Neuroferritinopathy (NF) (also known as hereditary ferritinopathy and neurodegenerative with brain iron accumulation type 3) was first identified in 2001 by Curtis et al.1 who initially made the connection between mutations in the ferritin light polypeptide (FTL) with the neurodegenerative disease. This finding was an important step in connecting ferritin, the primary iron storage protein in the body, to neurodegeneration, thereby introducing the concept that iron plays an active role in the pathophysiology of neurodegenerative disease.2
The incidence and prevalence of NF is unknown and fewer than 100 cases have been reported. Of the known cases, a majority of affected individuals have the same pathogenic variant. Initial theories suggested a common ancestor originating from the UK.3 However, more recent reports identifying the same pathogenic variants in families of geographically distant groups, as well as other mutations localized near the same genomic region, suggest the mutational events are more likely the result of DNA instability.2,4
NF is an inherited, autosomal dominant, monogenetic disorder caused by mutations in the FTL gene. FTL is located on chromosome19q13.33 and consists of 4 exons and 3 introns.2 Currently, twelve causative FTL mutations have been identified in the literature. Of note, the last part of exon 4 seems to be a region of DNA instability and consequently a hotspot for mutational events as ten of the known causative mutations are located in this region.5 Known mutations consist of either single or multiple nucleotide duplications or insertions in exon 4 resulting in frame-shift mutations and changes in the C-terminal sequence of the FTL peptide.5,6,7 Those with FTL mutations develop NF with 100% penetrance.8
Iron is necessary to sustain the respiratory demands of myelogenesis and neurotransmitter synthesis.6 The localized accumulation of iron is a common causes of multiple neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and NF.5 Ferritin plays a vital role in sustaining cellular iron homeostasis. Its primary function is to bind Fe(II), oxidize it, and keep it within its internal cavity.9
The structure of ferritin consists of essentially a hollow, spherical shell formed by the symmetrical assembly of 24 subunits containing up to 4,000-4,500 iron atoms within its internal cavity. The two polypeptide subunits that compose ferritin’s structure are termed the heavy (H) and light (L) polypeptide chains. The proportion of H to L subunits differs depending on the tissue. 9,10 The ferritin H chain exerts ferroxidase activity, which is critical to storing iron in the Fe(III) oxidation state, while the L chain imparts iron nucleation properties within the cavity surface, aiding iron storage. 5
A shared characteristic among the majority of NF variants involves the structural alteration of exon 4, the last portion of the L subunit, which corresponds to the C-terminal helix or E-helix. In the fully formed ferritin 24-mer, the E-helix of the L subunit is responsible for the formation of the 6 hydrophobic pores along the fourfold symmetric axes of the complete ferritin molecule. Incorporation of the altered L subunits hinders the correct formation of these channels, resulting in larger pores that are incapable of sufficiently retaining the deposited iron.2,10 Ferritin iron leakage and excess iron deposition are thought to catalyze the production of reactive oxygen species and result in oxidative cellular damage, of which the brain is especially sensitive to.10,11
The onset and clinical presentation of NF are highly variable not only between specific mutations but also within families who share the same mutation. The mean age of onset for NF is forty years of age; however, clinical signs and symptoms may manifest anywhere between the second to seventh decades of life.8,12 Initial signs of NF typically present as a movement disorder. Early in the disease course, cognitive deficits are typically subtle and may go unnoticed, but as the disease progresses, psychiatric and cognitive symptoms can become more prevalent.12 Frontal/subcortical deficits may be detected upon formal neurocognitive evaluation. Unlike in cases of Huntington disease, NF cognitive deficits are much milder, such as verbal fluency impairment, and usually do not progress to frank dementia.8
The motor manifestations may initially occur in only one to two limbs presenting as tremor, dystonia, or choreic movements. Cerebellar signs or Parkinsonism have also been reported as presenting features. As the disease progress, the movement disorder may begin to involve additional limbs within five to ten years after symptom onset followed by further generalization by twenty years.13 In the majority of cases, individuals develop orofacial dystonia and orolingual dyskinesia leading to dysarthria and dysphonia. Frontalis overactivity during speech are also common features of NF.13–16
