Medical management of hereditary optic neuropathies

Frontiers in Neurology

Volumn 5 JUL, Issue , 2014, Pages

  La Morgia, Chiara ^a,b   Carbonelli, Michele ^c   Barboni, Piero ^c,d   Sadun, Alfredo Arrigo ^e   Carelli, Valerio ^a,b  

^a IRCCS ISTITUTO DELLE SCIENZE NEUROLOGICHE DI BOLOGNA   (Italy)

^b UNIVERSITY OF BOLOGNA   (Italy)

^c Studio Oculistico d'Azeglio   (Italy)

^d SAN RAFFAELE HOSPITAL   (Italy)

^e UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

DOA; Hereditary; Leber; LHON; Mitochondria; OPA1; Optic atrophy; Optic nerve

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; ALPHA TOCOTRIENOL; BEZAFIBRATE; IDEBENONE; ISOPROTEIN; MITOCHONDRIAL DNA; RESVERATROL; ROSIGLITAZONE; UBIDECARENONE;

ANTIOXIDANT ACTIVITY; AUTOSOMAL DOMINANT OPTIC ATROPHY; BIOGENESIS; CLINICAL FEATURE; COLOR VISION DEFECT; COMPLEX I DEFICIENCY; FOLLOW UP; GENE; GENE MUTATION; GENE SEQUENCE; GENE THERAPY; GENETIC SCREENING; HUMAN; LEBER HEREDITARY OPTIC NEUROPATHY; MITOCHONDRIAL BIOGENESIS; NERVE FIBER; NERVE FIBER DEGENERATION; NEUROOPHTHALMOLOGY; NONHUMAN; ONSET AGE; OPA1 GENE; RETINA GANGLION CELL; SHORT SURVEY; VISUAL ACUITY; VISUAL IMPAIRMENT;

EID: 84907303886     PISSN: None     EISSN: 16642295     Source Type: Journal    
DOI: 10.3389/fneur.2014.00141     Document Type: Short Survey

References (80)

1. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies-disease mechanisms and therapeutic strategies. Prog Retin Eye Res (2011) 30:81-114. doi: 10.1016/j.preteyeres.2010.11.002
2. Carelli V, La Morgia C, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta (2009) 1787:518-28. doi:10.1016/j.bbabio.2009.02.024
3. Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissière A, et al. OPA1 mutations induce mitochondrial DNA instability and optic atrophy "plus" phenotypes. Brain (2008) 131:338-51. doi:10.1093/brain/awm298
4. Pulkes T, Eunson L, Patterson V, Siddiqui A, Wood NW, Nelson IP, et al. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann Neurol (1999) 46:916-9. doi:10.1002/1531-8249(199912)46:6<916::AID-ANA16>3.0.CO;2-R
5. Bruyn GW, Went LN. A sex-linked heredo-degenerative neurological disorder, associated with Leber's optic atrophy. I. Clinical studies. J Neurol Sci (1964) 1:59-80. doi:10.1016/0022-510X(64)90054-1
6. Novotny EJ Jr, Singh G, Wallace DC, Dorfman LJ, Louis A, Sogg RL, et al. Leber's disease and dystonia: a mitochondrial disease. Neurology (1986) 36:1053-60. doi:10.1212/WNL.36.8.1053
7. Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, et al. Phenotypic heterogeneity of the 8344A >G mtDNA "MERRF" mutation. Neurology (2013) 80:2049-54. doi:10.1212/WNL.0b013e318294b44c
8. Milone M, Wang J, Liewluck T, Chen LC, Leavitt JA, Wong LJ. Novel POLG splice site mutation and optic atrophy. Arch Neurol (2011) 68:806-11. doi:10.1001/archneurol.2011.124
9. Fortuna F, Barboni P, Liguori R, Valentino ML, Savini G, Gellera C, et al. Visual system involvement in patients with Friedreich's ataxia. Brain (2009) 132:116-23. doi:10.1093/brain/awn269
10. Rouzier C, Bannwarth S, Chaussenot A, Chevrollier A, Verschueren A, Bonello-Palot N, et al. The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy "plus" phenotype. Brain (2012) 135:23-34. doi:10.1093/brain/awr323
11. Ha AD, Parratt KL, Rendtorff ND, Lodahl M, Ng K, Rowe DB, et al. The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome. Mov Disord (2012) 27:1034-40. doi:10.1002/mds.25033
12. Klebe S, Depienne C, Gerber S, Challe G, Anheim M, Charles P, et al. Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain (2012) 135:2980-93. doi:10.1093/brain/aws240
13. Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr (2012) 24:512-7. doi:10.1097/MOP.0b013e328354ccdf
14. Stricker S, Oberwahrenbrock T, Zimmermann H, Schroeter J, Endres M, Brandt AU, et al. Temporal retinal nerve fiber loss in patients with spinocerebellar ataxia type 1. PLoS One (2011) 6:e23024. doi:10.1371/journal.pone.0023024
15. Moghadam KK, Pizza F, La Morgia C, Franceschini C, Tonon C, Lodi R, et al. Narcolepsy is a common phenotype in HSAN IE and ADCA-DN. Brain (2014) 37(Pt 6):1643-55. doi:10.1093/brain/awu069
16. Carelli V, La Morgia C, Sadun AA. Mitochondrial dysfunction in optic neuropathies: animal models and therapeutic options. Curr Opin Neurol (2013) 26:52-8. doi:10.1097/WCO.0b013e32835c5f0b
17. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res (2004) 23:53-89. doi:10.1016/j.preteyeres.2003.10.003
18. Achilli A, Iommarini L, Olivieri A, Pala M, Hooshiar Kashani B, Reynier P, et al. Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy. PLoS One (2012) 7:e42242. doi:10.1371/journal.pone.0042242
19. Kerrison JB, Arnould VJ, Ferraz Sallum JM, Vagefi MR, Barmada MM, Li Y, et al. Genetic heterogeneity of dominant optic atrophy, Kjer type: identification of a second locus on chromosome 18q12.2-12.3. Arch Ophthalmol (1999) 117:805-10.
20. Barbet F, Hakiki S, Orssaud C, Gerber S, Perrault I, Hanein S, et al. A third locus for dominant optic atrophy on chromosome 22q. J Med Genet (2005) 42:e1. doi:10.1136/jmg.2004.025502
21. Carelli V, Schimpf S, Fuhrmann N, Valentino ML, Zanna C, Iommarini L, et al. A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16. Hum Mol Genet (2011) 20:1893-905. doi:10.1093/hmg/ddr071
22. Reynier P, Amati-Bonneau P, Verny C, Olichon A, Simard G, Guichet A, et al. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet (2004) 41:e110. doi:10.1136/jmg.2003.016576
23. Rendtorff ND, Lodahl M, Boulahbel H, Johansen IR, Pandya A, Welch KO, et al. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. Am J Med Genet A (2011) 155A:1298-313. doi:10.1002/ajmg.a.33970
24. Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet (2001) 69:1218-24. doi:10.1086/324651
25. Assink JJ, Tijmes NT, ten Brink JB, Oostra RJ, Riemslag FC, de Jong PT, et al. A gene for X-linked optic atrophy is closely linked to the Xp11.4-Xp11.2 region of the X chromosome. Am J Hum Genet (1997) 61:934-9.
26. Barbet F, Gerber S, Hakiki S, Perrault I, Hanein S, Ducroq D, et al. A first locus for isolated autosomal recessive optic atrophy (ROA1) maps to chromosome 8q. Eur J Hum Genet (2003) 11:966-71. doi:10.1038/sj.ejhg.5201070
27. Hanein S, Perrault I, Roche O, Gerber S, Khadom N, Rio M, et al. TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy. Am J Hum Genet (2009) 84:493-8. doi:10.1016/j.ajhg.2009.03.003
28. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol (2005) 140:517-23. doi:10.1016/j.ajo.2005.03.017
29. Barboni P, Carbonelli M, Savini G, Ramos Cdo V, Carta A, Berezovsky A, et al. Natural history of Leber's hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology (2010) 117:623-7. doi:10.1016/j.ophtha.2009.07.026
30. La Morgia C, Ross-Cisneros FN, Sadun AA, Hannibal J, Munarini A, Mantovani V, et al. Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies. Brain (2010) 133:2426-38. doi:10.1093/brain/awq155
31. Moura AL, Nagy BV, La Morgia C, Barboni P, Oliveira AG, Salomão SR, et al. The pupil light reflex in Leber's hereditary optic neuropathy: evidence for preservation of melanopsin-expressing retinal ganglion cells. Invest Ophthalmol Vis Sci (2013) 54:4471-7. doi:10.1167/iovs.12-11137
32. Kawasaki A, Collomb S, Léon L, Münch M. Pupil responses derived from outer and inner retinal photoreception are normal in patients with hereditary optic neuropathy. Exp Eye Res (2014) 120:161-6. doi:10.1016/j.exer.2013.11.005
33. Ziccardi L, Sadun F, De Negri AM, Barboni P, Savini G, Borrelli E, et al. Retinal function and neural conduction along the visual pathways in affected and unaffected carriers with Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci (2013) 54:6893-901. doi:10.1167/iovs.13-12894
34. Stone EM, Newman NJ, Miller NR, Johns DR, Lott MT, Wallace DC. Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation. J Clin Neuroophthalmol (1992) 12:10-4.
35. Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, et al. Idebenone treatment in Leber's hereditary optic neuropathy. Brain (2011) 134:e188. doi:10.1093/brain/awr180
36. Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, et al. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain (2011) 134:220-34. doi:10.1093/brain/awq276
37. Harding AE, Sweeney MG, Govan GG, Riordan-Eva P. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet (1995) 57:77-86.
38. Carelli V, Achilli A, Valentino ML, Rengo C, Semino O, Pala M, et al. Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Am J Hum Genet (2006) 78:564-74. doi:10.1086/501236
39. Sadun AA, La Morgia C, Carelli V. Mitochondrial optic neuropathies: our travels from bench to bedside and back again. Clin Experiment Ophthalmol (2013) 41:702-12. doi:10.1111/ceo.12086
40. Kirkman MA, Yu-Wai-Man P, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, et al. Gene-environment interactions in Leber hereditary optic neuropathy. Brain (2009) 132:2317-26. doi:10.1093/brain/awp158
41. Nikoskelainen EK, Marttila RJ, Huoponen K, Juvonen V, Lamminen T, Sonninen P, et al. Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry (1995) 59:160-4. doi:10.1136/jnnp.59.2.160
42. La Morgia C, Achilli A, Iommarini L, Barboni P, Pala M, Olivieri A, et al. Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. Neurology (2008) 70:762-70. doi:10.1212/01.wnl.0000295505.74234.d0
43. Lodi R, Carelli V, Cortelli P, Iotti S, Valentino ML, Barboni P, et al. Phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry (2002) 72:805-7. doi:10.1136/jnnp.72.6.805
44. Montagna P, Plazzi G, Cortelli P, Carelli V, Lugaresi E, Barboni P, et al. Abnormal lactate after effort in healthy carriers of Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry (1995) 58:640-1. doi:10.1136/jnnp.58.5.640
45. Sadun AA, Salomao SR, Berezovsky A, Sadun F, Denegri AM, Quiros PA, et al. Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study. Trans Am Ophthalmol Soc (2006) 104:51-61.
46. Barboni P, Savini G, Feuer WJ, Budenz DL, Carbonelli M, Chicani F, et al. Retinal nerve fiber layer thickness variability in Leber hereditary optic neuropathy carriers. Eur J Ophthalmol (2012) 22:985-91. doi:10.5301/ejo.5000154
47. Ventura DF, Gualtieri M, Oliveira AG, Costa MF, Quiros P, Sadun F, et al. Male prevalence of acquired color vision defects in asymptomatic carriers of Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci (2007) 48:2362-70. doi:10.1167/iovs.06-0331
48. Sacai PY, Salomão SR, Carelli V, Pereira JM, Belfort R Jr, Sadun AA, et al. Visual evoked potentials findings in non-affected subjects from a large Brazilian pedigree of 11778 Leber's hereditary optic neuropathy. Doc Ophthalmol (2010) 121:147-54. doi:10.1007/s10633-010-9241-2
49. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet (2000) 26:207-10. doi:10.1038/79936
50. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet (2000) 26:211-5. doi:10.1038/79944
51. Votruba M, Moore AT, Bhattacharya SS. Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy. J Med Genet (1998) 35:793-800. doi:10.1136/jmg.35.10.793
52. Cohn AC, Toomes C, Potter C, Towns KV, Hewitt AW, Inglehearn CF, et al. Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations. Am J Ophthalmol (2007) 143:656-62. doi:10.1016/j.ajo.2006.12.038
53. Barboni P, Savini G, Parisi V, Carbonelli M, La Morgia C, Maresca A, et al. Retinal nerve fiber layer thickness in dominant optic atrophy measurements by optical coherence tomography and correlation with age. Ophthalmology (2011) 118:2076-80. doi:10.1016/j.ophtha.2011.02.027
