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Newborn Screening for SMA—State of the Art
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Newborn Screening for SMA—State of the Art

A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 10006

Special Issue Editors

Dr. Mei Baker

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Guest Editor
Wisconsin State Laboratory of Hygiene, Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA
Interests: emerging technologies in newborn screening (real-time PCR, next generation sequencing, droplet digital PCR); severe combined immunodeficiency; spinal muscular atrophy; cystic fibrosis
Special Issues, Collections and Topics in MDPI journals
Dr. Enzo Ranieri

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Guest Editor
Department of Newborn Screening, Sydney Children’s Hospital at Westmead, Westmead, NSW, Australia
Interests: metabolomics in newborn screening; cystic fibrosis; spinal muscular atrophy; high resolution mass spectrometry; next generation sequencing; advanced statistical procedures in data analysis; policies and governance of newborn screening programmes
Dr. Peter C. J. I. Schielen

E-Mail Website
Guest Editor
Office of the International Society for Neonatal Screening, Reigerskamp 273, 3607 HP Maarssen, The Netherlands
Interests: (neonatal screening in) Europe; (neonatal screening and) the Wilson and Jungner criteria; lysosomal storage diseases; application of next generation sequencing in neonatal screening; inherited errors of metabolism; tandem mass spectrometry; genomics; artificial intelligence in neonatal screening; cystic fibrosis; screening policies and governance; quality assurance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In 2018, spinal muscular atrophy (SMA) was included in the Recommended Uniform Screening Panel in the USA. Since then, in Europe, the USA and Australia, countries and states have begun to evaluate, operate or plan newborn screening programs for SMA.

On December 12th and 13th, 2023, we will host a virtual meeting of leaders in the field from around the world to discuss progress in programs, laboratory techniques and ELSI aspects of SMA screening. While we already have possible submissions for this Special Issue from the speakers of the virtual meeting, we warmly invite you to submit your contribution to this important issue. Thus, we hope to have an even more complete coverage of neonatal screening for SMA.

Dr. Mei Baker
Dr. Enzo Ranieri
Dr. Peter C. J. I. Schielen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Neonatal Screening is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • SMA bith prevalence
  • screening program
  • laboratory methods
  • case definition
  • SMN1 and SMN2 copy numbers
  • quality assurance
  • ELSI aspects
  • treatment
  • short-term follow-up
  • long-term follow-up
  • efficacy of treatment

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Published Papers (8 papers)

