Early spinal muscular atrophy treatment following newborn screening: A 20-month review of the first Italian regional experience

Abstract

Objectives: Mandatory newborn screening (NBS) for spinal muscular atrophy (SMA) was implemented for the first time in Italy at the end of 2021, allowing the identification and treatment of patients at an asymptomatic stage.

Methods: DNA samples extracted from dried blood spot (DBS) from newborns in Apulia region were analysed for SMA screening by using a real-time PCR-based assay. Infants harbouring homozygous deletion of SMN1 exon 7 confirmed by diagnostic molecular tests underwent clinical and neurophysiological assessment and received a timely treatment.

Results: Over the first 20 months since regional NBS introduction, four out of 42,492 (0.009%) screened children were found to carry a homozygous deletion in the exon 7 of SMN1 gene, with an annual incidence of 1:10,623. No false negatives were present. Median age at diagnosis was 7 days and median age at treatment was 20.5 days. Three of them had two copies of SMN2 and received gene therapy, while the one with three SMN2 copies was treated with nusinersen. All but one were asymptomatic at birth, showed no clinical signs of disease after a maximum follow-up of 16 months and reached motor milestones appropriate with their age. The minimum interval between diagnosis and the treatment initiation was 9 days.

Interpretation: The timely administration of disease-modifying therapies prevented presymptomatic subjects to develop disease symptoms. Mandatory NBS for SMA should be implemented on a national scale.

Figure 1

Workflow of diagnosis and treatment of SMA patients detected by newborn screening in Apulia region. Infants born in one of the 26 birth centres in Apulia are tested through a qPCR assay on dried blood spot (DBS) to look for biallelic deletions in the SMN1 gene. If positive, a secondary confirmatory test is performed, and if again positive, a third test is performed after obtaining parental consent on fresh blood samples to look for biallelic deletions in SMN1 gene and to quantify the number of SMN2 copies. After diagnosis, a neurological evaluation and CMAP recording with stimulation at the patient's wrist are performed. Patients are eligible for different treatments depending on the presence of signs and symptoms of SMA and the number of SMN2 copies. Patients with two copies are eligible for gene therapy or Nusinersen regardless of the presence of signs and symptoms. Patients with three copies are eligible for gene therapy or Nusinersen if symptomatic; if there are no signs or symptoms of SMA Nusinersen is the only treatment reimbursed by the Italian Medicines Agency (AIFA). Patients with four copies are only eligible for Nusinersen and are usually asymptomatic. For patients receiving Nusinersen, follow‐up includes CHOP‐INTEND administration, neurological evaluation and blood sampling at the first loading dose and at each maintenance dose (every 4 months). Patients treated with Onasemnogene abeparvovec will receive CHOP‐INTEND at months 0, 1, 3, 6, 12 and every year. In addition, neurological assessments and blood samples are taken weekly during the first month, every 2 weeks during the second and third months, and then at the same time points as CHOP‐INTEND. *Decision about treatment to be made with parents after explanations of risks and benefits. °After ruling out exclusion factors, including a positive anti‐AAV9 antibody titre.

Figure 2

CHOP‐INTEND scores over time in newborn patients with SMA. CHOP‐INTEND scores at time of diagnosis and after 1, 3, 6 and 12 months.