54. Votruba M, Thiselton D, Bhattacharya SS. Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy. Br J Ophthalmol (2003) 87:48-53. doi:10.1136/bjo.87.1.48
55. Barboni P, Carbonelli M, Savini G, Foscarini B, Parisi V, Valentino ML, et al. OPA1 mutations associated with dominant optic atrophy influence optic nerve head size. Ophthalmology (2010) 117:1547-53. doi:10.1016/j.ophtha.2009.12.042
56. Perganta G, Barnard AR, Katti C, Vachtsevanos A, Douglas RH, MacLaren RE, et al. Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy. PLoS One (2013) 8:e56350. doi:10.1371/journal.pone.0056350
57. Holder GE, Votruba M, Carter AC, Bhattacharya SS, Fitzke FW, Moore AT. Electrophysiological findings in dominant optic atrophy (DOA) linking to the OPA1 locus on chromosome 3q 28-qter. Doc Ophthalmol (1999) 95:217-28.
58. Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain (2010) 133:771-86. doi:10.1093/brain/awq007
59. Puomila A, Huoponen K, Mäntyjärvi M, Hämäläinen P, Paananen R, Sankila EM, et al. Dominant optic atrophy: correlation between clinical and molecular genetic studies. Acta Ophthalmol Scand (2005) 83:337-46. doi:10.1111/j.1600-0420.2005.00448.x
60. Nakamura M, Yamamoto M. Variable pattern of visual recovery of Leber's hereditary optic neuropathy. Br J Ophthalmol (2000) 84:534-5. doi:10.1136/bjo.84.5.534
61. Barboni P, Valentino ML, La Morgia C, Carbonelli M, Savini G, De Negri A, et al. Idebenone treatment in patients with OPA1-mutant dominant optic atrophy. Brain (2013) 136:e231. doi:10.1093/brain/aws280
62. Cornille K, Milea D, Amati-Bonneau P, Procaccio V, Zazoun L, Guillet V, et al. Reversible optic neuropathy with OPA1 exon 5b mutation. Ann Neurol (2008) 63:667-71. doi:10.1002/ana.21376
63. Altpeter EK, Blanke BR, Leo-Kottler B, Nguyen XN, Trauzettel-Klosinski S. Evaluation of fixation pattern and reading ability in patients with Leber hereditary optic neuropathy. J Neuroophthalmol (2013) 33:344-8. doi:10.1097/WNO.0b013e31829d1f5b
64. Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, et al. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol (2013) 9:474-81. doi:10.1038/nrneurol.2013.129
65. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain (2011) 134:2677-86. doi:10.1093/brain/awr170
66. Geromel V, Darin N, Chrétien D, Bénit P, DeLonlay P, Rötig A, et al. Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab (2002) 77:21-30. doi:10.1016/S1096-7192(02)00145-2
67. Rudolph G, Dimitriadis K, Büchner B, Heck S, Al-Tamami J, Seidensticker F, et al. Effects of idebenone on color vision in patients with leber hereditary optic neuropathy. J Neuroophthalmol (2013) 33:30-6. doi:10.1097/WNO.0b013e318272c643
68. Zanna C, Ghelli A, Porcelli AM, Karbowski M, Youle RJ, Schimpf S, et al. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain (2008) 131:352-67. doi:10.1093/brain/awm335
69. Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol (2012) 69:331-8. doi:10.1001/archneurol.2011.2972
70. Giordano C, Iommarini L, Giordano L, Maresca A, Pisano A, Valentino ML, et al. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy. Brain (2014) 137:335-53. doi:10.1093/brain/awt343
71. Wenz T, Williams SL, Bacman SR, Moraes CT. Emerging therapeutic approaches to mitochondrial diseases. Dev Disabil Res Rev (2010) 16:219-29. doi:10.1002/ddrr.109
72. Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, et al. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann Neurol (2002) 52:534-42. doi:10.1002/ana.10354
73. Bonnet C, Augustin S, Ellouze S, Bénit P, Bouaita A, Rustin P, et al. The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochim Biophys Acta (2008) 1783:1707-17. doi:10.1016/j.bbamcr.2008.04.018
74. Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, et al. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet (2008) 83:373-87. doi:10.1016/j.ajhg.2008.08.013
75. Guy J, Qi X, Koilkonda RD, Arguello T, Chou TH, Ruggeri M, et al. Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system. Invest Ophthalmol Vis Sci (2009) 50:4205-14. doi:10.1167/iovs.08-3214
76. Perales-Clemente E, Fernández-Silva P, Acín-Pérez R, Pérez-Martos A, Enríquez JA. Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task? Nucleic Acids Res (2011) 39:225-34. doi:10.1093/nar/gkq769
77. Yu H, Koilkonda RD, Chou TH, Porciatti V, Ozdemir SS, Chiodo V, et al. Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model. Proc Natl Acad Sci U S A (2012) 109:E1238-47. doi:10.1073/pnas.1119577109
78. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med (2008) 358:2240-8. doi:10.1056/NEJMoa0802315
79. Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, et al. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis type 2. Ophthalmology (2013) 120:1283-91. doi:10.1016/j.ophtha.2012.11.048
80. Bouaita A, Augustin S, Lechauve C, Cwerman-Thibault H, Bénit P, Simonutti M, et al. Downregulation of apoptosis-inducing factor in Harlequin mice induces progressive and severe optic atrophy which is durably prevented by AAV2-AIF1 gene therapy. Brain (2012) 135:35-52. doi:10.1093/brain/awr290