PDF herunterladen
Journal of Pediatric Neurology 2015; 13(04): 155-167
DOI: 10.1055/s-0035-1558861
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Update in Neurodegeneration with Brain Iron Accumulation: Advances in Molecular Diagnosis and Treatment Strategies

Barbara Csányi
1   Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
2   Department of Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, United Kingdom
,
Apostolos Papandreou
1   Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
2   Department of Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, United Kingdom
,
Sammie Cuka
3   Department of Pharmacology, UCL School of Pharmacy, London, United Kingdom
,
Ahad Abdul Rahim
3   Department of Pharmacology, UCL School of Pharmacy, London, United Kingdom
,
Wui Khean Kling Chong
4   Department of Radiology, Great Ormond Street Hospital for Children, London, United Kingdom
,
Manju Ann Kurian
1   Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
2   Department of Molecular Neurosciences, Developmental Neurosciences, UCL Institute of Child Health, London, United Kingdom
› Institutsangaben
Weitere Informationen

Publikationsverlauf

25. März 2015

26. März 2015

Publikationsdatum:
12. August 2015 (online)

    Lizenzen und Reprints

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term used to clinically describe a group of neurologic conditions associated with high brain iron. To date, there are 10 genetic subtypes described, which share several common clinical features. Novel technologies such as improved magnetic resonance imaging techniques and whole exome sequencing have provided new clinical and genetic insight into these disorders, thereby improving clinical diagnosis for patients. Indeed, precise diagnosis is now possible for approximately 60% of patients with NBIA. Despite these genetic advances, little is known about the exact underlying disease pathways governing many forms of NBIA. In fact, for most subtypes, the causative genes and affected proteins are not directly related to iron homeostasis. Management for all subtypes remains mainly supportive and based on a multidisciplinary approach, but there are promising advances in the development of novel therapeutic strategies. Focusing mainly on the newly described NBIA subtypes, we summarize the clinical phenotypes, genetic basis, and postulated pathophysiological disease mechanisms, and propose an NBIA diagnostic pathway to guide clinical testing and genetic councelling.

Keywords

neurodegeneration - mitochondrial membrane protein - β-Propeller protein - fatty acid hydroxylase - phospholipase A2
 

