LOOK OUT FOR EARLY WARNING SIGNS OF SPINAL MUSCULAR ATROPHY (SMA)1–3

REFER FOR DIAGNOSIS

Frequently asked questions

1) What is spinal muscular atrophy (SMA)?

SMA is a rare, progressive, inherited monogenic disease, characterized by lower motor neuron degeneration and muscle weakness1−5

References
  • 1. Verhaart IEC, et al. Orphanet J Rare Dis. 2017;12:124.
  • 2. Richter T, et al. Value Health. 2015;18(6):906–14.
  • 3. Mercuri E, et al. Neurology. 2019;93(13):e1241–7.
  • 4. Mercuri E, et al. Orphanet J Rare Dis. 2020;15(1):84.
  • 5. Schorling DC, et al. J Neuromuscl Dis. 2020;7:1–13.

2) What is the cause of spinal muscular atrophy (SMA)?

SMA is caused by an absent or dysfunctional survival motor neuron 1 (SMN1) gene1–4

SMN1 is the primary gene that encodes SMN protein, which is critical for neuronal survival and neuromuscular junction formation2,5

The body has a back-up gene, SMN2, however, it is only capable of producing a small amount of functional SMN protein, which is insufficient for motor neuron survival and function1,2,6

SMN protein deficiency leads to irreversible neuronal degeneration and loss of muscle function in SMA1,2,7

Click here for more information about what causes SMA

References
  • 1. Coovert DD, et al. Hum Mol Genet. 1997;6(8):1205–14.
  • 2. Anderton RS and Mastaglia FL. Expert Rev Neurother. 2015;15(8):895–908.
  • 3. Lefebvre S, et al. Cell. 1995;80:155–65.
  • 4. Monani UR, et al. Hum Mol Genet. 2000;9(3):333−9.
  • 5. Serra-Juhe C and Tizzano EF. Eur J Hum Genet. 2019;27(12):1774–82.
  • 6. Verhaart IEC, et al. Orphanet J Rare Dis. 2017;12:124.
  • 7. Glascock J, et al. J Neuromuscul Dis. 2018;5(2):145–58.

3) What is survival motor neuron 2 (SMN2)?

SMN2 gene is an almost identical copy of SMN1. However, a critical single base change in the coding region of the SMN2 gene causes alternative splicing, and exclusion of exon 7. As a result, only ~10% of SMN protein produced by SMN2 is functional1,2

References
  • 1. Coovert DD, et al. Hum Mol Genet. 1997;6(8):1205–14.
  • 2. Anderton RS and Mastaglia FL. Expert Rev Neurother. 2015;15(8):895–908.

4) What are the different types of spinal muscular atrophy (SMA)?

SMA is typically classified into 4 phenotypes: (Types 1−4) that range in severity. Types 1 and 2 are the most severe and common forms with onset between birth and 18 months1−3

References
  • 1. Wang CH, et al. J Child Neurol. 2007;22(8):1027–49.
  • 2. Glascock J, et al. J Neuromuscul Dis. 2018;5(2):145–58.
  • 3. Schorling DC, et al. J Neuromuscl Dis. 2020;7:1–13.

5) What are the differences between spinal muscular atrophy (SMA) Types 1−4?

There are different symptoms that may occur depending on the Type of SMA1

SMA Type 1 (Werdnig-Hoffmann)1

Unable to sit independently, onset age ≤6 months1,2

  • Hypotonia2,3
  • Areflexia1
  • Head lag4
  • Difficulty breathing3
  • Difficulty swallowing2,5
  • Tongue fasciculation1,2,5
  • Weak cry and cough5

SMA Type 2

Able to sit and may stand, but unable to walk independently, onset age 6–18 months1,2

  • Hypotonia2
  • Areflexia1,2
  • Fine tremor5
  • Progressive scoliosis and joint contractures1,2,5,6
  • Respiratory symptoms1
  • Delayed/lost motor milestones1,5

