Zeitschriftenartikel: „LGMDR8“

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Alonso-Pérez, Jorge, Lidia González-Quereda, Luca Bello, Michela Guglieri, Volker Straub, Pia Gallano, Claudio Semplicini et al. „New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy“. Brain 143, Nr. 9 (01.09.2020): 2696–708. http://dx.doi.org/10.1093/brain/awaa228.

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Abstract Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3–6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

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Lasa-Elgarresta, Jaione, Laura Mosqueira-Martín, Neia Naldaiz-Gastesi, Amets Sáenz, Adolfo López de Munain und Ainara Vallejo-Illarramendi. „Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations“. International Journal of Molecular Sciences 20, Nr. 18 (13.09.2019): 4548. http://dx.doi.org/10.3390/ijms20184548.

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Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a rare disease caused by mutations in the CAPN3 gene. It is characterized by progressive weakness of shoulder, pelvic, and proximal limb muscles that usually appears in children and young adults and results in loss of ambulation within 20 years after disease onset in most patients. The pathophysiological mechanisms involved in LGMDR1 remain mostly unknown, and to date, there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of Ca2+ homeostasis in the skeletal muscle is a significant underlying event in this muscular dystrophy. We also review and discuss specific clinical features of LGMDR1, CAPN3 functions, novel putative targets for therapeutic strategies, and current approaches aiming to treat LGMDR1. These novel approaches may be clinically relevant not only for LGMDR1 but also for other muscular dystrophies with secondary calpainopathy or with abnormal Ca2+ homeostasis, such as LGMD2B/LGMDR2 or sporadic inclusion body myositis.

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Tasca, Giorgio, Mauro Monforte, Jordi Díaz-Manera, Giacomo Brisca, Claudio Semplicini, Adele D’Amico, Fabiana Fattori et al. „MRI in sarcoglycanopathies: a large international cohort study“. Journal of Neurology, Neurosurgery & Psychiatry 89, Nr. 1 (09.09.2017): 72–77. http://dx.doi.org/10.1136/jnnp-2017-316736.

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ObjectivesTo characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C–2F) caused by mutations in one of the four genes coding for muscle sarcoglycans.MethodsLower limb MRI scans of patients with LGMD2C–2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well.ResultsScans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones.ConclusionsMuscle involvement on MRI is consistent in patients with LGMD2C–F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.

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Khadilkar, Satish V., Bhagyadhan A. Patel und Jamshed A. Lalkaka. „Making sense of the clinical spectrum of limb girdle muscular dystrophies“. Practical Neurology 18, Nr. 3 (22.02.2018): 201–10. http://dx.doi.org/10.1136/practneurol-2017-001799.

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The expansion of the spectrum of limb girdle muscular dystrophies (LGMDs) in recent years means that neurologists need to be familiar with the clinical clues that can help with their diagnosis. The LGMDs comprise a group of genetic myopathies that manifest as chronic progressive weakness of hip and shoulder girdles. Their inheritance is either autosomal dominant (LGMD1) or autosomal recessive (LGMD2). Their prevalence varies in different regions of the world; certain ethnic groups have documented founder mutations and this knowledge can facilitate the diagnosis. The clinical approach to LGMDs uses the age at onset, genetic transmission and clinical patterns of muscular weakness. Helpful clinical features that help to differentiate the various subtypes include: predominant upper girdle weakness, disproportionate respiratory muscle involvement, distal weakness, hip adductor weakness, ‘biceps lump’ and ‘diamond on quadriceps’ sign, calf hypertrophy, contractures and cardiac involvement. Almost half of patients with LGMD have such clinical clues. Investigations such as serum creatine kinase, electrophysiology, muscle biopsy and genetic studies can complement the clinical examination. In this review, we discuss diagnostic clinical pointers and comment on the differential diagnosis and relevant investigations, using illustrative case studies.

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Hadj Salem, Ikhlass, Fatma Kamoun, Nacim Louhichi, Souad Rouis, Mariam Mziou, Nourhene Fendri-Kriaa, Fatma Makni-Ayadi, Chahnez Triki und Faiza Fakhfakh. „Mutations in LAMA2 and CAPN3 genes associated with genetic and phenotypic heterogeneities within a single consanguineous family involving both congenital and progressive muscular dystrophies“. Bioscience Reports 31, Nr. 2 (23.11.2010): 125–35. http://dx.doi.org/10.1042/bsr20100026.

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LGMD (limb-girdle muscular dystrophy) and CMD (congenital muscular dystrophy) are two common forms of neuromuscular disorders which are distinguishable by their age of onset but with probably a similar underlying pathway. In the present study, we report immunohistochemical, Western-blot and genetic analyses in a large consanguineous Tunisian family with two branches, including seven patients sharing similar LGMD2 phenotype in one branch and one CMD patient in the other branch. Linkage analyses were compatible with the LGMD2A locus in one branch and the MDC1A (muscular dystrophy congenital type 1A) locus in the other branch. This result was supported by deficiency in merosin and calpain3 in the CMD patient and LGMD patients respectively. Mutation analysis revealed two distinct mutations: a c.8005delT frameshift deletion in exon 56 of the LAMA2 (laminin-α2) gene (MDC1A) was found in the CMD patient and a new homozygous mutation c.1536+1G>T in the donor splice site of intron 12 of the CAPN3 (calpain3) gene (LGMD2A) was found in the LGMD patients. RT–PCR (reverse transcription–PCR) performed on total RNA from a LGMD2A patient's muscle biopsy showed complete retention of intron 12 in CAPN3 cDNA, generating a PTC (premature termination codon) that potentially elicits degradation of the nonsense mRNA by NMD (nonsense-mediated mRNA decay). Our results indicate that mRNA analysis is necessary to clarify the primary effect of genomic mutations on splicing efficiency that alters mRNA processing and expression level.

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Cozma, Liviu, Maria Barsevschi, Cristina Mitu, Alexandra Bastian und Bogdan Ovidiu Popescu. „SURPRISING GENOTYPE EXPRESSED AS A COMMON LIMB-GIRDLE MUSCULAR DYSTROPHY“. Romanian Journal of Neurology 16, Nr. 2 (30.06.2017): 71–73. http://dx.doi.org/10.37897/rjn.2017.2.6.

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Limb-girdle muscular dystrophies (LGMDs) comprise a phenotypical spectrum of muscular dystrophies with a high degree of genotypical variability. We describe the case of a 56-year-old male with a history and clinical picture sugestive for LGMD with skeletal and cardiologic involvement. Histopathological examination shows a severe dystrophic picture and geneting testing revealed a unique never reported genotype association: a homozygous variant in the DES gene, associated with myofibrillar myopathy type 1 and LGMD2R, as well as a heterozygous variant in the CRYAB gene, associated with myofibrillar myopathy type 2, both of which could be responsible for the clinical picture.

