Introduction

Neuroferritinopathy (NF) is an autosomal dominant, late-onset basal ganglia disorder resulting from mutations in the gene for ferritin light chain 1 (FTL1) on chromosome 19q13.1,2 The pathogenic mutations in the FTL1 gene cause pathological iron deposition and ferritin inclusions in various brain regions, respecting the pattern observed in normal aging.1 NF belongs to the group of disorders collectively known as neurodegeneration with brain iron accumulation (NBIA). The NBIAs present as a progressive extrapyramidal syndrome with abnormally increased iron deposition in the brain, particularly affecting the basal ganglia.3 Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration are the two most common disorders in this group. NF is one of only two disorders in this expanding group of NBIAs caused by a mutation in genes directly involved in iron metabolism; the other being aceruloplasminemia.4 It is the only autosomal dominant NBIA disorder, and patients present late in adulthood with combinations of movement disorders.2 To date, 90 cases of NF have been identified with nine causative mutations. On the basis of recent advances in our knowledge about NF, we review the various aspects of NF, namely the pathophysiology, genetics, clinical manifestations, differential diagnosis, treatment options, and prognosis.

Pathophysiology

The brain requires iron for many of its essential activities including transport of oxygen, energy generation, development of oligodendrocytes, myelin synthesis, production of neurotransmitters (dopamine, serotonin, and norepinephrine), and metabolism of nitric oxide.5,6 The brain contains about 30–40 mg of iron, which forms less than 1% of the total iron in our body.7 Disturbances in the homeostatic mechanisms of iron metabolism cause oxidative stress and cellular damage.6 Iron content in the brain increases with age, but it is still unclear whether its accumulation in neurodegenerative disorders is a primary or a secondary phenomenon.3,4 The distribution of iron in the brain is not homogeneous. The basal ganglia (caudate, putamen, and globus pallidus) have the highest iron concentrations, while the cortex, brainstem, and cerebellum have relatively lower concentrations.6,8 Iron is mainly stored intracellularly in the ferritin complex; however, in the substantia nigra and locus ceruleus, neuromelanin is the major iron storage molecule.4

To get into the brain, iron needs to cross the blood–brain barrier and blood–cerebrospinal fluid (CSF) barrier. Iron is transported by transferrin (Tf), which binds to transferrin receptors (TfR) on the cell surface.9 Of the two TfRs (TfR1 and TfR2), TfR1 plays the primary role in iron transfer.9 The Tf–TfR system is mainly responsible for exporting iron from the vascular lumen into the vascular endothelial cells. Iron is exported out of the basolateral membrane through some unknown transporters, which may involve ferroportin.6 Extracellular iron then enters the astrocytes as low molecular weight complexes (e.g. citrate, adenosine triphosphate, ascorbate) or it may enter the neurons via the Tf–TfR pathways (Figure 1).9 Iron can be stored as ferritin in astrocytes and released through ferroportin and ceruloplasmin, the ferroxidase that oxidizes ferrous iron.10 Astrocytes are ideally positioned to take up iron from the circulation and disperse it among other central nervous system cells.10

Ferritin, the major iron storage protein, has a spherical shell with an internal cavity that can store 4,500 iron atoms.11 It is composed of two subunit types, heavy (H) and light (L), which are encoded by genes on chromosomes 11 and 19, respectively.7,11 Both H and L chains are essential as the heteropolymers assimilate iron more effectively than homopolymers.12 In NF, the mutations produce a lengthening of the C terminus of the L chain that impairs its normal interaction with the heavy chain, thereby impairing the iron-binding capacity of ferritin.11,13 This results in accumulation of ferrous or free iron (Fe²⁺), which causes damage by producing free radicals, and a compensatory upregulation of ferritin production (Figure 1).1,13 Oxidative stress leads to neurodegeneration.12 Mitochondrial dysfunction may also contribute to the cellular dysfunction in NF probably by affecting neuronal intramitochondrial iron handling.2,14–16

