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Biomarker for Duchenne Disease (BIODUCHENNE)
study id #: NCT02994030
condition: Increased Lordosis/Scoliosis, Hyporeflexia, Duchenne Muscular Dystrophy, Red-Green Color Blindness, Lordosis, Scoliosis, Muscular Atrophy, Muscular Weakness
Development of a new mass spectrometry-based biomarker for the early and sensitive diagnosis of Duchenne Muscular Dystrophy from dry-blood spot sample
mechanism of action: No pharmaceutical intervention
last updated: February 25, 2020
start date: August 20, 2018
estimated completion: July 2021
phase of development: N/A
size / enrollment: 1000
The dystrophinopathies cover a spectrum of X-linked muscle diseases, from mild to severe forms, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy and DMD-associated dilated cardiomyopathy.
Becker muscular dystrophy is a milder version of DMD. Its onset is usually in the teens or early adulthood, and the course is slower and less predictable than that of DMD.
DMD-associated dilated cardiomyopathy is characterized by left ventricular dilatation and congestive heart failure.
DMD can present as early as age 3 years with muscle weakness, and it is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all patients affected after 18 years.
DMD is the most common inherited neuromuscular disorder of childhood and mainly affects males.
Prevalence of DMD in France and UK is 10.9 and 2.2 per 100,000 males respectively. The incidence of DMD in Canada (Nova Scotia) is one in 4.700 live male births, and one in 3.917 live male births in southeast Norway.
Females are usually asymptomatic but a small percentage of female carriers manifest milder forms of the disease.
Few patients survive beyond the third decade, with respiratory and cardiac complications being common causes of death.
DMD is caused by deletions in the DMD gene (chromosome Xp21) in 60-65% of patients, by duplications in 5-10%, and by point mutations or small rearrangements in the remaining 20-30%.
If a pathogenic variant is identified, the diagnosis of a dystrophinopathy is established, but the distinction between DMD and Becker muscular dystrophy can be difficult in some cases.
Alterations of DMD gene, and transmitted in an X-linked recessive fashion, result in a deficiency of the sarcolemmal protein dystrophin.
Dystrophin protein is extremely long and bridges the inner cell cytoskeleton and a variety of proteins at the cell membrane and extracellular matrix, transferring the force of muscle contraction from the inside of the muscle cell to the periphery. Lack of the dystrophin protein in muscle cells causes them to be fragile and easily damaged. In this case, fibrous tissue begins to form in muscle and the immune system increases inflammation.
Apart from the full-length dystrophin, four shorter proteins are transcribed from the DMD gene: Dp260 (transcripts spliced to exon 30), Dp140 (transcripts spliced to exon 44), Dp116 (transcripts spliced to exon 56), and Dp71 (transcripts spliced to exon 63). Dp260 and Dp71 are expressed in the retina.
Patients affected with DMD present a progressive symmetric muscle weakness (more proximal than distal), often with calf hypertrophy, and delays in walking independently and standing up from the floor. Skeletal deformities as a lordosis or scoliosis may be present, as well as muscle cramps and myoglobinuria.
The incidence of cardiomyopathy increases in the teenage years: one third of patients show cardiac involvement by age 14 and all of them after 18 years.
DMD is associated with a decreased bone density and increased risk of fractures due to the reduced mobility of individuals affected.
Cognitive impairment has been described, and 44% of patients can have learning disabilities.
In addition, red-green color vision defect is highly prevalent (40%) in patients with DMD deletions of exon 30.
Few patients survive beyond the third decade. Respiratory and cardiac failures, as well as lung infections, are common causes of death.
The distinction between DMD and Becker muscular dystrophy is based on the age of wheelchair dependency: DMD patients need a wheelchair before age 13 and Becker muscular dystrophy patients after 16.
After a muscle biopsy, histological findings can be small atrophic fibers with large and rounded shape, necrosis and regeneration, increased endomysial fibrosis, fatty replacement of muscle, and sometimes inflammation signs.
Diagnosis of DMD is established after clinical suspicious (clinical symptoms and elevated creatine phosphokinase concentration in plasma) and a hemizygous pathogenic variant in DMD gene.
The multidisciplinary management of DMD includes physical and respiratory therapy, orthopedic procedures, wheelchair use, pharmacological treatment of heart failure (angiotensin II-receptor blockers, beta-receptor blockers, angiotensin convertor enzyme inhibitors, or digoxin), and corticosteroid therapy.
Specific treatments showing some effect in DMD patients include: Idebenone, Ataluren, and Eteplirsen. Gene therapy or gene repair therapies are under investigation.
New methods, like mass-spectrometry, give a good chance to characterize specific metabolic alterations in the blood of affected patients, that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.
Therefore it is the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.
- Sequencing of the Duchenne Muscular Dystrophy disease related genes [ Time Frame: 4 weeks ]
Next-Generation Sequencing (NGS) of the DMD gene will be performed. The mutation will be confirmed by Sanger sequencing.
- The Duchenne Muscular Dystrophy disease specific biomarker candidates finding [ Time Frame: 24 months ]
The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.
• Eligible Sexes: all
• Informed consent will be obtained from the patient or the parents before any study related procedures
• Patients of both genders older than 2 months
• The patient has a diagnosis of Duchenne disease or a high-grade suspicion for Duchenne disease
• High-grade suspicion present, if one or more inclusion criteria are valid:
-Positive family anamnesis for Duchenne disease
-Red-green color defect of the Eyes
-Calf muscle pseudohypertrophy
• No Informed consent from the patient or the parents before any study related procedures
• Patients of both genders younger than 2 months
• No diagnosis of Duchenne disease or no valid criteria for profound suspicion of Duchenne disease
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