Pathophysiology and Treatment of Neurodegeneration with Brain Iron Accumulation in the Pediatric Population

Current Treatment Options in Neurology

Volumn 15, Issue 5, 2013, Pages 652-667

  Schneider, Susanne A ^a   Zorzi, Giovanna ^b   Nardocci, Nardo ^b  

^a UNIVERSITY OF KIEL   (Germany)

^b DEPARTMENT OF NEUROSURGERY   (Italy)

Author keywords

Brain iron accumulation; Ceramide; Dystonia; Iron; Iron chelator; MPAN; NBIA; Neurodegeneration; Pediatric; PKAN; PLA2G6; Treatment

Indexed keywords

BACLOFEN; CHOLINERGIC RECEPTOR BLOCKING AGENT; DEFERIPRONE; DOPAMINE RECEPTOR STIMULATING AGENT; IRON; PANTOTHENATE KINASE; TETRABENAZINE;

ABDOMINAL DISCOMFORT; ADULTHOOD; AGRANULOCYTOSIS; ARTHRITIS; ARTICLE; ATP13A2 GENE; AUTOSOMAL RECESSIVE INHERITANCE; BASAL GANGLION; BETA PROPELLER ASSOCIATED NEURODEGENERATION; BURKE FAHN MARSDEN DYSTONIA RATING SCALE; CHILD; CHILDHOOD; CLINICAL FEATURE; CP GENE; DIAGNOSTIC TEST; DIFFERENTIAL DIAGNOSIS; DISEASE CLASSIFICATION; DRUG HALF LIFE; EROSIVE ARTHRITIS; FA2H GENE; FTL GENE; GENE; GENE MUTATION; GENETIC SCREENING; HUMAN; KUFOR RAKEB DISEASE; LEUKODYSTROPHY; MEDICAL INFORMATION; MITOCHONDRIAL MEMBRANE PROTEIN ASSOCIATED NEURODEGENERATION; NBIA SYNDROME; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION; NEUROIMAGING; NEUROLOGIC DISEASE; NEURONAL CEROID LIPOFUSCINOSIS; NEUTROPENIA; NUCLEAR MAGNETIC RESONANCE IMAGING; ONSET AGE; PANK2 GENE; PATHOPHYSIOLOGY; PLA2G6 GENE; RADIODIAGNOSIS; RATING SCALE; SPASTIC PARAPLEGIA; SYMPTOM; WDR45 GENE; WHITE MATTER;

EID: 84885187866     PISSN: 10928480     EISSN: 15343138     Source Type: Journal    
DOI: 10.1007/s11940-013-0254-5     Document Type: Article

References (99)

