Background: Early treatment after genetic newborn screening (NBS) for SMA significantly improves outcomes in infantile SMA. However, there is no consensus in the SMA treatment community about early treatment initiation in patients with four copies of SMN2.
Objective: Approach to a responsible treatment strategy for SMA patients with four SMN2 copies detected in newborn screening.
Methods: Inclusion criteria were a history of SMA diagnosed by NBS, age > 12 months at last examination, and diagnosis of four SMN2 copies at confirmatory diagnosis.
Results: 21 patients with SMA and four SMN2 copies were identified in German screening projects over a three-year period. In three of them, the SMN2 copy number had to be corrected later, and three patients were lost to follow-up. Eight of the fifteen patients who were subject to long-term follow-up underwent presymptomatic therapy between 3 and 36 months of age and had no definite disease symptoms to date. Five of the other seven patients who underwent a strict follow-up strategy, showed clinical or electrophysiological disease onset between 1.5 and 4 years of age. In two of them, complete recovery was not achieved despite immediate initiation of treatment after the onset of the first symptoms.
Conclusion: A remarkable proportion of patients with four copies of SMN2 develop irreversible symptoms within the first four years of life, if a wait-and-see strategy is followed. These data argue for a proactive approach, i.e., early initiation of treatment in this subgroup of SMA patients.
Keywords: 4 SMN2 copies; Spinal muscular atrophy; newborn screening; outcome; presymptomatic treatment.