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10 pages, 469 KiB  
Article
Newborn Screening for Spinal Muscular Atrophy: Variations in Practice and Early Management of Infants with Spinal Muscular Atrophy in the United States
by Craig M. Zaidman, Cameron D. Crockett, Ethan Wedge, Grace Tabatabai and Natalie Goedeker
Int. J. Neonatal Screen. 2024, 10(3), 58; https://doi.org/10.3390/ijns10030058 - 16 Aug 2024
Viewed by 1003
Abstract
In the United States (U.S.), newborn screening (NBS) for spinal muscular atrophy (SMA) is implemented by individual states. There is likely variation in the practice patterns of state NBS programs and among the providers caring for newborns with SMA. This is a prospective, [...] Read more.
In the United States (U.S.), newborn screening (NBS) for spinal muscular atrophy (SMA) is implemented by individual states. There is likely variation in the practice patterns of state NBS programs and among the providers caring for newborns with SMA. This is a prospective, descriptive, observational study that seeks to quantify and describe practice patterns and heterogeneities in state NBS programs and provider practices in the U.S. We surveyed U.S. state NBS programs and care providers of newborns with SMA. Thirty states and 41 practitioners responded. NBS program practices vary by state. Most (74%) state programs provide results to both primary care and specialist providers and also defer confirmatory SMA testing to those providers. Two states had relatively high rates of false-positive or inclusive results. The total birth prevalence of SMA was 1:13,862. Most providers were in tertiary care centers (90%) and were child neurologists (81%) and/or had fellowship training in Neuromuscular Medicine or Electromyography (76%). All providers see new referrals in less than a week, but many do not initiate treatment until >3 weeks of age (39%), with most commonly reported delays related to insurance processes. Most (81%) prefer onasemnogene abeparvovec-xioi (OA) as the treatment of choice, mainly due to perceived efficacy and the route/frequency of administration. NBS practice patterns in the U.S. vary by state but overall yielded the predicted birth prevalence of positive results. Providers evaluate these newborns urgently, but many do not initiate therapy until after 3 weeks of age. Treatment delays are mainly related to insurance processes. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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11 pages, 970 KiB  
Article
Our Journey from Individual Efforts to Nationwide Support: Implementing Newborn Screening for Spinal Muscular Atrophy in Serbia
by Miloš Brkušanin, Nemanja Garai, Jelena Karanović, Tamara Šljivančanin Jakovljević, Aleksandra Dimitrijević, Kristina Jovanović, Tanja Lazić Mitrović, Željko Miković, Goran Brajušković, Dimitrije Mihailo Nikolić and Dušanka Savić-Pavićević
Int. J. Neonatal Screen. 2024, 10(3), 57; https://doi.org/10.3390/ijns10030057 - 15 Aug 2024
Viewed by 851
Abstract
Innovative treatments for spinal muscular atrophy (SMA) yield the utmost advantages only within the presymptomatic phase, underlining the significance of newborn screening (NBS). We aimed to establish statewide NBS for SMA in Serbia. Our stepwise implementation process involved technical validation of a screening [...] Read more.
Innovative treatments for spinal muscular atrophy (SMA) yield the utmost advantages only within the presymptomatic phase, underlining the significance of newborn screening (NBS). We aimed to establish statewide NBS for SMA in Serbia. Our stepwise implementation process involved technical validation of a screening assay, collaboration with patient organizations and medical professionals, a feasibility study, and negotiation with public health representatives. Over 12,000 newborns were tested during the 17-month feasibility study, revealing two unrelated SMA infants and one older sibling. All three children received therapeutic interventions during the presymptomatic phase and have shown no signs of SMA. No false-negative results were found among the negative test results. As frontrunners in this field in Serbia, we established screening and diagnostic algorithms and follow-up protocols and raised awareness among stakeholders about the importance of early disease detection, leading to the incorporation of NBS for SMA into the national program on 15 September 2023. Since then, 54,393 newborns have been tested, identifying six SMA cases and enabling timely treatment. Our study demonstrates that effective collaborations between academia, non-profit organizations, and industry are crucial in bringing innovative healthcare initiatives to fruition, and highlights the potential of NBS to revolutionize healthcare outcomes for presymptomatic SMA infants and their families. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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10 pages, 1527 KiB  
Article
A Five-Year Review of Newborn Screening for Spinal Muscular Atrophy in the State of Utah: Lessons Learned
by Kristen N. Wong, Melissa McIntyre, Sabina Cook, Kim Hart, Amelia Wilson, Sarah Moldt, Andreas Rohrwasser and Russell J. Butterfield
Int. J. Neonatal Screen. 2024, 10(3), 54; https://doi.org/10.3390/ijns10030054 - 22 Jul 2024
Viewed by 1461
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and [...] Read more.
Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3–4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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10 pages, 2508 KiB  
Article
CDC’s Laboratory Activities to Support Newborn Screening for Spinal Muscular Atrophy
by Francis K. Lee, Christopher Greene, Kristina Mercer, Jennifer Taylor, Golriz Yazdanpanah, Robert Vogt, Rachel Lee, Carla Cuthbert and Suzanne Cordovado
