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Spinal muscular atrophy (SMA) causes progressive muscular atrophy, weakness, and bulbar dysfunction. It can lead to death, particularly in patients with a homozygous deletion of exon 7 or exons 7 and 8 of the survival motor of neuron 1 (SMN1) gene (5q11.2-q13.3).¹ Another gene, SMN2, formed because of duplication of a region on chromosome 5, expresses an unstable form of the SMN protein. The number of SMN2 copies affects the severity of the disease; the fewer the copies, the worse the symptoms.²

Newborn screening and early diagnosis of SMA 

Newborn screening (NBS) has facilitated early diagnosis of SMA in both presymptomatic and symptomatic preterm infants, which may result in earlier use of disease-modifying therapy (DMT).¹ Clinical trials have demonstrated that neonates with SMA who begin DMTs when they are presymptomatic have a greater response to treatment than neonates and young infants who are symptomatic. Thus, there is a need to begin DMTs as early as possible.¹ However, there are no national or international recommendations for treating preterm newborns and newborns < 38 weeks gestational age (GA).¹ The US Food and Drug Administration recommends that one of the DMTs, onasemnogene abeparvovec (OA), not be used in premature infants because of potential adverse events (AEs) from the steroids given in conjunction with OA.

Study process and patient characteristics

Regina Trollmann, MD, of the Division of Pediatric Neurology, Department of Pediatrics, Friedrich-Alexander-University of Erlangen-Nu虉rnberg, Erlangen, Germany, and colleagues, did a retrospective multicenter evaluation of the postnatal course of preterm infants with SMA since NBS was started in Germany and summarized the decision-making process for available DMTs. Their report, 鈥淧ostnatal management of preterm infants with spinal muscular atrophy: experience from German newborn screening,鈥� was published online in Orphanet Journal of Rare Diseases.

To amass information for the research, questionnaires were sent to 8 pediatric neurology clinics and treatment centers in Germany designated as SMA NBS follow-up centers. Clinical data, genetic findings, and the type and time of DMTs for 12 preterm newborns born at <38 weeks GA with positive screening on NBS between 2021 and 2024 were collected. All of the infants had a homozygous deletion in the SMN1 gene with an SMN2 copy number of 2 or 3 and their mean GA was 34.0 weeks.¹ Of the 12 patients, 11 (91.6%) were presymptomatic at birth; one infant, who had a GA of 31 + 5 weeks and 3 SNM2 copies, had muscular hypotonia, weak sucking, and areflexia at birth. One of the 11 with 2 SMN2 copies, who was presymptomatic at birth, developed muscle hypotonia at 5 weeks postnatally (postconceptional age [PCA] 41.8 weeks).¹ NBS led to being able to make a diagnosis of SMA in an average of 13.2 days, allowing earlier counseling and therapy planning (at mean PCA of 35.9 weeks).¹

Treatment options and what was chosen: available DMTs

DMT was started for all patients at a mean PCA of 38.8 weeks. Available DMTs were¹: 

• antisense oligonucleotide nusinersen, an SMN2 splicing modifier that is approved to treat all types of 5q-SMA, including presymptomatic neonates, and which is recommended as a lifelong intrathecal treatment
• OA, an intravenous gene replacement therapy, which uses the adeno-associated virus 9-mediated transfer of a new copy of the SMN1 gene to the host. OA was approved for treating patients with 5q-SMA with biallelic SMN1 mutations and clinically diagnosed with SMA type 1 or patients with 鈮�3 SMN2 gene copies (including presymptomatic newborns).
• oral risdiplam, an SMN2 splicing modifier, which binds to exonic splicing enhancer 2 (in exon 7) 

OA was started in 83.3% of the neonates at a mean PCA of 39.7 weeks; 2 patients were treated with nusinersen at PCAs of 38.7 and 38.1 weeks, and another 2 were treated with risdiplam at a PCA of 34.9 weeks as a bridge to gene replacement therapy once they reached term.¹ DMTs were started at a mean age of 32.9 days (PCA 38.8). Mean time between diagnosis confirmation and beginning of therapy was 20.7 days.¹

Adverse events

AEs seen were elevated liver function tests, vomiting, fever, and thrombocytopenia.¹ Several term infants treated with OA developed necrotizing enterocolitis; however, it could not be determined whether the treatment increased the risk.¹

Limitations and future directions

Study limitations mentioned by the authors were the retrospective design and small number of participants. Regarding the future, the authors suggest that further long-term studies should be done about the course of premature infants. The currently available data do not allow for a risk-benefit assessment of starting therapy at < 37 weeks GA vs starting at full-term GA.¹

Conclusions

The authors summarized their findings, stating, 鈥淥ur data confirms that SMA NBS enables early confirmation of diagnosis in preterm infants and early disease-modifying therapy, ideally in the presymptomatic stage of the disease, which is crucial for the future prognosis of the newborn.鈥�¹

Published: December 27, 2024