  • References

  • 1 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 (2) 493-500
    CrossrefPubMedGoogle Scholar
  • 2 Lehéricy S, Bardinet E, Poupon C, Vidailhet M, François C. 7 Tesla magnetic resonance imaging: a closer look at substantia nigra anatomy in Parkinson's disease. Mov Disord 2014; 29 (13) 1574-1581
    CrossrefPubMedGoogle Scholar
  • 3 Graham SF, Nasaruddin MB, Carey M , et al. Age-associated changes of brain copper, iron, and zinc in Alzheimer's disease and dementia with Lewy bodies. J Alzheimers Dis 2014; 42 (4) 1407-1413
    PubMedGoogle Scholar
  • 4 Muller M, Leavitt BR. Iron dysregulation in Huntington's disease. J Neurochem 2014; 130 (3) 328-350
    CrossrefPubMedGoogle Scholar
  • 5 Hayflick SJ, Hartman M, Coryell J, Gitschier J, Rowley H. Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. AJNR Am J Neuroradiol 2006; 27 (6) 1230-1233
    PubMedGoogle Scholar
  • 6 Baumeister FA, Auer DP, Hörtnagel K, Freisinger P, Meitinger T. The eye-of-the-tiger sign is not a reliable disease marker for Hallervorden-Spatz syndrome. Neuropediatrics 2005; 36 (3) 221-222
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 7 Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001; 28 (4) 345-349
    CrossrefPubMedGoogle Scholar
  • 8 Levi S, Finazzi D. Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms. Front Pharmacol 2014; 5: 99
    PubMedGoogle Scholar
  • 9 Khan AO, AlDrees A, Elmalik SA , et al. Ophthalmic features of PLA2G6-related paediatric neurodegeneration with brain iron accumulation. Br J Ophthalmol 2014; 98 (7) 889-893
    CrossrefPubMedGoogle Scholar
  • 10 Romani M, Kraoua I, Micalizzi A , et al. Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort. Eur J Neurol 2015; 22 (1) 178-186
    CrossrefPubMedGoogle Scholar
  • 11 Kurian MA, Hayflick SJ. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. Int Rev Neurobiol 2013; 110: 49-71
    PubMedGoogle Scholar
  • 12 Salih MA, Mundwiller E, Khan AO , et al. New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations. PLoS One 2013; 8 (10) e76831
    CrossrefPubMedGoogle Scholar
  • 13 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 (1) 42-53
    CrossrefPubMedGoogle Scholar
  • 14 Yoshino H, Tomiyama H, Tachibana N , et al. Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. Neurology 2010; 75 (15) 1356-1361
    CrossrefPubMedGoogle Scholar
  • 15 Kurian MA, Morgan NV, MacPherson L , et al. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology 2008; 70 (18) 1623-1629
    CrossrefPubMedGoogle Scholar
  • 16 Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009; 46 (2) 73-80
    PubMedGoogle Scholar
  • 17 Hartig MB, Hörtnagel K, Garavaglia B , et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol 2006; 59 (2) 248-256
    CrossrefPubMedGoogle Scholar
  • 18 Gregory A, Hayflick SJ. Pantothenate kinase-associated neurodegeneration. In: Pagon RA, Adam MP, Ardinger HH, , et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2015
    Google Scholar
  • 19 Kruer MC, Boddaert N. Neurodegeneration with brain iron accumulation: a diagnostic algorithm. Semin Pediatr Neurol 2012; 19 (2) 67-74
    CrossrefPubMedGoogle Scholar
  • 20 Alderson NL, Rembiesa BM, Walla MD, Bielawska A, Bielawski J, Hama H. The human FA2H gene encodes a fatty acid 2-hydroxylase. J Biol Chem 2004; 279 (47) 48562-48568
    CrossrefPubMedGoogle Scholar
  • 21 Potter KA, Kern MJ, Fullbright G , et al. Central nervous system dysfunction in a mouse model of FA2H deficiency. Glia 2011; 59 (7) 1009-1021
    CrossrefPubMedGoogle Scholar
  • 22 Edvardson S, Hama H, Shaag A , 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 (5) 643-648
    CrossrefPubMedGoogle Scholar
  • 23 Dick KJ, Al-Mjeni R, Baskir W , et al. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. Neurology 2008; 71 (4) 248-252
    CrossrefPubMedGoogle Scholar
  • 24 Kruer MC, Paisán-Ruiz C, Boddaert N , et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 2010; 68 (5) 611-618
    CrossrefPubMedGoogle Scholar
  • 25 Garone C, Pippucci T, Cordelli DM , 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) 958-961
    CrossrefPubMedGoogle Scholar
  • 26 Pierson TM, Simeonov DR, Sincan M , et al; NISC Comparative Sequencing Program. Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. Eur J Hum Genet 2012; 20 (4) 476-479