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Marchuk, Margarita, Tetiana Dovbonos, Halyna Makukh, Orest Semeryak und Yevheniya Sharhorodska. „Sarcotubular Myopathy Due to Novel TRIM32 Mutation in Association with Multiple Sclerosis“. Brain Sciences 11, Nr. 8 (31.07.2021): 1020. http://dx.doi.org/10.3390/brainsci11081020.

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Azerbaijani 28-year-old female showed weakness (MRC (Medical Research Council Scale for Muscle Strength) grade 4 in the proximal part of the upper and MRC grade 2–3 in the lower extremities), difficulty in stair lifting, positive symptom of Hoover’s rising, «waddling gait», decline deep reflexes symmetrical, lack of surface reflexes, positive Babinsky’s reflex on the right, urinary incontinence during sneezing, prolonged walking and exercise from puberty. Additional methods made it possible to identify minor violations of conduction of the left ventricle, electromyography signs of primary muscular disease with predominant involvement of the proximal muscles of the lower extremities, elevation of serum creatine kinase (746.81 U/l), active foci of demyelination in the left frontal lobe, intrathecal synthesis of oligoclonal IgG bands (type 2) in cerebrospinal fluid, atrophy and fatty degeneration of all muscles of the shins, homozygous Variant of Uncertain Significance (VUS) c.1855C > T (p.Pro619Ser) in TRIM32 gene and heterozygous VUS c.2300C > G (p.Thr767Arg) in KIF5A, c.2840G > A (p.Arg947Lys) in MYH2, c.1502G > C (p.Gly501Ala) in POMT1 genes. Comparison of the phenotypes of the mutations that have been identified with the clinical picture of the patient suggests that VUS c.1855C > T (p.Pro619Ser) in the TRIM32 gene can be pathological. Summarizing, it can be argued that the cause of the identified disorders is a homozygous variant c.1855C > T (p.Pro619Ser) in TRIM32 gene that causes LGMDR8 in a patient with MS.

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Pathak, Pankaj, Mehar Chand Sharma, Pankaj Jha, Chitra Sarkar, Mohammed Faruq, Prerana Jha, Vaishali Suri et al. „Mutational Spectrum of CAPN3 with Genotype-Phenotype Correlations in Limb Girdle Muscular Dystrophy Type 2A/R1 (LGMD2A/LGMDR1) Patients in India“. Journal of Neuromuscular Diseases 8, Nr. 1 (01.01.2021): 125–36. http://dx.doi.org/10.3233/jnd-200547.

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Background: Limb girdle muscular dystrophy recessive type 1 (LGMDR1, Previously LGMD2A) is characterized by inactivating mutations in CAPN3. Despite the significant burden of muscular dystrophy in India, and particularly of LGMDR1, its genetic characterization and possible phenotypic manifestations are yet unidentified. Material and Methods: We performed bidirectional CAPN3 sequencing in 95 LGMDR1 patient samples characterized by calpain-3 protein analysis, and these findings were correlated with clinical, biochemical and histopathological features. Results: We identified 84 (88.4%) cases of LGMDR1 harboring 103 CAPN3 mutations (71 novel and 32 known). At least two mutant alleles were identified in 79 (94.2%) of patients. Notably, 76% exonic variations were enriched in nine CAPN3 exons and overall, 41 variations (40%) correspond to only eight exonic and intronic mutations. Patients with two nonsense/out of frame/splice-site mutations showed significant loss of calpain-3 protein as compared to those with two missense/inframe mutations (P = 0.04). We observed a slow progression of disease and less severity in our patients compared to European population. Rarely, presenting clinical features were atypical, and mimicked other muscle diseases like FSHMD, distal myopathy and metabolic myopathies. Conclusion: This is first systematic study to characterize the genetic framework of LGMDR1 in the Indian population. Preliminary calpain-3 immunoblot screening serves well to direct genetic testing. Our findings prioritized nine CAPN3 exons for LGMDR1 diagnosis in our population; therefore, a targeted-sequencing panel of nine exons could serve well for genetic diagnosis, carrier testing, counseling and clinical trial feasibility study in LGMDR1 patients in India.

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Willis, Erin, Steven A. Moore, Mary O. Cox, Vikki Stefans, Akilandeswari Aravindhan, Murat Gokden und Aravindhan Veerapandiyan. „Limb-Girdle Muscular Dystrophy R9 due to a Novel Complex Insertion/Duplication Variant in FKRP Gene“. Child Neurology Open 9 (Januar 2022): 2329048X2210975. http://dx.doi.org/10.1177/2329048x221097518.

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Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein ( FKRP) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c.948_949insC) and an eighteen nucleotide duplication (c.999_1017dup18) predicted to result in premature translation termination (p.E389*). Based on the clinical features and course of the patient, heterozygosity for the common pathogenic FKRP variant, and abnormal glycosylation of alpha-dystroglycan, we suggest that the novel FKRP insertion and duplication are pathogenic. This case expands the genetic heterogeneity of LGMDR9 and emphasize the importance of muscle biopsy for precise diagnosis.

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Angelini, C., L. Nardetto, C. Borsato, R. Padoan, M. Fanin, A. C. Nascimbeni und E. Tasca. „The clinical course of calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B)“. Neurological Research 32, Nr. 1 (Februar 2010): 41–46. http://dx.doi.org/10.1179/174313209x380847.

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Prykhozhij, Sergey V., Lucia Caceres, Kevin Ban, Anna Cordeiro-Santanach, Kanneboyina Nagaraju, Eric P. Hoffman und Jason N. Berman. „Loss of calpain3b in Zebrafish, A Model of Limb-Girdle Muscular Dystrophy, Increases Susceptibility to Muscle Defects Due to Elevated Muscle Activity“. Genes 14, Nr. 2 (15.02.2023): 492. http://dx.doi.org/10.3390/genes14020492.

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Limb-Girdle Muscular Dystrophy Type R1 (LGMDR1; formerly LGMD2A), characterized by progressive hip and shoulder muscle weakness, is caused by mutations in CAPN3. In zebrafish, capn3b mediates Def-dependent degradation of p53 in the liver and intestines. We show that capn3b is expressed in the muscle. To model LGMDR1 in zebrafish, we generated three deletion mutants in capn3b and a positive-control dmd mutant (Duchenne muscular dystrophy). Two partial deletion mutants showed transcript-level reduction, whereas the RNA-less mutant lacked capn3b mRNA. All capn3b homozygous mutants were developmentally-normal adult-viable animals. Mutants in dmd were homozygous-lethal. Bathing wild-type and capn3b mutants in 0.8% methylcellulose (MC) for 3 days beginning 2 days post-fertilization resulted in significantly pronounced (20–30%) birefringence-detectable muscle abnormalities in capn3b mutant embryos. Evans Blue staining for sarcolemma integrity loss was strongly positive in dmd homozygotes, negative in wild-type embryos, and negative in MC-treated capn3b mutants, suggesting membrane instability is not a primary muscle pathology determinant. Increased birefringence-detected muscle abnormalities in capn3b mutants compared to wild-type animals were observed following induced hypertonia by exposure to cholinesterase inhibitor, azinphos-methyl, reinforcing the MC results. These mutant fish represent a novel tractable model for studying the mechanisms underlying muscle repair and remodeling, and as a preclinical tool for whole-animal therapeutics and behavioral screening in LGMDR1.

