The implementation of newborn screening for spinal muscular atrophy: the Australian experience

Kariyawasam, Didu; Russell, Jacqueline S.; Wiley, Veronica; Alexander, Ian E.; Farrar, Michelle A.

doi:10.1038/s41436-019-0673-0

Cited by 111 publications

(120 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Preliminary results of the SMA newborn screening program in Australia reported 9 positive cases, but none had 4 SMN2 copies. 37 It is important to highlight that copy number studies in positive patients detected by newborn screening should be performed in expertise centers and with a validated methodology. In the shared decision to immediately start treatment of neonates with 4 SMN2 copies or delay the initiation of treatment, several alternatives-each with advantages and disadvantages-have to be considered (outlined in table 5).…”

Section: Yesmentioning

confidence: 99%

Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy

et al. 2020

View full text Add to dashboard Cite

ObjectiveAssessment of SMN2 copy number in patients with spinal muscular atrophy (SMA) is essential to establish careful genotype-phenotype correlations and predict disease evolution. This issue is becoming crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatment, as this value is critical to stratify patients for clinical trials and to define those eligible to receive medication. Several technical pitfalls and interindividual variations may account for reported discrepancies in the estimation of SMN2 copy number and establishment of phenotype-genotype correlations.MethodsWe propose a management guide based on a sequence of specified actions once SMN2 copy number is determined for a given patient. Regardless of the method used to estimate the number of SMN2 copies, our approach focuses on the manifestations of the patient to recommend how to proceed in each case.ResultsWe defined situations according to SMN2 copy number in a presymptomatic scenario of screening, in which we predict the possible evolution, and when a symptomatic patient is genetically confirmed. Unexpected discordant cases include patients having a single SMN2 copy but noncongenital disease forms, 2 SMN2 copies compatible with type II or III SMA, and 3 or 4 copies of the gene showing more severe disease than expected.ConclusionsOur proposed guideline would help to systematically identify discordant SMA cases that warrant further genetic investigation. The SMN2 gene, as the main modifier of SMA phenotype, deserves a more in-depth study to provide more accurate genotype-phenotype correlations.

show abstract

Section: Yesmentioning

confidence: 99%

Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The data from human trials also support the importance of a therapeutic window for a SMN-augmented treatment [60]. Unfortunately, SMA newborn screening programs have not yet been extensively performed worldwide or even nationwide [61,62]. On the other hand, patients with later-onset type 2 SMA showed significant motor improvement after treatment [63]; however, whether the long-term effect will be seen when treatment is initiated in the later SMA phase with slow decline is still unclear [64].…”

Section: Nusinersen: the First Approved Splicing-modify Therapy For Smamentioning

confidence: 89%

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

Chen

2020

IJMS

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.

show abstract

“…44 On the other hand, the Australian pilot study reported only patients with 2 and 3 copies. 45 This was to avoid possible psychological harm by providing an early diagnosis with no immediate option for therapeutic intervention due to the reimbursement of nusineresen in Australia only for patients younger than 18 years and with disease onset <3 years. SMA was diagnosed in 9/103,903 newborns (frequency of potential SMA1 and SMA2 1:11545).…”

Section: Risdiplam (Evrysdi)mentioning

confidence: 99%

“…In the previously cited German and Australian pilot studies, attention was drawn to a very narrow therapeutic window for patients with acute SMA. [43][44][45] Four of the nine children identified in the Australian study had symptoms of the disease between 16 and 33 days of life. In one child, the full symptoms of SMA were present on day 16.…”

Section: Patients Diagnosed In Nbs -Too Late or Too Early For Treatment?mentioning

confidence: 99%

<p>Advances in Newborn Screening and Presymptomatic Diagnosis of Spinal Muscular Atrophy</p>

Jędrzejowska

2020

DNND

View full text Add to dashboard Cite

Spinal muscular atrophy 5q (SMA5q) is one of the most severe and common genetic diseases. In the natural course, the disease leads to premature death (in acute forms) or severe motor disability (in chronic forms). As the genetic basis of SMA is very homogenous, the diagnostics are based entirely on simple and sensitive genetic testing. In the last few years, innovative methods of therapy have been developed based on SMN2 gene modification, such as splicing, or replacement of the damaged SMN1 gene (gene therapy). Although these approaches have shown high efficacy, results depend on the age/disease stage at which therapy is initiated. The best results have been obtained in presymptomatic patients. Indeed, introduction of therapy in the pre- or early symptomatic stage of the disease seems to be crucial for maximizing effects. Thus, all the criteria for the implementation of neonatal screening for SMA have been met, and many countries, ie, the USA, Germany, Belgium, and Australia, have started NBS national/pilot programs for SMA. The initial results of these programs indicate a high frequency of the disease, reaching 1 per 7 thousand live births in Europe, as well as early symptomatology (first weeks of life in severe cases) and a high frequency of patients with 4 SMN2 copies. Overall, the time for therapy inclusion in patients with 4 SMN2 copies remain under discussion. More precise predictors/biomarkers of the clinical course are needed. At the same time, it seems advisable to offer other solutions, such as population carrier screening. As the long-term effects of different treatments on the natural history of SMA are unknown, the natural history of the disease needs to be re-evaluated.

show abstract

The implementation of newborn screening for spinal muscular atrophy: the Australian experience

Cited by 111 publications

References 29 publications

Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy

Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

<p>Advances in Newborn Screening and Presymptomatic Diagnosis of Spinal Muscular Atrophy</p>

Contact Info

Product

Resources

About