The changing face of Spinal Muscular Atrophy

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Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care. Schorling DJ, Peachmann A, Kirschner J. Journal of Neuromuscular Disease (2020)  vol. 7, no. 1, pp. 1-13, 2020 .

Overturning the Paradigm of Spinal Muscular Atrophy as just a Motor Neuron Disease. Jing Yeo CJ, Darras BT. Paediatric Neurology (2020).

False Negative Carrier Screening in Spinal Muscular Atrophy. Butcher S, Smith M, Woodcock I, Dalatycki M, Ryan M, Forbes R. Journal of Child Neurology 2020, Vol. 35(4) 274-277.

A Prospective, Crossover Survey Study of Child- and Proxy-Reported Quality of Life According to Spinal Muscular Atrophy Type and Medical Interventions. Weaver M, Hanna R, Hetzel S, Patterson K, Yurrof S, Sund S, Schultz M, Schroth M, Halanski M. Journal of Child Neurology 2020, Vol. 35(5) 322-330.

Advances in treatment of Spinal Muscular Atrophy (SMA) has been topical for a number of years. As new treatment options continue to gain FDA approval, the “snowball effect” continues to bring new insights into SMA management. Changing phenotypes, need for earlier patient identification and carrier testing, additional treatment avenues and the shifting of more attention to the non-neuromuscular aspects of SMA and quality of life were in the past, overwhelmingly overshadowed by the devastating neuromuscular consequences of SMA. The 4 articles that we have selected address some of these issues.

The articles in our review are include:

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care. Schorling DJ, Peachmann A, Kirschner J. Journal of Neuromuscular Disease (2020) vol. 7, no. 1, pp. 1-13, 2020 .

Overturning the Paradigm of Spinal Muscular Atrophy as just a Motor Neuron Disease. Jing Yeo CJ, Darras BT. Paediatric Neurology (2020).

False Negative Carrier Screening in Spinal Muscular Atrophy. Butcher S, Smith M, Woodcock I, Dalatycki M, Ryan M, Forbes R. Journal of Child Neurology 2020, Vol. 35(4) 274-277.

A Prospective, Crossover Survey Study of Child- and Proxy-Reported Quality of Life According to Spinal Muscular Atrophy Type and Medical Interventions. Weaver M, Hanna R, Hetzel S, Patterson K, Yurrof S, Sund S, Schultz M, Schroth M, Halanski M. Journal of Child Neurology 2020, Vol. 35(5) 322-330.

The first article focuses on the new treatment modalities and where we are at, in terms of treatment options and the direct implications of the new treatment modalities such as drug selection, delivery and candidate selection.

The second article focus on the non-neuromuscular aspects of SMA and how treatment may affect these aspects that in the past where completely overshadowed by the relentless neuromuscular degeneration that is now curtailed with emerging therapy.

The third article looks at carrier testing reports on a case of false negative results in expecting parents.

The fourth article reports of quality of life as an outcome of medical interventions and SMA type.

Commentary by 

Britta McLaren and Phindi Mteshana

Paediatric Neurology Fellows, University of the Witwatersrand


Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care Schorling DJ, Peachmann A, Kirschner J.


Splicing Modification of SMN2

Nusinersen (Spinaraza) (FDA approved 2016)

Administered Intrathecally and Chronically.

It is an antisense-oligonucleotide (ASO) that enhances the inclusion of exon 7 in mRNA transcripts of SMN2. SMN2 is a gene that is almost homologous to SMN1 (95% of SMA cases are caused by homozygous deletions and less frequently point mutations in the SMN1 gene). SMA’s vast phenotype is attributable to variable numbers of the SMN2 gene because it can produce small numbers of full-length and fully functional SMN-protein in the absence of SMN1. In healthy individuals SMN2 has no relevance, but in SMA patients – the more copies of SMN2 gene they have, the more fully functional SMN-protein will be produced, resulting in a less severe phenotype.

SMA type 1 has 1-2 copies of SMN2. SMA type2 has 2-3 copies of SMN2. SMA type 3 has 3-4 copies. SMA type 4 has 5 or more copies.

The reason SMN2 is normally only responsible for a small number of functional SMN protein is because a single nucleotide transition causes predominant exon 7 skipping and mainly results in the production of unstable protein, with only a small amount of stable protein.

ASO’s like Nusinersen enhances the inclusion of exon 7 in mRNA transcripts of SMN2 this results in an increased proportion of SMN2-mRNA with included exon 7 and therefore more functional full-length SMN2 protein.

