Clinical aspects of patients with sarcoglycanopathies under steroids therapy

Albuquerque, Marco Antônio Veloso; Abath-Neto, Osório; Maximino, Jéssica Ruivo; Chadi, Gerson; Zanoteli, Edmar; Reed, Umbertina Conti

doi:10.1590/0004-282x20140126

Cited by 10 publications

(6 citation statements)

References 23 publications

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“…On the other hand, providing differential diagnosis to the 17 individuals with other forms of MDs was also useful to determine the suitable standard of care and eligibility on gene-transfer therapies. They were prevented from a corticosteroid treatment, as for these diseases there is still no strong evidence for its efficacy ( Walter et al, 2013 ; Albuquerque et al, 2014 ). Furthermore, six of them could already be determined as candidates for gene-transfer therapies that are under preclinical or clinical tests.…”

Section: Discussionmentioning

confidence: 99%

“…Accurate molecular diagnosis, given by the identification and precise characterization of deleterious variants, is crucial for dystrophinopathy patients to confirm the clinical presumptive diagnosis, to access to the specific and optimal standard of care ( Bushby et al, 2010 ) and determine eligibility for the available pharmacogenetic treatments. For example, molecular confirmation of dystrophinopathy determines applicability of corticosteroid therapy, as DMD is one of the MDs showing fruitful results from this treatment ( Albuquerque et al, 2014 ; Bello et al, 2015 ). On the other hand, molecular diagnosis plays a key role in family planning and, therefore, prevention.…”

Section: Introductionmentioning

confidence: 99%

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Theragnosis for Duchenne Muscular Dystrophy

et al. 2021

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Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA’s metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Theragnosis for Duchenne Muscular Dystrophy

et al. 2021

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“…LGMD type 2E/R4 (LGMD2E/R4) is caused by mutations in the β-sarcoglycan gene ( SGCB ), leading to β-sarcoglycan (SGCB) protein deficiency and loss of sarcoglycan complex formation and preventing dystrophin-associated protein complex (DAPC) stabilization 4 , 5 . This loss of protein function manifests clinically in early childhood or late adolescence and progresses to loss of ambulation, potential respiratory insufficiency and often premature mortality 6 – 8 .…”

Section: Mainmentioning

confidence: 99%

Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results

Mendell,

Pozsgai,

Lewis

et al. 2024

Nat Med

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Limb-girdle muscular dystrophy 2E/R4 is caused by mutations in the β-sarcoglycan (SGCB) gene, leading to SGCB deficiency and consequent muscle loss. We developed a gene therapy approach based on functional replacement of the deficient SCB protein. Here we report interim results from a first-in-human, open-label, nonrandomized, phase 1/2 trial evaluating the safety and efficacy of bidridistrogene xeboparvovec, an adeno-associated virus-based gene therapy containing a codon-optimized, full-length human SGCB transgene. Patients aged 4–15 years with confirmed SGCB mutations at both alleles received one intravenous infusion of either 1.85 × 1013 vector genome copies kg−1 (Cohort 1, n = 3) or 7.41 × 1013 vector gene copies kg−1 (Cohort 2, n = 3). Primary endpoint was safety, and secondary endpoint was change in SGCB expression in skeletal muscle from baseline to Day 60. We report interim Year 2 results (trial ongoing). The most frequent treatment-related adverse events were vomiting (four of six patients) and gamma-glutamyl transferase increase (three of six patients). Serious adverse events resolved with standard therapies. Robust SGCB expression was observed: Day 60 mean (s.d.) percentage of normal expression 36.2% (2.7%) in Cohort 1 and 62.1% (8.7%) in Cohort 2. Post hoc exploratory analysis showed preliminary motor improvements using the North Star Assessment for Limb-girdle Type Muscular Dystrophies maintained through Year 2. The 2-year safety and efficacy of bidridistrogene xeboparvovec support clinical development advancement. Further studies are necessary to confirm the long-term safety and efficacy of this gene therapy. ClinicalTrials.gov registration: NCT03652259.

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“…Siblings with SGCA-related LGMD received deflazacort for 6 months and showed improved muscle strength and functional assessments [12]. A small retrospective study of 6 patients with LGMD on steroids for at least one year reported conflicting results [13].…”

Section: Introductionmentioning

confidence: 99%

An Open Label Exploratory Clinical Trial Evaluating Safety and Tolerability of Once-Weekly Prednisone in Becker and Limb-Girdle Muscular Dystrophy

Zelikovich

Joslin

Casey

et al. 2022

JND

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Background: Glucocorticoid steroids are standard of care in Duchenne Muscular Dystrophy (DMD) to slow disease course. Use of glucocorticoids in other muscular dystrophies, including Becker (BMD) and Limb Girdle (LGMD), has been less explored. Recently, preclinical studies conducted in DMD and LGMD mouse models showed once-weekly prednisone was associated with improved muscle performance without activation of muscle atrophy genes. Objective: To determine safety and tolerability of once-weekly prednisone in patients with LGMD and BMD. Methods: We conducted an open label, exploratory single center study of of once-weekly prednisone at 0.75–1 mg/Kg in LGMD (n = 19) and BMD (n = 1) (mean age 35, range 18–60). The LGMD participants represented multiple different LGMD subtypes, and the study included ambulatory and non-ambulatory participants. Participants were assessed at baseline and 24 weeks for vital signs, blood biomarkers, and for patient-reported side effects. As secondary endpoints, functional muscle testing and body composition were measured. Results: Over the 24-week study, there were no significant changes in blood pressure, HgbA1C, or lipid profiles. We observed a reduction in serum creatine kinase over the study interval. Whole body DEXA scanning suggested a possible increase in lean mass and a reduction in adiposity. Functional measures suggested trends in improved muscle performance. Conclusions: In this single center, open label pilot study, once-weekly prednisone was safe and well tolerated. Additional investigation of once-weekly prednisone in a larger cohort and for a longer period of time is warranted.

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Clinical aspects of patients with sarcoglycanopathies under steroids therapy

Cited by 10 publications

References 23 publications

Theragnosis for Duchenne Muscular Dystrophy

Theragnosis for Duchenne Muscular Dystrophy

Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results

An Open Label Exploratory Clinical Trial Evaluating Safety and Tolerability of Once-Weekly Prednisone in Becker and Limb-Girdle Muscular Dystrophy

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