What is the general diagnostic approach to spinal muscular atrophy (SMA)?

Diagnostic Approach to Spinal Muscular Atrophy

Genetic testing for homozygous deletion or mutation of the SMN1 gene is the gold standard for diagnosing spinal muscular atrophy (SMA), achieving up to 95% sensitivity and nearly 100% specificity. 1, 2

Initial Evaluation

• Clinical suspicion should arise with signs of proximal muscle weakness, particularly in infants or children showing delayed motor milestones, frequent falls, difficulty running/climbing stairs, or Gowers' sign (using hands to "climb up" the legs when rising from floor) 2
• Family history assessment for autosomal recessive inheritance pattern, though many cases occur without prior family history 3
• Neurological examination focusing on symmetrical muscle weakness pattern, with proximal muscles more affected than distal 2
• Assessment of deep tendon reflexes, which are typically diminished or absent 1

Diagnostic Testing Algorithm

First-Line Testing

• Molecular genetic testing for SMN1 gene deletions or mutations - this has replaced EMG and muscle biopsy as the primary diagnostic method 1
• Testing specifically looks for homozygous absence of SMN1 exon 7, which is present in approximately 95% of SMA patients 2

Second-Line Testing (if genetic testing is inconclusive)

• Electromyography (EMG) - shows denervation patterns with:
  • Fibrillations and positive sharp waves at rest
  • Fasciculations
  • High-amplitude, long-duration motor unit potentials 1
• Nerve conduction studies - typically normal sensory responses with reduced compound muscle action potentials 4
• Muscle biopsy - shows grouped atrophy of muscle fibers consistent with denervation 1

Prognostic Assessment

• SMN2 copy number determination - critical for prognosis and treatment decisions as SMN2 copy number inversely correlates with disease severity 5, 4
• Higher SMN2 copy numbers generally predict milder phenotypes, though exceptions exist 2

SMA Classification

Based on age of onset and maximum motor function achieved:

• Type I (Werdnig-Hoffmann disease): Onset before 6 months, never able to sit independently 2
• Type II (Intermediate): Onset between 6-18 months, able to sit but never walk independently 2
• Type III (Kugelberg-Welander disease): Onset after 18 months, able to walk independently at some point 2
• Type IV (Adult onset): Onset in second or third decade of life 2

Additional Assessments

• Pulmonary function testing - especially vital capacity in patients with more advanced disease 4
• Nutritional assessment - evaluating swallowing function and nutritional status 4
• Orthopedic evaluation - for scoliosis and joint contractures 4

Special Considerations

• Carrier testing should be offered to siblings of patients or parents of affected children to assist with reproductive planning 2
• Prenatal diagnosis should be offered to couples with a previous child affected by SMA (25% recurrence risk) 2
• Newborn screening for SMA is now recommended in many regions to enable early diagnosis and treatment 5

Common Pitfalls to Avoid

• Delaying genetic testing in favor of EMG or muscle biopsy, which can delay diagnosis 1
• Failing to determine SMN2 copy number, which is essential for prognosis and treatment planning 5
• Overlooking the need for multidisciplinary care coordination by a neuromuscular specialist 2
• Misinterpreting normal cognitive development (typically preserved in SMA) as evidence against the diagnosis 2

Early diagnosis is crucial as emerging treatments show better outcomes when initiated before significant motor neuron loss occurs 5, 3.