Proteins in the Urine Associated with Duchenne Muscular Dystrophy and other Neuromuscular Diseases

1981 ◽  
Vol 61 (2) ◽  
pp. 141-149 ◽  
Author(s):  
N. Frearson ◽  
R. D. Taylor ◽  
S. V. Perry
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Physical Disabilities ◽  
Protein Pattern ◽  
Neuromuscular Diseases ◽  
Two Dimensional Electrophoresis ◽  
Characteristic Features ◽  
Neuromuscular Conditions ◽  
Dimensional Electrophoresis ◽  
Healthy Persons

1. Up to 200 protein staining spots could be detected on two-dimensional electrophoresis of urine from healthy persons. Other minor spots were occasionally present. 2. Although the electropherograms exhibited constant characteristic features some variation in protein pattern was observed between individuals and with a given individual at different times. 3. Two additional proteins, spots C and D, were consistently present in urine from boys with Duchenne muscular dystrophy. Spot C was also present in the urine of about 60% of obligatory carriers of this dystrophy. 4. The protein responsible for spot C had a molecular weight of 26000 and an isoelectric point of 5.3. 5. Spot C was also detected in the urine of patients with other neuromuscular conditions. Neither spot C nor spot D could be detected in the urine of patients with physical disabilities other than those of neuromuscular origin. 6. It is concluded that the urinary excretion of spot C, and probably of spot D, is a consequence of muscle damage and that their detection has potential as a diagnostic tool.

Differential diagnosis of Duchenne muscular dystrophy

2021 ◽  
Vol 2 (3) ◽  
pp. 159-166
Author(s):  
Alexey L. Kurenkov ◽  
Lyudmila M. Kuzenkova ◽  
Lale A. Pak ◽  
Bella I. Bursagova ◽  
Tatyana V. Podkletnova ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Damage ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Neuromuscular Diseases ◽  
Muscular Dystrophies ◽  
Juvenile Form ◽  
Pathogenic Variants

Duchenne muscular dystrophy (DMD) is a disease with an X-linked recessive type of inheritance, belonging to a group of disorders with primary muscle damage, caused by pathogenic variants in the DMD gene and associated with dysfunction of the dystrophin protein. Since DMD is manifested by the gradual development of progressive, mainly proximal muscle weakness, the differential diagnosis is primarily carried out in the group of diseases with muscle damage - myopathies. Among these diseases, the leading candidates for differential diagnosis are hereditary myopathies (limb-girdle muscular dystrophies, facioscapulohumeral dystrophy, congenital muscular dystrophies, glycogenoses - the most common juvenile form of glycogenosis type II (Pompe disease)) and, much less often, congenital myopathies and other conditions of neuromuscular diseases). When conducting a differential diagnosis in a child with suspected DMD, the age of the onset of the disease, early initial clinical manifestations and the development of symptoms as they grow, genealogical analysis, laboratory tests (the level of creatine kinase, aspartate aminotransferase, alanine aminotransferase in blood serum), instrumental (electromyography, magnetic resonance imaging of the brain and muscles) and molecular genetics (polymerase chain reaction, multiplex ligation-dependent probe amplification, next-generation sequencing, Sanger sequencing, etc.) of studies, and in some cases, muscle biopsy data. Knowledge of the nuances of the differential diagnosis allows establishing a genetic diagnosis of DMD as early as possible, which is extremely important for the formation of the prognosis of the disease and the implementation of all available treatment methods, including pathogenetic therapy, and is also necessary for medical and genetic counselling of families with DMD patients.

scholarly journals Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy

2017 ◽  
Vol 114 (23) ◽  
pp. 6080-6085 ◽  
Author(s):  
Natassia M. Vieira ◽  
Janelle M. Spinazzola ◽  
Matthew S. Alexander ◽  
Yuri B. Moreira ◽  
Genri Kawahara ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Neuromuscular Diseases ◽  
Genetic Modifiers ◽  
Cardiorespiratory Failure ◽  
Transfer Protein ◽  
Phosphorylated Akt ◽  
Phosphatidylinositol Transfer Protein ◽  
Phosphatidylinositol Transfer ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN (DMD) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these “escaper” dogs revealed reduced expression of phosphatidylinositol transfer protein-α (PITPNA) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophin-deficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases.

scholarly journals First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases

2021 ◽  
pp. 183-190
Author(s):  
Laurent Servais ◽  
Eric Camino ◽  
Aude Clement ◽  
Craig M. McDonald ◽  
Jacek Lukawy ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Drug Development ◽  
Neuromuscular Diseases ◽  
European Medicines Agency ◽  
Motor Abilities ◽  
Stakeholder Perspective ◽  
Functional Outcome Measures ◽  
Multi Stakeholder ◽  
The Impact

<b><i>Background:</i></b> Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification. <b><i>Summary:</i></b> Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development.

scholarly journals An examination of heart proteins by two-dimensional electrophoresis.

