What is the diagnostic approach for a pediatric male patient with progressive muscle weakness or developmental delays suspected of having Duchenne Muscular Dystrophy (DMD)?

Diagnostic Approach for Duchenne Muscular Dystrophy

In any male child with progressive muscle weakness, developmental delays, or unexplained elevated transaminases, immediately measure serum creatine kinase (CK) levels and proceed directly to genetic testing for dystrophin gene deletions/duplications if CK is elevated, as this detects approximately 95% of DMD mutations. 1, 2

Initial Clinical Recognition

Key Presenting Features

• Unexplained elevated transaminases (AST/ALT) are a classic presentation of DMD because these enzymes are produced by both liver and muscle cells, and this may be detected incidentally even in infants as young as 2 months 1, 3
• Gowers sign (using hands to "climb up" the legs when rising from floor) accompanied by waddling gait should trigger immediate DMD investigation, particularly in children under 5 years 4
• Developmental delays including delayed motor milestones such as sitting and crawling 2
• Proximal muscle weakness with calf pseudohypertrophy 5, 2

Critical Age Considerations

• In children less than 5 years of age, a normal muscle examination cannot completely exclude DMD 5
• A boy older than 10 years with normal muscle function is highly unlikely to have DMD 5
• Diagnosis is typically delayed until about 5 years of age when proximal weakness becomes apparent, but early diagnosis in infancy is possible and beneficial 3

Diagnostic Testing Algorithm

Step 1: Creatine Kinase Measurement

• CK levels in DMD are characteristically very high, typically >10,000 U/L, with highest levels usually seen between 3-5 years of age 1, 2
• CK levels remain permanently elevated in DMD and do not show temporary fluctuations associated with exercise 2
• If initial CK is elevated but variable, re-measure after at least 48-72 hours of rest to distinguish from exercise-induced elevation (which normalizes within 24-120 hours in healthy individuals) 2
• Do not attribute high CK levels to "exercise effect" alone - continuous high CK levels (even 3,500-16,000 U/L range) are strong evidence for DMD 2

Step 2: Genetic Testing (First-Line)

• Proceed directly to genetic testing for dystrophin gene deletions/duplications from a blood sample - this is always necessary even if muscle biopsy is performed 5, 1
• Standard deletion/duplication analysis detects approximately 95% of DMD mutations using multiplex ligation-dependent probe amplification (MLPA) or similar techniques 1, 6
• If standard genetic testing is negative, perform complete dystrophin gene sequencing to detect point mutations or small deletions/insertions (the remaining ~5% of mutations) 1, 6
• Full characterization of the mutation is required to correlate the predicted effect on the reading frame, which determines disease progression and eligibility for mutation-specific therapies 5

Step 3: Muscle Biopsy (If Genetic Testing Negative or Inconclusive)

• Muscle biopsy with immunocytochemistry and immunoblotting for dystrophin protein should be interpreted by an experienced pathologist 5
• The absence of dystrophin protein on muscle biopsy is sufficient to confirm dystrophinopathy diagnosis, regardless of genetic test results, and patients should be managed as having DMD 1
• Muscle biopsy provides information on the amount and molecular size of dystrophin when protein is present 5

Supportive Diagnostic Findings

Additional Laboratory Tests

• Elevated aldolase (particularly aldolase A) in combination with elevated CK strongly supports primary muscle disease 1
• Normal C-reactive protein (CRP) indicates absence of infectious/inflammatory processes and supports muscle disease diagnosis 1, 2
• Mild elevation of CSF protein helps exclude Guillain-Barré syndrome, which presents with more pronounced albuminocytological dissociation and absent reflexes 1

Cardiac Evaluation

• Measure troponin to evaluate myocardial involvement 1
• Perform ECG and echocardiogram or cardiac MRI for all suspected DMD patients 1

Clinical Assessment Components

Neuromuscular Evaluation

• Assess motor development including sitting, crawling, and walking milestones 2
• Evaluate muscle tone and strength using manual muscle testing (MRC scale) or quantitative myometry 5
• Assess range of motion using goniometry 5
• Perform standardized timed function tests 5
• Evaluate presence of calf pseudohypertrophy 2

Family History

• Take detailed family history including affected male family members and potential carrier female family members 2
• 43.7% of mothers carry DMD gene mutations, indicating significant familial disease burden 6

Post-Diagnosis Requirements

Genetic Counseling

• All female family members at risk should receive genetic counseling and carrier testing should be offered to mothers and sisters 1, 6
• Family planning and prenatal diagnosis options must be discussed 1
• Carrier screening is crucial for prevention, particularly in rural or resource-limited settings 6

Immediate Management Initiation

• Early diagnosis allows timely initiation of glucocorticoid therapy, which slows disease progression and is typically started between 4-6 years of age when motor skills plateau or decline 1, 2
• Establish multidisciplinary follow-up with neurologist, physiotherapist, cardiologist, and respiratory specialist 2
• Develop individualized education plan 2

Common Pitfalls to Avoid

• Do not delay genetic testing waiting for clinical symptoms to fully manifest - infants with incidentally discovered elevated CK or transaminases warrant immediate testing 1, 3
• Do not stop at negative deletion/duplication testing - proceed to full gene sequencing as 5% of mutations are point mutations or small indels 1, 6
• Do not attribute elevated transaminases to liver disease without first checking CK in male children 1
• Do not dismiss variable CK levels as normal fluctuation - in DMD, CK remains permanently elevated despite some variability 2