This part of the website provides more background information about SMA.

A clinical overview of spinal muscular atrophy (SMA)

Spinal muscular atrophy is a rare and debilitating autosomal recessive neuromuscular disease characterised by motor neuron degeneration and loss of muscle strength1,2

Clinical literature shows a wide range of the incidence and prevalence of spinal muscular atrophy; in the United States, the estimated incidence of spinal muscular atrophy is 8.5 to 10.3 per 100,000 live births.2,3
In Europe the annual incidence varies greatly by country and type; global annual incidence per 100,000 live births ranged from 3.5 to 7.1 for type I, 1.0 to 5.3 for type II, and 1.5 to 4.6 for type III.13

In children with spinal muscular atrophy, degeneration of motor neurons in the spinal cord results in skeletal muscular atrophy and weakness commonly involving the limbs. The bulbar and respiratory muscles are more variably affected.1,2

The lower motor neurons, located in the spinal cord, are important cells involved in motor function in the central nervous system (CNS)4

Cognitive ability does not appear to be impacted by spinal muscular atrophy. Children with spinal muscular atrophy are often noted at diagnosis to have a bright, alert expression that contrasts with their general weakness.2

 

The genetic deficit underlying spinal muscular atrophy is well characterized

The role of the survival motor neuron 1 (SMN1) gene is to produce SMN protein, which is highly expressed in the spinal cord and is known to be essential for motor neuron survival.1,3

SMN1 gene3,5,6

The SMN1 gene is located on chromosome 5q13

In spinal muscular atrophy, homozygous mutations or deletions of SMN1 produce a shortage of SMN protein, which causes degeneration of motor neurons in the spinal cord.5,7

Nearly all people, including those with spinal muscular atrophy, have a second, virtually duplicate gene to SMN1, known as survival motor neuron 2 (SMN2)2,8

  • SMN2 is nearly identical in genomic sequence to SMN1; there are only 5 nucleotides different5
  • However, a C-to-T nucleotide difference at position 6 of SMN2 creates an exonic splicing suppressor (ESS) that leads to a skipping of exon 7 during transcription2
  • This results in SMN2 producing a truncated, nonfunctional, and rapidly degrading SMN protein2

SMN2 gene2,6

Approximately 10% of SMN2 transcripts result in full-length SMN protein, providing patients with an insufficient amount of SMN protein to sustain survival of spinal motor neurons in the CNS.2

The number of SMN2 gene copies is inversely related to the severity of spinal muscular atrophy

Copy number of SMN2 is variable in patients with spinal muscular atrophy, and higher copy numbers of SMN2 correlate with less-severe disease2:

  • More than 95% of individuals with spinal muscular atrophy retain at least 1 copy of SMN2
  • About 80% of individuals with Type I spinal muscular atrophy have 1 or 2 copies of SMN2
  • About 82% of individuals with Type II spinal muscular atrophy have 3 copies of SMN2
  • About 96% of individuals with Type III spinal muscular atrophy have 3 or 4 copies of SMN2

SMN2 copy number is related to, but not predictive of, disease severity, and care decisions should not be made based on copy number alone9,10

  • In any case of spinal muscular atrophy, SMN2 copy number is less predictive of prognosis than age of onset and functional abilities.11,12

Signs and symptoms of spinal muscular atrophy (SMA)

Spinal muscular atrophy is a single-gene disease with a spectrum of clinical presentation1,2

Clinical presentation for spinal muscular atrophy may differ according to the age of onset and severity, but hypotonia (floppy baby syndrome) and/or muscle weakness and atrophy are common signs or symptoms2,3:

  • Weakness is usually symmetrical
  • Weakness is more proximal than distal
  • Sensation is preserved
  • Tendon reflexes are absent or diminished
  • Weakness is greater in the legs than the arms
  • Severity of weakness generally correlates with the age of onset

Characteristics of spinal muscular atrophy

Click through the tabs to see additional details about each type.