1987 ◽  
Vol 33 (11) ◽  
pp. 2011-2018 ◽  
Author(s):  
E Gianazza ◽  
L Osio ◽  
G Grazioli ◽  
S Astrua-Testori ◽  
P G Righetti ◽  
...  
Keyword(s):  
Protein Pattern ◽  
Sodium Dodecyl ◽  
Individual Variability ◽  
Two Dimensional ◽  
Two Dimensional Electrophoresis ◽  
Cytoplasmic Proteins ◽  
Dilatative Cardiomyopathy ◽  
Nonionic Detergent ◽  
Control Organ ◽  
Dimensional Electrophoresis

Abstract We examined specimens from explanted human hearts by two-dimensional electrophoresis. The protocol selected includes: (a) solubilization of the sample in a urea-detergent mix; (b) charge fractionation in the presence of urea and nonionic detergent on a pH 4-10 immobilized pH gradient; (c) size fractionation on a polyacrylamide concentration gradient in the presence of sodium dodecyl sulfate; and (d) staining with silver nitrate. The method is sensitive enough for analysis of biopsies in the 1-3 mg range (wet tissue). We saw, for explanted hearts, variations in the protein pattern with the site of sample dissection. Results are presented for 11 explanted human hearts: one control organ and 10 pathological samples. The recorded pathologies included dilatative cardiomyopathy (six cases), valvulopathy (one case), ischemic cardiopathy (two cases), and graft rejection (one case). The patterns for whole extracts as well as for cytoplasmic proteins and myofibril components are compared. Extensive individual variability was observed both between control and pathological cases and among the abnormal samples.

scholarly journals New Perspectives on the Diagnosis and Management of Duchenne Muscular Dystrophy

2015 ◽  
Vol 10 (01) ◽  
pp. 73 ◽  
Author(s):  
Francesco Muntoni ◽  
Annemieke Aartsma-Rus ◽  
Eugenio Mercuri ◽  
Hanns Lochmüller ◽  
◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Patient Care ◽  
Neuromuscular Diseases ◽  
Test Reliability ◽  
Standards Of Care ◽  
Specialist Care ◽  
6Mwt Distance ◽  
Care And Treatment ◽  
The Impact

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disorder that occurs in around one in 5,000 male births. The prevalence of DMD is expected to rise due to improved standards of care and implementation of guidelines, leading to longer survival. Specialist genetic confirmation of a DMD diagnosis is typically followed by access to specialist care and treatment: the exact DMD-causing mutation should be identified because it can influence prognosis and identify patients eligible for treatment. Since the majority of patients has a deletion or duplication of one or more exons (~70 %), generally multiplex ligation-dependent probe amplification suffices to identify the mutation. Exon sequencing is performed to pick up small mutations (~30 %). Greater awareness of DMD is needed among healthcare professionals to enable earlier diagnosis, which would facilitate family planning, as well as patient care and treatment. In DMD patients who are still able to walk, the 6-minute walk test (6MWT) has been shown to be a valid measure of physical functioning and a predictor of disease progression, with high inter-test reliability. In a study of the natural history of DMD, change in 6MWT of around 30 metres has been indicated to be clinically relevant and clinically meaningful. DMD patients responded to treatment as shown by the improvement in the 6MWT score in the large multinational trial of the nonsense mutation readthrough agent, ataluren (Translarna™) 40 mg/kg/day, where treatment was associated with a 31.3 metres improvement on the 6MWT distance, after 48 weeks, compared with placebo. The Translational Research in Europe–Assessment & Treatment of Neuromuscular Diseases (TREAT-NMD) network was launched to provide an infrastructure to accelerate research and therapy development, increasing collaboration, improving patient care and helping to support ‘clinical trial readiness’. As such, the TREAT-NMD registry network is well placed to support further understanding of DMD and the impact of therapies that may be used over the long term, permitting a host of research questions to be explored.

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