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Bruge, Celine, Marine Geoffroy, Manon Benabides, Emilie Pellier, Evelyne Gicquel, Jamila Dhiab, Lucile Hoch, Isabelle Richard und Xavier Nissan. „Skeletal Muscle Cells Derived from Induced Pluripotent Stem Cells: A Platform for Limb Girdle Muscular Dystrophies“. Biomedicines 10, Nr. 6 (16.06.2022): 1428. http://dx.doi.org/10.3390/biomedicines10061428.

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Limb girdle muscular dystrophies (LGMD), caused by mutations in 29 different genes, are the fourth most prevalent group of genetic muscle diseases. Although the link between LGMD and its genetic origins has been determined, LGMD still represent an unmet medical need. Here, we describe a platform for modeling LGMD based on the use of human induced pluripotent stem cells (hiPSC). Thanks to the self-renewing and pluripotency properties of hiPSC, this platform provides a renewable and an alternative source of skeletal muscle cells (skMC) to primary, immortalized, or overexpressing cells. We report that skMC derived from hiPSC express the majority of the genes and proteins that cause LGMD. As a proof of concept, we demonstrate the importance of this cellular model for studying LGMDR9 by evaluating disease-specific phenotypes in skMC derived from hiPSC obtained from four patients.

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Zhu, Yuling, Huili Zhang, Yiming Sun, Yaqin Li, Langhui Deng, Xingxuan Wen, Huaqiao Wang und Cheng Zhang. „Serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy“. Disease Markers 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/543282.

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Background.Differentiation among types of muscular dystrophy (MD) has remained challenging. In this retrospective study, we sought to develop a methodology for differentiation of MD types using analysis of serum enzyme profiles.Methods.The serum levels of enzymes from 232 patients, including 120 with DMD, 36 with BMD, 36 with FSHD, 46 with LGMD, and 11 with EDMD, were evaluated.Results.The characteristic profiles of serum enzymes facilitated differentiation of these five types of MD. DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD were characterized by a lack of abnormal serum enzyme levels. We further developed discriminant functions to distinguish BMD and LGMD. For LGMD, LGMD2B patients had significantly higher ALP levels than non-LGMD2B patients (98±59 U/L versus45±9 U/L, resp.,p<0.05).Conclusions.Our approach enabled the determination of MD subtypes using serum enzyme profiles prior to genetic testing, which will increase the chance a mutation will be found in the first gene analyzed.

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Østergaard, Sofie Thurø, Katherine Johnson, Tanya Stojkovic, Thomas Krag, Willem De Ridder, Peter De Jonghe, Jonathan Baets et al. „Limb girdle muscular dystrophy due to mutations in POMT2“. Journal of Neurology, Neurosurgery & Psychiatry 89, Nr. 5 (24.11.2017): 506–12. http://dx.doi.org/10.1136/jnnp-2017-317018.

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BackgroundMutations in the gene coding for protein O-mannosyl-transferase 2 (POMT2) are known to cause severe congenital muscular dystrophy, and recently, mutations in POMT2 have also been linked to a milder limb-girdle muscular dystrophy (LGMD) phenotype, named LGMD type 2N (LGMD2N). Only four cases have been reported so far.ClinicalTrials.gov ID: NCT02759302MethodsWe report 12 new cases of LGMD2N, aged 18–63 years. Muscle involvement was assessed by MRI, muscle strength testing and muscle biopsy analysis. Other clinical features were also recorded.ResultsPresenting symptoms were difficulties in walking, pain during exercise, delayed motor milestones and learning disabilities at school. All had some degree of cognitive impairment. Brain MRIs were abnormal in 3 of 10 patients, showing ventricular enlargement in one, periventricular hyperintensities in another and frontal atrophy of the left hemisphere in a third patient. Most affected muscle groups were hip and knee flexors and extensors on strength testing. On MRI, most affected muscles were hamstrings followed by paraspinal and gluteal muscles. The 12 patients in our cohort carried 11 alleles with known mutations, whereas 11 novel mutations accounted for the remaining 13 alleles.ConclusionWe describe the first cohort of patients with LGMD2N and show that unlike other LGMD types, all patients had cognitive impairment. Primary muscle involvement was found in hamstring, paraspinal and gluteal muscles on MRI, which correlated well with reduced muscle strength in hip and knee flexors and extensors. The study expands the mutational spectrum for LGMD2N, with the description of 11 novel POMT2 mutations in the association with LGMD2N.Clinical trial registrationNCT02759302.

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Barp, Andrea, Pascal Laforet, Luca Bello, Giorgio Tasca, John Vissing, Mauro Monforte, Enzo Ricci et al. „European muscle MRI study in limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A)“. Journal of Neurology 267, Nr. 1 (25.09.2019): 45–56. http://dx.doi.org/10.1007/s00415-019-09539-y.

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Spadafora, Patrizia, Antonio Qualtieri, Francesca Cavalcanti, Gemma Di Palma, Olivier Gallo, Selene De Benedittis, Annamaria Cerantonio und Luigi Citrigno. „A Novel Homozygous Variant in DYSF Gene Is Associated with Autosomal Recessive Limb Girdle Muscular Dystrophy R2/2B“. International Journal of Molecular Sciences 23, Nr. 16 (11.08.2022): 8932. http://dx.doi.org/10.3390/ijms23168932.

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Mutations in the DYSF gene, encoding dysferlin, are responsible for Limb Girdle Muscular Dystrophy type R2/2B (LGMDR2/2B), Miyoshi myopathy (MM), and Distal Myopathy with Anterior Tibialis onset (MDAT). The size of the gene and the reported inter and intra familial phenotypic variability make early diagnosis difficult. Genetic analysis was conducted using Next Gene Sequencing (NGS), with a panel of 40 Muscular Dystrophies associated genes we designed. In the present study, we report a new missense variant c.5033G>A, p.Cys1678Tyr (NM_003494) in the exon 45 of DYSF gene related to Limb Girdle Muscular Dystrophy type R2/2B in a 57-year-old patient affected with LGMD from a consanguineous family of south Italy. Both healthy parents carried this variant in heterozygosity. Genetic analysis extended to two moderately affected sisters of the proband, showed the presence of the variant c.5033G>A in both in homozygosity. These data indicate a probable pathological role of the variant c.5033G>A never reported before in the onset of LGMDR2/2B, pointing at the NGS as powerful tool for identifying LGMD subtypes. Moreover, the collection and the networking of genetic data will increase power of genetic-molecular investigation, the management of at-risk individuals, the development of new therapeutic targets and a personalized medicine.

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Magri, Francesca, Simona Zanotti, Sabrina Salani, Francesco Fortunato, Patrizia Ciscato, Simonetta Gerevini, Lorenzo Maggi et al. „Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene“. International Journal of Molecular Sciences 23, Nr. 17 (29.08.2022): 9817. http://dx.doi.org/10.3390/ijms23179817.

