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Journal of Neurological Disorders & Stroke

Cite this article: Delicou S (2017) Neuroferritinopathy: A Neurodegenerative Disease with Brain Iron Accumulation. J Neurol Disord Stroke 5(3): 1129.1/4

*Corresponding authorSophia Delicou, Department of Hematology, Clinical Hematologist, Thalassemia and Sickle Cell Disease Unit, Hippokrateio General Hospital, Address: 114 Vassilisis, Sofias, 11527, Athens, Grecce, Tel: 213-2088-464; Mob: 306-9406-36397; Email:

Submitted: 02 October 2017

Accepted: 20 October 2017

Published: 23 October 2017

Copyright© 2017 Delicou

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Keywords• Neuroferritinopathy• Ferritin light chain• Ferritin• Chorea• Dystonia• Movement disorder

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Neuroferritinopathy: A Neurodegenerative Disease with Brain Iron AccumulationSophia Delicou*Department of Hematology, Hippokrateio General Hospital, Greece

Abstract

Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light chain gene.It presents in mid-adult life and is the only autosomal dominant disease in a group of conditions termed neurodegeneration with brain iron accumulation (NBIA). The most frequent presentation is with chorea (50%), followed by dystonia (42.5 %) and parkinsonism (7.5%).Brain magnetic resonance imaging demonstrates iron deposition in the basal ganglia and cavitation. Neuropathological studies have shown neuronal loss in the cerebral cortex, cerebellum and basal ganglia. Ferritin inclusion bodies were demonstrated within neurons and glia.

INTRODUCTIONIron plays important roles in many biological processes

ranging from facilitating cellular aerobic metabolism to participating in neurotransmitter synthesis and myelin production. However, if iron is not properly regulated, it can be detrimental to neurons and contributes to the pathogenesis of many neurological diseases.

Neuroferritinopathy (MIM 606159) is an autosomaldominant, adult-onset progressive movement disorder that results from mutations in the ferritin light-chain gene-FTL [1]. Nine mutations that result in the accumulation of ferritin and iron within the central nervous system have been described. Neurodegenerative disorders with brain iron accumulation (NBIA) were first described by Julius Hallervorden and Hugo Spatz in 1922 and until recently all patients with neurodegeneration and iron accumulation in the brain were given the diagnosis of Hallervorden-Spatz syndrome [2,3] -later renamed pantothenate kinase-associated neurodegeneration (PKAN). Currently the term NBIA encompasses a group of disorders including PKAN, infantile neuroaxonal dystrophy, hereditary aceruloplasminaemia and neuroferritinopathy. There is significant heterogeneity in the clinical presentation and progression of these disorders, as well as in their radiological and pathological findings. Recognition of neuroferritinopathy as a discrete neurological illness initially emerged from studies of a family from the Cumbrian Lake District of northwest England [4].

Genetics

Neuroferritinopathy is caused by 9 types of mutation in the FTL gene, the most common is the 460InsA, with more than 40 patients described [5]. The other mutations were found

in isolated cases and could not be followed in detail [6]. The first direct evidence that ferritin alteration can be involved in a neurodegenerative process came from the work of Curtis et al in 200116 who described a new genetic disease named neuroferritinopathy or dominant adult-onset basal ganglia disease; they studied a large family from the Cumbrian Lake District of northwest England. Pedigree analysis gave evidence of an autosomal dominant transmission of the disorder. A genome-wide linkage screen, followed by a molecular scrutiny of candidate genes, led to the discovery of a sequencevariant in the L-ferritin gene, on chromosome 19q13.3.16 The mutation consisted of an adenine insertion at position 460–461 in the exon 4 of the gene, which alters the reading frame so that the last 22 amino acids of L-ferritin are replaced by 26 other amino acids. The FTL460–461InsA mutation (here referred as 460InsA) was found in all the affected members of the Cumbrian family, and in ten further familiar cases in UK [7,8]. The same mutation has been reported in a French family that shares only one microsatellite marker (an approximately 100-kb telomeric region of the gene) with the British families [9]. It is not known whether this French family shares a common but distant ancestor with one of the British families or if the same mutation has arisen independently on two occasions. As no cases have been described elsewhere in the world, it is still not known how common neuroferritinopathyis or how wide is its geographical distribution.

