Síndrome do X frágil e outras patologias associadas ao gene FMR1
Resumo
A síndrome do X frágil é a causa mais comum de retardo psicomotor ligado ao cromossomo X em crianças, com prevalência de 1 : 5.000 em homens e 1 : 4.000 a 8.000 em mulheres. Além disso, é a causa mais hereditária associada à síndrome do espectro do autismo. Essa patologia tem como base etiológica a expansão do trigêmeo cgg na extremidade distal do gene fmr1, o que causa seu silenciamento. Pacientes com essa síndrome geralmente sofrem de problemas comportamentais, neurológicos, cardíacos e ortopédicos. Essa síndrome também está relacionada à insuficiência ovariana primária associada ao X frágil, à síndrome do tremor e à ataxia associada ao X frágil, que acometem a mãe e o avô materno, e que, devido à sua descrição recente, poderiam ser desconhecidas pelos profissionais de saúde, o que atrasa seu diagnóstico e tratamento. O objetivo deste artigo é analisar essas doenças, a fim de descrever o conhecimento atual sobre sua etiologia, manifestações clínicas, diagnóstico e tratamento. Isso foi feito através da recopilação de artigos no Pubmed, com algumas contribuições das bases de dados Scielo, Redalyc, Europe pmc, Science Direct, Google Academic e Genetics Home Reference. Dentre as principais conclusões, destaca-se que os fenótipos associados à premutação do gene fmr1 incluem outros mecanismos fisiopatológicos além da síndrome do X frágil, apesar de eles estarem intimamente relacionados.
Downloads
Referências
Ribate Molina MP, Pié Juste J, Ramos Fuentes FJ. Síndrome de X frágil. Protoc Diagn Ter Pediatr. 2010;(1):85-90.
McCary L, Roberts J. Early identification of autism in fragile X syndrome: a review. J Intellect Disabil. 2013;57(9):803-14. DOI: https://doi.org/10.1111/j.1365-2788.2012.01609.x
Kumar V, Abbas A, Aster J. Trastornos genéticos. In: Robbins y Cotran Patología Estructural y Funcional. 9 ed. Barcelona: Elsevier; 2015. P. 168-171.
Castro Volio I, Cuenca Berger P. Trastornos del neurodesarrollo (síndrome X frágil) y neurodegenerativos (síndrome de temblor/ataxia) asociados al "crecimiento" de un gen. Rev Neurol. 2005;40(7): 431-437. DOI: https://doi.org/10.33588/rn.4007.2004283
Genetics Home Reference. fmr1 gene. United States of America: NIH; 2020; fmr1 gene [aprox. 1 pant.]. https://ghr.nlm.nih.gov/gene/FMR1
Yang J-C, Simon C, Schneider A, Seritan AL, Hamilton L, Hagerman PJ, et al. Abnormal semantic processing in females with fragile X-associated tremor/ataxia syndrome. Gen Br Behav. 2014;13(2):152-62. DOI: https://doi.org/10.1111/gbb.12114
Saldarriaga G, Forero Forero J, González Teshima L, Hagerman R. Síndrome de temblor y ataxia asociado a frágil X (FXTAS): revisión de la literatura. Acta Neurol Colomb. 2015;31(3): 335-341. DOI: https://doi.org/10.22379/2422402248
Hall DA, O'keefe JA. Fragile x-associated tremor ataxia syndrome: the expanding clinical picture, pathophysiology, epidemiology, and update on treatment. Tremor Other Hyperkinet Mov (N Y). 2012;2. DOI: https://doi.org/10.5334/tohm.112
Genetics Home Reference. Fragile X-associated primary ovarian insufficiency [aprox. 1 pant.]. United States of America: National Institute of America; 2020. https://ghr.nlm.nih.gov/condition/fragile-x-associated-primary-ovarian-insufficiency#definition
