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Condition report · Neurological

Spinal Muscular Atrophy (SMA)

Whole genome sequencing identifies SMN1 deletions and SMN2 copy number, enabling presymptomatic treatment with gene therapy or disease-modifying medication.

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About this condition

Inherited conditions in which the motor neurons of the spinal cord are lost, causing muscle weakness and wasting. The most common form is caused by variants in SMN1, and its severity ranges from infancy (type 1) to adulthood (type 4).

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by loss of function of SMN1 (survival motor neuron 1) gene, resulting in degeneration of anterior horn motor neurons. Incidence is approximately 1 in 6,000 to 10,000 live births; carrier frequency is approximately 1 in 50 across populations. SMA is characterized by progressive weakness, starting proximally and advancing distally, with respiratory and bulbar involvement in severe forms. The disease is classified into types based on age of onset and maximum motor function achieved: Type I (severe, onset <6 months, never able to sit independently, often fatal by age 2 without treatment), Type II (intermediate, onset 6-18 months, able to sit but never walk), Type III (mild, onset >18 months, able to walk), and Type IV (adult-onset). Approximately 95-98% of SMA cases are caused by homozygous deletion of SMN1 exons 7-8; the remaining cases result from homozygous or compound heterozygous point mutations. Disease severity is dramatically modulated by SMN2 copy number: SMN2 encodes an almost identical protein but with a critical splicing difference that produces mostly non-functional truncated protein; however, approximately 15% of SMN2 transcripts include exon 7, producing functional SMN protein.

SMN1 and SMN2 are nearly identical genes (99.9% sequence homology) located in tandem in chromosome 5q13, a region of high sequence homology and frequent copy number variation. SMN encodes survival motor neuron protein, crucial for snRNP biogenesis and mRNA splicing in neurons; loss of SMN protein causes motor neuron degeneration. SMN2 is present in multiple copies in most individuals (1-4 copies, median 2) due to duplication. While SMN2 cannot fully compensate for SMN1 loss due to exon 7 splicing deficiency, the number of SMN2 copies critically determines disease severity: 1-2 copies typically produce Type I (severe); 3 copies produce Type II (intermediate); 3-4 copies correlate with Type III (mild). Presymptomatic SMA patients discovered through newborn screening with 2-3 SMN2 copies are at risk for Type I or II; those with ≥4 copies have lower immediate risk, though early treatment can prevent phenotype expression regardless.

SMN1/SMN2 genotyping is critical for SMA diagnosis and therapy selection. Three approved therapies are available: nusinersen (Spinraza), an antisense oligonucleotide administered intrathecally that modulates SMN2 splicing to increase exon 7 inclusion and full-length SMN2 protein production; onasemnogene abeparvovec (Zolgensma), a gene therapy using AAV9 to deliver functional SMN1 cDNA intravenously as a single infusion, a one-time curative approach now preferred in presymptomatic patients; and risdiplam (Evrysdi), an oral splicing modifier enabling home-based treatment. Presymptomatic treatment (newborn-diagnosed infants) produces dramatically improved outcomes: most treated presymptomatic infants never develop observable SMA symptoms and achieve normal or near-normal motor milestones. SMN2 copy number helps predict natural disease severity and guides prognostication, though early treatment can prevent phenotype expression even in patients destined to be Type I.

The condition we analyse

A group of disorders characterised by degeneration of spinal cord anterior horn cells, leading to progressive muscle weakness and atrophy.

What a diagnosis changes

Gene therapy (onasemnogene abeparvovec), antisense oligonucleotide therapy (nusinersen), oral splicing modifier (risdiplam), supportive care