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Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities.

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Thiruvengadam, Girija, Sen Chandra Sreetama, Karine Charton, Marshall Hogarth, James S. Novak, Laurence Suel-Petat, Goutam Chandra, Bruno Allard, Isabelle Richard und Jyoti K. Jaiswal. „Anoctamin 5 Knockout Mouse Model Recapitulates LGMD2L Muscle Pathology and Offers Insight Into in vivo Functional Deficits“. Journal of Neuromuscular Diseases 8, s2 (30.11.2021): S243—S255. http://dx.doi.org/10.3233/jnd-210720.

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Mutations in the Anoctamin 5 (Ano5) gene that result in the lack of expression or function of ANO5 protein, cause Limb Girdle Muscular Dystrophy (LGMD) 2L/R12, and Miyoshi Muscular Dystrophy (MMD3). However, the dystrophic phenotype observed in patient muscles is not uniformly recapitulated by ANO5 knockout in animal models of LGMD2L. Here we describe the generation of a mouse model of LGMD2L generated by targeted out-of-frame deletion of the Ano5 gene. This model shows progressive muscle loss, increased muscle weakness, and persistent bouts of myofiber regeneration without chronic muscle inflammation, which recapitulates the mild to moderate skeletal muscle dystrophy reported in the LGMD2L patients. We show that these features of ANO5 deficient muscle are not associated with a change in the calcium-activated sarcolemmal chloride channel activity or compromised in vivo regenerative myogenesis. Use of this mouse model allows conducting in vivo investigations into the functional role of ANO5 in muscle health and for preclinical therapeutic development for LGMD2L.

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Fischer, D., M. C. Walter, K. Kesper, J. A. Petersen, S. Aurino, V. Nigro, C. Kubisch et al. „Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs“. Journal of Neurology 252, Nr. 5 (23.02.2005): 538–47. http://dx.doi.org/10.1007/s00415-005-0684-4.

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Strafella, Claudia, Valerio Caputo, Giulia Campoli, Rosaria Maria Galota, Julia Mela, Stefania Zampatti, Giulietta Minozzi et al. „Genetic Counseling and NGS Screening for Recessive LGMD2A Families“. High-Throughput 9, Nr. 2 (10.05.2020): 13. http://dx.doi.org/10.3390/ht9020013.

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Genetic counseling applied to limb–girdle muscular dystrophies (LGMDs) can be very challenging due to their clinical and genetic heterogeneity and the availability of different molecular assays. Genetic counseling should therefore be addressed to select the most suitable approach to increase the diagnostic rate and provide an accurate estimation of recurrence risk. This is particularly true for families with a positive history for recessive LGMD, in which the presence of a known pathogenetic mutation segregating within the family may not be enough to exclude the risk of having affected children without exploring the genetic background of phenotypically unaffected partners. In this work, we presented a family with a positive history for LGMD2A (OMIM #253600, also known as calpainopathy) characterized by compound heterozygosity for two CAPN3 mutations. The genetic specialist suggested the segregation analysis of both mutations within the family as a first-level analysis. Sequentially, next-generation sequencing (NGS) analysis was performed in the partners of healthy carriers to provide an accurate recurrence/reproductive risk estimation considering the genetic background of the couple. Finally, this work highlighted the importance of providing a genetic counseling/testing service even in unaffected individuals with a carrier partner. This approach can support genetic counselors in estimating the reproductive/recurrence risk and eventually, suggesting prenatal testing, early diagnosis or other medical surveillance strategies.

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Gushchina, L., B. Bradley, K. Terry, S. Casey, B. Petrykowski, J. Lay, E. Frair et al. „P.172 AAV-mediated strategy for TCAP gene correction as a new treatment for LGMDR7/LGMD2G dystrophy“. Neuromuscular Disorders 32 (Oktober 2022): S117. http://dx.doi.org/10.1016/j.nmd.2022.07.310.

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Black, Carin, und Joanne Said. „Normal vaginal delivery in a patient with autosomal recessive limb-girdle muscular dystrophy“. Obstetric Medicine 3, Nr. 2 (Juni 2010): 81–82. http://dx.doi.org/10.1258/om.2010.090052.

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The limb-girdle muscular dystrophies (LGMDs) are a group of genetically determined disorders of skeletal muscle, predominantly affecting the pelvic and shoulder-girdle musculature. The clinical course is variable but steadily progressive. Type 2A LGMD is the most frequent form, accounting for approximately 30% of identified cases. There are few reports of patients with Type 2A LGMD undergoing pregnancy and delivery. This case outlines a successful vaginal delivery in a woman with this condition.

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Rind, F. C. „Intracellular characterization of neurons in the locust brain signaling impending collision“. Journal of Neurophysiology 75, Nr. 3 (01.03.1996): 986–95. http://dx.doi.org/10.1152/jn.1996.75.3.986.

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1. In response to a rapidly approaching object, intracellular recordings show that excitation in the locust lobula giant movement detecting (LGMD) neuron builds up exponentially, particularly during the final stages of object approach. After the cessation of object motion, inhibitory potentials in the LGMD then help to terminate this excitation. Excitation in the LGMD follows object recession with a short, constant latency but is cut back rapidly by hyperpolarizing potentials. The timing of these hyperpolarizing potentials in the LGMD is variable, and their latency following object recession is shortest with the highest velocities of motion simulated. The hyperpolarizing potentials last from 50-300 ms and are often followed by re-excitation. The observed hyperpolarizations of the LGMD can occur without any preceding excitation and are accompanied by a measurable conductance increase. The hyperpolarizations are likely to be inhibitory postsynaptic potentials (PSPs). The behavior of the intracellularly recorded inhibitory PSPs (IPSPs) closely parallels that of the feed forward inhibitory loop in the neural network described by Rind and Bramwell. 2. The preference of the LGMD for approaching versus receding objects remains over a wide range of starting and finishing distances. The response to object approach, measured both as membrane potential and spike rate, remains single peaked with starting distances of between 200 and 2,100 mm, and approach speeds of 0.5-2 m/s. These results confirm the behavior predicted by the neural network described by Rind and Bramwell but contradicts the findings of Rind and Simmons, forcing a re-evaluation of the suitability of some of the mechanical visual stimuli used in that study. 3. For depolarization of the LGMD neuron to be maintained or increased throughout the motion of image edges, the edges must move with increasing velocity over the eye. Membrane potential declines before the end of edge motion with constant velocities of edge motion. 4. A second identified neuron, the LGMD2 also is shown to respond directionally to approaching objects. In both the LGMD and LGMD2 neurons, postsynaptic inhibition shapes the directional response to object motion.

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Georganopoulou, Dimitra G., Vasilis G. Moisiadis, Firhan A. Malik, Ali Mohajer, Tanya M. Dashevsky, Shirley T. Wuu und Chih-Kao Hu. „A Journey with LGMD: From Protein Abnormalities to Patient Impact“. Protein Journal 40, Nr. 4 (10.06.2021): 466–88. http://dx.doi.org/10.1007/s10930-021-10006-9.

