Heterozygous Nonsense Variants in the Ferritin Heavy Chain GeneFTH1Cause a Novel Pediatric Neuroferritinopathy

Ferritin, the iron storage protein, is composed of light and heavy chain subunits, encoded byFTLandFTH1, respectively. Heterozygous variants inFTLcause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants inFTH1have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients withde novoheterozygousFTH1variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. NonsenseFTH1variants were identified using whole exome sequencing, with a recurrentde novovariant (p.F171*) identified in three unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. VariantFTH1mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminus variants inFTH1truncate ferritin’s E-helix, altering the four-fold symmetric pores of the heteropolymer and likely diminish iron-storage capacity.FTH1pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon ofFTH1cause a novel disorder in the spectrum of NBIA. Targeted knock-down of mutantFTH1transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this novel pediatric neurodegenerative disorder.