Patients treated with intrathecal Nusinersen have shown prolonged time to death or need for permanent ventilation and significantly improved motor ability and the studies have been terminated early due to good results. This drug is especially effective when started pre-symptomatically

Risdiplam and branaplam (Not FDA approved yet – Phase II studies ongoing)

Small molecules - RG7916 and LMI070 respectively. Administered orally (chronically) and cross the blood brain barrier to increase SMN2 expression in spinal motor neurons.

Interim reports show significant improvement in motor function with 41% of infants with SMA type 1 starting treatment between 1 and 7 months of age attaining independent sitting after a medium treatment duration of 14.8 months and 58% of patients with all types of SMA (age 6 months to 60 years) showing significant improvement in motor function scales.

Other types of small molecule ASO are in early development

Gene therapy with replacement of SMN1-gene

Zolgensma (AVXS-101) (FDA approved for intravenous application in May 2019)

It is a single intravenous infusion for patients <2 years old. It crosses the blood brain barrier. An Adeno-Associated Viral serotype 9 vector delivers an intact copy of wild-type SMN1. Comparison to a natural history cohort confirmed the improvement of survival, motor function and milestones by Zolgensma. Intrathecal use is now being studied in children – initial animal studies have shown that improved gene expression is achieved with lower doses of viral vectors with intrathecal use.

Upregulation of muscle growth


Myostatin is a member of the TGF-ß superfamily of growth factors that inhibits muscle over-growth and is primarily expressed in skeletal muscle. Myostatin inhibitor SRK-015 is in Phase II trials and has resulted in improved muscle mass and function in SMA-mice. Other Myostatin inhibitors: Activin Receptor Type IIB-antagonists and stand-alone approaches like inhibition of the p38MAPK pathway are in early development.

Fast Skeletal Muscle Troponin Activators (FSTA)

E.g. CK-2127107 (reldesemtiv) Slows the release of calcium leading to improved contractibility of muscle fibres and function. Interim reports show a mild but statistically significant improvement in the 6-minute walk test (6MWT).

Small molecules aiming to stabilize the SMN-protein

In early development


Validated biomarkers are necessary to predict the clinical course and response to drug treatment and improve clinical decision making.

They include:

Plasma phosphorylated neurofilament heavy chain (pNF-H)

Levels in symptomatic SMA 1 patients are higher than in healthy controls. Levels correlate positively with earlier onset of symptoms and inversely with motor function. Under treatment with Nusinersen, levels fall faster than in the control groups and this decrease is more pronounced the earlier treatment is started. Not useful in CSF measurement.

NSE and pTAU-protien

Show significant decrease under treatment

Electrophysiological biomarkers such as compound muscle action potential and motor unit number estimation.


Effect size of SMN2 splicing modification and gene therapy depends on the age of start of treatment. Most impressive results are when treatment is started before the first clinical symptoms become apparent.

** Denervation progresses rapidly during the first 6 months of life – rescue of these motor neurons before the denervation process is essential. Newborn screening is therefore necessary to identify patients in the pre-symptomatic stage.

Pilot projects using quantitative PCR (qPCR) assays to detect homozygous deletions in either exon 7 or intron 7 of SMN1 via dried blood spot analysis are underway. One assay also detects heterozygous carrier detection, and none are able to detect point mutations or SMN2 copy numbers. The qPCR has a positive predictive value of 100%. Techniques to decrease cost include simultaneous screening for severe combined immune deficiency (SCID). NBS for SMA is already implemented in some states and parts of Europe.

Once patients are detected with NBS, the issue of who should be treated is controversial. Two SMN2 copies were associated with SMA type 1 in 90% of patients. In patients with 3 or more copies, the clinical course and age of onset is more difficult to predict.

The consensus is that treatment should be initiated immediately in truly asymptomatic patients with one SMN2 copy and in infants with two or three copies with or without symptoms. Those with four or more copies should be closely monitored and only treated after the onset of signs or symptoms. This is a pragmatic approach but may be oversimplified and doesn’t consider modifying factors that can mitigate or exacerbate the clinical course.