Saldarriaga W, Tassone F, González-Teshima LY, Forero-Forero JV, Ayala-Zapata S, Hagerman R. Fragile X syndrome. Colomb médica (Cali, Colomb). 2014;45(4):190-8. DOI: https://doi.org/10.25100/cm.v45i4.1810
Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, et al. Fragile X syndrome: a review of associated medical problems. Pediatrics. 2014;134(5):99-1005. DOI: https://doi.org/10.1542/peds.2013-4301
Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A. 2014;164A(7):1648-58. DOI: https://doi.org/10.1002/ajmg.a.36511
Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey Jr DB, Moine H, Kooy RF, et al. Fragile X syndrome. Nat Rev Dis Prim. 2017. 29;3:1-19. DOI: https://doi.org/10.1038/nrdp.2017.65
Peprah, E. Fragile X Syndrome: The fmr1 cgg Repeat Distribution Among World Populations. Ann Hum Gen .2012;76:178-191. DOI: https://doi.org/10.1111/j.1469-1809.2011.00694.x
Niu M, Han Y, Dy ABC, Du J, Jin H, Qin J, et al. Fragile X Syndrome: Prevalence, Treatment, and Prevention in China. Front. Neurol. 2017;8:1-7. DOI: https://doi.org/10.3389/fneur.2017.00254
Beresford RG, Tatlidir C, Riddell DC, Welch JP, Ludman MD, Neumann PE, et al. Absence of fragile X syndrome in Nova Scotia. J Med Genet. 2000;37(1):77-79. DOI: https://doi.org/10.1136/jmg.37.1.77
Peprah E, Allen E, Williams S, Woodard L and Sherman S. Genetic Diversity of the Fragile X Syndrome gene (fmr1) in a large Sub‐Saharan West African population. Ann Hum Genet. 2010;74(4):316-25. DOI: https://doi.org/10.1111/j.1469-1809.2010.00582.x
Vindas-Smith R, Cuenca-Berger P, Brenes-Pino F and Castro-Volio I. Tamizaje mediante inmunohistoquímica del síndrome del cromosoma X frágil en una población de niños y adolescentes costarricenses. Acta Méd Costarric. 2011;53(2):93-98. DOI: https://doi.org/10.51481/amc.v53i2.731
Yrigollen CM, Sweha S, Durbin-Johnson B, Zhou L, Berry-Kravis E, Fernandez-Carvajal I, et al. Distribution of agg interruption patterns within nine world populations. Intractable rare Dis Res. 2014;3(4):153-61 DOI: https://doi.org/10.5582/irdr.2014.01028
Ciaccio C, Fontana L, Milani D, Tabano S, Miozzo M, Esposito S. Fragile X syndrome: a review of clinical and molecular diagnoses. Ital J Pediatr. 2017;43(1):39. DOI: https://doi.org/10.1186/s13052-017-0355-y
Hunter JE, Berry-Kravis E, Hipp H, et al. fmr1 Disorders[Internet]. Seattle (WA):University of Washington, Seattle;1998. https://www.ncbi.nlm.nih.gov/books/NBK1384/pdf/Bookshelf_NBK1384.pdf
Till SM, Li HL, Miniaci MC, Kandel ER, Choi1 YB. A presynaptic role for fmrP during protein synthesis -dependent long-term plasticity in Aplysia. Learn Mem. 2011;18(1):39-48. DOI: https://doi.org/10.1101/lm.1958811
Rajaratnam A, Shergill J, Salcedo-Arellano M, Saldarriaga W, Duan X, Hagerman R. Fragile X syndrome and fragile X-associated disorders. F1000Research. 2017;6:2112. DOI: https://doi.org/10.12688/f1000research.11885.1
Goncalves-Fernandez T, Mendonça-dos Santos J, Pereira-Goncalves A, Tassone F, Mendoza-Morales G, Gonçalves Ribeiro M, et al. Finding fmr1 mosaicism in Fragile X syndrome. Expert Rev Mol Diagn. 2016;16(4):501-7. DOI: https://doi.org/10.1586/14737159.2016.1135739
