FTL – Neuroferritinopathy

Neuroferritinopathy is a rare autosomal dominant movement disorder caused by mutations in the ferritin light chain gene (FTL) that lead to abnormal iron and ferritin aggregation in the brain, initially described in adult‐onset generalized dystonia (PMID:15390032). Affected individuals present with progressive extrapyramidal features including chorea, dystonia, parkinsonism, cerebellar signs and late cognitive decline, with characteristic basal ganglia iron deposition on MRI.

Genetic studies have identified nine distinct pathogenic FTL variants in over 90 patients from more than 30 unrelated families worldwide, including Caucasian, Japanese and Chinese pedigrees (PMID:27022507). One recurrent frameshift mutation, c.498_499insTC (p.Phe167SerfsTer26), has been reported in multiple families and serves as a molecular hotspot for the disease. A Chinese pedigree with five affected members further confirms the autosomal dominant inheritance and phenotypic consistency of FTL mutations (PMID:27158664).

Segregation analysis across these families demonstrates at least 12 additional affected relatives with co-segregating FTL variants, supporting high penetrance in adult carriers (PMID:19514068). All reported mutations cluster in exon 4 of FTL and result in C-terminal alterations that disrupt ferritin function.

Functional assays reveal that mutant FTL homopolymers exhibit disrupted E-helices and 4-fold pore architecture, leading to impaired iron incorporation and enhanced aggregation in vitro (PMID:19923220). Transgenic mouse models expressing the human FTL498_499insTC mutation recapitulate brain iron accumulation, oxidative stress markers, and age-dependent motor coordination deficits, corroborating a dominant-negative mechanism (PMID:25447222).

No studies to date have refuted the FTL–neuroferritinopathy association or identified phenocopies with alternative molecular causes under similar imaging findings. The consistency of genetic, segregation, and functional data supports a definitive gene–disease relationship.

Key take-home: FTL sequencing should be included in diagnostic panels for adult-onset hyperkinetic movement disorders with MRI evidence of brain iron deposition, enabling accurate diagnosis, genetic counseling, and targeted research into iron-modulating therapies.

References

• Movement disorders • 2005 • Adult-onset generalized dystonia due to a mutation in the neuroferritinopathy gene. PMID:15390032
• Movement disorders • 2009 • A novel ferritin light chain gene mutation in a Japanese family with neuroferritinopathy: description of clinical features and implications for genotype-phenotype correlations. PMID:19117339
• Movement disorders • 2009 • Clinical phenotype and neuroimaging findings in a French family with hereditary ferritinopathy (FTL498-499InsTC). PMID:19514068
• Tremor and other hyperkinetic movements • 2016 • Neuroferritinopathy: Pathophysiology, Presentation, Differential Diagnoses and Management. PMID:27022507
• Parkinsonism & related disorders • 2012 • Neuroferritinopathy. PMID:22818529
• Neurobiology of disease • 2015 • A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits. PMID:25447222
• The Journal of biological chemistry • 2010 • Unraveling of the E-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration. PMID:19923220
• Neurology. Genetics • 2016 • FTL mutation in a Chinese pedigree with neuroferritinopathy. PMID:27158664

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