Bengt Kayser, Isabel C Lopez-Mejia, Nicolas Place, Nadège Zanou
BACKGROUND: Decreased ryanodine receptor type 1 (RyR1) protein levels are a well-described feature of recessive RYR1-related myopathies. The aim of the present study was twofold: (1) to determine whether RyR1 content is also decreased in other myopathies and (2) to investigate the mechanisms by which decreased RyR1 protein triggers muscular disorders. METHODS: We used publicly available datasets, muscles from human inflammatory and mitochondrial myopathies, an inducible muscle-specific RYR1 recessive mouse model and RyR1 knockdown in C2C12 muscle cells to measure RyR1 content and endoplasmic reticulum (ER) stress markers...
November 15, 2023: Journal of Cachexia, Sarcopenia and Muscle
Antoinette Cheung, Ivana F Audhya, Shelagh M Szabo, Michael Friesen, Conrad C Weihl, Katherine L Gooch
OBJECTIVES: As the clinical course of autosomal recessive limb-girdle muscular dystrophy (LGMDR) is highly variable, this study characterized the frequency of loss of ambulation (LOA) among patients by subtype (LGMDR1, LGMDR2, LGMDR3-6, LGMDR9, LGMDR12) and progression to cardiac and respiratory involvement among those with and without LOA. METHODS: Systematic literature review. RESULTS: From 2929 abstracts screened, 418 patients were identified with ambulatory status data (LOA: 265 [63...
December 1, 2023: Journal of Clinical Neuromuscular Disease
Ping Wei, Huahua Zhong, Qian Xie, Jin Li, Sushan Luo, Xueni Guan, Zonghui Liang, Dongyue Yue
OBJECTIVES: This study aimed to assess the feasibility of a machine learning-based radiomics tools to discriminate between Limb-girdle muscular dystrophy R2 (LGMDR2) and immune-mediated necrotizing myopathy (IMNM) using lower-limb muscle magnetic resonance imaging (MRI) examination. METHODS: After institutional review board approval, 30 patients with genetically proven LGMDR2 (12 females; age, 34.0 ± 11.3) and 45 patients with IMNM (28 females; age, 49...
2023: Frontiers in Neurology
Niharika Kashyap, Anish Nikhanj, Dina Labib, Easter Prosia, Sandra Rivest, Jacqueline Flewitt, Gerald Pfeffer, Jeffrey A Bakal, Zaeem A Siddiqi, Richard A Coulden, Richard Thompson, James A White, Gavin Y Oudit
Background The prognostic utility of cardiovascular magnetic resonance imaging, including strain analysis and tissue characterization, has not been comprehensively investigated in adult patients with muscular dystrophy. Methods and Results We prospectively enrolled 148 patients with dystrophinopathies (including heterozygotes), limb-girdle muscular dystrophy, and type 1 myotonic dystrophy (median age, 36.0 [interquartile range, 23.0-50.0] years; 51 [34.5%] women) over 7.7 years in addition to an age- and sex-matched healthy control cohort (n=50)...
November 6, 2023: Journal of the American Heart Association
Miranda D Grounds, Erin M Lloyd
This commentary provides an independent consideration of data related to the drug vamorolone (VBP15) as an alternative steroid proposed for treatment of Duchenne muscular dystrophy (DMD). Glucocorticoids such as prednisone and deflazacort have powerful anti-inflammatory benefits and are the standard of care for DMD, but their long-term use can result in severe adverse side effects; thus, vamorolone was designed as a unique dissociative steroidal anti-inflammatory drug, to retain efficacy and minimise these adverse effects...
October 27, 2023: Journal of Neuromuscular Diseases
Synnøve M Jensen, Oddgeir Friborg, Svein Ivar Mellgren, Kai Ivar Müller, Svein Bergvik, Kjell Arne Arntzen
BACKGROUND: Limb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care. OBJECTIVE: To investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality. METHODS: Participants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i...
October 31, 2023: Journal of Neuromuscular Diseases
Nam Chung Tran, Nguyen Thi Kim Lien, Thanh Dat Ta, Van Hung Nguyen, Huy Thinh Tran, Nguyen Van Tung, Nguyen Thi Xuan, Nguyen Huy Hoang, Van Khanh Tran
Background: Limb-girdle muscular dystrophy (LGMD) is a group of inherited neuromuscular disorders characterized by atrophy and weakness in the shoulders and hips. Over 30 subtypes have been described in five dominant (LGMD type 1 or LGMDD) and 27 recessive (LGMD type 2 or LGMDR). Each subtype involves a mutation in a single gene and has high heterogeneity in age of onset, expression, progression, and prognosis. In addition, the lack of understanding of the disease and the vague, nonspecific symptoms of LGMD subtypes make diagnosis difficult...
2023: Frontiers in Genetics
Marine Geoffroy, Louna Pili, Valentina Buffa, Maëlle Caroff, Anne Bigot, Evelyne Gicquel, Grégory Rouby, Isabelle Richard, Romain Fragnoud
Limb-Girdle Muscular Dystrophy R9 (LGMDR9) is a dystroglycanopathy caused by Fukutin-related protein (FKRP) defects leading to the deficiency of α-DG glycosylation, essential to membrane integrity. Recombinant adeno-associated viral vector (rAAV) gene therapy offers great therapeutic promise for such neuromuscular disorders. Pre-clinical studies have paved the way for a phase 1/2 clinical trial aiming to evaluate the safety and efficacy of FKRP gene therapy in LGMDR9 patients. To demonstrate product activity, quality, and consistency throughout product and clinical development, regulatory authorities request several quality controls, including a potency assay aiming to demonstrate and quantify the intended biological effect of the gene therapy product...
