Is a muscle biopsy necessary to determine the treatment for Suspected Muscular Dystrophy (SMD)?

Muscle Biopsy in Suspected Muscular Dystrophy: When Is It Necessary?

Muscle biopsy is NOT routinely necessary to determine treatment for suspected muscular dystrophy when genetic testing can be performed first on a blood sample, but it becomes essential when genetic testing is negative or when the clinical presentation is atypical.

Algorithmic Diagnostic Approach

Step 1: Initial Screening and Genetic Testing

• Begin with serum creatine kinase (CK) measurement as the initial screening test, which can be performed in primary care settings 1
• In suspected Duchenne muscular dystrophy (DMD), CK levels are typically very high, often exceeding 10,000 U/L 2
• If CK is elevated, proceed directly to genetic testing for dystrophin gene deletions or duplications on a blood sample 2, 1
• Standard genetic tests detect approximately 95% of DMD mutations 2

Step 2: When Muscle Biopsy IS Required

Muscle biopsy becomes necessary in the following specific scenarios:

• When genetic testing is negative: If standard deletion/duplication analysis and subsequent dystrophin gene sequencing fail to identify a mutation, muscle biopsy is required to evaluate dystrophin protein expression 2
• Atypical presentations: When clinical features don't fit classic muscular dystrophy patterns 3
• Suspected inflammatory myopathy: When symptoms suggest inflammatory rather than dystrophic disease, as muscle biopsy remains the gold standard for confirming inflammatory myopathy and is essential for subclassification 4
• Diagnostic uncertainty: When differentiation between myopathy and neuropathy is needed 3

Step 3: Critical Diagnostic Principle

• The absence of dystrophin protein on muscle biopsy is sufficient to confirm dystrophinopathy and guide management as DMD, regardless of genetic test results 2
• This is particularly important because 5% of mutations may be missed by standard genetic testing 2

Treatment Implications

Why This Approach Matters for Treatment Decisions

• Early diagnosis through genetic testing allows timely initiation of glucocorticoid therapy, which can slow disease progression and improve outcomes 2
• The specific genetic mutation identified may determine eligibility for mutation-specific therapies that have recently achieved conditional approval 5
• Different muscular dystrophy subtypes have varying cardiac and respiratory complications, requiring subtype-specific anticipatory care 5

When Biopsy Changes Treatment

• A 2018 study found that muscle biopsy changed treatment in 37% of pediatric patients with suspected muscular disease 6
• The highest likelihood of treatment change occurred in inflammatory diseases (44% of cases where treatment changed), not in dystrophic conditions 6
• In contrast, patients with hypotonia who underwent biopsy were least likely to have treatment changes 6

Common Pitfalls to Avoid

Pitfall 1: Ordering Biopsy Before Genetic Testing

• Do not proceed to muscle biopsy before attempting genetic testing in suspected DMD or other dystrophinopathies 2, 1
• Genetic testing is less invasive, can be done on blood samples, and provides mutation-specific information crucial for emerging targeted therapies 2

Pitfall 2: Misinterpreting Early Biopsies

• Initial muscle biopsies may show only minimal, nonspecific abnormalities in congenital muscular dystrophy, with characteristic dystrophic changes only evident on repeat biopsies 7
• The clinical course cannot be predicted from initial pathologic findings alone 7

Pitfall 3: Wrong Muscle Selection

• If biopsy is performed, select a muscle that is affected but not too weak or atrophic 8
• Use electromyography (EMG) to identify the optimal muscle for biopsy 4
• For proximal involvement, quadriceps or biceps are typically biopsied; for suspected mitochondrial disorders, the deltoid is preferred 8

Special Considerations

Genetic Counseling Requirements

• All female family members at risk should receive genetic counseling, and carrier testing should be offered to mothers and sisters 2
• This is essential regardless of whether diagnosis was made by genetic testing or muscle biopsy 2

Advanced Testing When Standard Genetics Are Negative

• If standard deletion/duplication analysis is negative, perform dystrophin gene sequencing to detect point mutations or small deletions/insertions 2
• Advanced molecular analysis including multiplex ligation-dependent probe amplification (MLPA) should be used 2