Introducing a novel variant in the FTH1 gene; A closer look at FTH1-related neuroferritinopathy as a neurodegeneration with brain iron accumulation (NBIA) disorder.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) refers to a group of disorders with characteristic iron deposition in the basal ganglia. As an NBIA disorder, hereditary neuroferritinopathy is unique for its autosomal dominant inheritance pattern and the direct defect in iron metabolism. Caused by pathogenic variants in the FTL and FTH1 genes encoding ferritin light and heavy chains respectively, neuroferritinopathy presents clinically with a combination of dystonia, spasticity, parkinsonism, dysarthria, and cognitive decline. FTH1-related neuroferritinopathy is an exceedingly rare form which, unlike FTL-related neuroferritinopathy, typically presents in infancy.

METHODS AND RESULTS: Using whole-exome sequencing, we identified a novel variant in FTH1, c.465_466insG​; p.Leu156Valfs*17 in two brothers, confirmed by Sanger sequencing. To better understand FTH1 and its related disorders, especially neuroferritinopathy, we conducted a systematic search of the literature and identified seven variants in FTH1, four of which caused neuroferritinopathy.

CONCLUSIONS: Here we report an Iranian FTH1-related neuroferritinopathy family carrying a novel variant. All neuroferritinopathy-related variants, including ours, result in frameshift and are located within the last exon. Contrary to previous cases, this study reports two brothers presenting with a late-onset form of the disease, with normal development. The location of the variant, gender, or the presence of other genetic, epigenetic or environmental factors might explain this clinical trajectory. Our findings emphasize the need to characterize individual FTH1 variants as not all of them have the same consequences and to consider FTH1 in patients with unexplained movement disorders and brain magnetic resonance imaging evidence of iron accumulation across a wider age range.