Disease trajectories now differ significantly from pre-treatment patients. It is now possible that patients with SMA type 1 can sit. To define clinical phenotypes in the context of new treatment modalities, it is now more appropriate to use a combination of:

  1. Age of onset.
  2. Number of SMN2 Copies
  3. Age of start of drug treatment

Counselling of parents should also incorporate new expectations in light of treatment effects. Some pre-symptomatic children in which treatment is initiated, may have normal motor development. In severe, prenatal, type 0 SMA – treatment is less likely to have relevant improvements and is therefore not advisable.


In rare diseases such as SMA it is almost inevitable that post-hoc reports will surface after a drug has been approved, due to the weaker evidence on which drug approval is granted. In post approval publications, the results have been slightly less positive, especially with respect to ventilation and nutritional support, with increased tracheostomy / permanent ventilation and feeding tube placement, even in patients with motor improvements – possibly treatment is less effective on respiratory and bulbar muscles or these centers have a more aggressive approach then pre-approval studies.

There is very little data available on treatment in SMA type 2, 3 and 4 and it is difficult to predict the effect in these patients. The duration of treatment effects is also difficult to predict.

The collection of real-world data via registries with standardised outcomes is necessary to better understand these issues.


Despite improvements in motor function, scoliosis is reported at a higher rate – this needs to be surveyed for and treatment options such as a ‘growing rod’ need to be explored. Furthermore, scoliosis can make intrathecal administration difficult, as can spinal surgery. Surgical ‘bone gaps’ and fluoroscopy, intrathecal catheters and cervical puncture are options to consider.


Overturning the Paradigm of Spinal Muscular Atrophy as just a Motor Neuron Disease - Jing Yeo CJ, Darras BT.

SMA is typically characterised as a motor neuron disease and untreated patients with SMA Type 1 die early. Such patients are now living longer due to new treatment modalities as discussed above. This has created a new area of clinical need: As these patients survive into childhood and adulthood, dysfunction of peripheral tissues and organs may become significant comorbidities.

This paper looks at the evidence for peripheral tissue involvement in SMA and whether the peripheral or the central expression of SMN is necessary and or sufficient for motor neuron function and survival. This question is especially relevant considering the intrathecal use of certain disease modifying drugs which may not increase peripheral expression of SMN.

Evidence that non-motor neuron cell autonomous SMN rescue AND motor neuron cell autonomous SMN rescue is important for motor neuron function and survival

In mice studies: ASO administered systemically by subcutaneous injection improves survival in severe SMA mice. Survival is also improved by intracerebroventricularly administered ASO. Survival is best when administered both subcutaneously and intracerebroventricularly. This data demonstrates the important role of peripheral SMN expression in tissues such as the kidney, liver and skeletal muscle in driving motor neuron pathology and in survival.

Systemically administered ASO can penetrate the blood brain barrier (BBB) and likewise intracerebrovascularly administered ASO can cross into the periphery. When techniques are employed to neutralise these effects, interestingly, abrogation of the effect of ASO in the brain and spinal cord in peripherally administered ASO did not reduce survival, motor function, motor neuron counts or neuromuscular integrity. This provides evidence for the importance of peripheral expression of SMN in maintaining the motor neuron and evidence that non-motor neuron cells contribute to SMA pathology.

The BBB permeability of ASOs plays an important role and agents with high BBB permeability in some studies have shown equal effects when administered intracerebroventricularly and intravenously – probably due to simultaneous increased peripheral and central SMN2 expression.

Overall these studies support both a central and peripheral role of SMN in maintaining motor function and how this translates in children and adults with SMA is yet to be seen.

Does expression of the SMN protein have a non-motor function in peripheral tissues and organs?

SMN is ubiquitously expressed in almost all tissues with the highest expression being during embryogenesis. It has a fundamental role in cellular processes which is why complete depletion leads to death in early embryonic development. Overall, evidence in human and animal studies show that SMN deficiency is implicated in tissue degeneration as well as tissue development and is differentially required by different organs and tissues – peripheral expression in milder phenotypes could be sufficient to maintain function in some tissues and is probably moderated by other factors (such as IGF ß). These findings are supported by a study of insurance claims in patients with SMA type 1 to 4 which show numerous non-neuromuscular claims.

The non-motor neuron effects of SMN deficiency are summarised below:

Skeletal Muscle:

In SMA there is dysregulation of muscle growth and differentiation. Delayed maturation and impaired expression of acetylcholine receptors and mitochondrial dysfunction is implicated as the cause. This is independent of and prior to the effects of denervation that occurs with SMA. In animal studies, expression of SMN in muscles alone makes no difference to survival, whereas expression in neurons rescues the phenotype suggesting the SMN rescue in muscles alone is not sufficient to rescue the phenotype, despite changes in muscle that are independent to the motor neuron.