Genes analysed

Includes 59 related subtypes ↓
  • adult-onset proximal spinal muscular atrophy, autosomal dominant
  • autosomal dominant childhood-onset proximal spinal muscular atrophy
  • autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
  • autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures
  • autosomal recessive distal spinal muscular atrophy 1
  • autosomal recessive distal spinal muscular atrophy 2
  • bulbospinal muscular atrophy
  • distal hereditary motor neuropathy type 2
  • distal hereditary motor neuropathy type 7
  • hereditary spastic paraplegia 17
  • infantile-onset X-linked spinal muscular atrophy
  • lower motor neuron syndrome with late-adult onset
  • myopathy, myofibrillar, 13, with rimmed vacuoles
  • neuronopathy, distal hereditary motor, autosomal dominant
  • neuronopathy, distal hereditary motor, autosomal dominant 1
  • neuronopathy, distal hereditary motor, autosomal dominant 10
  • neuronopathy, distal hereditary motor, autosomal dominant 11
  • neuronopathy, distal hereditary motor, autosomal dominant 15
  • neuronopathy, distal hereditary motor, autosomal dominant 8
  • neuronopathy, distal hereditary motor, autosomal recessive 3
  • neuronopathy, distal hereditary motor, autosomal recessive 4
  • neuronopathy, distal hereditary motor, autosomal recessive 5
  • neuronopathy, distal hereditary motor, type 2A
  • neuronopathy, distal hereditary motor, type 2B
  • neuronopathy, distal hereditary motor, type 2C
  • neuronopathy, distal hereditary motor, type 2D
  • neuronopathy, distal hereditary motor, type 5
  • neuronopathy, distal hereditary motor, type 5A
  • neuronopathy, distal hereditary motor, type 5B
  • neuronopathy, distal hereditary motor, type 5C
  • neuronopathy, distal hereditary motor, type 7A
  • neuronopathy, distal hereditary motor, type 7B
  • neuronopathy, distal hereditary motor, type 9
  • pontocerebellar hypoplasia type 1
  • pontocerebellar hypoplasia type 1A
  • pontocerebellar hypoplasia type 1B
  • pontocerebellar hypoplasia type 2
  • pontocerebellar hypoplasia type 2A
  • pontocerebellar hypoplasia type 2B
  • pontocerebellar hypoplasia type 2C
  • pontocerebellar hypoplasia type 2D
  • pontocerebellar hypoplasia, type 1C
  • pontocerebellar hypoplasia, type 2F
  • proximal spinal muscular atrophy
  • scapuloperoneal spinal muscular atrophy, autosomal dominant
  • scapuloperoneal spinal muscular atrophy, autosomal recessive
  • spinal atrophy-ophthalmoplegia-pyramidal syndrome
  • spinal muscular atrophy type 0
  • spinal muscular atrophy with respiratory distress type 2
  • spinal muscular atrophy-progressive myoclonic epilepsy syndrome
  • spinal muscular atrophy, facioscapulohumeral type
  • spinal muscular atrophy, lower extremity-predominant, 2b, prenatal onset, autosomal dominant
  • spinal muscular atrophy, Ryukyuan type
  • spinal muscular atrophy, segmental
  • spinal muscular atrophy, type 1
  • spinal muscular atrophy, type II
  • spinal muscular atrophy, type III
  • spinal muscular atrophy, type IV
  • X-linked distal spinal muscular atrophy type 3
MONDO:0001516MedGen 7755

Why whole genome sequencing

Standard sequencing cannot reliably distinguish SMN1 from SMN2 due to high sequence homology. Specialized copy number analysis is required.

SMN1/SMN2 copy number determination requires specialized analysis

SMA is now on the RUSP (recommended uniform newborn screening panel) in most US states, and carrier screening is increasingly common. Standard sequencing cannot reliably distinguish between SMN1 and SMN2 copies due to their 99.9% sequence homology; specialized copy number analysis techniques (comparative genomic hybridization, MLPA, or targeted NGS with specialized read-mapping) are required. Carrier screening panels typically detect SMN1 deletion but may not accurately determine SMN2 copy number. Whole genome sequencing with specialized copy number detection algorithms can provide accurate SMN1/SMN2 copy number assessment, enabling comprehensive carrier screening and disease severity prediction.

SMN2 copy number determines severity and guides presymptomatic therapy

SMN2 copy number is the primary severity modifier: 1-2 copies predict Type I disease (severe, infantile-onset); 3 copies predict Type II (intermediate, onset 6-18 months); 3-4 copies correlate with Type III (mild, ability to walk). Presymptomatic SMA patients discovered through newborn screening with 2-3 SMN2 copies are at risk for rapid disease progression and require immediate therapy initiation. Those with ≥4 copies have lower immediate risk but benefit from early treatment. Three approved therapies offer transformative outcomes: gene therapy (Zolgensma) is a one-time cure; antisense therapy (Spinraza) requires repeated intrathecal infusions; oral therapy (Evrysdi) enables home-based treatment. Documented in the medical record, SMN genotype enables presymptomatic diagnosis and rapid therapy initiation, preventing disease development and enabling normal motor development.

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