Int. J. Neonatal Screen. 2024, 10(3), 51; https://doi.org/10.3390/ijns10030051 - 17 Jul 2024
Viewed by 1018
Abstract
Spinal muscular atrophy (SMA) was added to the HHS Secretary’s Recommended Uniform Screening Panel for newborn screening (NBS) in 2018, enabling early diagnosis and treatment of impacted infants to prevent irreversible motor neuron damage. In anticipation of supporting SMA newborn screening, scientists at [...] Read more.
Spinal muscular atrophy (SMA) was added to the HHS Secretary’s Recommended Uniform Screening Panel for newborn screening (NBS) in 2018, enabling early diagnosis and treatment of impacted infants to prevent irreversible motor neuron damage. In anticipation of supporting SMA newborn screening, scientists at the U.S. Centers for Disease Control and Prevention (CDC) have worked towards building resources for public health laboratories in four phases since 2013. In Phase 1, CDC established a real-time PCR assay, which uses a locked nucleic acid probe to attain the needed specificity, to detect SMN1 exon 7. In Phase 2, we developed quality assurance dried blood spot materials made with transduced lymphoblast cell lines established from de-identified SMA patients, carriers, and unaffected donors. In 2021, CDC implemented Phase 3, a proficiency testing program, that now supports 115 NBS labs around the world. We are currently completing Phase 4, which includes the implementation of an external SMA quality control material program. Also, during this time, CDC has provided individual technical assistance to NBS programs and bench training to NBS scientists during our annual molecular workshop. These CDC-led activities have contributed to the rapid and full implementation of SMA screening in all 50 U.S. states as of February 2024. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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9 pages, 1103 KiB  
Article
One-Year Pilot Study Results of Newborn Screening for Spinal Muscular Atrophy in the Republic of Croatia
by Darija Šimić, Ana Šarić, Ana Škaričić, Ivan Lehman, Branka Bunoza, Ivana Rako and Ksenija Fumić
Int. J. Neonatal Screen. 2024, 10(3), 50; https://doi.org/10.3390/ijns10030050 - 16 Jul 2024
Viewed by 895
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular and neurodegenerative disease caused by the homozygous deletion of SMN1 exon 7 in 95% of cases. The prognosis for SMA patients has improved with the development of disease-modifying therapies, all of which are available in Croatia. [...] Read more.
Spinal muscular atrophy (SMA) is a neuromuscular and neurodegenerative disease caused by the homozygous deletion of SMN1 exon 7 in 95% of cases. The prognosis for SMA patients has improved with the development of disease-modifying therapies, all of which are available in Croatia. The best treatment outcomes occur when therapy is applied before symptoms appear, making newborn screening (NBS) for SMA a crucial factor. Since SMA NBS is the first genetic test performed in our laboratory, for successful implementation of the program, we had to overcome logistical and organizational issues. Herein, we present the results of the SMA NBS during the one-year pilot project in Croatia and verify the suitability of the Targeted qPCR™ SMA assay for SMA NBS. The pilot project started on 1 March 2023 in the Department for Laboratory Diagnostics of the University Hospital Center Zagreb. A total of 32,655 newborns were tested. Five SMA patients were detected, and their diagnoses were confirmed by the multiplex ligation-dependent probe amplification (MLPA) assay. There have been no false positive or false negative results, to our knowledge so far. The incidence of SMA determined during the pilot study is consistent with the SMA incidence data from other European countries. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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11 pages, 788 KiB  
Article
Establishment of a Pilot Newborn Screening Program for Spinal Muscular Atrophy in Saint Petersburg
by Anton Kiselev, Marianna Maretina, Sofia Shtykalova, Haya Al-Hilal, Natalia Maslyanyuk, Mariya Plokhih, Elena Serebryakova, Marina Frolova, Natalia Shved, Nadezhda Krylova, Arina Il’ina, Svetlana Freund, Natalia Osinovskaya, Iskender Sultanov, Anna Egorova, Anastasia Lobenskaya, Alexander Koroteev, Irina Sosnina, Yulia Gorelik, Olesya Bespalova, Vladislav Baranov, Igor Kogan and Andrey Glotovadd Show full author list remove Hide full author list
Int. J. Neonatal Screen. 2024, 10(1), 9; https://doi.org/10.3390/ijns10010009 - 25 Jan 2024
Cited by 4 | Viewed by 1638
Abstract
Spinal muscular atrophy 5q (SMA) is one of the most common neuromuscular inherited diseases and is the most common genetic cause of infant mortality. SMA is associated with homozygous deletion of exon 7 in the SMN1 gene. Recently developed drugs can improve the [...] Read more.