Patients with SMA 0 and 1 been found to have cardiac abnormalities (congenital structural defects, dilated cardiomyopathy - survivin dysregulation is implicated as the cause). This is ‘dose-dependent’ effect as patients with SMA 2 and 3 do not have cardiac abnormalities.

Autonomic nervous system:

Symptomatic bradycardia, orthostatic intolerance, cold intolerance and abnormal vasodilation have been noted with increased incidence.


Microvascular injury, reduced numbers of endothelial progenitor cells, impaired vascular repair are seen.


Intolerance to bolus feeding, poor motility and abnormal intestinal villi are seen.


Fatty liver, dyslipidaemia and dysregulation of IGF1 are seen.


Decreased insulin producing cells in pancreatic islets is seen.

Bone and connective tissue:

RANK signalling defects, osteopenia, joint hypermobility, joint pain, abdominal hernias and poor wound healing have been reported.


Proteinuria, renal tubular dysfunction, nephrocalcinosis and medullary fibrosis are reported.

Spleen and immune dysfunction:

Acute phase response in liver and gut bacteria translocation are seen.

These systemic features of SMA may become significant comorbidities in patients with SMA 1 who are now living longer due to SMN rescue therapies, especially those receiving CNS- directed treatment. It is likely that peripheral rescue of SMN is necessary to improve long term survival and well-being of patients with SMA.

Biomarkers such as neurofilament to measure motor neuron survival (discussed in the previous article) will become increasingly important.

SMN has a necessary role in both central and peripheral tissue – both for motor neuron cell and non-motor neuron cell survival. The peripheral SMN expression probably modulates motor neuron cell survival through expression of neurotrophic factors. Understanding these factors will provide other avenues of treatment possibilities.

Nusinersen is only given chronically and intrathecally at this time, small molecules that are given orally such as Risdipalm will probably provide CNS and peripheral SMN expression – this is currently under investigation. Single dose Adeno-Associated Viral Vector-mediated gene therapy is given once off, intavenously and can rescue SMN in the periphery and centrally (crosses BBB). Peripheral rescue is likely to be short term with this gene therapy as the peripheral tissues continue to replicate. The feasibility of repeated gene therapy is still to be investigated.


False Negative Carrier Screening in Spinal Muscular Atrophy  - Butcher S, Smith M, Woodcock I, Dalatycki M, Ryan M, Forbes R.

This paper reports an interesting case of a couple who underwent prenatal screening whereby the mother was confirmed to have a single Survivor Motor Neuron (SMN) 1 exon 7 deletion and her husband showed no deletion (2 copies of the SMN1 exon 7). The baby was well at birth and was discharged home. At four weeks the baby presented with signs of Spinal Muscular Atrophy (SMA) type 1 and was confirmed to have a single SMN1 gene deletion. In this scenario, it is possible that either the father was a carrier of an unusual mutation that was missed by the prenatal screening that is based on qPCR and MLPA. Or, the baby had an unusual ‘de novo’ mutation in the remaining SMN1 gene. After further testing, it was discovered that the father was a carrier of an unusual SMN1 ‘de novo’ mutation. The baby did show improvement in her motor function after treatment was started.

SMA is inherited in an autosomal recessive (AR) pattern. It is the second most common AR condition after cystic fibrosis and is one of the leading causes of morbidity and mortality in children under the age of two years. Carrier screening is essential in order to give couples reproductive choices as well as early diagnosis and treatment for the baby.

95% of SMA cases are due to a homozygous deletion of SMN1 exon7. Heterozygous carriers of an SMN1 deletion can be identified by a quantitative polymerase chain reaction (qPCR) or multiplex ligation-dependent probe amplification (MLPA). However, 5% of SMA carriers carry a different variant within the SMN1 gene, and not the classic SMN1exon 7 deletion. The qPCR / MLPA alone is likely to miss these variants. Gene sequencing is necessary to identify these carriers, but it is costly.

In the event that one parent shows a SMN1 gene deletion and the other does not, gene sequencing could be performed on the parent without the deletion in order to detect other variants of SMN1 gene mutations. Alternatively, the infant can be tested at birth for early identification and treatment.