    CrossrefPubMedGoogle Scholar
  • 27 Liao X, Luo Y, Zhan Z , et al. SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations. Clin Genet 2015; 87 (1) 85-89
    CrossrefPubMedGoogle Scholar
  • 28 Donkervoort S, Dastgir J, Hu Y , et al. Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia. Clin Genet 2014; 85 (4) 393-395
    CrossrefPubMedGoogle Scholar
  • 29 Zöller I, Meixner M, Hartmann D , 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 (39) 9741-9754
    CrossrefPubMedGoogle Scholar
  • 30 Kruer MC, Gregory A, Hayflick SJ. Fatty acid hydroxylase-associated neurodegeneration. In: Pagon RA, Adam MP, Ardinger HH, , et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. –2015
    Google Scholar
  • 31 Gregory A, Hayflick S. Neurodegeneration with brain iron accumulation disorders overview. Available at: http://www.ncbi.nlm.nih.gov/books/NBK121988 . Accessed February 28, 2013
    PubMedGoogle Scholar
  • 32 Hartig MB, Iuso A, Haack T , 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 (4) 543-550
    CrossrefPubMedGoogle Scholar
  • 33 Hogarth P, Gregory A, Kruer MC , et al. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 2013; 80 (3) 268-275
    CrossrefPubMedGoogle Scholar
  • 34 Iuso A, Sibon OC, Gorza M , et al. Impairment of Drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration. PLoS ONE 2014; 9 (2) e89439
    CrossrefPubMedGoogle Scholar
  • 35 Dogu O, Krebs CE, Kaleagasi H , et al. Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration. Clin Genet 2013; 84 (4) 350-355
    CrossrefPubMedGoogle Scholar
  • 36 Landouré G, Zhu PP, Lourenço CM , et al; NIH Intramural Sequencing Center. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat 2013; 34 (10) 1357-1360
    CrossrefPubMedGoogle Scholar
  • 37 Gregory A, Hayflick SJ. Genetics of neurodegeneration with brain iron accumulation. Curr Neurol Neurosci Rep 2011; 11 (3) 254-261
    CrossrefPubMedGoogle Scholar
  • 38 Haack TB, Hogarth P, Kruer MC , et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet 2012; 91 (6) 1144-1149
    CrossrefPubMedGoogle Scholar
  • 39 Horvath R. Brain iron takes off: a new propeller protein links neurodegeneration with autophagy. Brain 2013; 136 (Pt 6) 1687-1691
    CrossrefPubMedGoogle Scholar
  • 40 Saitsu H, Nishimura T, Muramatsu K , et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 2013; 45 (4) 445-449 , e1
    CrossrefPubMedGoogle Scholar
  • 41 Hayflick SJ, Kruer MC, Gregory A , et al. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 2013; 136 (Pt 6) 1708-1717
    CrossrefPubMedGoogle Scholar
  • 42 Okamoto N, Ikeda T, Hasegawa T , et al. Early manifestations of BPAN in a pediatric patient. Am J Med Genet A 2014; 164A (12) 3095-3099
    PubMedGoogle Scholar
  • 43 Verhoeven WM, Egger JI, Koolen DA , et al. Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients. Parkinsonism Relat Disord 2014; 20 (3) 332-336
    CrossrefPubMedGoogle Scholar
  • 44 Kruer MC, Boddaert N, Schneider SA , et al. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am J Neuroradiol 2012; 33 (3) 407-414
    CrossrefPubMedGoogle Scholar
  • 45 Dusi S, Valletta L, Haack TB , et al. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am J Hum Genet 2014; 94 (1) 11-22
    CrossrefPubMedGoogle Scholar
  • 46 Aghajanian S, Worrall DM. Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho-CoA kinase bifunctional enzyme (CoA synthase). Biochem J 2002; 365 (Pt 1) 13-18
    CrossrefPubMedGoogle Scholar
  • 47 Tahiliani AG, Beinlich CJ. Pantothenic acid in health and disease. Vitam Horm 1991; 46: 165-228
    PubMedGoogle Scholar
  • 48 Begley TP, Kinsland C, Strauss E. The biosynthesis of coenzyme A in bacteria. Vitam Horm 2001; 61: 157-171
    PubMedGoogle Scholar
  • 49 Bosveld F, Rana A, van der Wouden PE , et al. De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system. Hum Mol Genet 2008; 17 (13) 2058-2069
    CrossrefPubMedGoogle Scholar
  • 50 Frucht S. Movement Disorder Emergencies: Diagnosis and Treatment. New York, NY: Humana Press; 2011
    Google Scholar
  • 51 Lumsden DE, Lundy C, Fairhurst C, Lin JP. Dystonia Severity Action Plan: a simple grading system for medical severity of status dystonicus and life-threatening dystonia. Dev Med Child Neurol 2013; 55 (7) 671-672
