Treatment of spinal muscular atrophy (SMA) has been transformed since the development of targeted therapies such as nusinersen, 1 risdiplam, 2 and onasemogene abeparvovec-xioi (Zolgensma). 3 The disease-modifying impact of gene therapy for SMA and the advent of newborn screening accompanied by early treatment have made single-dose therapy a preferred choice for parents and providers. It has been difficult to differentiate the severe nature of the underlying condition and safety events following Zolgensma, which have been attributed to the therapy. Ascertainment of safety events is further complicated by the lack of a Risk Evaluation and Mitigation Strategy (REMS) program for the drug. Therefore, individual providers who have identified safety events must take the initiative to report those findings in the literature, 4 or they must be reported by sponsor-driven post-marketing findings. 5 In a recent report by Galletta et al., 6 the authors describe a case of acquired hemophagocytic lymphohistiocytosis (HLH) that occurred in a patient with SMA who was treated with Zolgensma in Italy. The observations in this case report expand on the findings of immune response to systemic administration of adenoassociated virus (AAV) vectors and provide insight into adverse events in humans that have been difficult to model in non-clinical studies.

SMA type 1 is a severe inherited neurodegenerative disease that results in the degeneration and loss of alpha motor neurons due to bi-allelic mutations in the survival of motor neuron (SMN) 1 gene. The severity and age of onset are linked to the copy number of a gene duplication, SMN2, which provides partial correction of the defect in SMN1. The clinical manifestations of SMA include severe hypotonia, progressive proximal muscle weakness, motor delay, and ventilatory failure. 7 Zolgensma is a gene therapy comprising an AAV9-based vector carrying the SMN1 gene under control of a synthetic promoter. 3