This case demonstrates the limitations of antenatal screening with qPCR/ MLPA modalities and a high index of clinical suspicion still remains important for early diagnosis and treatment of SMA. Diagnostic screening may be necessary regardless of the prenatal risk prediction. The available carrier screening tests may give a false negative results for SMA if gene sequencing is not done.


A Prospective, Crossover Survey Study of Child- and Proxy-Reported Quality of Life According to Spinal Muscular Atrophy Type and Medical Interventions - Weaver M, Hanna R, Hetzel S, Patterson K, Yurrof S, Sund S, Schultz M, Schroth M, Halanski M.

Survival and quality of life in children with spinal muscular atrophy (SMA) are both important outcome measures in the management of children with SMA. Most interventions in SMA management, such as assistive respiratory devices, gastrostomy tubes, spinal surgery and more recently pharmaceutical intervention, such as Nusinersen are aimed mainly at extending survival but what impact do they have on quality of life? There is not a lot of research that has been that aims to answer this question from a patient / family perspective.

Study type

Prospective longitudinal crossover survey study


To report on the quality of life and family experience for children with spinal muscular atrophy using validated scales for spinal muscular atrophy patient- and proxy-reported outcomes with attentiveness to patient and proxy concordance.


All patients with a diagnosis of SMA receiving neuromuscular consultation care at the American Family Children’s Hospital Specialty Clinics, in Midwest America, from November 2016 to September 2018 were eligible for enrolment. The study setting was a tertiary academic-affiliated referral centre with a longstanding history of multidisciplinary neuromuscular care.


Neuromuscular clinic patients are seen twice per year. The participants were randomized to receive either the Peds QL 3.0 Neuromuscular Module (for child report and proxy report) COUPLED with the Peds QL Family Impact Module at their odd visit (first bi-annual visit) OR the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire. At their even visits (second bi-annual visit), the participants were crossed over so that arm 1 completes the CPCHILD questionnaire and arm 2 completes the Peds QL 3.0 Neuromuscular Module (for child report and proxy report) COUPLED with the Peds QL Family Impact Module Mod .


Children’s reports on their quality of life and family experiences for children with SMA. Impact of SMA type on quality of life as reported by children and their caregivers. Impact of medical interventions (like respiratory support, gastrostomy tube, spinal surgery and nusinersen) on quality of life as reported by children and their caregivers.


Quality of life by SMA type:

The Peds QL Family Impact Module questionnaire demonstrated significant differences between SMA types I and II in key functioning domains (physical, emotional, social); family relations; family functioning; and parent quality of life scales. Children’s scales were consistently higher than the correlating parent’s perception of the child’s quality of life. Authors thought that this may be a function of ego-resiliency, or advanced levels of children’s coping strategies, or that this is the child’s known norm.

Impact of medical interventions:

Respiratory support

Better quality of life reported by those who were not ventilated (patient and proxy reports) No difference to the family

Gastrostomy tube

Better quality of life reported by those without gastrostomy tubes (patient and proxy reports)

Nusinersen use

Patient and proxy reports show better quality of life for those on nusinersen, but this is not statistically. Parental quality of life and family impact scores were worse for those taking nusinersen than for those not taking nusinersen.

Spinal surgery

Better proxy-reported quality of life after surgery Children reported lower quality of life compared with those children who had not required or undergone spinal surgery, although not a statistically significant finding.

Conclusion and limitations

This study shows meaningful and clinically significant differences in QOL and family impact reporting according to SMA type with lower quality of life reports for SMA type I as compared to SMA type II. It clearly reports better child-reported quality of life than proxy-reported quality of life.

It emphasises the needs to ‘give children a voice’ by including patient-reported quality of life in outcomes assessments, both in research and also clinically. It is hoped that new disease modifying agents may improve quality of life in the more severe SMA types, however this study did not demonstrate this. A big limitation identified by the authors however, was that the children (only 6) that had received Nusinersen in this study, had only received it for a very short period of time and perhaps longer treatment duration would be needed for a better indication of its impact on quality of life.

Although this was a “longitudinal” study, it does not represent a longitudinal / chronological assessment of interventions. It does not look at quality of life assessments before and after the particular intervention. The perceived decreased quality of life reported by patients with respiratory support, gastrostomy tubes and spinal surgery, could merely be representative of the fact that patients that have had these interventions were likely to be more severely affected by SMA than the patients that have not had these interventions, and not that these interventions decrease quality of life per se. This limitation was not identified by the authors.

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