October 12, 2023: Cells
Amy Doody, Lindsay Alfano, Jordi Diaz-Manera, Linda Lowes, Tahseen Mozaffar, Kathy Mathews, Conrad C Weihl, Matthew Wicklund, Jeffery Statland, Nicholas E Johnson, Grasp-Lgmd Consortium
Background The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. Methods/design: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes...
October 6, 2023: Research Square
Nahla O Mousa, Ahmed Abdellatif, Nagia Fahmy, Hassan El-Fawal, Ahmed Osman
Neuromuscular disorders (NMD) are a class of progressive disorders that are characterized by wasting of the muscles. Some of the disorders like Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophies (CMDs), limb-girdle muscular dystrophies (LGMD), and mild spinal muscular atrophy (SMA) type III share several presenting clinical features, and hence, diagnosis is usually a challenging task. In this study, the diagnostic potential of some species of microRNAs (miRNAs) that are known to play roles in normal and pathological contexts of myocytes (myomiRs) were evaluated to assess their potential in differential diagnosis of NMDs...
October 19, 2023: Neuromolecular Medicine
Paulo José Lorenzoni, Cláudia Suemi Kamoi Kay, Renata Dal-Pra Ducci, Otto Jesus Hernandez Fustes, Paula Raquel do Vale Pascoal Rodrigues, Nyvia Milicio Coblinski Hrysay, Raquel Cristina Arndt, Lineu Cesar Werneck, Rosana Herminia Scola
Limb-girdle muscular dystrophy (LGMD) is a group of myopathies that lead to progressive muscle weakness, predominantly involving the shoulder and pelvic girdles; it has a heterogeneous genetic etiology, with variation in the prevalence of subtypes according to the ethnic backgrounds and geographic origins of the populations. The aim of the present study was to analyze a series of patients with autosomal recessive LGMD (LGMD-R) to contribute to a better characterization of the disease and to find the relative proportion of the different subtypes in a Southern Brazil cohort...
October 18, 2023: Arquivos de Neuro-psiquiatria
Xiaojie Cao, Li Zeng, Zhijie Lu, Jin Fan, Song Tan, Mingjie Zhang, Zegang Yin
We report the case of a 31-year-old Chinese woman with a chief complaint of weakness in the lower limbs, which was diagnosed as limb-girdle muscular dystrophy 2B (LGMD2B) with compound heterozygous mutations of the DYSF gene. Meanwhile, this woman is an asymptomatic carrier with the mutation of the X-linked DMD gene. The electromyography, muscle MRI, and muscle biopsy indicated a chronic myogenic injury with dysferlin deletion. As a result of genetic testing, compound heterozygous G-to-T base substitution at position 5,497 in exon 49 of the DYSF gene, leading to a codon change from glutamic acid to termination codon at position 1,833, and a heterozygous C-to-G base change at position 4,638 + 8 in intron 42 of the DYSF gene with a consequence of splice, which has never been reported, were identified as candidate causative mutations...
2023: Frontiers in Neurology
Anabel Rico, Andrea Valls, Garazi Guembelzu, Margarita Azpitarte, Ana Aiastui, Mónica Zufiria, Oihane Jaka, Adolfo López de Munain, Amets Sáenz
BACKGROUND: Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy due to mutations in the CAPN3 gene. While the pathophysiology of this disease has not been clearly established yet, Wnt and mTOR signaling pathways impairment in LGMDR1 muscles has been reported. RESULTS: A reduction in Akt phosphorylation ratio and upregulated expression of proteins implicated in glycolysis (HK-II) and in fructose and lactate transport (GLUT5 and MCT1) in LGMDR1 muscle was observed...
October 10, 2023: Orphanet Journal of Rare Diseases
Camille Bouchard, Jacques P Tremblay
Dysferlinopathy is a disease caused by a dysferlin deficiency due to mutations in the DYSF gene. Dysferlin is a membrane protein in the sarcolemma and is involved in different functions, such as membrane repair and vesicle fusion, T-tubule development and maintenance, Ca2+ signalling, and the regulation of various molecules. Miyoshi Myopathy type 1 (MMD1) and Limb-Girdle Muscular Dystrophy 2B/R2 (LGMD2B/LGMDR2) are two possible clinical presentations, yet the same mutations can cause both presentations in the same family...
September 16, 2023: Journal of Clinical Medicine
Zahra Alaei, Nasrin Zamani, Bahareh Rabbani, Nejat Mahdieh
BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most frequent cardiomyopathies that cause acute heart failure and sudden cardiac death. Previous genetic reports have shown that pathogenic variants of genes encoding Z-disc components such as telethonin protein (TCAP) are the primary cause of DCM and HCM. METHODS: This study was the first investigation on the TCAP gene among the Iranian cardiomyopathies population wherein the TCAP gene was analyzed in 40 unrelated patients (17 females and 23 males) who were clinically diagnosed with HCM and DCM...
September 26, 2023: European Journal of Medical Research
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