1. Schneider SA, Hardy J, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation (NBIA): an update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Mov Disord. 2012;27:42-53.
2. Schenck JF, Zimmerman EA. High-field magnetic resonance imaging of brain iron: birth of a biomarker? NMR Biomed. 2004;17:433-45.
3. Stankiewicz J, Panter SS, Neema M, Arora A, Batt CE, Bakshi R. Iron in chronic brain disorders: imaging and neurotherapeutic implications. Neurotherapeutics. 2007;4:371-86.
4. Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med. 2003;348:33-40.
5. Hayflick SJ. Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Semin Pediatr Neurol. 2006;13:182-5.
6. Egan RA, Weleber RG, Hogarth P, Gregory A, Coryell J, Westaway SK, et al. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). Am J Ophthalmol. 2005;140:267-74.
7. Antonini A, Goldwurm S, Benti R, Prokisch H, Ebhardt M, Cilia R, et al. Genetic, clinical, and imaging characterization of one patient with late-onset, slowly progressive, pantothenate kinase-associated neurodegeneration. Mov Disord. 2006;21:417-8.
8. Aggarwal A, Schneider SA, Houlden H, Silverdale M, Paudel R, Paisan-Ruiz C, et al. Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms. Mov Disord. 2010;25:1424-31.
9. Yoon WT, Lee WY, Shin HY, Lee ST, Ki CS. Novel PANK2 gene mutations in korean patient with pantothenate kinase-associated neurodegeneration presenting unilateral dystonic tremor. Mov Disord. 2010;25:245-7.
10. Chung SJ, Lee JH, Lee MC, Yoo HW, Kim GH. Focal hand dystonia in a patient with PANK2 mutation. Mov Disord. 2008;23:466-8.
11. Delgado RF, Sanchez PR, Speckter H, Then EP, Jimenez R, Oviedo J, et al. Missense PANK2 mutation without "Eye of the tiger" sign: MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN). J Magn Reson Imaging. 2012;35:788-94.
12. Fermin-Delgado R, Roa-Sanchez P, Speckter H, Perez-Then E, Rivera-Mejia D, Foerster B, et al. Involvement of globus pallidus and midbrain nuclei in pantothenate kinase-associated neurodegeneration: measurement of T2 and T2 time. Clin Neuroradiol. Clin Neuroradiol. 2013;23(1):11-5.
13. Hayflick SJ, Penzien JM, Michl W, Sharif UM, Rosman NP, Wheeler PG. Cranial MRI changes may precede symptoms in Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:166-9.
14. Chiapparini L, Savoiardo M, D'Arrigo S, Reale C, Zorzi G, Zibordi F, et al. The "eye-of-the-tiger" sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration. Neuropediatrics. 2011;42:159-62.
15. Grandas F, Fernandez-Carballal C, Guzman-de-Villoria J, Ampuero I. Treatment of a dystonic storm with pallidal stimulation in a patient with PANK2 mutation. Mov Disord. 2011;26:921-2.
16. Awasthi R, Gupta RK, Trivedi R, Singh JK, Paliwal VK, Rathore RK. Diffusion tensor MR imaging in children with pantothenate kinase-associated neurodegeneration with brain iron accumulation and their siblings. AJNR Am J Neuroradiol. 2010;31:442-7.
17. Hajek M, Adamovicova M, Herynek V, Skoch A, Jiru F, Krepelova A, et al. MR relaxometry and 1H MR spectroscopy for the determination of iron and metabolite concentrations in PKAN patients. Eur Radiol. 2005;15:1060-8.
18. Cossu G, Cella C, Melis M, Antonini A, Floris GL, Ruffini L, et al. [123I]FP-CIT SPECT findings in two patients with Hallervorden-Spatz disease with homozygous mutation in PANK2 gene. Neurology. 2005;64:167-8.
19. Hermann W, Barthel H, Reuter M, Georgi P, Dietrich J, Wagner A. Hallervorden-Spatz disease: findings in the nigrostriatal system. Nervenarzt. 2000;71:660-5.
20. Hartig MB, Hortnagel K, Garavaglia B, Zorzi G, Kmiec T, Klopstock T, et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol. 2006;59:248-56.
21. McNeill A, Birchall D, Hayflick SJ, Gregory A, Schenk JF, Zimmerman EA, et al. T2 and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology. 2008;70:1614-9.
22. Seo JH, Song SK, Lee PH. A Novel PANK2 Mutation in a Patient with Atypical Pantothenate-Kinase-Associated Neurodegeneration Presenting with Adult-Onset Parkinsonism. J Clin Neurol. 2009;5:192-4.
23. Mak CM, Sheng B, Lee HH, Lau KK, Chan WT, Lam CW, et al. Young-onset parkinsonism in a Hong Kong Chinese man with adult-onset Hallervorden-Spatz syndrome. Int J Neurosci. 2011;121:224-7.