Han X-D, Powell BR, Phalin JL, Chehab FF. Mosaicism for a full mutation, premutation, and deletion of the cgg repeats results in 22 % fmrP and elevated fmr1 mRNA levels in a high-functioning fragile X male. Am J Med Genet A. 2006;140(13):1463-71. DOI: https://doi.org/10.1002/ajmg.a.31291
Yu TW, Berry-Kravis E. Autism and Fragile X Syndrome. Semin Neurol. 2014;34(03):258-65. DOI: https://doi.org/10.1055/s-0034-1386764
Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, et al. De Novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74(2):285-99. DOI: https://doi.org/10.1016/j.neuron.2012.04.009
Cheng C, Sourial M, Doering LC. Astrocytes and Developmental plasticity in fragile X. Neural Plas. 2012;2012:1-12. DOI: https://doi.org/10.1155/2012/197491
Petrelli F, Pucci L, Bezzi P. Astrocytes and microglia and their potential link with autism spectrum disorders. Front. Cell. Neurosci. 2016; 10:21. DOI: https://doi.org/10.3389/fncel.2016.00021
Muzar Z, Lozano R, Kolevzon A, Hagerman RJ. The neurobiology of the prader-willi phenotype of fragile x syndrome. Intractable Rare Dis Res. 2016;5(4):255-61. DOI: https://doi.org/10.5582/irdr.2016.01082
Nowicki ST, Tassone F, Ono MY, Ferranti J, Croquette MF, Goodlin-Jones B, et al. The Prader-Willi phenotype of fragile X syndrome. J Dev Behav Pediatr. 2007;28(2):133-8. DOI: https://doi.org/10.1097/01.DBP.0000267563.18952.c9
Abekhoukh S, Sahin HB, Grossi M, Zongaro S, Maurin T, Madrigal I, et al. New insights into the regulatory function of CYFIP1 in the context of WAVE- and fmrP-containing complexes. Dis Model & Mech. 2017;10(4):463-474. DOI: https://doi.org/10.1242/dmm.025809
Bozdagi O, Sakurai T, Dorr N, Pilorge M, Takahashi N, Buxbaum JD. Haploinsufficiency of Cyfip1 Produces Fragile X-Like Phenotypes in Mice. PLoS One. 2012;7(8):e42422. DOI: https://doi.org/10.1371/journal.pone.0042422
Verónica M, Mirna L, Stephen N, Jeanelle A, Paul H, Randi H. fmr1 premutation with Prader-Willi phenotype and fragile X‐associated tremor/ataxia syndrome. Clin Case Reports. 2017;5(5):625-9. DOI: https://doi.org/10.1002/ccr3.834
Søren S, Henrik H, H. OJ, Ursula F. Evidence of decreased risk of cancer in individuals with fragile X. Am J Med Genet. 2001;103(3):226-30. DOI: https://doi.org/10.1002/ajmg.1533
Sund R, Pukkala E, Patja K. Cancer incidence among persons with fragile X syndrome in Finland: a population‐based study. J Intellect Disabil Res. 2008;53(1):85-90. DOI: https://doi.org/10.1111/j.1365-2788.2008.01116.x
Zalfa F, Panasiti V, Carotti S, Zingariello M, Perrone G, Sancillo L, et al. The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells. Cell Death Dis. 2017;8:e3169. DOI: https://doi.org/10.1038/cddis.2017.521
Lucá R, Averna M, Zalfa F, Vecchi M, Bianchi F, Fata G La, et al. The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation. EMBO Mol Med. 2013;5(10):1523-1536. DOI: https://doi.org/10.1002/emmm.201302847
Ajay S. A novel link between fmr gene and the JNK pathway provides clues to possible role in malignant pleural mesothelioma. FEBS Open Bio. 2015;5(1):705-11. DOI: https://doi.org/10.1016/j.fob.2015.07.005