Curtis et al. were the first group to report NF cases in a large north England family from the Cumbria region who had dominantly inherited, adult-onset basal ganglia disease.1 They found a mutation of an adenine insertion at position 460–461 in exon 4 of the FTL1 gene, which caused a frameshift and led to alterations at the C terminus of the gene product. The number of reported cases and mutations in NF are gradually increasing, thus underlining the fact that NF is neither purely confined to the population of north England nor confined to a common founder, as was once thought (Table 1).2,13,14,16–22 Most FTL1 mutations are located on exon 4, commonly resulting in a frameshift, suggesting that this part of the gene is particularly vulnerable to mutation.11

Clinical features

NF usually presents in the second to fifth decade of life with the mean age of onset being around 40 years.1,2,13,15,19 Those with mutations other than 460InsA appear to have an earlier age of onset (Table 1). The gender of the patients does not affect the age of disease onset or clinical phenotype. Although no predilection was seen for any gender in the largest series,2 some series report male predominance.19,27,31 It was suggested that females might be less vulnerable to abnormal iron deposition owing to menstruation,19 which may explain an asymptomatic 40-year-old female carrier in one of the reports.17 The disorder is thought to be fully penetrant by the age of 60.2,33 Clinical presentation does not differ with the age of onset. A strong family history is reported in most of the series.1,2,13 The disease progresses gradually, first involving basal ganglionic and/or cerebellar functions, and spreads to involve cortical functions in the late stages.13 The clinical manifestations vary among NF patients, which may be related to the variability in length of the mutant polypeptide and the resulting dominant negative effect of the modified last alpha-helix domain.14 However, there is no known correlation between the length of the mutant polypeptide and the age of onset. Environmental factors like dietary iron intake and other genes influencing iron metabolism may affect the clinical picture.21

Motor symptoms

NF may present with varied movement disorders. Three of the 90 cases reported to date were asymptomatic,2,17 and clinical data were not available for four additional reported NF patients.13,31 On analyzing all the symptomatic reported cases of NF (n = 83; Figure 2), we found chorea (39.7%; n = 33) and dystonia (38.5%; n = 32) to be the commonest presenting features; however, these were not specific for any particular FTL1 mutation or a geographical region. Parkinsonism (6%; n = 5) and tics (1.2%; n = 1) as initial presentation were seen in only those patients with 460InsA mutations. Tremor (7.2%; n = 6) at the disease onset was seen in patients of French ancestry with 498InsTC, and in Japanese patients with 469_484dup16nt. The 469_484dup16nt mutation is also seen in Italy, presenting with similar clinical features. Cerebellar ataxia (4.8%; n = 4) as the presenting movement disorder was common in patients of French ancestry with 498InsTC mutations. Those with 460InsA mutations are unlikely to present with tremor and cerebellar ataxia.

Figure 2 

Initial Presentations of Neuroferritinopathy Patients with Respective Mutations in Reported Symptomatic Cases. Chorea (39.7%) and dystonia (38.5%) are the most common initial presentations, followed by tremor (7.2%), parkinsonism (6%), cerebellar ataxia (4.8%), psychiatric symptoms (2.4%) and tics (1.2%). The associated mutations are listed alongside the symptoms.

The abnormal movements may remain asymmetric throughout the disease course in almost two-thirds of patients.2 Irrespective of the initial presentation, most patients develop dystonia (83%), predominantly in the lower limbs, and/or chorea (70%).2 Cerebellar symptoms such as dysmetria, ataxia, and palatal tremor are reported in patients with NF and may appear at any stage of the disease.2,13,14,16,17,20,22,23,26,31 Although unsteady gait and repeated falls may appear early in NF,14,27 the majority of patients remain mobile even after 20 years of disease onset.2 Patients with dystonic presentation have the most severe physical disability.2 Dysarthria and dysphagia have been reported in many patients.2,16,19,20,22,26,27,30,34 Oromandibular dyskinesia (65%), impairment of voice and speech (dysarthrophonia) with action-specific facial dystonia (63%) are commonly seen,2,13,20,22,24 and felt by one group to be specific to NF.24 Facial tics may be seen.26 Although changes in handwriting are expected to occur in most of the patients, micrographia has been specifically reported.16 Rarely, patients may present with ballistic movements,2 alien limb phenomenon,2 blepharospasm,2,24,30 or writer’s cramp.2

