🧬 652.2 · Spinal Muscular Atrophy (SMA)

Nelson Textbook of Pediatrics 22nd Edition — 5q SMA: homozygous SMN1 deletion (95%). SMN2 copy number modifies severity (type 1: 2 copies, type 3: 3-4 copies). Disease-modifying therapies: nusinersen (intrathecal), risdiplam (oral), onasemnogene abeparvovec (IV gene therapy, <2 years). Newborn screening, multidisciplinary care.

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📋 30 Clinical Scenarios — Spinal Muscular Atrophy

📇 High‑Yield Review Cards — SMA

🩺 Clinical Recognition: Spinal Muscular Atrophy

Select a presentation for diagnostic clues and management.

📋 Stepwise Management of SMA

    ⚡ Reflex Prompts — Clinical Decisions in SMA

    📊 SMA Classification & Therapies

    SMA Types (based on age of onset & motor milestones)

    TypeOnsetMax Motor MilestoneSMN2 Copies (typical)Natural History (untreated)
    Type 0PrenatalNone; severe weakness at birth1Death within weeks
    Type 1 (Werdnig-Hoffmann)<6 monthsNever sit2Death by age 2 (respiratory failure)
    Type 26-18 monthsSit independently, never walk3Live into adulthood, wheelchair, scoliosis
    Type 3 (Kugelberg-Welander)>18 monthsWalk independently3-4Slowly progressive, ambulatory into adulthood
    Type 4AdulthoodNormal early, mild weakness4+Mild, normal lifespan

    FDA-Approved Disease-Modifying Therapies for SMA

    TherapyMechanismRouteApproved AgesKey Monitoring
    Nusinersen (Spinraza)ASO promotes SMN2 exon 7 inclusionIntrathecalAll SMA typesLP-related AEs, thrombocytopenia, hydrocephalus (rare)
    Risdiplam (Evrysdi)Oral small molecule splice modifierOral≥2 monthsGastrointestinal, rash; animal retinal/testicular toxicity
    Onasemnogene abeparvovec (Zolgensma)AAV9 gene therapy (SMN1)IV<2 years (≤21 kg)Hepatotoxicity (prednisolone), thrombotic microangiopathy, thrombocytopenia
    🧬 Genetics of SMA

    SMN1 gene (5q13): Telomeric copy, produces full-length SMN protein. Homozygous deletion in 95% of SMA patients.

    SMN2 gene (5q13): Centromeric copy, differs by C→T transition in exon 7 → majority of transcripts lack exon 7 (unstable protein). Produces ~10-15% functional SMN protein.

    SMN2 copy number inversely correlates with severity: Type 1: 2 copies, Type 2: 3 copies, Type 3: 3-4 copies, Type 4: 4+ copies. Higher copies = milder disease.

    Carrier frequency: 1/40-1/60; 1/10,000 births.

    Newborn screening: DNA from dried blood spot detects SMN1 deletion. Early treatment dramatically improves outcomes.

    Data from Nelson 652.2; Manzur AY. Spinal muscular atrophies.

    📖 Summary: Spinal Muscular Atrophy — Nelson 652.2