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Spinal Muscular Atrophy (SMA): Genetics, Diagnosis, Treatment, and the Promise of Newborn Screening

24 July 2023

Author: Tamsin Glenwright, Molecular Biology Technical Sales Specialist at VH Bio

Spinal Muscular Atrophy (SMA) is a devastating group of autosomal recessive disorders that profoundly affects individuals and their families. Caused by deletions or mutations of the Survival Motor Neuron Gene 1 (SMN1), SMA ranks as the second most fatal autosomal recessive disorder in children, just after Cystic Fibrosis(1). This comprehensive blog piece will delve into the genetics of SMA, how it is diagnosed, the available treatment options, and the promising prospects of SMA Newborn Screening.

What is Spinal Muscular Atrophy?

SMA leads to the degeneration and loss of functionality of motor neurons in the spinal cord, resulting in muscle weakness and hypotonia in the neck, trunk, legs, arms, and even breathing muscles. The severity of symptoms varies based on SMA type (table 1), categorised as type I (around 60% of cases), type II (~30%), and type III (~10%)(3).

Table 1: SMA disorders are categorised based on onset age and symptom severity.

SMA type Milestones Onset age Life expectancy SMN1 Copy numbers
0 None Achieved Birth potentially fatal within 1 month 1
I (Werdnig-Hoffman disease) No ability to sit, minimal head control 0-6 months potentially fatal within 2 years 2
II No ability to walk/stand independently < 2 years old, delayed developmental milestones, life expectancy to young adulthood Young adulthood 3
III (Kudelberg-Welander disease Limited walking/independent standing >18 months Adulthood 3-4
IV Ability to sit, stand and walk 10-30 years Adulthood >4


Genetics and Causes of SMA

SMA is a result of genetic mutations, with 94-98% of SMA sufferers having homozygous exon 7 deletions within the SMN1 gene(2). This mutation leads to the skipping of exon 7 during RNA transcription, producing non-functional SMN proteins. As a consequence, motor neuron cells, crucial for transmitting nerve signals from the spinal cord to muscles, begin to die. SMA carriers, who have one functional copy of SMN1 on one chromosome and the deletion on the other chromosome (heterozygous deletion), do not exhibit symptoms but can pass the mutation to their children in a recessive fashion (at a frequency of 1/50)(1).

Diagnosing SMA

Accurate and timely diagnosis is vital for SMA management. Diagnostic tests involve quantifying the number of copies of SMN1 present in a patient’s DNA using a blood sample. This helps to confirm SMA and determine the specific type. However, due to several multi-genic factors, quantification of SMN1 copy numbers alone can detect around 71-95% of cases (depending on ethnicity)(2). Additionally, the presence of the SMN2 gene, producing SMN protein in smaller quantities due to alternative splicing, influences a patient’s SMA phenotype. The copy number of SMN2  can vary greatly in the population, with most patients retaining at least one copy but can range up to 4 copies(1). Determining the copy number of the SMN2 gene aids in assessing disease severity, patient prognosis, and treatment decisions.

Diagnostic methods such as Polymerase Chain Reaction followed by Capillary Electrophoresis (PCR/CE), Multiplex Ligation-Dependent Probe Amplification (MLPA), or Next-Generation Sequencing (NGS) can be utilised to determine the SMN1 and SMN2 copy number of a patient. PCR/CE methods tend to be quicker and simpler when compared to MLPA based workflows. However, with these techniques, further sequencing may be required to identify specific complex mutations. NGS technologies can provide comprehensive coverage across related genes and allow labs to test for many rare diseases simultaneously, but can be time-intensive and require specialised trained staff and equipment which can be costly to diagnostic labs.

Treatment Options for SMA

Promisingly, several approved SMA treatment drugs, including Spinraza (nusinersen), Zolgensma, and Risdiplam, have revolutionised care for SMA sufferers. Spinraza and Risdiplam are anti-sense oligonucleotides that alter post-transcription splicing of the SMN2 gene, boosting the production of functional SMN protein. Furthermore, Gene Therapy, an investigational treatment, shows potential by introducing new functional SMN1 genes into a patient’s DNA. Early diagnosis plays a pivotal role in timely administration of these treatments, preventing disease progression and excessive neuron degradation.

SMA Newborn Screening

Implementing SMA Newborn Screening schemes offers the prospect of maximising therapeutic benefits through early intervention.  Identifying SMA patients using NBS schemes prior to symptom onset significantly improves patient outcomes, especially in those with more severe phenotypes(3). In new-born screening schemes, a sample of blood is taken from a heel-prick and stored as a dried blood spot on an absorbent Guthrie card. This sample can be tested for several genetic disorders simultaneously. As SMN1 is the primary indicator of disease, a positive result for SMN1 deletion alone could be used to highlight SMA sufferers and trigger further testing to determine SMN2 copy number.

The SMA NBS alliance has recommended implementing a SMA NBS scheme across Europe by 2025 (Map – SMA Newborn Screening Alliance), although its realisation requires consideration of extensive genetic counselling capabilities and economic impact on healthcare systems. A pilot study in the UK is currently evaluating the efficiency and economic viability of including SMA in the Newborn Screening scheme (First UK pilot study of new-born screening for spinal muscular atrophy launched in Oxford | University of Oxford), showing promising potential for early diagnosis and substantial cost savings.

Amplidex® PCR/CE SMA Plus Kit: A Breakthrough in SMA Testing

In partnership with Asuragen, VH Bio Ltd offers the Amplidex® PCR/CE SMA Plus Kit, a CE-IVD accredited in-vitro nucleic acid amplification kit that simplifies SMA screening and diagnosis. This kit allows for simultaneous quantification of the number of copies of exon 7 for both SMN1 and SMN2 and can detect four common variants associated with disease modification. With a quick and simple workflow time of only 60 minutes, it offers faster turnaround times for obtaining results than traditional MLPA methods. The Amplidex® Reporter software, included with the kit, aids Healthcare Scientists in easily analysing raw data and creating clinical reports within minutes. For more information about the Amplidex® kit and software and their applications within the UK and Ireland, please contact [email protected].


Spinal Muscular Atrophy is a complex and devastating group of disorders, demanding timely diagnosis and early intervention to improve patient outcomes. With promising treatments available and ongoing research, there is hope for a better future for those affected by SMA. By raising awareness, supporting research efforts, and advancing SMA Newborn Screening programs, we can make a significant impact in the fight against this life-changing condition.

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(1) D’Amico, A., Mercuri, E., Tiziano, F., & Bertini, E (2011). Spinal Muscular Atrophy. Orphanet Journal of Rare Diseases, 6(71).

(2) Milligan, J., Blasco-Perez, L., Costa-Roger, M., Codina-Sola, M., & Tizzano, E. (2022). Recommendations of interpreting and reporting silent carrier and diseases modifying variants in SMA testing workflows. Genes, 13(9).

(3) Glascock, J., Jacinda, S., Haidet, Phillips, A., Connolly, A., Darras, B., Day, J., Finkel, R., Howell, R., Klinger, K., Kuntz, N., Prior, T., Shieh, P., Crawford, T., Kerr, D., Jarecki, J. (2018). Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. Journal of Neuromuscular Diseases, 5(2), 145-158.

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