24. Doi H, Koyano S, Miyatake S, Matsumoto N, Kameda T, Tomita A, et al. Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: clinical features and (99m)Tc-ECD brain perfusion SPECT findings. J Neurol Sci. 2010;290:172-6.
25. Kostic VS, Svetel M, Mijajlovic M, Pavlovic A, Jecmenica-Lukic M, Kozic D. Transcranial sonography in pantothenate kinase-associated neurodegeneration. J Neurol. 2012;259:959-65.
26. Liman J, Wellmer A, Rostasy K, Bahr M, Kermer P. Transcranial ultrasound in neurodegeneration with brain iron accumulation (NBIA). Eur J Paediatr Neurol. 2012;16:175-8.
27. Kruer MC, Hiken M, Gregory A, Malandrini A, Clark D, Hogarth P, et al. Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration. Brain. 2011;134:947-58. This paper reported pathological findings in gene-proven cases. Importantly, in contrast to previous reports (of clinically-diagnosed cases) the authors emphasize absence of Lewy bodies in PKAN.
28. Hallervorden J, Spatz H. Eigenartige Erkrankung im extrapyramidalen System mit besonderer Beteiligung des Globus pallidus und der Substantia nigra.: Ein Beitrag zu den Beziehungen zwischen diesen beiden Zentren. Z Ges Neurol Psychiat. 1922;79:254-302.
29. Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM. Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci. 2005;25:689-98.
30. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443:787-95.
31. Kurian MA, Morgan NV, MacPherson L, Foster K, Peake D, Gupta R, et al. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008;70:1623-9.
32. Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S, et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006;38:752-4.
33. Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, Wood NW, et al. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol. 2009;65:19-23.
34. Deng H, Liang H, Jankovic J. The F-box only protein 7 gene in parkinsonian-pyramidal disease. JAMA Neurol. 2013;70(1):20-4.
35. Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet. 2009;46:73-80.
36. Paisan-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R, Kidd D, et al. Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging. 2012;33:814-23.
37. Malik I, Turk J, Mancuso DJ, Montier L, Wohltmann M, Wozniak DF, et al. Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am J Pathol. 2008;172:406-16.
38. Gregory A, Westaway SK, Holm IE, Kotzbauer PT, Hogarth P, Sonek S, et al. Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology. 2008;71:1402-9.
39. Vinters H, Farrell M, Mischel P, Anders K. Diagnostic neuropathology. New York: Marcel Dekker Incorporated; 1998.
40. Kruer MC, Paisan-Ruiz C, Boddaert N, Yoon BS, Hama H, Gregory A, et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol. 2010;68:611-8.
41. Dick KJ, Eckhardt M, Paisan-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat. 2010;31:E1251-60.
42. Edvardson S, Hama H, Shaag A, Gomori JM, Berger I, Soffer D, et al. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am J Hum Genet. 2008;83:643-8.
43. Garone C, Pippucci T, Cordelli DM, Zuntini R, Castegnaro G, Marconi C, et al. FA2H-related disorders: a novel c.270 + 3A > T splice-site mutation leads to a complex neurodegenerative phenotype. Dev Med Child Neurol. 2011;53(10):958-61.
44. Pierson TM, Simeonov DR, Sincan M, Adams DA, Markello T, Golas G, et al. Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. Eur J Hum Genet. 2012;20:476-9.
45. Bras J, Singleton A, Cookson MR, Hardy J. Potential role of ceramide metabolism in Lewy body disease. Eur J Biochem (FEBS). 2008;275:5767-73.
46. Potter KA, Kern MJ, Fullbright G, Bielawski J, Scherer SS, Yum SW, et al. Central nervous system dysfunction in a mouse model of Fa2h deficiency. Glia. 2011;59:1009-21.
47. Zoller I, Meixner M, Hartmann D, Bussow H, Meyer R, Gieselmann V, et al. Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration. J Neurosci. 2008;28:9741-54.
48. Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, et al. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet. 2011;89:543-50.
49. Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, et al. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology. 2013;80:268-75.
50. Horvath R, Holinski-Feder E, Neeve V, Neeve V, Pyle A, Griffin H, et al. A new phenotype of brain iron accumulation with dystonia, optic atrophy and peripheral neuropathy. Mov Disord. 2012;27:789-93.
51. Goldman JG, Eichenseer SR, Berry-Kravis E, Zimnowodzki S, Gregory A, Hogarth P et al. Clinical features of neurodegeneration with brain iron accumulation due to a C19orf12 gene mutation. Mov Disord. 2013 Mar 13.
52. Hayflick SJ, Kruer MC, Gregory A, Haack TB, Kurian MA, Houlden HH, et al. Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain. 2013;136(Pt 6):1708-17.
53. Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. 2013;45:445-9.
54. Di Fonzo A, Chien HF, Socal M, Giraudo S, Tassorelli C, Iliceto G, et al. ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology. 2007;68:1557-62.
55. Najim al-Din AS, Wriekat A, Mubaidin A, Dasouki M, Hiari M. Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurol Scand. 1994;89:347-52.
56. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38:1184-91.
57. Williams DR, Hadeed A. al Din, A. S.; Wreikat, A. L.; Lees, A. J. Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord. 2005;20:1264-71.
58. Behrens MI, Bruggemann N, Chana P, Venegas P, Kagi M, Parrao T, et al. Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations. Mov Disord. 2010;25:1929-37.
59. Paisan-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E, et al. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Disord. 2010;25:1791-800.
60. Park JS, Mehta P, Cooper AA, Veivers D, Heimbach A, Stiller B, et al. Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset Parkinsonism. Hum Mutat. 2011;32(8):956-64.
61. Bras J, Verloes A, Schneider SA, Mole SE, Guerreiro R. Mutation of the Parkinsonism Gene ATP13A2 Causes Neuronal Ceroid-Lipofuscinosis. Hum Mol Genet. 2012;21:2646-50.
62. McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H. The neurological presentation of ceruloplasmin gene mutations. Eur Neurol. 2008;60:200-5.
63. Chinnery PF, Crompton DE, Birchall D, Jackson MJ, Coulthard A, Lombes A, et al. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain. 2007;130:110-9.
64. Chinnery PF, Curtis AR, Fey C, Coulthard A, Crompton D, Curtis A, et al. Neuroferritinopathy in a French family with late onset dominant dystonia. J Med Genet. 2003;40:e69.
65. Kubota A, Hida A, Ichikawa Y, Momose Y, Goto J, Igeta Y, 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. Mov Disord. 2009;24:441-5.
66. Devos D, Tchofo PJ, Vuillaume I, Destee A, Batey S, Burn J, et al. Clinical features and natural history of neuroferritinopathy caused by the 458dupA FTL mutation. Brain. 2009;132:e109.
67. 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;25:2470-2.
68. Brueggemann N, Wuerfel JT, Petersen D, Klein C, Hagenah J, Schneider SA. Idiopathic NBIA - clinical spectrum and transcranial sonography findings. Eur J Neurol. 2011;18:e58-9.
69. Dusek P, Jankovic J, Weidong L. Iron dysregulation in movement disorders. Neurobiol Dis. 2012;46:1-18.
70. Crichton RR, Dexter DT, Ward RJ. Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm. 2011;118:301-14.
71. Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med. 2012;366:348-59.
72. Taylor EM, Morgan EH. Developmental changes in transferrin and iron uptake by the brain in the rat. Brain Res Dev Brain Res. 1990;55:35-42.
73. Zecca L, Gallorini M, Schunemann V, Trautwein AX, Gerlach M, Riederer P, et al. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes. J Neurochem. 2001;76:1766-73.
74. Connor JR, Menzies SL, St Martin SM, Mufson EJ. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res. 1990;27:595-611.
75. Schenck JF, Zimmermann FA. High-field magnetic resonance imaging of brain iron: birth of a biomarker? NMR Biomed. 2004;17:433-45.
76. HALLGREN B, SOURANDER P. The effect of age on the non-haemin iron in the1461 human brain. J Neurochem. 1958;3:41-51.
77. Morris CM, Candy JM, Oakley AE, Bloxham CA, Edwardson JA. Histochemical distribution of non-haem iron in the human brain. Acta Anat (Basel). 1992;144:235-57.
