What are the guidelines for diagnosing muscular dystrophy in a patient with suspected muscle weakness and potential family history of the disease?

Diagnostic Guidelines for Muscular Dystrophy

Begin with serum creatine kinase (CK) testing in any male child presenting with delayed walking (>16-18 months), Gowers' sign, frequent falls, difficulty running/climbing stairs, or unexplained elevated transaminases (AST/ALT), as markedly elevated CK levels (typically 10-100 times normal) strongly suggest muscular dystrophy and should trigger immediate genetic testing. 1, 2

Clinical Suspicion Triggers

Suspect muscular dystrophy irrespective of family history in three scenarios: 1

• Abnormal muscle function in a male child, including delayed walking beyond 16-18 months, frequent falls, difficulty with running and climbing stairs, or presence of Gowers' sign (especially under 5 years old) 1, 2
• Elevated serum creatine kinase detected during testing for unrelated indications 1
• Unexplained elevated transaminases (AST/ALT) in any male child—these enzymes are produced by muscle cells as well as liver, and DMD diagnosis should be considered before proceeding to liver biopsy 1, 2

With positive family history of DMD, maintain a very low threshold for testing with any suspicion of abnormal muscle function. 1

Diagnostic Algorithm

Step 1: Initial Screening

Measure serum creatine kinase concentrations—markedly elevated levels (typically 10-100 times the upper limit of normal) confirm the need for definitive diagnostic testing. 1

Step 2: Genetic Testing (First-Line)

Proceed directly to dystrophin deletion/duplication testing using PCR multiplex and multiplex ligation-dependent probe amplification (MLPA) as the initial diagnostic approach. 1, 2

• If deletion or duplication mutation is found, diagnosis is confirmed 1
• If deletion/duplication testing is negative, perform dystrophin gene sequencing to detect point mutations or small insertions/deletions 2
• Genetic testing identifies approximately 95-98% of DMD cases 1

Step 3: Muscle Biopsy (Selective Use)

Muscle biopsy is now optional when genetic testing confirms the diagnosis, but remains necessary in specific circumstances: 1

• When all genetic testing is negative but clinical suspicion remains high (rare cases can show absent dystrophin protein on biopsy despite negative genetic tests) 1
• To distinguish DMD from milder phenotypes (Becker muscular dystrophy) when genetic testing alone is inconclusive 1
• To evaluate for alternative muscular dystrophies when dystrophinopathy is ruled out 1

Muscle biopsy findings diagnostic of muscular dystrophy include: 3, 4

• Absent or reduced dystrophin protein on immunohistochemistry 5, 4
• Connective tissue proliferation in perimysium and endomysium 3
• Variation in muscle fiber size with degeneration and regeneration of myofibers 3, 4
• Cytoarchitectural alterations including internal nuclei, myofibrillar whorls, and fiber splitting 3

When muscle biopsy is performed, immunohistochemistry should test for dystrophin, merosin, sarcoglycan, emerin, and dysferlin proteins to identify specific muscular dystrophy subtypes. 5

Post-Diagnosis Requirements

All patients require: 1

• Referral to specialized multidisciplinary neuromuscular care within days of diagnosis 1
• Genetic counseling for all at-risk female family members to identify carriers 1
• Baseline cardiac evaluation with ECG and echocardiogram at diagnosis or by age 6 years 6, 2
• Comprehensive neuropsychological assessment at diagnosis and before school entry to establish baseline cognitive function 6
• Connection with patient support organizations and family counseling services 1

Diagnostic Pitfalls to Avoid

Do not perform liver biopsy in male children with elevated transaminases before ruling out muscular dystrophy with CK testing—this is a classic presentation of DMD, not liver disease. 1, 2

Do not delay genetic testing while waiting for muscle biopsy—genetic testing is now the first-line diagnostic approach and provides faster, less invasive diagnosis. 1, 2

Do not assume negative family history rules out DMD—approximately one-third of cases result from de novo mutations. 1

For patients diagnosed by muscle biopsy, always perform dystrophin genetic testing afterward—full characterization of the mutation is essential for understanding disease progression, genetic counseling, and eligibility for mutation-specific therapies. 1, 2

Evaluation by Neuromuscular Specialist

Diagnosis must be performed by a neuromuscular specialist who can assess the child clinically and rapidly access and interpret appropriate investigations in the clinical context. 1

The specialist should evaluate: 1

• Pattern and distribution of muscle weakness (proximal versus distal, symmetric versus asymmetric) 3, 7
• Presence of pseudohypertrophy, particularly in calf muscles 1
• Gait abnormalities including waddling gait and toe walking 1
• Developmental milestone delays beyond muscle weakness alone 1