“Treatment of Spinal Muscular Atrophy (SMA) with Onasemnogene Abeparvovec is reported to be associated with thrombotic microangiopathies (TMA). Hemolytic uremic syndrome (HUS) is a type of TMA, characterized primarily by renal failure.

We report on a child, 10 months old, affected by spinal muscular atrophy type 1 (3 copies SMN2). She was candidate to gene therapy, but it was discontinued due to isolated finding of C3 hypocomplementemia with negative ANA screening: on blood exams C3 was stable <0.29 g/L. Moreover, pharyngeal swabs showed candida albicans, staphylococcus aureus, and acinetobacter baumanii complex; rhinovirus positivity was found on nasal swab; Escherichia coli positivity was found on urine examination. NGS analysis of a panel of genes associated with complement disorders and HUS identified a likely pathogenic variant in heterozygosity at the C3 gene, c.3489+1G>A, inherited from the mother and associated with high risk for HUS, and a likely pathogenic variant in heterozygosity at the Complement Factor I (CFI) gene, c.148C>G p. (Pro50Ala), inherited from the father. C3 factor plays a central role in activation of the complement system. CFI gene encodes for a serine proteinase essential for regulating the complement cascade. The two associated variants could play a role in the dysregulation of the complement system and predispose to the development of TMA-HUS. The mother too was counselled about the risk.

In conclusion, comprehending the risk factors associated with severe adverse events in gene therapy for spinal muscular atrophy (SMA) is of utmost importance, and gathering comprehensive data on this subject is essential.”