Rosales-Reynoso MA, Ochoa-Hernández AB, Aguilar-Lemarroy A, Jave-Suárez LF, Troyo-Sanromán R, Barros-Núñez P. Gene expression profiling identifies WNT7A as a possible candidate gene for decreased cancer risk in fragile X syndrome patients. Arch Med Res. 2010;41(2):110-118. DOI: https://doi.org/10.1016/j.arcmed.2010.03.001
Li Y, Stockton ME, Bhuiyan I, Eisinger BE, Gao Y, Miller JL, et al. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. Sci Transl Med. 2016;8(336):1-14. DOI: https://doi.org/10.1126/scitranslmed.aad9370
Tassone F. Advanced technologies for the molecular diagnosis of fragile X syndrome. Expert Rev Mol Diagn. 2015;15(11):1465-73. DOI: https://doi.org/10.1586/14737159.2015.1101348
Lyons JI, Kerr GR, Mueller PW. Fragile X syndrome scientific background and screening technologies. J Mol Diagnostics. 2015;17(5):463-71. DOI: https://doi.org/10.1016/j.jmoldx.2015.04.006
LaFauci G, Adayev T, Kascsak R, Brown TW. Detection and quantification of the fragile X mental retardation protein 1 (fmrp). Genes. 2016; 7(12): 1-16. DOI: https://doi.org/10.3390/genes7120121
Schenkel LC, Schwartz C, Skinner C, Rodenhiser DI, Ainsworth PJ, Pare G, et al. Clinical validation of fragile X syndrome screening by DNA methylation array. J Mol Diagnostics. 2016;18(6):834-41. DOI: https://doi.org/10.1016/j.jmoldx.2016.06.005
Leigh MJS, Nguyen D V, Mu Y, Winarni TI, Schneider A, Chechi T, et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J Dev Behav Pediatr. 2013;34(3):147-55. DOI: https://doi.org/10.1097/DBP.0b013e318287cd17
Schneider A, Leigh MJ, Adams P, Nanakul R, Chechi T, Olichney J, et al. Electrocortical changes associated with minocycline treatment in fragile X syndrome. J Psychopharmacol. 2013;27(10):956-63. DOI: https://doi.org/10.1177/0269881113494105
Reinhard SM, Razak K, Ethell IM. A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders. Front Cell Neurosci. 2015;9:280. DOI: https://doi.org/10.3389/fncel.2015.00280
Dy ABC, Tassone F, Eldeeb M, Salcedo‐Arellano M, Tartaglia N, Hagerman R. Metformin as targeted treatment in fragile X syndrome. Clin Genet. 2017;93(2):216-22. DOI: https://doi.org/10.1111/cge.13039
Castagnola S, Bardoni B, Maurin T. The search for an effective therapy to treat fragile X syndrome: dream or reality? Front Synaptic Neurosci. 2017; 9(5). DOI: https://doi.org/10.3389/fnsyn.2017.00015
Bakhashab S, Ahmed F, Schulten H-J, Ahmed FW, Glanville M, Al-Qahtani MH, et al. Proangiogenic effect of metformin in endothelial cells is via upregulation of VEGFR1/2 and their signaling under hyperglycemia-hypoxia. Int J Mol Sci. 2018 en;19(1):293. DOI: https://doi.org/10.3390/ijms19010293
Belagodu AP, Zendeli L, Slater BJ, Galvez R. Blocking elevated VEGF-A attenuates non-vasculature Fragile X syndrome abnormalities. Dev Neurobiol. 2017;77(1):14-25. DOI: https://doi.org/10.1002/dneu.22404
Hanson AC, Hagerman RJ. Serotonin dysregulation in Fragile X Syndrome: implications for treatment. Intractable rare Dis Res.2014;3(4):110-7. DOI: https://doi.org/10.5582/irdr.2014.01027
Greiss Hess L, Fitzpatrick SE, Nguyen D V, Chen Y, Gaul KN, Schneider A, et al. A randomized, double-blind, placebo-controlled trial of low-dose sertraline in young children with fragile x syndrome. J Dev Behav Pediatr. 2016;37(8):619-28. DOI: https://doi.org/10.1097/DBP.0000000000000334
Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, et al. Advances in the treatment of fragile x syndrome. Ped. 2009;123(1):378-390. DOI: https://doi.org/10.1542/peds.2008-0317
Eroglu Ç, Allen NJ, Susman MW, O'Rourke NA, Park CY, Özkan E, et al. Gabapentin Receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139(2):380-92. DOI: https://doi.org/10.1016/j.cell.2009.09.025
Protic D, Salcedo-Arellano MJ, Dy JB, Potter LA, Hagerman RJ. New Targeted Treatments for Fragile X Syndrome. Curr Pediatr Rev. 2019;15(4):251-8. DOI: https://doi.org/10.2174/1573396315666190625110748
Berry-Kravis E, Hagerman R, Visootsak J, Budimirovic D, Kaufmann WE, Cherubini M, et al. Arbaclofen in fragile X syndrome: results of phase 3 trials. J Neurodev Disord. 2017;9(1):3. DOI: https://doi.org/10.1186/s11689-016-9181-6
Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J, et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the fmr1 Gene Cell. 2018;172(5):979-992. DOI: https://doi.org/10.1016/j.cell.2018.01.012
Capelli LP, Gonçalves MR, Leite C, Barbosa E, Nitrini R, Vianna-Morgante A. The fragile x-associated tremor and ataxia syndrome (FXTAS). Arq Neuro-Psiquiatr. 2010;68(5):791-798. DOI: https://doi.org/10.1590/S0004-282X2010000500023
Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V. Síndrome de temblor y ataxia asociado al X frágil: presentación clínica, patología y tratamiento. Rev Neurol 2019;68 (05):199-206. DOI: https://doi.org/10.33588/rn.6805.2018457
Conca Dioguardi C, Uslu B, Haynes M, Kurus M, Gul M, Miao D-Q, et al. Granulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X primary ovarian insufficiency. MHR Basic Sci Reprod Med. 2016;22(6):384-96. DOI: https://doi.org/10.1093/molehr/gaw023
Hukema RK, Buijsen RA, Raske C, Severijnen LA, Nieuwenhuizen-Bakker I, Minneboo M, et al. Induced expression of expanded cgg RNA causes mitochondrial dysfunction in vivo. Cell Cycle. 2014;13(16):2600-8. DOI: https://doi.org/10.4161/15384101.2014.943112
Loesch DZ, Godler DE, Evans A, Bui QM, Gehling F, Kotschet KE, et al. Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small cgg expansions in the fmr1 gene in patients with parkinsonism. Genet Med. 2011;13(5):392-9. DOI: https://doi.org/10.1097/GIM.0b013e3182064362
Hagerman R, Hagerman P. Advances in clinical and molecular understanding of the fmr1 premutation and fragile X-associated tremor/ataxia syndrome. J Neurol Sci. 2014;12(6):812-6. DOI: https://doi.org/10.1016/S1474-4422(13)70125-X
Filley CM. Fragile X tremor ataxia syndrome and white matter dementia. Clin Neuropsychol. 2016;30(6):901-12. DOI: https://doi.org/10.1080/13854046.2016.1165805
López Villaverde V, Flores Aznar E, Romeu Sarrió A. Insuficiencia Ovárica Primaria (Iop). Guía de Práctica Clínica. Sevilla: Hospital Universitario Virgen de Valme.; 2015. p. 1-21. http://www.sefertilidad.net/docs/biblioteca/guiasPracticaClinicas/guia9.pdf
Man L, Lekovich J, Rosenwaks Z, Gerhardt J. Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations. Front Mol Neurosci. 2017;10(290):1-17. DOI: https://doi.org/10.3389/fnmol.2017.00290
Nelson LM. Primary Ovarian Insufficiency. N. Engl. J. Med. 2009; 360(6):606-614. DOI: https://doi.org/10.1056/NEJMcp0808697