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AbstractThe limb-girdle muscular dystrophies (LGMD) are a collection of genetic diseases united in their phenotypical expression of pelvic and shoulder area weakness and wasting. More than 30 subtypes have been identified, five dominant and 26 recessive. The increase in the characterization of new genotypes in the family of LGMDs further adds to the heterogeneity of the disease. Meanwhile, better understanding of the phenotype led to the reconsideration of the disease definition, which resulted in eight old subtypes to be no longer recognized officially as LGMD and five new diseases to be added to the LGMD family. The unique variabilities of LGMD stem from genetic mutations, which then lead to protein and ultimately muscle dysfunction. Herein, we review the LGMD pathway, starting with the genetic mutations that encode proteins involved in muscle maintenance and repair, and including the genotype–phenotype relationship of the disease, the epidemiology, disease progression, burden of illness, and emerging treatments.

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Frosk, Patrick, Marc R. Del Bigio, Klaus Wrogemann und Cheryl R. Greenberg. „Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I“. European Journal of Human Genetics 13, Nr. 8 (11.05.2005): 978–82. http://dx.doi.org/10.1038/sj.ejhg.5201436.

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Passos-Bueno, Maria Rita, Mariz Vainzof, Eloisa S. Moreira und Mayana Zatz. „Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G“. American Journal of Medical Genetics 82, Nr. 5 (19.02.1999): 392–98. http://dx.doi.org/10.1002/(sici)1096-8628(19990219)82:5<392::aid-ajmg7>3.0.co;2-0.

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Peron, Simon P., Holger G. Krapp und Fabrizio Gabbiani. „Influence of Electrotonic Structure and Synaptic Mapping on the Receptive Field Properties of a Collision-Detecting Neuron“. Journal of Neurophysiology 97, Nr. 1 (Januar 2007): 159–77. http://dx.doi.org/10.1152/jn.00660.2006.

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The lobula giant movement detector (LGMD) is a visual interneuron of Orthopteran insects involved in collision avoidance and escape behavior. The LGMD possesses a large dendritic field thought to receive excitatory, retinotopic projections from the entire compound eye. We investigated whether the LGMD's receptive field for local motion stimuli can be explained by its electrotonic structure and the eye's anisotropic sampling of visual space. Five locust ( Schistocerca americana) LGMD neurons were stained and reconstructed. We show that the excitatory dendritic field and eye can be fitted by ellipsoids having similar geometries. A passive compartmental model fit to electrophysiological data was used to demonstrate that the LGMD is not electrotonically compact. We derived a spike rate to membrane potential transform using intracellular recordings under visual stimulation, allowing direct comparison between experimental and simulated receptive field properties. By assuming a retinotopic mapping giving equal weight to each ommatidium and equally spaced synapses, the model reproduced the experimental data along the eye equator, though it failed to reproduce the receptive field along the ventral-dorsal axis. Our results illustrate how interactions between the distribution of synaptic inputs and the electrotonic properties of neurons contribute to shaping their receptive fields.

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Croissant, Coralie, Romain Carmeille, Charlotte Brévart und Anthony Bouter. „Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies“. International Journal of Molecular Sciences 22, Nr. 10 (17.05.2021): 5276. http://dx.doi.org/10.3390/ijms22105276.

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Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

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Hajer, Foddha, Seo Go Hun, Lee Hane, Zemzem Firas, Naouar Ines, Boughammoura Amel, Gribaa Moez und Khelil Amel Haj. „Exome sequencing reveals a homozygous frameshift variant in CAPN3 in a Tunisian patient with a neuromuscular disorder“. Annals of Molecular and Genetic Medicine 6, Nr. 1 (27.09.2022): 001–4. http://dx.doi.org/10.17352/amgm.000010.

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Muscular dystrophy (MD) is a heterogeneous group of diseases that cause progressive weakness and loss of muscle mass. Specific signs and symptoms begin at different ages and in different muscle groups, depending on the type of muscular dystrophy. We report here a case of a Tunisian patient suffering from a neuromuscular disorder, highly suspicious of a Limb-Girdle Muscular Dystrophy (LGMD). Exome Sequencing revealed a one-base deletion variant in exon 4 of the CAPN3 gene. CAPN3 is associated with a recessive form of LGMD, also known as Muscular Dystrophy, Limb-Girdle, Type 2a (LGMD2A). The variant was shown to segregate with the disease in the family. The identification of the molecular defect in this family provided a rapid genotyping for the sister and an accurate diagnosis for the patient, allowing appropriate clinical management at an early stage of the disease.

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Zhu, Ying, und Fabrizio Gabbiani. „Fine and distributed subcellular retinotopy of excitatory inputs to the dendritic tree of a collision-detecting neuron“. Journal of Neurophysiology 115, Nr. 6 (01.06.2016): 3101–12. http://dx.doi.org/10.1152/jn.00044.2016.

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Individual neurons in several sensory systems receive synaptic inputs organized according to subcellular topographic maps, yet the fine structure of this topographic organization and its relation to dendritic morphology have not been studied in detail. Subcellular topography is expected to play a role in dendritic integration, particularly when dendrites are extended and active. The lobula giant movement detector (LGMD) neuron in the locust visual system is known to receive topographic excitatory inputs on part of its dendritic tree. The LGMD responds preferentially to objects approaching on a collision course and is thought to implement several interesting dendritic computations. To study the fine retinotopic mapping of visual inputs onto the excitatory dendrites of the LGMD, we designed a custom microscope allowing visual stimulation at the native sampling resolution of the locust compound eye while simultaneously performing two-photon calcium imaging on excitatory dendrites. We show that the LGMD receives a distributed, fine retinotopic projection from the eye facets and that adjacent facets activate overlapping portions of the same dendritic branches. We also demonstrate that adjacent retinal inputs most likely make independent synapses on the excitatory dendrites of the LGMD. Finally, we show that the fine topographic mapping can be studied using dynamic visual stimuli. Our results reveal the detailed structure of the dendritic input originating from individual facets on the eye and their relation to that of adjacent facets. The mapping of visual space onto the LGMD's dendrites is expected to have implications for dendritic computation.

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Rico, Anabel, Garazi Guembelzu, Valle Palomo, Ana Martínez, Ana Aiastui, Leire Casas-Fraile, Andrea Valls, Adolfo López de Munain und Amets Sáenz. „Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related“. International Journal of Molecular Sciences 22, Nr. 14 (08.07.2021): 7367. http://dx.doi.org/10.3390/ijms22147367.

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Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients’ muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3β (GSK-3β), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.

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Richardson, Mark, Anna Mayhew, Robert Muni-Lofra, Lindsay B. Murphy und Volker Straub. „Prevalence of Pain within Limb Girdle Muscular Dystrophy R9 and Implications for Other Degenerative Diseases“. Journal of Clinical Medicine 10, Nr. 23 (25.11.2021): 5517. http://dx.doi.org/10.3390/jcm10235517.

