Ferritin, the
iron storage
protein, is composed of light and heavy chain subunits, encoded by FTL and FTH1 , respectively. Heterozygous variants in FTL cause hereditary
neuroferritinopathy, a type of
neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay,
epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole exome sequencing, with a recurrent de novo variant (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. Variant FTH1
mRNA 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 in FTH1 truncate
ferritin's E-helix, altering the four-fold symmetric pores of the heteropolymer and likely diminish
iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a novel disorder in the spectrum of NBIA. Targeted knock-down of mutant FTH1 transcript with
antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this novel pediatric
neurodegenerative disorder.