Duchenne muscular dystrophy (DMD) is a progressive genetic disorder characterized by muscle degeneration and weakness, primarily affecting boys. It is caused by mutations in the DMD gene, which provides instructions for making the dystrophin protein, which maintains muscle fiber integrity. Diagnosis involves observing physical signs, conducting non-invasive blood tests, and culminating in definitive genetic analysis. This approach allows for timely intervention and management.
Recognizing the Early Indicators
The diagnostic process begins by recognizing subtle clinical signs suggesting a muscle disorder. Parents and pediatricians often first notice a delay in achieving motor milestones. This might include not walking until around 18 months of age or having difficulty keeping up with peers during physical activities.
These early indicators progress to specific signs of muscle weakness, particularly in the hip and thigh muscles. Children may struggle with movements such as running, jumping, or climbing stairs. A frequent tendency to fall or a waddling gait is often noticeable during the preschool years.
One characteristic sign is the Gower’s maneuver, where a child uses their hands to “walk” up their own legs to achieve a standing position. This maneuver reflects significant weakness in the proximal muscles of the lower body. Another common sign is pseudohypertrophy, an apparent enlargement of the calf muscles caused by muscle tissue being replaced by fat and connective tissue.
Initial Diagnostic Screening with Biomarkers
If DMD is suspected based on clinical observations, the next step is a simple blood test to measure Creatine Kinase (CK) levels. CK is an enzyme normally residing inside muscle cells. When muscle tissue is damaged, CK leaks into the bloodstream, making it a reliable biomarker for muscle injury.
In boys with DMD, CK levels are typically elevated, often ranging from 10 to 200 times the upper limit of the normal range. These high levels indicate significant, ongoing muscle damage, even before obvious symptoms appear. The elevation suggests that the weakness is originating in the muscles rather than the nerves. CK levels usually peak around age two and then gradually decline as muscle mass is replaced by scar tissue and fat later in the disease progression.
While an elevated CK level strongly indicates a muscular disorder, it is not conclusive for DMD, as other conditions can also cause high CK. Therefore, a positive CK screen necessitates moving immediately to genetic testing. This biomarker analysis confirms the presence of muscle breakdown and prompts further investigation.
Definitive Genetic Analysis
The definitive diagnosis of Duchenne muscular dystrophy is achieved through genetic testing, identifying a mutation in the large DMD gene located on the X chromosome. This gene contains 79 exons, and mutations prevent the production of functional dystrophin protein. The majority of DMD cases (approximately 60% to 80%) are caused by a large deletion or duplication of one or more exons within the gene.
The primary initial method for detecting these large changes is Multiplex Ligation-dependent Probe Amplification (MLPA). MLPA rapidly and accurately assesses the copy number of all 79 exons, revealing if any are missing (deletion) or duplicated. Because deletions are the most common type of mutation, MLPA is highly effective as a first-line genetic test.
If the MLPA test is negative for deletions or duplications, but clinical suspicion remains high, sequencing the entire DMD gene is necessary. About 20% of cases are caused by smaller changes, such as point mutations or small insertions, which MLPA cannot detect. Techniques like Sanger sequencing or Next-Generation Sequencing (NGS) are used to scan the gene for these subtle mutations.
Once a pathogenic mutation in the DMD gene is identified, the diagnosis is confirmed, regardless of the CK level or the severity of symptoms. Genetic testing is crucial not only for diagnosis but also for determining eligibility for mutation-specific therapies and for genetic counseling regarding inheritance and future family planning.