Pyramidal signs including spasticity,1 brisk deep tendon reflexes,32 and Babinski signs13,16,22 have been reported in patients with NF. Hypotonia may be seen.19,22,32 Although extraocular movements are usually well preserved, some patients may develop saccadic pursuit,2,16,23 slow saccades,16,22,23 and apraxia of eyelid opening.16,23 Limitation of vertical eye movements20 and horizontal oculomotor dysmetria21 are reported.

Differential diagnoses

The varied clinical presentations of NF make for a long list of differential diagnoses. Common differential diagnoses are listed in Table 2. Others may include Niemann–Pick type C (NPC) and mitochondrial disease.2 Marked supranuclear gaze impairment favors a diagnosis of NPC.2 Although there are overlaps in the clinical, radiological, and muscle biopsy findings between NF and mitochondrial disorders, positive genetic testing for FTL1 mutation confirms the diagnosis of NF.2 Additional brain immunocytochemical abnormalities indicate a secondary defect of the respiratory chain in NF.16 Early in the course of NF, patients may present with features of writer’s cramp, blepharospasm, or restless leg syndrome.2 A family history of NF, decreased serum ferritin, and magnetic resonance imaging (MRI) brain suggestive of abnormal iron storage in the basal ganglia may point to the diagnosis of NF in such patients.2

Investigations

Neuropathology

Mild cerebral and cerebellar atrophy with basal ganglia cavitation and numerous iron-positive inclusions especially in the globus pallidus and putamen are seen on neuropathological examination.1,13,16 Intranuclear and intracytoplasmic ferritin deposition in astrocytes and oligodendroglia are seen in the caudate nucleus, putamen, globus pallidus, and in gray and white matter regions.13,16 Ferritin deposits are also seen in cerebellar granule cells and Purkinje cells.13 The ferritin deposits may be seen in the parenchymal cells of other organs like skin fibroblasts, renal tubule cells, and endothelial cells of muscle capillaries.13 Intranuclear iron and ferritin inclusions are also found in hepatocytes.16 This points to the fact that the pathology of NF is not limited to the brain tissue only and some authors suggested that “hereditary ferritinopathy” is a better term than the more restrictive “neuroferritinopathy.”4,13,16 Muscle biopsy in a few NF patients showed evidence of mitochondrial respiratory chain defects.2,14–16 Chinnery et al.2 found a higher percentage of cytochrome c oxidase negative fibers than expected for age in two out of nine NF patients who underwent muscle biopsy. Respiratory chain complex assays reported in eight patients found isolated or combined defects in seven of them. While isolated defects in complex I2 and complex III14 were seen in three and one patient respectively, three other patients had a combined defect involving multiple respiratory chain complexes.2,16 A generalized deficiency was reported in a sample of post-mortem cerebellar tissue.16 These respiratory chain defects suggest mitochondrial dysfunction in NF.