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Our primary aim was to establish the prevalence of pain within limb girdle muscular dystrophy R9 (LGMDR9). As part of the Global FKRP Registry, patients are asked to complete the Short Form McGill Pain Questionnaire (SF-MPQ) annually. We used the results of this questionnaire to determine individuals’ maximum pain score and total pain score and examined overall pain intensity and associations between pain intensity and LGMDR9 genotypes, age, and ambulatory status. We also considered the pain descriptors used and pain progression over time. Of the 502 patients, 87% reported current pain and 25% reported severe current pain. We found no associations in pain severity between the different genotypes of LGMDR9. However, we did find statistically significant associations between pain severity and ambulatory status and between our paediatric and adult populations. We found pain descriptors to be more common words that one may associate with non-neural pain, and we found that a significant number of individuals (69%) reported a fluctuating pain pattern over time. We concluded that pain should be considered a significant issue among individuals with LGMDR9 requiring management. Implications regarding assessment of pain for other degenerative diseases are discussed.

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Lostal, William, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg, Heather Best et al. „Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A“. Science Translational Medicine 11, Nr. 520 (27.11.2019): eaat6072. http://dx.doi.org/10.1126/scitranslmed.aat6072.

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Limb-girdle muscular dystrophy type 2A (LGMD2A or LGMDR1) is a neuromuscular disorder caused by mutations in the calpain 3 gene (CAPN3). Previous experiments using adeno-associated viral (AAV) vector–mediated calpain 3 gene transfer in mice indicated cardiac toxicity associated with the ectopic expression of the calpain 3 transgene. Here, we performed a preliminary dose study in a severe double-knockout mouse model deficient in calpain 3 and dysferlin. We evaluated safety and biodistribution of AAV9-desmin-hCAPN3 vector administration to nonhuman primates (NHPs) with a dose of 3 × 1013 viral genomes/kg. Vector administration did not lead to observable adverse effects or to detectable toxicity in NHP. Of note, the transgene expression did not produce any abnormal changes in cardiac morphology or function of injected animals while reaching therapeutic expression in skeletal muscle. Additional investigation on the underlying causes of cardiac toxicity observed after gene transfer in mice and the role of titin in this phenomenon suggest species-specific titin splicing. Mice have a reduced capacity for buffering calpain 3 activity compared to NHPs and humans. Our studies highlight a complex interplay between calpain 3 and titin binding sites and demonstrate an effective and safe profile for systemic calpain 3 vector delivery in NHP, providing critical support for the clinical potential of calpain 3 gene therapy in humans.

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Sihombing, Nydia Rena Benita, Nurin Aisyiyah Listyasari und Sultana MH Faradz. „Autosomal Recessive Limb Girdle Muscular Dystrophy In A Complex Consanguineous Family: The First Cases Series In Indonesia“. Journal of Biomedicine and Translational Research 3, Nr. 2 (31.12.2017): 26. http://dx.doi.org/10.14710/jbtr.v3i2.1500.

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ABSTRACTBackground: Limb girdle muscular dystrophy (LGMD) is a neuromuscular abnormality with clinical heterogeneity and various severity, where over 30 subtypes have been identified. Meanwhile, molecular diagnosis of LGMD is not commonly carried out in Indonesia. We present a large pedigree of familial LGMD, with over 14 years of follow-up.Case Presentation: A 12-year old female patient came with muscle weakness. She had toe walking since age of 6, followed by calf hypertrophy for over three years. Family history revealed complex consanguinity. Her younger sister and her parents’ cousin had similar condition, with the latter was already bedridden.Physical examination results were waddling gait, lordotic spine, and absent deep tendon reflexes. Muscle biopsy showed sign of dystrophic process. Immunoperoxidase staining of some proteins resulted normal. Single nucleotide polymorphism (SNP) array in two siblings revealed homozygosity on chromosome 15 containing CAPN3 gene of LGMD2A subtype.Recently, the patient is wheelchair bound and undergoes rehabilitation. Her sister is still able to walk with abnormal gait, while her parents’ cousin had passed away in age 55. From the multiple consanguinity, it could be concluded as autosomal recessive type LGMD.Conclusion: A large family with LGMD from Indonesia was presented with more than 14 years of care. Clinical diagnosis was made based on physical and additional examination, however molecular analysis for establishing definitive diagnosis is still limited. Further studies such as targeted or whole exome sequencing is warranted to elucidate the cause of disease. Long-term evaluation and supportive care, in addition to proper counseling may increase quality of life.

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Sarkozy, Anna, Mariacristina Scoto, Francesco Muntoni und Joana Domingos. „Dystrophinopathies and Limb-Girdle Muscular Dystrophies“. Neuropediatrics 48, Nr. 04 (20.04.2017): 262–72. http://dx.doi.org/10.1055/s-0037-1601860.

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AbstractMuscular dystrophies are a heterogeneous group of inherited diseases. The natural history of these disorders along with their management have changed mainly due to a better understanding of their pathophysiology, the evolution of standards of care, and new treatment options. Dystrophinopathies include both Duchenne's and Becker's muscular dystrophies, but in reality they are a spectrum of muscle diseases caused by mutations in the gene that encodes the protein dystrophin. Duchenne's muscular dystrophy is the most common form of inherited muscle disease of childhood. The current standards of care considerably prolong independent ambulation and survival. Several therapeutic options either aiming at substituting/correcting the primary protein defect or limiting the progression of the dystrophic process are currently being explored in clinical trials.Limb-girdle muscular dystrophies (LGMDs) are rare and heterogeneous conditions, characterized by weakness and wasting of the pelvic and shoulder girdle muscles. Originally classified into dominant and recessive, > 30 genetic forms of LGMDs are currently recognized. Further understanding of the pathogenic mechanisms of LGMD will help identifying novel therapeutic approaches that can be tested in clinical trials.

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Bushby, K., R. Bashir, S. Keers, S. Britton, M. Zatz, M. R. Passos-Bueno, M. Lovett, I. Mahjneh, G. Marconi und T. Strachan. „The molecular biology of LGMD2B — Towards the identification of the LGMD gene on chromosome 2p13“. Neuromuscular Disorders 6, Nr. 6 (Dezember 1996): 491–92. http://dx.doi.org/10.1016/s0960-8966(96)00393-8.

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Wang, Xike, Yue Wu, Yuxia Cui, Nan Wang, Lasse Folkersen und Yuchuan Wang. „Novel TRAPPC11 Mutations in a Chinese Pedigree of Limb Girdle Muscular Dystrophy“. Case Reports in Genetics 2018 (16.07.2018): 1–6. http://dx.doi.org/10.1155/2018/8090797.

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Limb girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic myopathies leading primarily to proximal muscle weakness. It is caused by mutations at over 50 known genetic loci typically from mutations in genes encoding constituents of the sarcolemmal dystrophin complex or related functions. Herein we describe the case of two siblings with LGMD that were investigated using whole-exome sequencing followed by Sanger sequencing validation of a specific double-mutation in the TRAPPC11 gene. Further, from parental sequencing we determined the mode of transmission, a double heterozygous mutation at the maternal and paternal alleles. The two mutations detected have not been described in other patients.