Spinal muscular atrophy 5q (SMA) is one of the most common neuromuscular inherited diseases and is the most common genetic cause of infant mortality. SMA is associated with homozygous deletion of exon 7 in the SMN1 gene. Recently developed drugs can improve the motor functions of infants with SMA when they are treated in the pre-symptomatic stage. With aim of providing an early diagnosis, newborn screening (NBS) for SMA using a real-time PCR assay with dried blood spots (DBS) was performed from January 2022 through November 2022 in Saint Petersburg, which is a representative Russian megapolis. Here, 36,140 newborns were screened by the GenomeX real-time PCR-based screening test, and three genotypes were identified: homozygous deletion carriers (4 newborns), heterozygous carriers (772 newborns), and wild-type individuals (35,364 newborns). The disease status of all four newborns that screened positive for the homozygous SMN1 deletion was confirmed by alternate methods. Two of the newborns had two copies of SMN2, and two of the newborns had three copies. We determined the incidence of spinal muscular atrophy in Saint Petersburg to be 1 in 9035 and the SMA carrier frequency to be 1 in 47. In conclusion, providing timely information regarding SMN1, confirmation of disease status, and SMN2 copy number as part of the SMA newborn-screening algorithm can significantly improve clinical follow-up, testing of family members, and treatment of patients with SMA. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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34 pages, 629 KiB  
Systematic Review
Systematic Review of Presymptomatic Treatment for Spinal Muscular Atrophy
by Katy Cooper, Gamze Nalbant, Anthea Sutton, Sue Harnan, Praveen Thokala, Jim Chilcott, Alisdair McNeill and Alice Bessey
Int. J. Neonatal Screen. 2024, 10(3), 56; https://doi.org/10.3390/ijns10030056 - 14 Aug 2024
Viewed by 886
Abstract
Spinal muscular atrophy (SMA) causes the degeneration of motor neurons in the spinal cord. Treatments including nusinersen, risdiplam, and onasemnogene abeparvovec have been shown to be effective in reducing symptoms, with recent studies suggesting greater effectiveness when treatment is initiated in the presymptomatic [...] Read more.
Spinal muscular atrophy (SMA) causes the degeneration of motor neurons in the spinal cord. Treatments including nusinersen, risdiplam, and onasemnogene abeparvovec have been shown to be effective in reducing symptoms, with recent studies suggesting greater effectiveness when treatment is initiated in the presymptomatic stage. This systematic review synthesises findings from prospective studies of presymptomatic treatment for 5q SMA published up to December 2023. The review identified three single-arm interventional studies of presymptomatic treatment (NURTURE, RAINBOWFISH, and SPR1NT), six observational studies comparing presymptomatic or screened cohorts versus symptomatic cohorts, and twelve follow-up studies of screened cohorts only (i.e., babies identified via newborn screening for SMA). Babies with three SMN2 copies met most motor milestones in the NURTURE study of nusinersen and in the SPR1NT study of onasemnogene abeparvovec. Babies with two SMN2 copies in these two studies met most motor milestones but with some delays, and some required ventilatory or feeding support. The RAINBOWFISH study of risdiplam is ongoing. Naïve comparisons of presymptomatic treatment in SPR1NT, versus untreated or symptomatic treatment cohorts, suggested improved outcomes in patients treated presymptomatically. Comparative observational studies supported the finding that presymptomatic treatment, and early treatment following screening, may improve outcomes compared with treatment at the symptomatic stage. Further research should assess the long-term clinical outcomes and cost-effectiveness of presymptomatic treatment for SMA. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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33 pages, 772 KiB  
Systematic Review
Systematic Review of Newborn Screening Programmes for Spinal Muscular Atrophy
by Katy Cooper, Gamze Nalbant, Anthea Sutton, Sue Harnan, Praveen Thokala, Jim Chilcott, Alisdair McNeill and Alice Bessey
Int. J. Neonatal Screen. 2024, 10(3), 49; https://doi.org/10.3390/ijns10030049 - 15 Jul 2024
Viewed by 1235
Abstract
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder causing the degeneration of motor neurons in the spinal cord. Recent studies suggest greater effectiveness of treatment in the presymptomatic stage. This systematic review synthesises findings from 37 studies (and 3 overviews) of newborn [...] Read more.
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder causing the degeneration of motor neurons in the spinal cord. Recent studies suggest greater effectiveness of treatment in the presymptomatic stage. This systematic review synthesises findings from 37 studies (and 3 overviews) of newborn screening for SMA published up to November 2023 across 17 countries to understand the methodologies used; test accuracy performance; and timing, logistics and feasibility of screening. All studies screened for the homozygous deletion of SMN1 exon 7. Most (28 studies) used RT-PCR as the initial test on dried blood spots (DBSs), while nine studies also reported second-tier tests on DBSs for screen-positive cases. Babies testing positive on DBSs were referred for confirmatory testing via a range of methods. Observed SMA birth prevalence ranged from 1 in 4000 to 1 in 20,000. Most studies reported no false-negative or false-positive cases (therefore had a sensitivity and specificity of 100%). Five studies reported either one or two false-negative cases each (total of six cases; three compound heterozygotes and three due to system errors), although some false-negatives may have been missed due to lack of follow-up of negative results. Eleven studies reported false-positive cases, some being heterozygous carriers or potentially related to heparin use. Time to testing and treatment varied between studies. In conclusion, several countries have implemented newborn screening for SMA in the last 5 years using a variety of methods. Implementation considerations include processes for timely initial and confirmatory testing, partnerships between screening and neuromuscular centres, and timely treatment initiation. Full article
(This article belongs to the Special Issue Newborn Screening for SMA—State of the Art)
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