Buijsen RAM, Visser JA, Kramer P, Severijnen EAWFM, Gearing M, Charlet-Berguerand N, et al. Presence of inclusions positive for polyglycine containing protein, fmrpolyG, indicates that repeatassociated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency. Hum Reprod. 2016;31(1): 158-168. DOI: https://doi.org/10.1093/humrep/dev280
Albizua I, Rambo-Martin BL, Allen EG, He W, Amin AS, Sherman SL. Women who carry a fragile X premutation are biologicallyolder than noncarriers as measured by telomere length. Am. J. Med. Genet. 2017;173(1):2985-2994. DOI: https://doi.org/10.1002/ajmg.a.38476
Yang W, Fan C, Chen L, Cui Z, Bai Y, Lan F. Pathological Effects of the fmr1 cgg -Repeat Polymorphism (5-55 Repeat Numbers): Systematic Review and Meta-Analysis. Tohoku J Exp Med. 2016 ;239(1):57-66. DOI: https://doi.org/10.1620/tjem.239.57
Lu C-L, Li R, Chen X-N, Xu Y-Y, Yan L-Y, Yan J, et al. The "normal" range of FMR triple CQQ repeats may be associated with primary ovarian insufficiency in China. Reprod Biomed Online. 2017;34(2):175-80. DOI: https://doi.org/10.1016/j.rbmo.2016.11.001
Adamsheck HC, Petty EM, Hong J, Baker MW, Brilliant MH, Mailick MR. Is Low fmr1 cgg Repeat Length in Males Correlated with Family History of BRCA-Associated Cancers? An Exploratory Analysis of Medical Records. J Genet Couns. 2017;26(6):1401-10. DOI: https://doi.org/10.1007/s10897-017-0116-5
Hall DA, Berry-Kravis E, Zhang W, Tassone F, Spector E, Zerbe G, et al. fmr1 gray-zone alleles: association with Parkinson's disease in women? Mov Disord. 2011;26(10):1900-6. DOI: https://doi.org/10.1002/mds.23755
Wang X-H, Song X-H, Wang Y-L, Diao X-H, Li T, Li Q-C, et al. Expanded alleles of the fmr1 gene are related to unexplained recurrent miscarriages. Biosci Rep. 2017;37(6). DOI: https://doi.org/10.1042/BSR20170856
Lyons K. Síndrome de cromosoma X frágil. En: Smith Patrones reconocibles de malformaciones humanas. 6ª ed. Barcelona: Elseriver; 2007. p. 160-2.
Dean DD, Muthuswamy S, Agarwal S. Fragile X syndrome: Current insight. Egypt J Med Hum Genet. 2016;17(4):303-9. DOI: https://doi.org/10.1016/j.ejmhg.2016.01.005
Cedillo IS, Gutiérrez AD, De E, Ángeles T. Aspectos estomatológicos en el síndrome del X frágil. Revisión de la literatura y presentación de un caso clínico. Rev Odontológica Mex. 2014;18(4):236-40. DOI: https://doi.org/10.1016/S1870-199X(14)70310-6
Hagerman R. Fragile X SYNDROME and premutation-associated disorders. En: Cassidy S, Allanson E. Management of genetics syndromes. 1a ed. Nueva Jersey: Wiley- Blackwell; 2010. 397-411 DOI: https://doi.org/10.1002/9780470893159.ch27
Raspa M, Wheeler AC, Riley C. Public health literature review of fragile X syndrome. Ped. 2017;139(3):153-171. DOI: https://doi.org/10.1542/peds.2016-1159C
Muzzi F, Santini F, Romanini G, Bartuli FN, Arcuri C. Fragile-X syndrome: genetic aspects and stomatologic evaluations. Oral Implantol (Rome). 2010;3(3):38-44.
Lubala TK, Lumaka A, Kanteng G, Mutesa L, Mukuku O, Wembonyama S, et al. Fragile X checklists: a meta-analysis and development of a simplified universal clinical checklist. Mol Genet Genomic Med. 2018; 1-7. DOI: https://doi.org/10.1002/mgg3.398
Federación Española Síndrome X Frágil. Síndrome X frágil. Madrid: Ministerio de trabajo y asuntos sociales de España; 2006.
