Neuroferritinopathy is a neurodegenerative disease which demonstrates brain iron accumulation caused by the mutations in the ferritin light chain gene. On brain MRI in neuroferritinopathy, iron deposits are observed as low-intensity areas on T2WI and as signal loss on T2*WI. On T2WI, hyperintense abnormalities reflecting tissue edema and gliosis are also seen. Another characteristic finding is the presence of symmetrical cystic changes in the basal ganglia, which are seen in the advanced stages of this disorder. Atrophy is sometimes noted in the cerebellar and cerebral cortices. The variety in the MRI findings is specific to neuroferritinopathy. Based on observations of an excessive iron content in patients with chronic neurologic disorders, such as Parkinson disease and Alzheimer disease, the presence of excess iron is therefore recognized as a major risk factor for neurodegenerative diseases. The future development of multimodal and advanced MRI techniques is thus expected to play an important role in accurately measuring the brain iron content and thereby further elucidating the neurodegenerative process. 1. Introduction Neuroferritinopathy is an autosomal dominant neurodegenerative disorder characterized by the deposition of iron and ferritin in the brain and a decreased level of serum ferritin. The disease is caused by a mutation in the ferritin light chain gene [1]. Seven different pathogenic mutations of the ferritin light chain gene have been identified [1–7]. These mutations are predicted to affect the tertiary structure and stability of the ferritin light chain polypeptide and may cause inappropriate iron release from ferritin polymers [8, 9]. It is supposed that the excess iron induces free toxic radical production, which leads to tissue oxidative stress and neuronal cell death [10–12]. The clinical features of neuroferritinopathy are characterized by the adult onset of extrapyramidal motor symptoms: dystonia, chorea, choreoathetosis, parkinsonism, and tremor. Some patients may present cerebellar ataxia, cognitive decline, and pyramidal signs [2, 3, 5–7]. The phenotypic signs of the disease are variable, even among members of the same family [1, 3]. Generally, there are no nonneurological symptoms [13], different from in other neurodegenerative brain iron accumulation diseases. The clinical features of neuroferritinopathy are not specific, and they overlap with those of common extrapyramidal disorders. It is difficult to diagnose neuroferritinopathy solely based on the clinical findings. Brain MR imaging in the disease is quite characteristic
References
[1]
A. R. J. Curtis, C. Fey, C. M. Morris et al., “Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease,” Nature Genetics, vol. 28, no. 4, pp. 350–354, 2001.
[2]
R. Vidal, B. Ghetti, M. Takao et al., “Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 4, pp. 363–380, 2004.
[3]
M. Mancuso, G. Davidzon, R. M. Kurlan et al., “Hereditary ferritinopathy: a novel mutation, its cellular pathology, and pathogenetic insights,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 4, pp. 280–294, 2005.
[4]
P. Maciel, V. T. Cruz, M. Constante et al., “Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement,” Neurology, vol. 65, no. 4, pp. 603–605, 2005.
[5]
E. Ohta, T. Nagasaka, K. Shindo et al., “Neuroferritinopathy in a Japanese family with a duplication in the ferritin light chain gene,” Neurology, vol. 70, no. 16, part 2, pp. 1493–1494, 2008.
[6]
D. Devos, P. J. Tchofo, I. Vuillaume et al., “Clinical features and natural history of neuroferritinopathy caused by the 458dupA FTL mutation,” Brain, vol. 132, no. 6, p. e109, 2009.
[7]
A. Kubota, A. Hida, Y. Ichikawa et al., “A novel ferritin light chain gene mutation in a Japanese family with neuroferritinopathy: description of clinical features and implications for genotype-phenotype correlations,” Movement Disorders, vol. 24, no. 3, pp. 441–445, 2009.
[8]
S. Levi, A. Cozzi, and P. Arosio, “Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation,” Best Practice and Research: Clinical Haematology, vol. 18, no. 2, pp. 265–276, 2005.
[9]
R. Vidal, L. Miravalle, X. Gao et al., “Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice,” Journal of Neuroscience, vol. 28, no. 1, pp. 60–67, 2008.
[10]
T. A. Rouault, “Iron on the brain,” Nature Genetics, vol. 28, no. 4, pp. 299–300, 2001.
[11]
Y. Ke and Z. M. Qian, “Iron misregulation in the brain: a primary cause of neurodegenerative disorders,” Lancet Neurology, vol. 2, no. 4, pp. 246–253, 2003.
[12]
A. Cozzi, E. Rovelli, G. Frizzale et al., “Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy,” Neurobiology of Disease, vol. 37, no. 1, pp. 77–85, 2010.
[13]
P. F. Chinnery, D. E. Crompton, D. Birchall et al., “Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation,” Brain, vol. 130, no. 1, pp. 110–119, 2007.
[14]
A. McNeill, D. Birchall, S. J. Hayflick et al., “T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation,” Neurology, vol. 70, no. 18, pp. 1614–1619, 2008.
[15]
P. Mir, M. J. Edwards, A. R. J. Curtis, K. P. Bhatia, and N. P. Quinn, “Adult-onset generalized dystonia due to a mutation in the neuroferritinopathy gene,” Movement Disorders, vol. 20, no. 2, pp. 243–245, 2005.