Pathophysiology

Ferritin is a ubiquitous iron storage protein, composed of 24 subunits, which form a shell enclosing a cavity where large amounts of iron are stored in a soluble, non-toxic form. Cytosolic ferritins are assembled from variable amounts of two types of polypeptide chain, heavy (H) and light (L). H-chains

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have a ferroxidase site that catalyses the oxidation of iron, the reaction consumes Fe2þ and O2, producing H2O2, which may react with Fe2þ to produce free radicals. L-chains have no enzymatic activity, but facilitate the transfer of iron from the ferroxidase site to the iron core. H-rich ferritins are found in organs with a high metabolic rate, such as the heart and brain. L-rich ferritins in the spleen and liver have a more pronounced iron storage function [10,11]. Mitochondrial ferritin is mainly expressed in testes, neuronal cells, islets of Langerhans and it is abundant in the erythroblasts of patients with sideroblasticanaemia. Its main biological function is to sequester excess iron, in a similar manner to cytosolic ferritins. It has been shown to protect mitochondria from oxidative damage [12]. The ferritin molecule comprises a dodecahedron, a 12-sided hollow ball made up of 24 ferritin subunits, which are usually a mix of light and heavy chain. Protein modeling shows the terminal part of the FTL, which is elongated in neuroferritinopathy to be involved in formation of the pore structures at the points of the dodecahedron through which the iron molecules must pass. Up to 4,500 molecules can be stored, and the rapid production of ferritin in response to free iron indicates a strong likelihood that the abnormal pore formation results in oxidative damage because of failure to effectively contain elemental iron [13]. An alternative mechanism suggested is that in neuroferritinopathies the mutated L-subunit (Ln) co-assembles with the normal and H- and L-subunits to form abnormal ferritin shells with anatypical conformation possibly resulting in the exposure of the altered C-terminus. This can favor theaggregation of the iron-containing ferritin molecules observed in the brains of the patients. The HeLa cell model indicates that the abnormal ferritin is degraded at faster rates, thusreleasing larger amounts of labile iron which makes the cells more sensitive to oxidative damage and, in turn, upregulates the three ferritin chains [14]. Mitochondrial dysfunction may play a part in the pathophysiology of neuroferritinopathy, because abnormalities of mitochondrial respiratory chain function measured in skeletal muscle have been observed in some reported cases [15].

Clinical features

Patients with neuroferritinopathy typically present with a movement disorder in the fourth to sixth decade but symptom onset has been described as early as the late teens [16].

The main clinical features are that of an extrapyramidal disorder, with the most common movement disorder on presentation being chorea (50%), followed by focal dystonia (43%) and parkinsonism (7.5%) [16]. Patients often have a typical facies with activated frontalis muscles. Other features are: apraxia of eyelid opening, bilateral blepharospasm, orolingual, mandibular and cervical dystonia, saccadic ocular pursuit movements with slow saccades, dystonia of the trunk and all limbs, mild proximal weakness of both legs, brisk reflexes throughout and unsteadygait due to dystonia [17]. Although changes in handwriting are expected to occur in most of the patients, micrographia has been specifically reported [18].

Neuroferritinopathy shares clinical features with other neurogenetic disorders. Adult-onset chorea raises the possibility of Huntington’s disease but personality change and frontal/subcortical cognitive impairment are not prominent in the

