SMA is a hereditary disease with a well-characterised genetic cause.1-3 SMA is an autosomal recessive genetic disease in which two deleted or mutated SMN1 genes are inherited—1 from each parent.4


The American College of Medical Genetics and Genomics (ACMG) recommends that because SMA is found in all populations, carrier screening should be offered to couples of all races and ethnicities.

The ACMG suggests that the testing be performed either before conception or early in pregnancy to allow carriers to make informed reproductive choices.5

Molecular genetic testing is an important tool in the diagnosis of spinal muscular atrophy6,7

Adapted from D’Amico et al.6

The SMN gene deletion test is recommended as the first diagnostic step for a patient suspected to have SMA.

If a patient is found to have a single copy of the SMN1 gene and the clinical presentation is compatible with SMA, sequencing of the remaining SMN1 gene may identify subtle mutations and confirm the diagnosis.7


SMA results from homozygous deletions or mutations involving the SMN gene at locus 5q13 of chromosome 5. There are many rare neuromuscular disorders (e.g., Lambert-Eaton myasthenic syndrome, affecting 0.05-0.08/100,000 people a year).8 These disorders may involve mutations in a variety of different genes that are not associated with 5q13.

The differential diagnosis of 5q spinal muscular atrophy includes, but is not limited to:9

Spinal cord disorders

  • Neoplasms
  • Other myelopathies


Congenital myopathies:

  • Congenital myotonic dystrophy
  • Congenital muscular dystrophies
  • Muscular dystrophies
  • Mitochondrial myopathies
  • Acid maltase / Pompe disease

Other metabolic myopathies:

  • Inflammatory myopathies
  • Channelopathies


  • Congenital hypomyelinating or axonal neuropathy
  • Hereditary motor and sensory neuropathies
  • Chronic inflammatory demyelinating polyneuropathy

Neuromuscular junction disorders

  • Botulism
  • Congenital myasthenic syndromes
  • Lambert-Eaton myasthenic syndrome
  • Autoimmune myasthenia gravis

Other motor neuron diseases

  • Spinal muscular atrophy with respiratory distress (SMARD)
  • Juvenile muscular atrophy of distal upper extremity (Hirayama disease)
  • Fazio-Londe disease
  • Brown-Vialetto-van Laere syndrome
  • Juvenile amyotrophic lateral sclerosis
  • Other non-5q SMAs

Other disorders

  • Chromosomal abnormalities
  • Prader-Willi syndrome
  • Central nervous system abnormalities

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.4


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1. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80(1):155-165.

2. Kolb SJ, Kissel JT. Spinal muscular atrophy. Arch Neurol 2011;68(8):979-984.

3. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008;371(9630):21‌20-21‌33.

4. National Organization for Rare Diseases. Spinal muscular atrophy. [online] 2012 [cited 2016 Apr 17]. Available from: URL:

5. Prior TW; Professional Practice Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med 2008;10(11):840-842.

6. D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis 2011;6:71.

7. Mercuri E, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscl Disord 2018;28(2):103-115.

8. Wirtz PW, Nijnuis MG, Sotodeh M, et al. The epidemiology of myasthenia gravis, Lambert–Eaton myasthenic syndrome and their associated tumours in the northern part of the province of South Holland. J Neurol. 2003;250(6):698–701. doi: 10.1007/ s00415-003-1063-7

9. Darras BT, Royden Jones H Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. 2nd Ed. London, UK: Elsevier; 2015.