scholarly journals Transcriptome analysis of collagen VI‐related muscular dystrophy muscle biopsies

2021 ◽  
Author(s):  
Eleonora Guadagnin ◽  
Payam Mohassel ◽  
Kory R. Johnson ◽  
Lin Yang ◽  
Mariarita Santi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Transcriptome Analysis ◽  
Collagen Vi ◽  
Muscle Biopsies

scholarly journals Muscle Protein Alterations in LGMD2I Patients With Different Mutations in the Fukutin-related Protein Gene

2008 ◽  
Vol 56 (11) ◽  
pp. 995-1001 ◽  
Author(s):  
Lydia U. Yamamoto ◽  
Fernando J. Velloso ◽  
Bruno L. Lima ◽  
Luciana L.Q. Fogaça ◽  
Flávia de Paula ◽  
...  
Keyword(s):  
Muscle Protein ◽  
Congenital Muscular Dystrophy ◽  
Clinical Severity ◽  
Variable Degree ◽  
Related Protein ◽  
Collagen Vi ◽  
Rimmed Vacuoles ◽  
Calpain 3 ◽  
Protein Alterations ◽  
Muscle Biopsies

Fukutin-related protein (FKRP) is a protein involved in the glycosylation of cell surface molecules. Pathogenic mutations in the FKRP gene cause both the more severe congenital muscular dystrophy Type 1C and the milder Limb-Girdle Type 2I form (LGMD2I). Here we report muscle histological alterations and the analysis of 11 muscle proteins: dystrophin, four sarcoglycans, calpain 3, dysferlin, telethonin, collagen VI, α-DG, and α2-laminin, in muscle biopsies from 13 unrelated LGMD2I patients with 10 different FKRP mutations. In all, a typical dystrophic pattern was observed. In eight patients, a high frequency of rimmed vacuoles was also found. A variable degree of α2-laminin deficiency was detected in 12 patients through immunofluorescence analysis, and 10 patients presented α-DG deficiency on sarcolemmal membranes. Additionally, through Western blot analysis, deficiency of calpain 3 and dystrophin bands was found in four and two patients, respectively. All the remaining proteins showed a similar pattern to normal controls. These results suggest that, in our population of LGMD2I patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions, and the deficiencies of α2-laminin and α-DG on sections are prevalent, independently of mutation type or clinical severity.

scholarly journals Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (21) ◽  
pp. e2270-e2282 ◽  
Author(s):  
Diane E. Frank ◽  
Frederick J. Schnell ◽  
Cody Akana ◽  
Saleh H. El-Husayni ◽  
Cody A. Desjardins ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Western Blot ◽  
Exon Skipping ◽  
Study Drug ◽  
Dose Titration ◽  
Open Label ◽  
Double Blind ◽  
Dystrophin Protein ◽  
Muscle Biopsies

ObjectiveTo report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.MethodsPart 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.ResultsTwelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%–4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.ConclusionGolodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.Clinicaltrials.gov identifierNCT02310906.Classification of evidenceThis study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

Transportin 3 (TNPO3) and related proteins in limb girdle muscular dystrophy D2 muscle biopsies: A morphological study and pathogenetic hypothesis

2020 ◽  
Vol 30 (8) ◽  
pp. 685-692
Author(s):  
Roberta Costa ◽  
Maria Teresa Rodia ◽  
Sara Vianello ◽  
Spartaco Santi ◽  
Giovanna Lattanzi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Morphological Study ◽  
Limb Girdle Muscular Dystrophy ◽  
Related Proteins ◽  
Muscle Biopsies

scholarly journals Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

2019 ◽  
Vol 5 (2) ◽  
pp. e315 ◽  
Author(s):  
Angela J. Lee ◽  
Karra A. Jones ◽  
Russell J. Butterfield ◽  
Mary O. Cox ◽  
Chamindra G. Konersman ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Founder Mutation ◽  
Congenital Muscular Dystrophy ◽  
Clinical Severity ◽  
Muscle Pathology ◽  
Clinical Genetic ◽  
End Stage ◽  
Muscle Biopsies ◽  
Normal Cognition

ObjectiveTo characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation.MethodsStandardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA.ResultsWe report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous FKRP c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy.ConclusionsThe clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200–1,500 years).

scholarly journals Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy

EBioMedicine ◽  
2017 ◽  
Vol 15 ◽  
pp. 193-202 ◽  
Author(s):  
Satoru Noguchi ◽  
Megumu Ogawa ◽  
May Christine Malicdan ◽  
Ikuya Nonaka ◽  
Ichizo Nishino
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Weakness ◽  
Congenital Muscular Dystrophy ◽  
Collagen Vi

scholarly journals Laminin α2 Deficiency-Related Muscular Dystrophy Mimicking Emery-Dreifuss and Collagen VI related Diseases

2015 ◽  
Vol 2 (3) ◽  
pp. 229-240 ◽  
Author(s):  
Isabelle Nelson ◽  
Tanya Stojkovic ◽  
Valérie Allamand ◽  
France Leturcq ◽  
Henri-Marc Bécane ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Collagen Vi ◽  
Laminin Α2

Unusual clinical presentation of dystrophin-deficient feline muscular dystrophy in the UK

2020 ◽  
Vol 8 (1) ◽  
pp. e000983
Author(s):  
Aldara Eiras-Diaz ◽  
Francesco Prisco ◽  
Orlando Paciello ◽  
Katie Waine ◽  
Kerstin Baiker ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Differential Diagnosis ◽  
Muscular Dystrophy ◽  
Alanine Aminotransferase ◽  
Clinical Presentation ◽  
Postmortem Examination ◽  
Short Hair ◽  
Recent Onset ◽  
The Uk ◽  
Muscle Biopsies

An eight-month-old, male, neutered, domestic short hair cat was presented for further investigation of white granuloma-like lesions on the tongue and recent onset regurgitation. The owner reported that the cat had an ‘unusual’ gait. Moderate increases in alanine aminotransferase, aspartate aminostransferase and markedly elevated creatine kinase were present. Thoracic radiographs revealed moderate-to-severe oesophageal impaction, cardiomegaly and an irregular appearance of the diaphragm. Endoscopy revealed a distended oesophagus with accumulation of ingesta. Difficulties were encountered when passing the endoscope through the cardia. Histology of the white granuloma-like lesions were pathognomonic of calcinosis circumscripta. These features raised the suspicion of feline muscular dystrophy. Muscle biopsies and electromyography were declined, and the patient was euthanased. Postmortem examination, histopathology and immunohistochemistry were suggestive of dystrophin-deficient muscular dystrophy (DDMD). This case emphasises the importance of including DDMD as a differential diagnosis for regurgitation and lingual calcinosis circumscripta in cats.

scholarly journals Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach

2007 ◽  
Vol 65 (1) ◽  
pp. 73-76 ◽  
Author(s):  
Aline Andrade Freund ◽  
Rosana Herminia Scola ◽  
Raquel Cristina Arndt ◽  
Paulo José Lorenzoni ◽  
Claudia Kamoy Kay ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscular Atrophy ◽  
Hot Spot ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Congenital Myopathy ◽  
Specific Method ◽  
Dystrophin Deficiency ◽  
Muscle Biopsies ◽  
Female Carriers

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains). The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.

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