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Biomarker for Patients With Duchenne Disease
study id #: NCT02994030
condition: Red-green Color Defect, Increased Lordosis/Scoliosis, Hyporeflexia
Patients with Duchenne disease or high-grade suspicion for Duchenne disease
mechanism of action: No pharmaceutical intervention
last updated: March 14, 2019
start date: August 20, 2018
estimated completion: July 2021
size / enrollment: 1000
Duchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. It is usually recognized between three and six years of age. DMD is characterized by weakness and wasting (atrophy) of the muscles of the pelvic area followed by the involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles of the body. In addition, the calves appear enlarged in most patients. The disease is progressive and most affected individuals require a wheelchair by the teenage years. Serious life-threatening complications may ultimately develop including disease of the heart muscle (cardiomyopathy) and breathing (respiratory) difficulties.
DMD is caused by changes (mutations) of the DMD gene on the X chromosome. The gene regulates the production of a protein called dystrophin that is found in association with the inner side of the membrane of skeletal and cardiac muscle cells. Dystrophin is thought to play an important role in maintaining the membrane (sarcolemma) of muscle cells.
Muscular dystrophies are characterized by specific abnormalities (e.g. variation of muscle fiber size, muscle fiber necrosis, scar tissue formation and inflammation) in muscle biopsy from the patients. Approximately 30 different genetic conditions make up the muscular dystrophies. DMD is classified as a dystrophinopathy. The dystrophinopathies are a spectrum of muscle diseases, each caused by alterations in the dystrophin gene. The most severe end of the spectrum is known as Duchenne muscular dystrophy lacking completely dystrophin protein. Decreased or truncated dystrophin protein is associated with less severe form is Becker muscular dystrophy.
DMD usually becomes apparent early during childhood. Affected children develop weakness and wasting (atrophy) of the muscles closest to the trunk (proximal muscles) such as those of the upper legs and pelvic area and upper arms and shoulder area. However, a few other muscles appear disproportionally bulky. As the disease progresses, muscle weakness and atrophy spread to affect the lower legs, forearms, neck and trunk. The rate of progression is quite similar from person to person but individual variation may happen.
In children with DMD, initial findings may include delays in reaching developmental mile-stones such as sitting or standing without assistance; toe walking; an unusual, waddling manner of walking (gait); difficulty climbing stairs or rising from a sitting position (Gower's sign); and repeated falling. Toddlers and young children may seem awkward and clumsy and may exhibit abnormal enlargement of the calves due to scarring of muscles (pseudo-hypertrophy). As the disease progresses, additional abnormalities may develop such as progressive curvature of the spine (scoliosis or lordosis), wasting of thigh and pectoral muscles, and abnormal fixation of certain joints (contractures). A contracture occurs when thickening and shortening of tissue such as muscle fibers causes deformity and restricts movement of affected areas, especially the joints. Without physical therapy treatment, leg braces may be needed by age 8-9 to assist affected individuals to walk. By approximately ages 10 to 12, most affected individuals require a wheelchair.
Children with DMD have reduced bone density and an increased risk of developing fractures of certain bones, such as hips and spine. Many affected individuals will display mild to moderate degrees of non-progressive intellectual impairment and learning disabilities.
By the late teens, DMD may also be characterized by additional potentially life-threatening complications including weakness and deterioration of the heart muscle (cardiomyopathy). Cardiomyopathy can result in impairment in the ability of the heart to pump blood, irregular heartbeats (arrhythmias), and heart failure. Another serious complication associated with DMD is weakness and deterioration of muscles in the rib cage. This can result in an in-creased susceptibility to respiratory infections (e.g., pneumonia), difficulty coughing, and, ultimately, respiratory failure.
Involvement of muscles within the gastrointestinal tract may result in dysmotility, a condition in which the passage of food through the digestive tract usually because of slow and uncoordinated movements of the muscles of the digestive tract. Gastrointestinal dysmotility may result in constipation and diarrhea.