early stages of neuroferritinopathy, only appearing at later in the illness [18]. Other diagnoses that were considered in these patients included the Westphal variant of Huntington’s disease and X-linked dystonia–parkinsonism (Lubag disease), but standard diagnostic genetic testing excludes the former diagnosis and male to male transmission excludes the latter rare disorder [19]. A significant outcome from Bennaroh’s iron overload study was that the overall impact of systemic iron overload in the CNS was not as noticeable as in the systemic compartment. The relative independence of the brain from iron in the systemic compartment may have protected the brain from acute changes in systemic iron [20]. Our data suggest that a small variation in iron body levels (from diet or other sources) may not significantly enhance CNS-related symptoms in patients with neuroferitinopathy; however, changes in systemic iron levels may increase systemic ferritin deposition and lead to organ dysfunction. Since iron overload has a significant effect in systemic iron metabolism, as seen here in the liver and spleen of FTL-Tg mice, additional studies are needed to determine whether patients with neuroferritinopathy may be more susceptible to hepatotoxicity and spleen dysfunction, the most common pathological findings in patients with iron overload [21]. Various systemic diseases have been reported in individuals affected by neuroferritinopathy, often before the onset of neurological symptoms. These diseases include hypertension, diabetes mellitus, thrombosis, dyslipidemia, hepatitis, and chronic renal failure [3]. Whether these conditions are associated with the systemic deposition of ferritin in the organs involved awaits further investigation.

Laboratory investigations

Full blood count and film, urea and electrolytes, liver and bone biochemistry, plasma glucose, HbA1c, and serum creatine kinase are normal [20]. However, serum ferritin is often low in patients with neuroferritinopathy and this is a useful initial test when neuroferritinopathy is clinically suspected. On review of all published cases of neuroferritinopathyand using a cut-off of 30 mg/l, 64% of males and 84% of females had low ferritin levels [20-22]. Electroretinography, electromyography, and peripheral nerve conduction studies are normal.

Even in an asymptomatic carrier, a characteristic pattern of iron deposition is seen on gradient echo sequences, consisting of loss of T2* signal within the dentate nuclei, red nuclei, substantianigra, putamina, globipallidi, thalami, caudate nuclei and the Rolandic prefrontal cortex. In early cases, the only discernible abnormality on conventional spin echo MR sequences in this group was a mild reduction in T2 signal within the red nuclei and substantianigra. With disease progression, the T2 hypointense signal and T2∗ signal loss become more pronounced [23,24]. The changes eventually extend to the thalamus, dentate nucleus,substantianigra, red nucleus, and cerebral cortex. In the middle stage of the disorder, T2 hyperintenseabnormalities reflecting tissue edema and gliosis are observed. In the basal ganglia, this change is thought to represent precysticdegeneration. The hypersignal lesions are often intermixed with decreased intensity areas corresponding to iron deposits. In advanced stages cystic cavitation of the basal ganglia evolves which may be preceded by hyperintenseT1-weighted signal changes, particularly in the putamen and globuspallidus. Also mild cerebral and cerebellar atrophy may be seen [25].

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Management

So far no medication has been shown to have a disease-modifying effect. Iron depletion therapy by iron chelation in symptomatic patients has not been shown to be beneficial. Iron chelating therapies to reduce the amount of free iron continue to be of great interest, but have showed disappointing results in the past. This is most likely because at diagnosis neuronal damage is already too advanced to allow for a significant clinical response. Coenzyme Q10 (ubiquinone); the therapeutic role is being evaluated based on evidence of mitochondrial respiratory chain dysfunction in neuroferritinopathy. Symptomatic treatments such as L-dopa, benzhexol, tetrabenazine,Deanol, and sulpiride in these patients at standard doses have been tried without major effect [26,27].

Genetic counseling

The definitive diagnosis of neuroferritinopathy relies upon molecular genetic tests. The most frequently reported mutation is 460insA, being reported in families from England, France and the United States.Testing of at-risk asymptomatic adults for neuroferritinopathyis not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for neuroferritinopathy, an affected family member should be tested first to confirm the molecular diagnosis in the family. Testing for the pathogenic variant in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Once the FTL pathogenic variant has been identified in the family, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for neuroferritinopathy are possible options [28].

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Delicou S (2017) Neuroferritinopathy: A Neurodegenerative Disease with Brain Iron Accumulation. J Neurol Disord Stroke 5(3): 1129.

Cite this article

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