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Stec, I., W. Kress, G. Meng, B. Muller, C. R. Muller und T. Grimm. „Estimate of severe autosomal recessive limb-girdle muscular dystrophy (LGMD2C, LGMD2D) among sporadic muscular dystrophy males: a study of 415 familes.“ Journal of Medical Genetics 32, Nr. 12 (01.12.1995): 930–33. http://dx.doi.org/10.1136/jmg.32.12.930.

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Wu, Bo, Morgan Drains, Sapana N. Shah, Pei Juan Lu, Victoria Leroy, Jessalyn Killilee, Raegan Rawls, Jason D. Tucker, Anthony Blaeser und Qi Long Lu. „Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model“. PLOS ONE 17, Nr. 12 (01.12.2022): e0278482. http://dx.doi.org/10.1371/journal.pone.0278482.

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Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-dystroglycan (matriglycan) resulting from mutations of Fukutin-related protein (FKRP). There is no effective therapy currently available. We recently demonstrated that ribitol supplement increases levels of matriglycan in cells in vitro and in FKRP-P448L (P448L) mutant mouse model through drinking water administration. To be clinically relevant, we have now conducted a dose-escalating efficacy study by gavage in P448L mutant mice. Six months of ribitol treatment daily significantly rescued functions of skeletal, respiratory, and cardiac muscles dose-dependently. This was associated with a dose dependent increase in matriglycan and improvement in muscle pathology with reductions in muscle degeneration, inflammatory infiltration and fibrosis. Importantly, ribitol significantly increased life span and muscle functions of the female animals receiving treatment from 10 months of age. The only observed side effect was gastrointestinal tract bloating with loose stool and this effect is also dose dependent. The results validate the mechanism that ribitol as a pre-substrate of glycosyltransferase is able to compensate for the decreased function of mutant FKRP with restoration of matriglycan expression and provide a guidance for future clinical trial design.

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Dewell, Richard B., und Fabrizio Gabbiani. „Active membrane conductances and morphology of a collision detection neuron broaden its impedance profile and improve discrimination of input synchrony“. Journal of Neurophysiology 122, Nr. 2 (01.08.2019): 691–706. http://dx.doi.org/10.1152/jn.00048.2019.

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How neurons filter and integrate their complex patterns of synaptic inputs is central to their role in neural information processing. Synaptic filtering and integration are shaped by the frequency-dependent neuronal membrane impedance. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper Schistocerca americana. This neuron, the lobula giant movement detector (LGMD), exhibits consistent impedance properties across frequencies and membrane potentials. Two common active conductances gH and gM, mediated respectively by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and by muscarine-sensitive M-type K+ channels, promote broadband integration with high temporal precision over the LGMD’s natural range of membrane potentials and synaptic input frequencies. Additionally, we found that a model based on the LGMD’s branching morphology increased the gain and decreased the delay associated with the mapping of synaptic input currents to membrane potential. More generally, this was true for a wide range of model neuron morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings show the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration. NEW & NOTEWORTHY Neuronal filtering and integration of synaptic input patterns depend on the electrochemical properties of dendrites. We used an identified collision detection neuron in grasshoppers to examine how its morphology and two conductances affect its membrane impedance in relation to the computations it performs. The neuronal properties examined are ubiquitous and therefore promote a general understanding of neuronal computations, including those in the human brain.

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Prumes, Marcelo, Talita Dias da Silva, Camila Aparecida de Oliveira Alberissi, Camila Miliani Capellini, Lilian Del Ciello de Menezes, João Batista Francalino da Rocha, Francis Meire Favero und Carlos Bandeira de Mello Monteiro. „Motor learning through a non-immersive virtual task in people with limb-girdle muscular dystrophies“. Journal of Human Growth and Development 30, Nr. 3 (15.10.2020): 461–71. http://dx.doi.org/10.7322/jhgd.v30.11115.

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Introduction: Limb-girdle muscular dystrophies (LGMDs) are neuromuscular and genetic disorders that progress with weakness and damage of the proximal muscles, developing with loss of functionality. Virtual reality environments are suggested as an effective alternative for performance of daily life activities. However, there is no evidence in the literature on the use of virtual reality in this population. Objective: Assess motor performance through a motor learning protocol in a coincident timing task. Methods: 10 participants with LGMD and 10 healthy individuals were selected and included in the study to perform a non-immersive virtual reality task divided into three phases: acquisition (20 attempts), retention (5 attempts), and transfer (5 attempts, with speed increase). Results: It is observed that the accuracy of movement improves from the beginning to the end of the acquisition (p = 0.01); however, there is a marginal difference between the groups in block A1 (p = 0.089). Regarding the variability of touches, observed by the variable error, both groups improved performance in all phases. Conclusion: Even with lower performance than the control group at the beginning of the practice, individuals with LGMD showed the potential to optimize motor function during the practice of a non-immersive virtual reality activity and were able to match their performance with the control group after a few attempts.

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Mateos-Aierdi, A. J., M. Dehesa-Etxebeste, M. Goicoechea, A. Aiastui, Y. Richaud-Patin, S. Jiménez-Delgado, A. Raya, N. Naldaiz-Gastesi und A. López de Munain. „Patient-specific iPSC-derived cellular models of LGMDR1“. Stem Cell Research 53 (Mai 2021): 102333. http://dx.doi.org/10.1016/j.scr.2021.102333.

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Albuquerque, Keila Maruze de França, Isabella Araújo Mota, Larissa Nadjara Alves Almeida, Maria Lucrécia Golveia, Priscilla Alves Nóbrega Gambarra Souto und Alzira Alves de Siqueira Carvalho. „Disfunções na motricidade orofacial em pacientes com Distrofia Muscular de Cinturas R2 por deficiência de disferlina“. VITTALLE - Revista de Ciências da Saúde 32, Nr. 3 (22.12.2020): 128–33. http://dx.doi.org/10.14295/vittalle.v32i3.12086.

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As distrofias musculares das cinturas constituem um grupo de doenças genéticas musculares progressivas, nas quais a musculatura das cinturas pélvica e ou escapular estão predominantemente envolvidas. Os músculos da face não são comumente afetados nesta patologia, por este motivo não são frequentemente investigados em estudos. Objetivou-se identificar a existência de possíveis alterações na motricidade orofacial (MO) de pessoas com a distrofia muscular de cinturas R2 relacionada à disferlina (LGMDR2). Essa pesquisa é do tipo caso-controle, duplo cego, descritiva e transversal. Foi realizada avaliação estrutural dos órgãos fonoarticulatórios. Os dados foram registrados em um protocolo criado pelas fonoaudiólogas examinadoras, baseado na pesquisa dos sintomas mais presentes na literatura em pessoas com doenças neuromuculares, categorizados e alocados em planilha digital. Posteriormente, as variáveis foram analisadas através do teste Qui-quadrado. Utilizou-se o software estatístico R com nível de significância igual a 5%. Foram avaliados 21 homozigotos e 61 controles para a variante patogênica c.5979 dupA (p. Glu1994Argfs). A alteração da MO foi encontrada em 85,7% dos homozigotos e 27% dos controles (p-valor 0,001%), sendo as alterações da mobilidade de lábios e de assimetria facial estatisticamente significantes. Estas alterações na MO associada a LGMDR2 não foram descritos em estudos multicêntricos, sendo necessário realizar estudos com descrição de protocolo de avaliação e inclusão do fonoaudiólogo na equipe de investigação a fim de detectar se os achados são característicos da variante investigada. Em conclusão, alterações de MO, especificamente a mobilidade de lábios e a simetria facial podem estar associadas à LGMDR2.