Management

At present, there are no established guidelines or specific management recommendations for patients with NF.27 An individualized symptomatic approach to treatment is recommended. A number of drugs have been used for symptomatic management in NF with variable success. Dystonia either showed some2,21,23,35 or no14,16,19,22 improvement with anticholinergics such as trihexyphenidyl. While variable improvement in chorea, tics, and stereotypy were reported with sulpiride (D2 receptor blocker) and tetrabenazine (dopamine depleting agent) in some patients, the latter is associated with complications including sedation, parkinsonism, and depression.2,26,27,35 One report showed excellent response of facial tic/stereotype and chorea with tetrabenazine.26 Parkinsonian symptoms of NF showed either no2,22,27 or only some initial benefit20,35 with levodopa. Benzodiazepines (diazepam, clonazepam, and lorazepam) have been shown to improve dystonia in a few patients,2,35 but not in others.19,22 Antidepressants, like fluoxetine, were helpful in treating depression.16,19 Muscle relaxants, like baclofen, gave either partial35 or no2,22 benefit in treating dystonia. Various other drugs that have failed to improve the movement disorders include risperidone2, haloperidol,13,19,27 tiapride,19 olanzapine,2 amitriptyline,2,16,35 apomorphine,2,35 amantadine,2 dopamine agonists,14 deanol,2 dantrolene,2 paroxetine,2 mirtazapine,2 gabapentin,2 sodium valproate,2,22 and carbamazepine.2,35 One author reported improvement in the finger dystonia of a patient with herbal medicine (Shakuyaku-kanzo-to).22 Physiotherapy in addition to drugs improved dystonia and gait in one patient.22 Speech amplification may help hypophonia.2

Moderate benefits have been reported with the use of botulinum toxin for dystonia affecting the neck, orofacial region (including blepharospasm), and extremities.2,16,21,35 Other symptomatic treatments include non-invasive positive pressure ventilation for sleep apnea and percutaneous endoscopic gastrostomy feeding for severe weight loss due to dysphagia.20,27 Dysphagia should be monitored and managed with swallowing assessment and dietary modification.2

A number of treatments have been used for modulating the brain iron stores in the hope of reversing the pathology, but none have been reported to be successful. A low-iron diet did not show benefit after 6 months of its institution.16 Iron chelation therapy with desferrioxamine (4,000 mg weekly subcutaneously for up to 14 months)2 and deferiprone (15 mg/kg/day for 6 months) have not been effective.2,14 No improvement was seen with monthly venesection.2,16,19 Although no benefit has been reported in the short term with iron-modulating therapies, the long-term response has yet to be studied.

Although NF progresses gradually but relentlessly in most of the patients,2,13 patients with a 458dupA mutation show a relatively rapid progression of parkinsonism, ataxia, and neuropsychiatric symptoms.20 Patients usually die of aspiration pneumonia.16,19 Other reported causes of death include community-acquired pneumonia,27 asphyxiation of food,19 and cardiomyopathy.20 It is not known whether this last cause was related to NF.

Conclusion

NF is a rare autosomal dominant disease with FTL1 mutation leading to abnormal excessive iron accumulation in the brain (predominantly in the basal ganglia) and other organ systems. In people of British descent, the most common mutation is 460InsA. Nine variant mutations in the FTL1 gene have been reported in various geographical regions. NF patients with mutations other than 460InsA appear to have an earlier age of onset. Although NF has heterogeneous clinical presentations, chorea and dystonia are the most common presenting symptoms; however, these are not specific to a mutation. There are however specific features that depend on the genetic mutation and hence on regional distribution as reviewed in this manuscript.

NF must be considered in patients presenting clinically as a relentlessly progressive movement disorder with variable phenotype and imaging evidence of iron deposition within the brain, decreased serum ferritin, and negative genetic testing for other more common movement disorders like Huntington’s disease. The FTL1 gene mutation should be suspected despite the lack of a positive family history, as new genetic mutations of this gene may occur in any population. Brain MRI is helpful, even during the pre-symptomatic period in relatives of affected patients, and unilateral or asymmetric lesions do not exclude the diagnosis. Although MRI features may overlap with other NBIAs, basal ganglia cavitation and cortical “pencil-lining” on susceptibility-weighted imaging favors NF. Standard symptomatic drug treatment for specific movement disorders may be used with variable success. Chelation therapies have not been shown to be effective.