Genetic susceptibility to thrombotic microangiopathy in a 10-month-old patient with SMA type 1: a caveat for gene therapy eligibility.

Gene therapy with onasemnogene abeparvovec (OA) has dramatically improved the prognosis of spinal muscular atrophy (SMA) since its approval. Thrombotic microangiopathies (TMA), including atypical complement-mediated hemolytic uremic syndrome (aHUS), represent rare but potentially life-threatening complications associated with OA. Complement activation and immune response against the viral vector capsid are considered the main pathogenic mechanisms. We report a 10-month-old girl with SMA type 1 and three SMN2 gene copies, initially eligible for OA. Baseline assessment revealed persistently undetectable Complement Component 3 (C3) levels (<0.29 g/L) and multiple concurrent infections. Next-generation sequencing identified likely pathogenic heterozygous C3 (c.3489+1G>A) and heterozygous CFI gene variants of uncertain significance (c.148C>G, p.Pro50Ala), both associated with increased risk of aHUS. The multidisciplinary team considered the patient at high risk and OA was withheld to prevent a potentially fatal TMA event. This case highlights how systematic complement screening prior to gene therapy may help identify high-risk individuals.