[16]
D. E. Crompton, P. F. Chinnery, D. Bates et al., “Spectrum of movement disorders in neuroferritinopathy,” Movement Disorders, vol. 20, no. 1, pp. 95–98, 2005.
[17]
D. Caparros-Lefebvre, A. Destée, and H. Petit, “Late onset familial dystonia: could mitochondrial deficits induce a diffuse lesioning process of the whole basal ganglia system?” Journal of Neurology, Neurosurgery and Psychiatry, vol. 63, no. 2, pp. 196–203, 1997.
[18]
D. E. Crompton, P. F. Chinnery, C. Fey et al., “Neuroferritinopathy: a window on the role of iron in neurodegeneration,” Blood Cells, Molecules and Diseases, vol. 29, no. 3, pp. 522–531, 2002.
[19]
P. M. Harrison and P. Arosio, “The ferritins: molecular properties, iron storage function and cellular regulation,” Biochimica et Biophysica Acta, vol. 1275, no. 3, pp. 161–203, 1996.
[20]
C. W. Olanow and G. W. Arendash, “Metals and free radicals in neurodegeneration,” Current Opinion in Neurology, vol. 7, no. 6, pp. 548–558, 1994.
[21]
C. M. Morris, J. M. Candy, A. E. Oakley, C. A. Bloxham, and J. A. Edwardson, “Histochemical distribution of non-haem iron in the human brain,” Acta Anatomica, vol. 144, no. 3, pp. 235–257, 1992.
[22]
J. Stankiewicz, S. S. Panter, M. Neema, A. Arora, C. E. Batt, and R. Bakshi, “Iron in chronic brain disorders: imaging and neurotherapeutic implications,” Neurotherapeutics, vol. 4, no. 3, pp. 371–386, 2007.
[23]
A. Gregory, B. J. Polster, and S. J. Hayflick, “Clinical and genetic delineation of neurodegeneration with brain iron accumulation,” Journal of Medical Genetics, vol. 46, no. 2, pp. 73–80, 2009.
[24]
P. F. Chinnery, A. R. J. Curtis, C. Fey et al., “Neuroferritinopathy in a French family with late onset dominant dystonia,” Journal of Medical Genetics, vol. 40, no. 5, p. e69, 2003.
[25]
F. Ory-Magne, C. Brefel-Courbon, P. Payoux et al., “Clinical phenotype and neuroimaging findings in a French family with hereditary ferritinopathy (FTL498-499InsTC),” Movement Disorders, vol. 24, no. 11, pp. 1676–1683, 2009.
[26]
E. Ohta, T. Nagasaka, K. Shindo et al., “Clinical features of neuroferritinopathy,” Clinical Neurology, vol. 49, no. 5, pp. 254–261, 2009.
[27]
A. J. Wills, G. V. Sawle, P. R. Guilbert, and A. R. J. Curtis, “Palatal tremor and cognitive decline in neuroferritinopathy,” Journal of Neurology Neurosurgery and Psychiatry, vol. 73, no. 1, pp. 91–92, 2002.
[28]
J. Burn and P. F. Chinnery, “Neuroferritinopathy,” Seminars in Pediatric Neurology, vol. 13, no. 3, pp. 176–181, 2006.
[29]
B. Zhou, S. K. Westaway, B. Levinson, M. A. Johnson, J. Gitschier, and S. J. Hayflick, “A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome,” Nature Genetics, vol. 28, no. 4, pp. 345–349, 2001.
[30]
S. J. Hayflick, M. Hartman, J. Coryell, J. Gitschier, and H. Rowley, “Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations,” American Journal of Neuroradiology, vol. 27, no. 6, pp. 1230–1233, 2006.
[31]
S. J. Hayflick, S. K. Westaway, B. Levinson et al., “Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome,” New England Journal of Medicine, vol. 348, no. 1, pp. 33–40, 2003.
[32]
M. C. Sharma, N. Aggarwal, M. Bihari et al., “Hallervorden Spatz disease: MR and pathological findings of a rare case,” Neurology India, vol. 53, no. 1, pp. 102–104, 2005.
[33]
H. Morita, S. Ikeda, K. Yamamoto et al., “Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family,” Annals of Neurology, vol. 37, no. 5, pp. 646–656, 1995.
[34]
J. Kóbor, A. Javaid, and M. F. Omojola, “Cerebellar hypoperfusion in infantile neuroaxonal dystrophy,” Pediatric Neurology, vol. 32, no. 2, pp. 137–139, 2005.
[35]
C. Paisan-Ruiz, K. P. Bhatia, A. Li et al., “Characterization of PLA2G6 as a locus for dystonia-parkinsonism,” Annals of Neurology, vol. 65, no. 1, pp. 19–23, 2009.
[36]
P. Péran, G. Hagberg, G. Luccichenti et al., “Voxel-based analysis of R2* maps in the healthy human brain,” Journal of Magnetic Resonance Imaging, vol. 26, no. 6, pp. 1413–1420, 2007.
[37]
A. Cherubini, P. Péran, C. Caltagirone, U. Sabatini, and G. Spalletta, “Aging of subcortical nuclei: microstructural, mineralization and atrophy modifications measured in vivo using MRI,” Neuroimage, vol. 48, no. 1, pp. 29–36, 2009.