0-6 MONTHS (infant-onset)1,2,4

Highest motor
milestone achieved

Sit with support only
(“nonsitters”)

Life expectancy

< 2 years of age

Phenotype

TYPE 1
(also known as Werdnig-Hoffmann disease)

Clinical characteristics

  • Hypotonia and impaired head control
  • “Frog leg” presentation
  • Weak cry
  • Weak cough
  • Swallowing, feeding, and handling of oral secretion are affected before 1 year of age
  • Atrophy and fasciculation of the tongue
  • Weakness and hypotonia in the limbs and trunk
  • Intercostal muscle weakness (note, the diaphragm is relatively spared)
  • Paradoxical breathing
  • Bell-shaped trunk with chest wall collapse and abdominal protrusion

7-18 MONTHS (intermediate)2-6

Highest motor
milestone achieved

Independent sitting (“sitters”)

Life expectancy

> 2 years of age
~70% alive at age 25

Phenotype

Type 2 (also known as Dubowitz disease)

Clinical characteristics

  • Bulbar weakness with chewing and swallowing difficulties that may lead to poor weight gain
  • Weak intercostal muscles
  • Diaphragmatic breathing
  • Difficulty coughing and clearing tracheal secretion
  • Fine tremors with extended fingers or when attempting hand grips
  • Kyphoscoliosis, or scoliosis requiring bracing or spinal surgery
  • Joint contractures

18 MONTHS+ (juvenile-onset)1,2,7

Highest motor
milestone achieved

Independent stand and walk (“walkers” - although they may progressively lose this ability)

Life expectancy

Normal

SMA Type

Type 3 (also known as Kugelberg-Welander disease)

Clinical characteristics

  • Scoliosis
  • Swallowing difficulty
  • Cough, and nocturnal hypoventilation
  • Muscle aching
  • Joint overuse symptoms

LATE ADOLESCENCE/ADULTHOOD (adult-onset)1,2,4

Highest motor
milestone achieved

All

Life expectancy

Normal

SMA Type

Type 4

Clinical characteristics

  • Physical symptoms are similar to juvenile-onset SMA, with the gradual onset of weakness, tremor, and muscle twitching first noted in late teens or adulthood

Genetics and diagnosing spinal muscular atrophy (SMA)

Spinal muscular atrophy is a hereditary disease with a well-characterised genetic cause1-3

Spinal muscular atrophy is an autosomal recessive genetic disease in which a child inherits 2 deleted or mutated SMN1 genes—1 from each parent4:

Molecular genetic testing is an important tool in the diagnosis of spinal muscular atrophy5,6

REFERENCES

    Biology

  1. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120-2133.
  2. 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.
  3. Kolb SJ, Kissel JT. Spinal muscular atrophy. Arch Neurol. 2011;68(8):979-984.
  4. Islander G. Anesthesia and spinal muscular atrophy. Paediatr Anaesth. 2013;23(9):804-816.
  5. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165.
  6. Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn. 2004;4(1):15-29.
  7. Genetics Home Reference. SMN1. https://ghr.nlm.nih.gov/gene/SMN1. Published 20 April 2016. Accessed 25 April 2016.
  8. Swoboda KJ. Romancing the spliceosome to fight spinal muscular atrophy. N Engl J Med. 2014;371(18):1752-1754.
  9. TREAT-NMD. Diagnostic testing and care of new SMA patients. http://www.treat-nmd.eu/downloads/file/standardsofcare/sma/english/sma_soc_en.pdf. Accessed 10 May 2016.
  10. Butchbach ME. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7.
  11. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85(3):408-413.
  12. Burnett BG, Crawford TO, Sumner CJ. Emerging treatment options for spinal muscular atrophy. Curr Treat Options Neurol. 2009;11(2):90-101.
  13. Jones C. PP09. 1–2352: Systematic review of incidence and prevalence of spinal muscular atrophy (SMA). European Journal of Paediatric Neurology. 2015, 19, Supp 1: S64–S65.

    Signs & symptoms

  1. http://www.ncbi.nlm.nih.gov/books/NBK1352/?report=printable. Updated November 14, 2013. Accessed April 15, 2016.
  2. 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.
  3. MedlinePlus. Medical Encyclopedia. https://www.nlm.nih.gov/medlineplus/encyclopedia.html. Updated April 21, 2016. Accessed April 25, 2016.
  4. Markowitz JA, Singh P, Darras BT. Spinal muscular atrophy: a clinical and research update. Pediatr Neurol. 2012;46(1):1-12.
  5. 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.
  6. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008;371(9630):21 20-21 33.
  7. Online Mendelian Inheritance in Man. Spinal muscular atrophy, Type III; SMA3. [online] 2013 Feb 7 [cited 2016 Apr 26]. Available from: URL: http://www.omim.org/entry/253400.

    Genetics & Diagnosis

  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. http://rarediseases.org/rarediseases/spinal-muscular-atrophy/. Updated 2012. Accessed April 17, 2016.
  5. D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;6:71.
  6. 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.

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