Biallelic mutations in SUPV3L1 cause a variable leukodystrophy due to impaired mitochondrial degradosome function

Purpose Sensing and degradation of double stranded RNA (dsRNA) in the cell is tightly regulated to avoid activation of type I interferon signalling. The mitochondrial dsRNA degradosome complex is formed by PNPT1 and SUPV3L1. While biallelic PNPT1 mutations are an established cause of early-onset encephalopathy, the clinical and radiological impact of SUPV3L1 dysfunction is yet to be fully defined. Methods Through an international collaboration, we identified 21 patients with biallelic SUPV3L1 mutations. Available clinical and radiological data were compared. A supv3l1 knock-out zebrafish was generated to investigate the impact of supv3l1 loss in vivo . Results Fifteen different biallelic loss-of-function SUPV3L1 variants were identified in twenty-one individuals presenting with a wide clinical spectrum including neonatal haematological disturbance, infant-onset motor disorder and acute encephalopathy. Most individuals demonstrated significant neurodevelopmental involvement, manifesting as moderate to severe motor delay with intellectual impairment. Other common clinical features include microcephaly and spasticity. Three out of four patients tested showed an increased interferon signature in peripheral blood. A supv3l1 knock-out zebrafish exhibited defective mitochondria morphology and microglial function, with a significant activation of type 1 interferon signalling. Conclusion We define the genetic, clinical and radiological spectrum of SUPV3L1 -asociated disease and suggest activation of the type 1 interferon innate immune pathway by dysplastic microglia as a possible underlying cause.