    CrossrefPubMedGoogle Scholar
  • 52 Allen NM, Lin JP, Lynch T, King MD. Status dystonicus: a practice guide. Dev Med Child Neurol 2014; 56 (2) 105-112
    CrossrefPubMedGoogle Scholar
  • 53 McNeill A, Birchall D, Hayflick SJ , et al. T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 2008; 70 (18) 1614-1619
    CrossrefPubMedGoogle Scholar
  • 54 Langkammer C, Krebs N, Goessler W , et al. Quantitative MR imaging of brain iron: a postmortem validation study. Radiology 2010; 257 (2) 455-462
    CrossrefPubMedGoogle Scholar
  • 55 Ghadery C, Pirpamer L, Hofer E , et al. R2* mapping for brain iron: associations with cognition in normal aging. Neurobiol Aging 2015; 36 (2) 925-932
    CrossrefPubMedGoogle Scholar
  • 56 Crompton D, Rehal PK, MacPherson L , et al. Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: implications for molecular diagnosis. Mol Genet Metab 2010; 100 (2) 207-212
    CrossrefPubMedGoogle Scholar
  • 57 The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. Available at: http://www.hgmd.cf.ac.uk/ac/index.php
    PubMedGoogle Scholar
  • 58 Keogh MJ, Chinnery PF. Current concepts and controversies in neurodegeneration with brain iron accumulation. Semin Pediatr Neurol 2012; 19 (2) 51-56
    CrossrefPubMedGoogle Scholar
  • 59 Abbruzzese G, Cossu G, Balocco M , et al. A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 2011; 96 (11) 1708-1711
    CrossrefPubMedGoogle Scholar
  • 60 Zorzi G, Zibordi F, Chiapparini L , 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 (9) 1756-1759
    PubMedGoogle Scholar
  • 61 Pratini NR, Sweeters N, Vichinsky E, Neufeld JA. Treatment of classic pantothenate kinase-associated neurodegeneration with deferiprone and intrathecal baclofen. Am J Phys Med Rehabil 2013; 92 (8) 728-733
    CrossrefPubMedGoogle Scholar
  • 62 Chinnery PF, Crompton DE, Birchall D , et al. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain 2007; 130 (Pt 1) 110-119
    PubMedGoogle Scholar
  • 63 Velasco-Sánchez D, Aracil A, Montero R , et al. Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. Cerebellum 2011; 10 (1) 1-8
    CrossrefPubMedGoogle Scholar
  • 64 Yang Y, Wu Z, Kuo YM, Zhou B. Dietary rescue of fumble—a Drosophila model for pantothenate-kinase-associated neurodegeneration. J Inherit Metab Dis 2005; 28 (6) 1055-1064
    CrossrefPubMedGoogle Scholar
  • 65 Rana A, Seinen E, Siudeja K , et al. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration. Proc Natl Acad Sci U S A 2010; 107 (15) 6988-6993
    CrossrefPubMedGoogle Scholar
  • 66 Brunetti D, Dusi S, Giordano C , et al. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model. Brain 2014; 137 (Pt 1) 57-68
    CrossrefPubMedGoogle Scholar
  • 67 Strokin M, Sergeeva M, Reiser G. Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br J Pharmacol 2003; 139 (5) 1014-1022
    CrossrefPubMedGoogle Scholar
  • 68 Strokin M, Sergeeva M, Reiser G. Role of Ca2+-independent phospholipase A2 and n-3 polyunsaturated fatty acid docosahexaenoic acid in prostanoid production in brain: perspectives for protection in neuroinflammation. Int J Dev Neurosci 2004; 22 (7) 551-557
    CrossrefPubMedGoogle Scholar
  • 69 Horrocks LA, Farooqui AA. Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. Prostaglandins Leukot Essent Fatty Acids 2004; 70 (4) 361-372
    CrossrefPubMedGoogle Scholar
  • 70 Shinzawa K, Sumi H, Ikawa M , et al. Neuroaxonal dystrophy caused by group VIA phospholipase A2 deficiency in mice: a model of human neurodegenerative disease. J Neurosci 2008; 28 (9) 2212-2220
    CrossrefPubMedGoogle Scholar
  • 71 Haag M. Essential fatty acids and the brain. Can J Psychiatry 2003; 48 (3) 195-203
    PubMedGoogle Scholar
  • 72 Basselin M, Rosa AO, Ramadan E , et al. Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)β (VIA)-deficient mice. J Lipid Res 2010; 51 (11) 3166-3173
    CrossrefPubMedGoogle Scholar
  • 73 Calon F, Lim GP, Yang F , et al. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron 2004; 43 (5) 633-645
    CrossrefPubMedGoogle Scholar
  • 74 Igarashi M, Gao F, Kim HW, Ma K, Bell JM, Rapoport SI. Dietary n-6 PUFA deprivation for 15 weeks reduces arachidonic acid concentrations while increasing n-3 PUFA concentrations in organs of post-weaning male rats. Biochim Biophys Acta 2009; 1791 (2) 132-139
