Congenital hydrocephalus secondary to Walker-Warburg syndrome identified on the Manitoba Neonatal Screening Programme for Duchenne muscular dystrophy.
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ABSTRACT:
SUBMITTER: Greenberg CR
PROVIDER: S-EPMC1016068 | biostudies-other | 1992 Aug
REPOSITORIES: biostudies-other
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Congenital hydrocephalus secondary to Walker-Warburg syndrome identified on the Manitoba Neonatal Screening Programme for Duchenne muscular dystrophy.
Greenberg C R CR Jacobs H K HK Nylen T E TE Gibb M M Chodirker B N BN Moffatt M M Lacson A A Halliday W W Bernier F F el-Husseini A A
Journal of medical genetics 19920801 8
This report describes our first experience with a clinically important true false positive neonatal screening test for Duchenne muscular dystrophy (DMD). Neonatal screening for DMD began as a pilot programme in Manitoba on 1 January 1986 by analysis of creatine kinase (CK) activity in dried filter paper blood spots. To date, all except two males with positive initial and follow up neonatal CK screening tests were subsequently diagnosed as having DMD. Of these two, one was a newborn male with con ...[more]
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Project description: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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Project description:The phenotypes associated with pathogenic variants in the ryanodine receptor 1 gene (RYR1, OMIM# 180901) have greatly expanded over the last few decades as genetic testing for RYR1 variants has become more common. Initially described in association with malignant hyperthermia, pathogenic variants in RYR1 are typically associated with core pathology in muscle biopsies (central core disease or multiminicore disease) and symptomatic myopathies with symptoms ranging from mild weakness to perinatal lethality. We describe a 2-week-old male patient with multiple congenital dysmorphisms, severe perinatal weakness, and subsequent demise, whose histopathology on autopsy was consistent with congenital muscular dystrophy. Immunohistochemical analysis of dystrophy-associated proteins was normal. Rapid exome sequencing revealed a novel heterozygous nonsense variant (p.Trp661Ter) in RYR1, as well as a previously described RYR1 pathogenic variant associated with congenital myopathy (p.Phe4976Leu). This highlights the potential for RYR1 pathogenic variants to produce pathological findings most consistent with congenital muscular dystrophy.
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Project description:Dystrophin deficiency results in lethal Duchenne muscular dystrophy (DMD). Substituting missing dystrophin with abbreviated microdystrophin has dramatically alleviated disease in mouse DMD models. Unfortunately, translation of microdystrophin therapy has been unsuccessful in dystrophic dogs, the only large mammalian model. Approximately 70% of the dystrophin-coding sequence is removed in microdystrophin. Intriguingly, loss of ?50% dystrophin frequently results in severe disease in patients. To test whether the small gene size constitutes a fundamental design error for large mammalian muscle, we performed a comprehensive study using 22 dogs (8 normal and 14 dystrophic). We delivered the ?R2-15/?R18-19/?R20-23/?C microdystrophin gene to eight extensor carpi ulnaris (ECU) muscles in six dystrophic dogs using Y713F tyrosine mutant adeno-associated virus (AAV)-9 (2.6 × 10(13) viral genome (vg) particles/muscle). Robust expression was observed 2 months later despite T-cell infiltration. Major components of the dystrophin-associated glycoprotein complex (DGC) were restored by microdystrophin. Treated muscle showed less inflammation, fibrosis, and calcification. Importantly, therapy significantly preserved muscle force under the stress of repeated cycles of eccentric contraction. Our results have established the proof-of-concept for microdystrophin therapy in dystrophic muscles of large mammals and set the stage for clinical trial in human patients.
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Project description:We developed a novel somite-based step-wise strategy for the efficient derivation of functional human myocytes, suggesting that past failures were due to incomplete specification. Treatment with two small molecules inhibiting glycogen synthase kinase 3β (GSK-3β) and the Notch signaling pathway in undifferentiated hPSCs results in the formation of somite-like cells by Day 4 and, subsequently contractile myotubes in vitro around Day 25 with the ability to engraft and actively participate in muscle repair in vivo. Antibody-based purification can enrich homogenous myocyte populations exhibiting genuine myogenic molecular and cellular characteristics, including extraocular muscle-like features. Furthermore, hPSCs derived from patients with multiple neuromuscular diseases successfully give rise to patient-specific skeletal muscle cells bearing signature phenotypes. Human embryonic stem cell were differentiated to skeletal muscle and compared to non-differentiated cells in triplicate biological replicates. For the confirmation of differentiated cell's characteristics and the global mRNA profiles, We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Further more, we used microarrys for the comparing control and disease gene expression profiles, again in triplicate.
2016-06-16 | E-GEOD-70955 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed.
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Project description:Duchenne muscular dystrophy (DMD) represents one of the most devastating types of muscular dystrophies which affect boys already at early childhood. Despite the fact that the primary cause of the disease, namely the lack of functional dystrophin is known already for more than 30 years, DMD still remains an incurable disease. Thus, an enormous effort has been made during recent years to reveal novel mechanisms that could provide therapeutic targets for DMD, especially because glucocorticoids treatment acts mostly symptomatic and exerts many side effects, whereas the effectiveness of genetic approaches aiming at the restoration of functional dystrophin is under the constant debate. Taking into account that dystrophin expression is not restricted to muscle cells, but is present also in, e.g., endothelial cells, alterations in angiogenesis process have been proposed to have a significant impact on DMD progression. Indeed, already before the discovery of dystrophin, several abnormalities in blood vessels structure and function have been revealed, suggesting that targeting angiogenesis could be beneficial in DMD. In this review, we will summarize current knowledge about the angiogenesis status both in animal models of DMD as well as in DMD patients, focusing on different organs as well as age- and sex-dependent effects. Moreover, we will critically discuss some approaches such as modulation of vascular endothelial growth factor or nitric oxide related pathways, to enhance angiogenesis and attenuate the dystrophic phenotype. Additionally, we will suggest the potential role of other mediators, such as heme oxygenase-1 or statins in those processes.
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Project description:Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile.Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings.Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis and decreasing oxidative stress. Additional targets include inhibiting NF-?B to reduce inflammation or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect.
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