78. Drayer B, Burger P, Darwin R, Riederer S, Herfkens R, Johnson GA. MRI of brain iron. AJR Am J Roentgenol. 1986;147:103-10.
79. Yao B, Li TQ, Gelderen P, Shmueli K, de Zwart JA, Duyn JH. Susceptibility contrast in high field MRI of human brain as a function of tissue iron content. NeuroImage. 2009;44:1259-66.
80. Pfefferbaum A, Adalsteinsson E, Rohlfing T, Sullivan EV. MRI estimates of brain iron concentration in normal aging: comparison of field-dependent (FDRI) and phase (SWI) methods. NeuroImage. 2009;47:493-500.
81. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease - systematic review and meta-analysis. Neurobiol Aging. 2009;30:337-52.
82. Faucheux BA, Bonnet AM, Agid Y, Hirsch EC. Blood vessels change in the mesencephalon of patients with Parkinson's disease. Lancet. 1999;353:981-2.
83. Matsunaga T, Kotamraju S, Kalivendi SV, Dhanasekaran A, Joseph J, Kalyanaraman B. Ceramide-induced intracellular oxidant formation, iron signaling, and apoptosis in endothelial cells: protective role of endogenous nitric oxide. J Biol Chem. 2004;279:28614-24.
84. Tsukamoto H, Inui K, Taniike M, Nishimoto J, Midorikawa M, Yoshimine T, et al. A case of Hallervorden-Spatz disease: progressive and intractable dystonia controlled by bilateral thalamotomy. Brain Dev. 1992;14:269-72.
85. Balas I, Kovacs N, Hollody K. Staged bilateral stereotactic pallidothalamotomy for life-threatening dystonia in a child with Hallervorden-Spatz disease. Mov Disord. 2006;21:82-5.
86. Kyriagis M, Grattan-Smith P, Scheinberg A, Teo C, Nakaji N, Waugh M. Status dystonicus and Hallervorden-Spatz disease: treatment with intrathecal baclofen and pallidotomy. J Paediatr Child Health. 2004;40:322-5.
87. Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report J Neurosurg. 1999;90:551-4.
88. Castelnau P, Cif L, Valente EM, Vayssiere N, Hemm S, Gannau A, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol. 2005;57:738-41.
89. Mikati MA, Yehya A, Darwish H, Karam P, Comair Y. Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration. Eur J Paediatr Neurol. 2009;13:61-4.
90. Krause M, Fogel W, Tronnier V, Pohle S, Hortnagel K, Thyen U, et al. Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration. Mov Disord. 2006;21:2255-7.
91. Szumowski J, Bas E, Gaarder K, Schwarz E, Erdogmus D, Hayflick S. Measurement of brain iron distribution in Hallevorden-Spatz syndrome. J Magn Reson Imaging. 2010;31:482-9.
92. Timmermann L, Pauls KA, Wieland K, Jech R, Kurlemann G, Sharma N, et al. Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation. Brain. 2010;133:701-12. The authors summarize the effects of deep brain stimulation of the globus pallidus on clinical symptoms and imaging findings in 23 NBIA (mainly PKAN) patients. Clinical improvement ranged around 20%.
93. Adamovicova M, Jech R, Urgosik D, Spackova N, Krepelova A. Pallidal stimulation in siblings with pantothenate kinase-associated neurodegeneration: four-year follow-up. Mov Disord. 2011;26:184-7.
94. Li X, Jankovic J. Iron chelation and neuroprotection in neurodegenerative diseases. J Neural Transm. 2011;118:473-7.
95. Zhu W, Li X, Luo F, Kaur D, Andersen JK, Jankovic J, et al. Genetic iron chelation protects against proteasome inhibition-induced dopamine neuron degeneration. Neurobiol Dis. 2010;37:307-13.
96. Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, et al. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: Results of a phase II pilot trial. Mov Disord. 2011;26:1756-9. This is the first phase II clinical study to assess the effect of iron chelators on clinical symptoms and imaging abnormalities in PKAN. A randomized placebo-controlled study is on the way.
97. Abbruzzese G, Cossu G, Balocco M, Marchese R, Murgia D, Melis M, et al. A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica. 2011;96:1708-11.
98. Rana A, Seinen E, Siudeja K, Muntendam R, Srinivasan B, van der Want JJ, et al. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration. Proc Natl Acad Sci U S A. 2010;107:6988-93.
99. Kruer M, Boddaert N, Schneider SA, Houlden H, Bhatia KP, Gregory A, et al. Neuroimaging features of Neurodegeneration with Brain Iron Accumulation (NBIA). Am J Neuroradiol. 2012;33:407-14.