Spinal Muscular Atrophy: A Comprehensive Review of Newborn Screening, Treatment, and Ethical Considerations

Understanding Spinal Muscular Atrophy (SMA) and the Importance of Early Detection

Spinal Muscular Atrophy (SMA) is a rare genetic neuromuscular disorder characterised by significant morbidity and mortality. The condition results in irreversible degeneration of motor neurons in the spinal cord, leading to progressive muscle wasting and weakness. The severity of SMA varies across a gradient, with some individuals experiencing mild symptoms and others facing life-threatening complications.

Newborn screening for SMA has emerged as a potential strategy for early identification and intervention. The proposed screening method accurately identifies homozygous deletions of the SMN1 gene. These are associated with at least 95% of cases of SMA. However, it does not detect cases of SMA that do not involve homozygous SMN1 gene deletion, accounting for 2-5% of SMA cases.

The benefit of screening is largely tied to earlier access to disease-modifying treatment. Leading to improved clinical outcomes for those who would otherwise develop type I to type III disease. The correlation between SMN2 copy number and SMA type is not perfect. Making it impossible to predict with certainty which patients will develop severe disease. As such, the benefit-harm balance in the context of screening varies.

Ethical and Clinical Considerations in SMA Screening

One should consider if the screening aim is to identify all SMA cases resulting from a homozygous deletion of SMN1 or to pinpoint cases most likely to develop significant clinical disease. We could devise a screen positivity definition based on SMN2 copy number. However, this method poses ethical challenges. These include the potential harm to children who could have been identified through screening and the implications of labelling babies with a condition without a clear correlation between genotype and phenotype.

The treatment landscape for SMA is rapidly evolving. These include three SMN-dependent drugs licensed by the European Medicines Agency: nusinersen, onasemnogene abeparvovec (OA), and risdiplam. Treatments aim to increase the production of the SMN protein and thereby alter disease processes. However, their high cost and the lack of long-term effectiveness data contribute to significant uncertainty regarding the cost-effectiveness and affordability of screening.

Implementing SMA Screening within the Current Newborn Bloodspot Screening Program

Implementing SMA screening within the current Newborn Bloodspot Screening Program (NNBSP) is anticipated to result in minimal changes to the overall practice. The addition of SMA screening would necessitate updates to written material and processes associated with informed consent for testing. Laboratory considerations for SMA screening involve the same PCR-based technology as screening for severe combined immunodeficiency (SCID). Thus, enabling operational efficiencies in terms of equipment requirements, physical space requirements, training needs of staff, and verification and screening processes. The incremental budget impact associated with the addition of SMA screening to the NNBSP was estimated at approximately €17.7 million over a five-year time horizon. The majority of expenditure related to drug costs, primarily due to changes in treatments received by individuals under screening.

Evaluating the Cost-Effectiveness of Newborn SMA Screening

The international evidence on the cost effectiveness of newborn screening for SMA varies greatly. This variation stems from changes in treatment methods over time and different methodological approaches. Some studies claim that newborn bloodspot screening for SMA saves costs. This is particularly true when a significant number of patients identified by screening receive OA treatment. However, other studies report high costs per quality-adjusted life year (QALY) gained. These findings suggest that newborn bloodspot screening with nusinersen treatment might not be cost-effective. The evidence base has limitations, such as the lack of long-term clinical effectiveness data and evidence for those with higher copy numbers. Therefore, we cannot draw definitive conclusions on the cost effectiveness of screening. 

The suggested screening tool for SMA shows promise as it can detect a significant percentage of SMA cases tied to SMN1 homozygous deletions. However, the method isn’t flawless as there is no perfect correlation between SMN2 copy number and SMA type. This means it cannot predict the severity of the disease. We must weigh the clinical benefits of screening, such as early detection and treatment, against the risks and ethical issues it presents. These include the chance of missed diagnoses and the ethical dilemmas that emerge when a baby’s genotype and phenotype do not obviously link. The cost-effectiveness and affordability of the screening program remain uncertain. This is due to the unclear epidemiology of SMA types, advances in treatment, lack of long-term effectiveness data, and reimbursement criteria. Therefore, we must monitor the results closely whenever we suggest screening to maximize the benefits of the program and address these uncertainties.