Reported ophthalmologic findings in NF include blepharospasm and apraxia of eyelid opening that occur with simultaneously with other facial dystonias.8,14 Extraocular muscle abnormalities such as saccadic intrusions on ocular pursuit, saccadic hypometria, and up-gaze limitation have also been reported. Although in a majority of cases, extraocular muscle function tends to be unaffected. 8,13 Fundoscopic examination is unremarkable, yet electroretinography can reveal subclinical retinopathy.8,17
The diagnosis of NF is made based on clinical features combined with evidence of iron accumulation by MRI.18 Confirmatory genetic testing is also an available option. However, the vast majority of individuals diagnosed with NF already have an affected relative.10 Routine lab tests are typically normal except for serum ferritin levels, which are generally low in individuals affected, and can be an indication for further evaluation.2,15 Ultimately, the most effective diagnostic tool is MRI which can detect evidence of iron accumulation throughout all stages of the disease course including early-stage detection.10
The initial MRI findings in early symptomatic and even asymptomatic carriers is a slight hypointensity on T2-weighted imaging within the basal ganglia, dentate nuclei, red nuclei, and substantia nigra.19 As the disease progresses, high T2-weighted hyperintensity, due to edema and gliosis, can develop within the basal ganglia. Neural degradation and further iron accumulation eventually lead to T2 hypointensity.10 Additionally, the thalamus and caudate may also become further involved at this stage. Other late-stage findings include cerebellar and cerebral atrophy as well as cystic cavitation, particularly within the globus pallidus and putamen. Pre-cystic degeneration may be accompanied by T1-weighted hyperintensity.18
Another interesting radiographic finding reported in NF is the “eye of the tiger” sign. Typically associated with pantothenate kinase-associated neurodegeneration, the “eye of the tiger” sign describes a region of T2 hypointensity surrounding and area of hyperintensity focused in the anteromedial globus pallidus bilaterally. The hypointense signal corresponds to areas of iron deposition, while the hyperintensity signal corresponds to the areas of gliosis and increased water content.20
• Huntington disease
• Parkinson disease
• Spinocerebellar ataxia
• Tardive dyskinesia
• X-linked dystonia-parkinsonism
• Pantothenate kinase-associated neurodegeneration
• Neuroacanthocytosis syndrome
• Dystonia musculorum deformans
Currently, no disease-modifying therapy exists for NF. Several attempts at iron chelation and depletion, while effective at reducing systemic and brain iron content, have not been shown to confer any significant clinical benefit.2,17 The movement disorders of NF are notably non-responsive to established symptomatic treatments.14 The parkinsonian features of NF in particular appear to be universally resistant to treatment with L-Dopa. 19 Deep brain stimulation has also been attempted in one case but was ineffective.17
Botulinum toxin injections for painful focal dystonia and anticholinergics to reduce hyperkinetic movements have been beneficial, however.19 The most disabling aspect of NF is the dysphagia and dystonic hypophonia which may require dietary modification and speech amplification. Genetic counseling and genetic testing for at-risk relatives should be offered. 8,17
1) Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet. 2001 Aug;28(4):350-4. doi: 10.1038/ng571. PMID: 11438811.
2) Cozzi A, Santambrogio P, Ripamonti M, Rovida E, Levi S. Pathogenic mechanism and modeling of neuroferritinopathy. Cell Mol Life Sci. 2021 Apr;78(7):3355-3367. doi: 10.1007/s00018-020-03747-w. Epub 2021 Jan 13. PMID: 33439270.
3) Chinnery PF, Curtis AR, Fey C, Coulthard A, Crompton D, Curtis A, Lombés A, Burn J. Neuroferritinopathy in a French family with late onset dominant dystonia. J Med Genet. 2003 May;40(5):e69. doi: 10.1136/jmg.40.5.e69. PMID: 12746423; PMCID: PMC1735466.
4) Ondo WG, Adam OR, Jankovic J, Chinnery PF. Dramatic response of facial stereotype/tic to tetrabenazine in the first reported cases of neuroferritinopathy in the United States. Mov Disord. 2010 Oct 30;25(14):2470-2. doi: 10.1002/mds.23299. PMID: 20818611.
5) Cozzi A, Santambrogio P, Privitera D, Broccoli V, Rotundo LI, Garavaglia B, Benz R, Altamura S, Goede JS, Muckenthaler MU, Levi S. Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome. J Exp Med. 2013 Aug 26;210(9):1779-91. doi: 10.1084/jem.20130315. Epub 2013 Aug 12. PMID: 23940258; PMCID: PMC3754865.
6) Levi S, Cozzi A, Arosio P. Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. Best Pract Res Clin Haematol. 2005 Jun;18(2):265-76. doi: 10.1016/j.beha.2004.08.021. PMID: 15737889.
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12) Muhoberac BB, Vidal R. Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration. Front Neurosci. 2019 Dec 11;13:1195. doi: 10.3389/fnins.2019.01195. PMID: 31920471; PMCID: PMC6917665.
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