DMD is inherited as an X-linked disease. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
DMD is caused by mutations of the DMD gene located on the short arm (p) of the X chromosome (Xp21.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y.
The DMD gene regulates (encodes for) the production of dystrophin, a protein that appears to play an essential role in maintaining the integrity of cell membrane in skeletal (voluntary) and cardiac muscle cells. Dystrophin is found attached to the inner side of the membrane that surrounds muscle fibers. Mutation of the DMD gene will result in absence of the dystrophin protein, leading to degeneration of muscle fibers. The body can replace (regenerate) some muscle fibers, but over time more and more muscle fiber is lost. Such degeneration leads to the symptoms and findings associated with DMD. In Becker muscular dystrophy, a related disorder, dystrophin is present, but it is truncated or only present in insufficient levels to properly perform its functions.
DMD is the most common childhood onset form of muscular dystrophy and affects males almost exclusively. The prevalence is estimated to be 1 in every 3,500 live male births. Age of onset is usually between 3 and 5 years of age.
Symptoms of the following disorders can be similar to those of DMD. Comparisons may be useful for a differential diagnosis.
Becker muscular dystrophy is in the category of inherited muscle wasting diseases caused by gene abnormalities (mutations) that result in deficient or abnormal production of the dystrophin protein (dystrophinopathies). The abnormal gene is the same as for DMD and is located on the X chromosome. Becker muscular dystrophy also follows X-linked inheritance so it mostly affects males, but some female carriers are affected. Becker muscular dystrophy usually begins in the teens or early twenties, but can begin as late as the six-ties and symptoms vary greatly between affected individuals. Muscle weakness and deterioration progress slowly but usually results in the need for a wheelchair. Muscles of the heart deteriorate (cardiomyopathy) in some affected individuals more seriously than the skeletal muscles of the body, and this process can become life threatening potentially causing heart failure. Learning disabilities involving visual abilities may be present but rarely. In Becker muscular dystrophy, dystrophin levels are reduced where in DMD they are absent or nearly absent. Consequently, the symptoms of these two disorders are similar, but most cases of Becker muscular dystrophy are less severe. (For more information on this disorder, choose "Becker" as your search term in the Rare Disease Database.) Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive genetic disorder affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of the clinical trial of weakness and degeneration (atrophy) of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy) in mainly adults. Major symptoms may include muscle wasting and weakness particularly in arms and lower legs (humeroperoneal regions) and contractures of the elbows, Achilles tendons, and upper back muscles. In some patients, additional abnormalities may be present. In most cases, EDMD is inherited as an X-linked or autosomal dominant trait. In extremely rare cases, autosomal recessive inheritance has been reported. Although EDMD has different modes of inheritance, the symptoms are nearly the same. (For more information on this disorder, choose "Emery Dreifuss" as your search term in the Rare Disease Database.) Limb-girdle muscular dystrophy (LGMD) is a general term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disease; other may have a rapidly progressive form that may cause severe disability. The various forms of LGMDs can now be distinguished by genetic and/or protein analysis. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMDA-E). Autosomal recessive LGMD is known as LGMD2 and has 10 subtypes (LGMDA-J). (For more information on this disorder, choose "limb-girdle muscular dystrophy" as your search term in the Rare Disease Database.) Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (lower motor neurons) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose "spinal muscular atrophy" as your search term in the Rare Disease Database.) A diagnosis of DMD is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests including molecular genetic tests. If the genetic tests are not informative, surgical removal and microscopic examination (biopsy) of affect-ed muscle tissue that may reveal characteristic changes to muscle fibers. Specialized blood tests (e.g. creatine kinase) that evaluate the presence and levels of certain proteins in muscle (immunohistochemistry) are also used.
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.
• 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 gender younger than 2 months
• No diagnosis of Duchenne disease or no valid criteria for profound suspicion of Duchenne disease
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