Click here for more information about the signs and symptoms of SMA Types 1 and 2

SMA Type 3

Independent walking, onset age >18 months–teens1,2

  • Proximal muscle weakness that is greater in the legs than in the arms2
  • Loss of motor skills1
  • Progressive scoliosis5
  • Difficulty swallowing and coughing5
  • Fatigue1
  • Tremor1

SMA Type 4

Independent walking into adulthood, onset age >18 years1,2

  • In the mildest form of SMA, symptoms don’t appear until adulthood1
  • Fatigue1
  • Mild weakness, without breathing difficulties1,5
References
  • 1. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 2. Kolb SJ and Kissel JT. Neurol Clin. 2015;33(4):831–46.
  • 3. Pera MC, et al. PLoS One. 2020;15(3):e0230677.
  • 4. Markowitz JA, et al. J Obstet Gynecol Neonatal Nurs. 2004;33:12–20.
  • 5. Wang CH, et al. J Child Neurol. 2007;22(8):1027–49.
  • 6. Fujak A, et al. BMC Musculoskelet Disord. 2013 Oct 4;14:283.

6) Is spinal muscular atrophy (SMA) genetic?

Yes, SMA is a genetic disease caused by a dysfunctional or absent survival motor neuron 1 (SMN1) gene, which is the primary gene that encodes SMN protein.1−5 SMA is an autosomal recessive disorder6

References
  • 1. Coovert DD, et al. Hum Mol Genet. 1997;6(8):1205–14.
  • 2. Anderton RS and Mastaglia FL. Expert Rev Neurother. 2015;15(8):895–908.
  • 3. Lefebvre S, et al. Cell. 1995;80:155–65.
  • 4. Monani UR, et al. Hum Mol Genet. 2000;9(3):333−9.
  • 5. Serra-Juhe C and Tizzano EF. Eur J Hum Genet. 2019;27(12):1774–82.
  • 6. D’Amico A, et al. Orphanet J Rare Dis. 2011;6:71.

7) Is spinal muscular atrophy (SMA) dominant or recessive?

SMA is an autosomal recessive disorder. Untreated, SMA is the second most common fatal autosomal recessive disorder after cystic fibrosis1

Reference
  • 1. D’Amico A, et al. Orphanet J Rare Dis. 2011;6:71.

8) What are spinal muscular atrophy (SMA) symptoms in carriers?

SMA is a recessive disease, therefore heterogenous carriers are unaffected, showing no symptoms of the disease1

Carriers are typically unaware of their status until they have a child with SMA, unless there is a family history of the disease2

More than 1 in 58 people are carriers of the disease mutation3

References
  • 1. Verhaart IEC, et al. Orphanet J Rare Dis. 2017;12:124.
  • 2. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 3. Verhaart IEC, et al. Additional file 2: Table S1. Overview carrier frequencies of SMA. Supplementary material to Verhaart IEC, et al. Orphanet J Rare Dis. 2017;12:124. Available at: https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0671-8. Date accessed: November 2022.

9) What is the incidence of spinal muscular atrophy (SMA)?

SMA is a rare condition affecting approximately 1 in 10,000–12,000 live births, and can impact any race or sex.1,2 More than 1 in 58 people are carriers of the disease mutation3

References
  • 1. Verhaart IEC, et al. Orphanet J Rare Dis. 2017;12:124.
  • 2. Richter T, et al. Value Health. 2015;18(6):906–14.
  • 3. Verhaart IEC, et al. Additional file 2: Table S1. Overview carrier frequencies of SMA. Supplementary material to Verhaart IEC, et al. Orphanet J Rare Dis. 2017;12:124. Available at: https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0671-8. Date accessed: November 2022.

10) Is spinal muscular atrophy (SMA) more common in males or females?

SMA is an autosomal recessive condition, this type of inheritance pattern typically affects males and females equally1,2

References
  • 1. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 2. Gulani A and Weiler T. Genetics, Autosomal Recessive. 2021 Jan [Updated 2021 May]. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan.

