Neonatal screening for spinal muscular atrophy reduced the severity of future symptoms
A non-randomised study by German scientists found that patients diagnosed with spinal muscular atrophy as part of neonatal screening showed better motor development with disease-modifying treatment compared to those diagnosed after symptoms appeared. As reported in JAMA Pediatrics, more children in the early diagnosis group learned to sit and walk.
Most cases of spinal muscular atrophy (SMA) are caused by homozygous deletions in the SMN1 gene, with the number of copies of SMN2, a highly homologous SMN1 paralogue gene, being the most important predictor of disease severity. Patients with three copies or fewer usually show symptoms within the first 18 months of life, while children with more than three copies of SMN2 often have symptoms later in life. With the approval of three different disease-modifying drugs (Spinraza, Zolgensma and Risdiplam), there is growing evidence that early diagnosis and treatment determine better clinical outcomes, especially in patients with a predicted severe phenotype.
In 2021, Germany introduced neonatal screening for SMA, which makes it possible to determine the presence of genetic variants of the disease in a child almost immediately after birth (in Russia, such screening has been included in the expanded neonatal screening programme since 2023). During the first two years, a total of 297163 children were screened and 43 children with homozygous deletion for SMN1 were identified. Notably, children who would have been expected to develop severe SMA showed significant improvement in motor development provided they started modifying therapy immediately after diagnosis. Although clinical trials for pre-symptomatic patients and pilot projects on newborn screening show promising results, all of these studies lack an adequate control group directly assessing the effectiveness of newborn screening.
A team of researchers led by Janbernd Kirschner of the University of Freiburg conducted a non-randomised clinical trial that included children born in Germany, Austria and Switzerland, of whom those born in the two German federal states were given neonatal screening for SMA. Other patients were diagnosed with SMA after the onset of clinical symptoms, and only patients with two or fewer copies of SMN2 were included in the analysis.
A total of 234 children met the inclusion criteria and were included in the study. Of these, 44 cases of SMA were confirmed at neonatal screening and 190 were confirmed after the onset of clinical symptoms. In the cohort of screened neonates, 11 patients with two copies of SMN2 had symptoms of the disease at the time of treatment initiation. All but four infants received immediate treatment after confirmation of SMN1 deletion in a second independent sample. Two patients with three copies of SMN2 were treated only after the onset of symptoms at eight months of age at the parents' request.
Forty patients (90.9 per cent) from the neonatal screening group and 141 patients (74.2 per cent) developed the ability to sit up independently after the start of treatment, with children in the screening group sitting up at an average age of nine months and in the second group at 14 months. The ability to move independently at 17 months was acquired by 28 children (63.6 per cent) in the screening group and 28 patients (14.7 per cent) in the late group (at 23.5 months of age; everywhere p < 0.001). Before treatment, only one patient in the newborn screening group and 54 patients in the clinical symptom detection group regained the ability to sit up. In addition, in the cohort of patients with late onset of symptoms, two patients lost the ability to sit and three lost the ability to walk before treatment.
In addition, children in the neonatal screening group had greater changes in scores on the CHOP scale, which assesses motor function in children and adults with SMA. Also, earlier treatment reduced the number of children who required artificial ventilation and feeding through a feeding tube.
According to clinicians and scientists, these results support the clinical efficacy of neonatal screening for SMA because of the early initiation of pathogenetic treatment. The efficacy of such screening in other SMN2 copy number variants remains to be studied in the future.