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Ferrans, C. E. „Differences in What Quality-of-Life Instruments Measure“. JNCI Monographs 2007, Nr. 37 (01.10.2007): 22–26. http://dx.doi.org/10.1093/jncimonographs/lgm008.

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Dewell, Richard B., und Fabrizio Gabbiani. „M current regulates firing mode and spike reliability in a collision-detecting neuron“. Journal of Neurophysiology 120, Nr. 4 (01.10.2018): 1753–64. http://dx.doi.org/10.1152/jn.00363.2018.

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All animals must detect impending collisions to escape and reliably discriminate them from nonthreatening stimuli, thus preventing false alarms. Therefore, it is no surprise that animals have evolved highly selective and sensitive neurons dedicated to such tasks. We examined a well-studied collision-detection neuron in the grasshopper ( Schistocerca americana) using in vivo electrophysiology, pharmacology, and computational modeling. This lobula giant movement detector (LGMD) neuron is excitable by inputs originating from each ommatidia of the compound eye. It possesses many intrinsic properties that increase its selectivity to objects approaching on a collision course, including switching between burst and nonburst firing. In this study, we demonstrate that the LGMD neuron exhibits a large M current, generated by noninactivating K+ channels, that shortens the temporal window of dendritic integration, regulates a firing mode switch between burst and isolated spiking, increases the precision of spike timing, and increases the reliability of spike propagation to downstream motor centers. By revealing how the M current increases the LGMD’s ability to detect impending collisions, our results suggest that similar channels may play an analogous role in other collision detection circuits. NEW & NOTEWORTHY The ability to reliably detect impending collisions is a critical survival skill. The nervous systems of many animals have developed dedicated neurons for accomplishing this task. We used a mix of in vivo electrophysiology and computational modeling to investigate the role of M potassium channels within one such collision-detecting neuron and show that through regulation of burst firing and enhancement of spiking reliability, the M current increases the ability to detect impending collisions.

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Findlay, Andrew R., Rocio Bengoechea, Sara K. Pittman, Tsui-Fen Chou, Heather L. True und Conrad C. Weihl. „Lithium chloride corrects weakness and myopathology in a preclinical model of LGMD1D“. Neurology Genetics 5, Nr. 2 (April 2019): e318. http://dx.doi.org/10.1212/nxg.0000000000000318.

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ObjectiveTo understand DNAJB6's function in skeletal muscle and identify therapeutic targets for limb-girdle muscular dystrophy 1D (LGMD1D).MethodsDNAJB6 knockout (KO) myoblasts were generated with Crispr/cas9 technology, and differentially accumulated proteins were identified using stable isotope labeling, followed by quantitative mass spectrometry. Cultured KO myotubes and mouse muscle from DNAJB6b-WT or DNAJB6b-F93L mice were analyzed using histochemistry, immunohistochemistry, and immunoblot. Mouse functional strength measures included forelimb grip strength and inverted wire hang.ResultsDNAJB6 inactivation leads to the accumulation of sarcomeric proteins and hypertrophic myotubes with an enhanced fusion index. The increased fusion in DNAJB6 KO myotubes correlates with diminished glycogen synthase kinase-β (GSK3β) activity. In contrast, LGMD1D mutations in DNAJB6 enhance GSK3β activation and suppress β-catenin and NFAT3c signaling. GSK3β inhibition with lithium chloride improves muscle size and strength in an LGMD1D preclinical mouse model.ConclusionsOur results suggest that DNAJB6 facilitates protein quality control and negatively regulates myogenic signaling. In addition, LGMD1D-associated DNAJB6 mutations inhibit myogenic signaling through augmented GSK3β activity. GSK3β inhibition with lithium chloride may be a therapeutic option in LGMD1D.

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Neudecker, S., M. Deschauer und M. Krasnianski. „Die Gliedergürtelmuskeldystrophie vom Typ 2I“. Nervenheilkunde 23, Nr. 08 (2004): 438–41. http://dx.doi.org/10.1055/s-0038-1626404.

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ZusammenfassungDie Gliedergürtelmuskeldystrophie von Typ 2I (LGMD2I) beruht auf Mutationen des »fukutin-related protein«-(FKRP-)Gens und folgt einem autosomal-rezessiven Erbgang. Der Großteil der europäischen Patienten mit LGMD2I weist eine Mutation in Exon 4 dieses Gens (C826A-Mutation) auf. Klinisch zeigt die Erkrankung eine ausgeprägte Variabilität, die von schweren, in der ersten Lebensdekade beginnenden und schnell progredienten Formen mit Paresen sowie Atrophien der Schultergürtel-und proximalen Extremitätenmuskulatur und Wadenhypertrophie bis zu Varianten mit spätem Beginn und mildem Verlauf reichen kann. Gelegentlich beschränkt sich die Erkrankung auf Myalgien, Kardiomyopathien oder HyperCKämie ohne manifeste Paresen. Die Diagnose der LGMD2I beruht allein auf dem molekulargenetischen Nachweis der Mutation im FKRP-Gen, da elektrophysiologische und myohistologische Untersuchungen keine krankheitsspezifischen Befunde ergeben. Aufgrund der Vielfalt der klinischen Manifestationen sollte die LGMD2I nicht nur in die Differenzialdiagnose der Gliedergürtelsyndrome, sondern auch der HyperCKämie, Myalgien, Krampi und Kardiomyopathien aufgenommen werden.

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San Millan, B., S. Ortolano, S. Teijeira, J. Gamez, A. Andreu, R. Marti und C. Navarro. „LGMD1F: A morphological study“. Neuromuscular Disorders 25 (Oktober 2015): S236. http://dx.doi.org/10.1016/j.nmd.2015.06.186.

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Renard, Dimitri, Carla Fernandez, Celine Bouchet-Seraphin und Pierre Labauge. „Cortical heterotopia in LGMD2I“. Neuromuscular Disorders 22, Nr. 5 (Mai 2012): 443–44. http://dx.doi.org/10.1016/j.nmd.2011.11.005.

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Richard, I., L. Brenguier, B. Bady, M. Fardeau, C. A. Garcia, C. E. Jackson, D. M. Kurnit et al. „Survey of LGMD2A mutations“. Neuromuscular Disorders 6, Nr. 2 (März 1996): S9. http://dx.doi.org/10.1016/0960-8966(96)88964-4.

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