11) What are the early symptoms of spinal muscular atrophy (SMA)?

The early signs of SMA are important to look out for1

As a healthcare professional, you are uniquely placed to spot whether a baby is developing as they should, whether this is at a routine check-up, or if parents or caregivers raise any concerns2

For babies aged 0–6 months:2

  • Hypotonia3,4
  • Areflexia1
  • Head lag5
  • Difficulty breathing4
  • Difficulty swallowing3,6
  • Tongue fasciculation1,3,6
  • Weak cry and cough6

For babies aged 6–18 months:1

  • Hypotonia3
  • Areflexia1,3
  • Fine tremor6
  • Progressive scoliosis and joint contractures1,3,6,7
  • Respiratory symptoms1
  • Delayed/lost motor milestones1,6

Babies with these signs remain alert, attentive and cognition is not affected3

Click here for more information about the signs and symptoms

References
  • 1. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 2. Qian Y, et al. BMC Neurol. 2015;15:217.
  • 3. Kolb SJ and Kissel JT. Neurol Clin. 2015;33(4):831–46.
  • 4. Pera MC, et al. PLoS One. 2020;15(3):e0230677.
  • 5. Markowitz JA, et al. J Obstet Gynecol Neonatal Nurs. 2004;33:12–20.
  • 6. Wang CH, et al. J Child Neurol. 2007;22(8):1027–49.
  • 7. Fujak A, et al. BMC Musculoskelet Disord. 2013 Oct 4;14:283.

12) What are the symptoms of spinal muscular atrophy (SMA) in adults?

In adults with SMA Type 4, the onset of weakness is usually in the second or third decade of life. Motor impairment is mild in these patients, without respiratory or gastrointestinal problems1

Reference
  • 1. Wang CH, et al. J Child Neurol. 2007;22(8):1027–49.

13) What causes hypotonia in spinal muscular atrophy (SMA)?

SMN protein deficiency in SMA leads to irreversible neuronal degeneration and loss of muscle function and weakness, meaning children with SMA will present with hypotonia1–4

References
  • 1. Glascock J, et al. J Neuromuscul Dis. 2018;5(2):145–58.
  • 2. Coovert DD, et al. Hum Mol Genet. 1997;6(8):1205–14.
  • 3. Anderton RS and Mastaglia FL. Expert Rev Neurother. 2015;15(8):895–908.
  • 4. Kolb SJ and Kissel JT. Neurol Clin. 2015;33(4):831–46.

14) What is fasciculation of the tongue?

Tongue fasciculations, is a twitching of the tongue, which is often seen together with atrophy1–4

References
  • 1. Kolb SJ and Kissel JT. Neurol Clin. 2015;33(4):831–46.
  • 2. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 3. Wang CH, et al. J Child Neurol. 2007;22(8):1027–49.
  • 4. Emmady PD and Bodle J. Werdnig Hoffmann Disease. [Updated 2022 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558933/. Date accessed: November 2022.

15) What is areflexia?

Areflexia is the reduction or absence of deep tendon reflexes1−3

References
  • 1. Kolb SJ and Kissel JT. Neurol Clin. 2015;33(4):831–46.
  • 2. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 3. Goswami JN, et al. Indian J Pediatr. 2018;85(8):702.

16) Can you cure spinal muscular atrophy (SMA)?

There is currently no cure for SMA.1 However, there are treatments available that can modify disease outcomes for patients2,3

References

17) Is there a treatment for spinal muscular atrophy (SMA)?

Yes, there are medications approved for use to treat SMA.1–4 Speak to a specialist for more information about treatment options and patient care1–4

References
  • 1. Glascock J, et al. J Neuromuscul Dis. 2018;5(2):145–58.
  • 2. Novartis Gene Therapies (2022). ZOLGENSMA (onasemnogene abeparvovec) Summary of Product Characteristics.
  • 3. Roche (2021). EVRYSDI (risdiplam) Summary of Product Characteristics.
  • 4. Biogen (2021). SPINRAZA (nusinersen) Summary of Product Characteristics.