    CrossrefPubMedGoogle Scholar
  • 75 Kim HW, Rao JS, Rapoport SI, Igarashi M. Dietary n-6 PUFA deprivation downregulates arachidonate but upregulates docosahexaenoate metabolizing enzymes in rat brain. Biochim Biophys Acta 2011; 1811 (2) 111-117
    CrossrefPubMedGoogle Scholar
  • 76 Blanchard H, Taha AY, Cheon Y, Kim HW, Turk J, Rapoport SI. iPLA2β knockout mouse, a genetic model for progressive human motor disorders, develops age-related neuropathology. Neurochem Res 2014; 39 (8) 1522-1532
    CrossrefPubMedGoogle Scholar
  • 77 Castelnau P, Cif L, Valente EM , et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol 2005; 57 (5) 738-741
    CrossrefPubMedGoogle Scholar
  • 78 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 (1) 61-64
    CrossrefPubMedGoogle Scholar
  • 79 Timmermann L, Pauls KA, Wieland K , et al. Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation. Brain 2010; 133 (Pt 3) 701-712
    CrossrefPubMedGoogle Scholar
  • 80 Air EL, Ostrem JL, Sanger TD, Starr PA. Deep brain stimulation in children: experience and technical pearls. J Neurosurg Pediatr 2011; 8 (6) 566-574
    CrossrefPubMedGoogle Scholar
  • 81 Lumsden DE, Kaminska M, Gimeno H , et al. Proportion of life lived with dystonia inversely correlates with response to pallidal deep brain stimulation in both primary and secondary childhood dystonia. Dev Med Child Neurol 2013; 55 (6) 567-574
    CrossrefPubMedGoogle Scholar
  • 82 Kaminska M, Lumsden DE, Ashkan K, Malik I, Selway R, Lin JP. Rechargeable deep brain stimulators in the management of paediatric dystonia: well tolerated with a low complication rate. Stereotact Funct Neurosurg 2012; 90 (4) 233-239
    CrossrefPubMedGoogle Scholar
  • 83 Cif L, Kurian MA, Gonzalez V , et al. Atypical PLA2G6-associated neurodegeneration: social communication impairment, dystonia and response to deep brain stimulation. Mov Disord Clin Pract 2014; 2: 128-131
    PubMedGoogle Scholar
  • 84 Biffi A, Montini E, Lorioli L , et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013; 341 (6148) 1233158
    CrossrefPubMedGoogle Scholar
  • 85 Hwu WL, Muramatsu S, Tseng SH , et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med 2012; 4 (134) 134ra61
    PubMedGoogle Scholar
  • 86 Palfi S, Gurruchaga JM, Ralph GS , et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet 2014; 383 (9923) 1138-1146
    CrossrefPubMedGoogle Scholar
  • 87 Takahashi K, Tanabe K, Ohnuki M , et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131 (5) 861-872
    CrossrefPubMedGoogle Scholar
  • 88 Brown ME, Rondon E, Rajesh D , et al. Derivation of induced pluripotent stem cells from human peripheral blood T lymphocytes. PLoS One 2010; 5 (6) e11373
    CrossrefPubMedGoogle Scholar
  • 89 Qu X, Liu T, Song K, Li X, Ge D. Induced pluripotent stem cells generated from human adipose-derived stem cells using a non-viral polycistronic plasmid in feeder-free conditions. PLoS One 2012; 7 (10) e48161
    CrossrefPubMedGoogle Scholar
  • 90 Tabar V, Studer L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat Rev Genet 2014; 15 (2) 82-92
    CrossrefPubMedGoogle Scholar
  • 91 Tuszynski MH, Wang Y, Graham L , et al. Neural stem cells in models of spinal cord injury. Exp Neurol 2014; 261: 494-500
    CrossrefPubMedGoogle Scholar
  • 92 Rivera FJ, Aigner L. Adult mesenchymal stem cell therapy for myelin repair in multiple sclerosis. Biol Res 2012; 45 (3) 257-268
    CrossrefPubMedGoogle Scholar
  • 93 Tatarishvili J, Oki K, Monni E , et al. Human induced pluripotent stem cells improve recovery in stroke-injured aged rats. Restor Neurol Neurosci 2014; 32 (4) 547-558
    PubMedGoogle Scholar
  • 94 Kriks S, Shim JW, Piao J , et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 2011; 480 (7378) 547-551
    PubMedGoogle Scholar
  • 95 Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci U S A 2008; 105 (43) 16707-16712
    CrossrefPubMedGoogle Scholar
  • 96 ClinicalTrials.gov registry and results database of publicly and privately supported clinical studies of human participants conducted around the world: Available at: https://clinicaltrials.gov
    PubMed