18) How do you test for spinal muscular atrophy (SMA)?

The diagnosis of SMA is based on molecular genetic testing. Genetic testing of survival motor neuron 1/2 (SMN1/SMN2) is highly reliable and should be the first line of investigation if SMA is suspected. Unless there is a family history, diagnosis is generally prompted by the clinical signs of SMA1

Genetic testing is carried out via quantitative analysis of both SMN1 and SMN2 using multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase chain reaction (qPCR) or next generation sequencing (NGS)1

The absence of both full SMN1 copies provides a diagnosis of SMA. If only 1 full copy is present and clinical phenotype is compatible with SMA, the remaining SMN1 gene should be sequenced looking for other subtle mutations1

The number of SMN2 copies is not essential to reach a diagnosis of SMA but should be assessed as an important factor influencing the severity of the SMA phenotype1

Reference
  • 1. Mercuri E, et al. Neuromuscul Disord. 2018;28(2):103–15.

19) Can spinal muscular atrophy (SMA) be detected during pregnancy?

Yes, prenatal testing for pregnancies at increased risk is possible if the diagnosis of SMA has been confirmed by molecular genetic testing in an affected family member

Although it would be predicted that a fetus with the same genotype (i.e., molecular genetic test result) as a previously affected sibling would have similar clinical findings, there can be intrafamilial variability in phenotypic presentation

An survival motor neuron 2 (SMN2) copy number determination on the prenatal specimen may help to better predict the phenotype of the affected child. Interpretation of test results and prediction of clinical findings in an affected child may be difficult and should be done in the context of formal genetic counseling1

Reference
  • 1. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.

20) What is the life expectancy of a child with spinal muscular atrophy (SMA)?

This depends on the type of SMA the child has and whether they are receiving any disease-modifying therapies1

Typical life expectancy in untreated SMA:1–3

  • Type 1: <2 years
  • Type 2: 70% alive at 25 years
  • Type 3: Normal
  • Type 4: Normal

As current therapies are novel, how these will impact life expectancies for the different SMA types is not yet clear1

References
  • 1. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 2. Kolb SJ and Kissel JT. Neurol Clin. 2015;33(4):831–46.
  • 3. Wang CH, et al. J Child Neurol. 2007;22(8):1027–49.

21) Spinal muscular atrophy (SMA) differential diagnosis vs: Duchenne muscular dystrophy; amyotrophic lateral sclerosis (ALS); cerebral palsy

Certain signs of SMA are readily identifiable, but symptoms can overlap with other common infantile neuromuscular diseases (NMDs)1,2

Hypotonia is the most common reason for referral in children with NMDs but other signs and symptoms are often described by parents of children with suspected NMDs1

Disorders to consider in the differential diagnosis of SMA:3

Duchenne muscular dystrophy:3

  • Signs in common: muscle weakness and motor regression
  • Signs distinct: serum creatine kinase concentration >10–20x normal

Amyotrophic lateral sclerosis (ALS):3

  • Signs in common: often begins with lower motor neuron signs
  • Signs distinct: onset in adulthood only, progressive neurodegeneration involves both the upper and lower motor neurons

Cerebral palsy:3,4

  • Signs in common: hypotonia and weakness, delay in motor development
  • Signs distinct: spasticity, dystonia, ataxia, choreoathetosis, hyperreflexia and incoordination
References
  • 1. McDonald CM. Phys Med Rehabil Clin N Am. 2012;23(3):495–563.
  • 2. Lee HN and Lee Y-M. J Genet Med. 2018;15(2):55–63.
  • 3. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
  • 4. Hallman-Cooper JL and Rocha Cabrero F. Cerebral Palsy. 2021 Jan [Updated 2021 April]. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan.