Advertisement

Vis-à-vis: a focus on genetic features of cerebral cavernous malformations and brain arteriovenous malformations pathogenesis

  • Concetta Scimone
  • Luigi Donato
  • Silvia Marino
  • Concetta Alafaci
  • Rosalia D’Angelo
  • Antonina Sidoti
Review Article
  • 18 Downloads

Abstract

Cerebrovascular malformations include a wide range of blood vessel disorders affecting brain vasculature. Neuroimaging differential diagnosis can result unspecific due to similar phenotypes of lesions and their deep localization. Next-generation sequencing (NGS) platforms simultaneously analyze several hundreds of genes and can be applied for molecular distinction of different phenotypes within the same disorder’s macro-area. We discuss about the main criticisms regarding molecular bases of cerebral cavernous malformations (CCM) and brain arteriovenous malformations (AVM), highlighting both common pathogenic aspects and genetic differences leading to lesion development. Many recent studies performed on human CCM and AVM tissues aim to detect genetic markers to better understand molecular bases and pathogenic mechanism, particularly for sporadic cases. Several genes involved in angiogenesis show different expression patterns between CCM and AVM, and these could represent a valid starting point to project a NGS panel to apply for differential cerebrovascular malformation diagnosis.

Keywords

Cerebral cavernous malformations Arteriovenous malformations Genetics Differential molecular diagnosis 

Notes

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

The author declares that the manuscript has not been submitted to more than one journal for simultaneous consideration and has not been published previously.

All the authors read and approved the final version of the manuscript.

Human and animal rights

The manuscript is a collection of literature data and does not involve animals or human participants.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Gault J, Sarin H, Awadallah NA, Shenkar R, Awad IA (2004) Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance. Neurosurgery 55:1–16PubMedGoogle Scholar
  2. 2.
    Català A, Roé E, Vikkula M, Baselga E (2013) Capillary malformation-arteriovenous malformation syndrome: a report of 2 cases, diagnostic criteria, and management. Actas Dermosifiliogr 104:710–713CrossRefPubMedGoogle Scholar
  3. 3.
    Brugulat-Serrat A, Rojas S, Bargalló N, Conesa G, Minguillón C, Fauria K, Gramunt N, Molinuevo JL, Gispert JD (2017) Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer’s disease: a cross-sectional analysis from the ALFA (Alzheimer and families) project. BMJ Open 7:e013215CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Scimone C, Bramanti P, Alafaci C, Granata F, Piva F, Rinaldi C, Donato L, Greco F, Sidoti A, D’Angelo R (2017) Update on novel CCM gene mutations in patients with cerebral cavernous malformations. J Mol Neurosci 61:189–198CrossRefPubMedGoogle Scholar
  5. 5.
    Spiegler S, Rath M, Paperlein C, Felbor U (2018) Cerebral cavernous malformations: an update on prevalence, molecular genetic analyses, and genetic counselling. Mol Syndromol 9:60–69CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Riant F, Bergametti F, Ayrignac X, Boulday G, Tournier-Lasserve E (2010) Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. FEBS J 277:1070–1075CrossRefPubMedGoogle Scholar
  7. 7.
    Haasdijk RA, Cheng C, Maat-Kievit AJ, Duckers HJ (2012) Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management. Eur J Hum Genet 20:134–140CrossRefPubMedGoogle Scholar
  8. 8.
    Sirvente J, Enjolras O, Wassef M, Tournier-Lasserve E, Labauge P (2009) Frequency and phenotypes of cutaneous vascular malformations in a consecutive series of 417 patients with familial cerebral cavernous malformations. J Eur Acad Dermatol Venereol 23:1066–1072CrossRefPubMedGoogle Scholar
  9. 9.
    Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, De Souza JM, Lee C, Marchuk DA, Awad IA (2015) Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med 17:188–196CrossRefPubMedGoogle Scholar
  10. 10.
    Brinjikji W, El-Masri AE, Wald JT, Flemming KD, Lanzino G (2017) Prevalence of cerebral cavernous malformations associated with developmental venous anomalies increases with age. Childs Nerv Syst 33:1539–1543CrossRefPubMedGoogle Scholar
  11. 11.
    De Souza JM, Domingue RC, Cruz LC Jr, Domingues FS, Iasbeck T, Gasparetto EL (2008) Susceptibility-weighted imaging for the evaluation of patients with familial cerebral cavernous malformations: a comparison with t2-weighted fast spin-echo and gradient-echo sequences. AJNR Am J Neuroradiol 29:154–158CrossRefPubMedGoogle Scholar
  12. 12.
    Nagpal K, Prakash S (2018) An unusual presentation of superficial siderosis with focal dystonia and 'Giant panda morphology' on MRI: atypical clinicoradiological amalgam. Neurol Sci 1–4.  https://doi.org/10.1007/s10072-018-3650-5
  13. 13.
    Akers A, Al-Shahi Salman R, Awad IA, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whitehead K (2017) Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel. Neurosurgery 80:665–680CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hauptman JS, Moftakhar P, Dadour A, Malkasian D, Martin NA (2010) Advances in the biology of cerebral cavernous malformations. SurgNeurolInt 1:63Google Scholar
  15. 15.
    Zawistowski JS, Serebriiskii IG, Lee MF, Golemis EA, Marchuk DA (2002) KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Hum Mol Genet 11:389–396CrossRefPubMedGoogle Scholar
  16. 16.
    Faurobert E, Rome C, Lisowska J, Manet-Dupé S, Boulday G, Malbouyres M, Balland M, Bouin AP, Kéramidas M, Bouvard D, Coll JL, Ruggiero F, Tournier-Lasserve E, Albiges-Rizo C (2013) CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and fibronectin remodelling. J Cell Biol 202:545–561CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Glading AJ, Ginsberg MH (2010) Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signalling. Dis Model Mech 3:73–83CrossRefPubMedGoogle Scholar
  18. 18.
    Bravi L, Malinverno M, Pisati F, Rudini N, Cuttano R, Pallini R, Martini M, Larocca LM, Locatelli M, Levi V, Bertani GA, Dejana E, Lampugnani MG (2016) Endothelial cells lining sporadic cerebral cavernous malformation cavernomas under goendothelial-to-mesenchymal transition. Stroke 47:886–890CrossRefPubMedGoogle Scholar
  19. 19.
    Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini MF, Maddaluno L, Baeyens N, Adams RH, Jain MK, Owens GK, Schwartz M, Lampugnani MG, Dejana E (2016) KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Mol Med 8:6–24CrossRefPubMedGoogle Scholar
  20. 20.
    Schulz GB, Wieland E, Wüstehube-Lausch J, Boulday G, Moll I, Tournier-Lasserve E, Fischer A (2015) Cerebral cavernous Malformation-1 protein controls DLL4-Notch3 signaling between the endothelium and Pericytes. Stroke 46:1337–1343CrossRefPubMedGoogle Scholar
  21. 21.
    Draheim KM, Fisher OS, Boggon TJ, Calderwood DA (2014) Cerebral cavernous malformation proteins at a glance. J Cell Sci 127:701–707CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Fisher OS, Zhang R, Li X, Murphy JW, Demeler B, Boggon TJ (2013) Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus. FEBS Lett 587:272–277CrossRefPubMedGoogle Scholar
  23. 23.
    Fong B, Watson PH, Watson AJ (2007) Mouse preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation. BMC Dev Biol 7:2CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Crose LE, Hilder TL, Sciaky N, Johnson GL (2009) Cerebral cavernous malformation 2 protein promotes smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells. J Biol Chem 284:13301–13305CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Miura K, Nojiri T, Akitake Y, Ando K, Fukuhara S, Zenitani M, Kimura T, Hino J, Miyazato M, Hosoda H, Kangawa K (2017) CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading. Biochem J 474:1897–1918CrossRefPubMedGoogle Scholar
  26. 26.
    Rosen JN, Sogah VM, Ye LY, Mably JD (2013) Ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway. Dev Biol 76:74–85CrossRefGoogle Scholar
  27. 27.
    Chen L, Tanriover G, Yano H, Friedlander R, Louvi A, Gunel M (2009) Apoptotic functions of PDCD10/CCM3, the gene mutated in cerebral cavernous malformation 3. Stroke 40:1474–1481CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Li X, Zhang R, Zhang H, He Y, Ji W, Min W, Boggon TJ (2010) Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J Biol Chem 285:24099–24107CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Schleider E, Stahl S, Wüstehube J, Walter U, Fischer A, Felbor U (2011) Evidence for anti-angiogenic and pro-survival functions of the cerebral cavernous malformation protein 3. Neurogenetics 12:83–86CrossRefPubMedGoogle Scholar
  30. 30.
    Jenny Zhou H, Qin L, Zhang H, Tang W, Ji W, He Y, Liang X, Wang Z, Yuan Q, Vortmeyer A, Toomre D, Fuh G, Yan M, Kluger MS, Wu D, Min W (2016) Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation. Nat Med 22:1033–1042CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Louvi A, Chen L, Two AM, Zhang H, Min W, Günel M (2011) Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology. Proc Natl Acad Sci U S A 108:3737–3742CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jung KH, Han DM, Jeong SG, Choi MR, Chai YG, Cho GW (2015) Proteomic analysis reveals KRIT1 as a modulator for the antioxidant effects of valproic acid in human bone-marrow mesenchymal stromal cells. Drug Chem Toxicol 38:286–292CrossRefPubMedGoogle Scholar
  33. 33.
    Goudreault M, D'Ambrosio LM, Kean MJ, Mullin MJ, Larsen BG, Sanchez A, Chaudhry S, Chen GI, Sicheri F, Nesvizhskii AI, Aebersold R, Raught B, Gingras AC (2009) A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Mol Cell Proteomics 8:157–171CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    D'Angelo R, Marini V, Rinaldi C, Origone P, Dorcaratto A, Avolio M, Goitre L, Forni M, Capra V, Alafaci C, Mareni C, Garrè C, Bramanti P, Sidoti A, Retta SF, Amato A (2011) Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation. Brain Pathol 21:360CrossRefGoogle Scholar
  35. 35.
    Scimone C, Bramanti P, Ruggeri A, Donato L, Alafaci C, Crisafulli C, Mucciardi M, Rinaldi C, Sidoti A, D'Angelo R (2016) CCM3/SERPINI1 bidirectional promoter variants in patients with cerebral cavernous malformations: a molecular and functional study. BMC Med Genet 17:74CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kar S, Samii A, Bertalanffy H (2015) PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev 38:229–236CrossRefPubMedGoogle Scholar
  37. 37.
    Altas M, Bayrak OF, Cerci A, Isik N, Celik M, Culha M, Sahin F, Elmaci I (2010) Angiotensin-converting enzyme insertion/deletion gene polymorphism in patients with familial multiple cerebral cavernous malformations. J Clin Neurosci 17:1034–1037CrossRefPubMedGoogle Scholar
  38. 38.
    Zhu Y, Wu Q, Fass M, Xu JF, You C, Müller O, , Sandalcioglu IE, Zhang JM, Sure U (2011) In vitro characterization of the angiogenic phenotype and genotype of the endothelia derived from sporadic cerebral cavernous malformations. Neurosurgery 69:722–732CrossRefPubMedGoogle Scholar
  39. 39.
    Chen IH, Lin YH, Wu MN, Lai CL, Liou LM (2018) Cerebral arteriovenous malformation presenting as isolated bilateral pupil-sparing oculomotor, pseudoabducens palsy, and hemiataxia. NeurolSci 39:1289–1290Google Scholar
  40. 40.
    Zhang R, Zhu W, Su H (2016) Vascular integrity in the pathogenesis of brain arteriovenous malformation. ActaNeurochirSuppl 121:29–35Google Scholar
  41. 41.
    Thomas JM, Surendran S, Abraham M, Rajavelu A, Kartha CC (2016) Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain. Clin Epigenetics 8:78CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Brinjikji W, Iyer VN, Wood CP, Lanzino G (2017) Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg 127:302–310CrossRefPubMedGoogle Scholar
  43. 43.
    Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H (2000) Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91:66–67CrossRefPubMedGoogle Scholar
  44. 44.
    van Beijnum J, van der Worp HB, Schippers HM, van Nieuwenhuizen O, Kappelle LJ, Rinkel GJ, Berkelbach van der Sprenkel JW, Klijn CJ (2007) Familial occurrence of brain arteriovenous malformations: a systematic review. J Neurol Neurosurg Psychiatry 78:1213–1217CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Komiyama M (2016) Pathogenesis of brain arteriovenous malformations. Neurol Med Chir (Tokyo) 56:317–325CrossRefGoogle Scholar
  46. 46.
    Shi S, Sun J, Meng Q, Yu Y, Huang H, Ma T, Yang Z, Liu X, Yang J, Shen Z (2018) Sonic hedgehog promotes endothelial differentiation of bone marrow mesenchymal stem cells via VEGF-D. J Thorac Dis 10:5476–5488CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM (2001) Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675–3683PubMedGoogle Scholar
  48. 48.
    Hashimoto T, Wu Y, Lawton MT, Yang GY, Barbaro NM, Young WL (2005) Co-expression of angiogenic factors in brain arteriovenous malformations. Neurosurgery 56:1058–1065PubMedGoogle Scholar
  49. 49.
    Hashimoto T, Wen G, Lawton MT, Boudreau NJ, Bollen AW, Yang GY, Barbaro NM, Higashida RT, Dowd CF, Halbach VV, Young WL, University of California, San Francisco BAVM Study Group (2003) Abnormal expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in brain arteriovenous malformations. Stroke 34:925–9231CrossRefPubMedGoogle Scholar
  50. 50.
    Mouchtouris N, Jabbour PM, Starke RM, Hasan DM, Zanaty M, Theofanis T, Ding D, Tjoumakaris SI, Dumont AS, Ghobrial GM, Kung D, Rosenwasser RH, Chalouhi N (2015) Biology of cerebral arteriovenous malformations with a focus on inflammation. J Cereb Blood Flow Metab 35:167–175CrossRefPubMedGoogle Scholar
  51. 51.
    Ng I, Tan WL, Ng PY, Lim J (2005) Hypoxia inducible factor-1alpha and expression of vascular endothelial growth factor and its receptors in cerebral arteriovenous malformations. J Clin Neurosci 12:794–799CrossRefPubMedGoogle Scholar
  52. 52.
    McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P (2015) Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 6:1CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Blanco FJ, Santibanez JF, Guerrero-Esteo M, Langa C, Vary CP, Bernabeu C (2005) Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex. J Cell Physiol 204:574–584CrossRefPubMedGoogle Scholar
  54. 54.
    Tillet E, Bailly S (2015) Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Front Genet 5:456CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Yılmaz B, Toktaş ZO, Akakın A, Işık S, Bilguvar K, Kılıç T, Günel M (2017) Familial occurrence of brain arteriovenous malformation: a novel ACVRL1 mutation detected by whole exome sequencing. J Neurosurg 126:1879–1883PubMedGoogle Scholar
  56. 56.
    Yu J, Streicher JL, Medne L, Krantz ID, Yan AC (2017) EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome: a case report. PediatrDermatol 34:e227–e230Google Scholar
  57. 57.
    Lapinski PE, Doosti A, Salato V, North P, Burrows PE, King PD (2017) Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. Eur J Med Genet S1769–7212:30256–30262Google Scholar
  58. 58.
    Luissint AC, Artus C, Glacial F, Ganeshamoorthy K, Couraud PO (2012) Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS 9:23CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Uranishi R, Baev NI, Kim JH, Awad IA (2001) Vascular smooth muscle cell differentiation in human cerebral vascular malformations. Neurosurgery 49:671–679PubMedGoogle Scholar
  60. 60.
    Yildirim O, Bicer A, Ozkan A, Kurtkaya O, Cirakoglu B, Kilic T (2010) Expression of platelet-derived growth factor ligand and receptor in cerebral arteriovenous and cavernous malformations. J Clin Neurosci 17:1557–1562CrossRefPubMedGoogle Scholar
  61. 61.
    Seker A, Yildirim O, Kurtkaya O, Sav A, Günel M, Pamir NM, Kiliç T (2006) Expression of integrins in cerebral arteriovenous and cavernous malformations. Neurosurgery 58:159–168CrossRefPubMedGoogle Scholar
  62. 62.
    Choquet H, Pawlikowska L, Nelson J, CE MC, Akers A, Baca B, Khan Y, Hart B, Morrison L, Kim H, Brain Vascular Malformation Consortium (BVMC) Study (2014) Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity. Cerebrovasc Dis 38:433–440CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kamiyama H, Nishimura S, Kaimori M, Watanabe M, Furuno Y, Saito A, Nishijima M (2010) Cavernous angioma associated with arteriovenous malformation of the brain. Neurol Med 50:131–134CrossRefGoogle Scholar
  64. 64.
    Awad IA, Robinson JR Jr, Mohanty S, Estes ML (1993) Mixed vascular malformations of the brain: clinical and pathogenetic considerations. Neurosurgery 33:179-188CrossRefGoogle Scholar
  65. 65.
    Gan D, Li M, Wu J, Sun X, Tian G (2017) Analysis of genetic mutations in a cohort of hereditary optic neuropathy in Shanghai, China. J Ophthalmol 2017:6186052CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bendjilali N, Kim H, Weinsheimer S, Guo DE, Kwok PY, Zaroff JG, Sidney S, Lawton MT, McCulloch CE, Koeleman BP, Klijn CJ, Young WL, Pawlikowska L (2013) A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation. PLoS One 8:e71434CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ellingford JM, Horn B, Campbell C, Arno G, Barton S, Tate C, Bhaskar S, Sergouniotis PI, Taylor RL, Carss KJ, Raymond LFL, Michaelides M, Ramsden SC, Webster AR, Black GCM (2018) Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases. J Med Genet 55:114–121CrossRefPubMedGoogle Scholar
  68. 68.
    Gawlik KI (2018) At the crossroads of clinical and preclinical research for muscular dystrophy-are we closer to effective treatment for patients? Int J MolSci 19:E1490CrossRefGoogle Scholar
  69. 69.
    D'Angelo R, Scimone C, Rinaldi C, Trimarchi G, Italiano D, Bramanti P, Amato A, Sidoti A (2012) CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study. Int J Mol Med 29:1113–1120PubMedGoogle Scholar
  70. 70.
    Rinaldi C, Bramanti P, Scimone C, Donato L, Alafaci C, D'Angelo R, Sidoti A (2017) Relevance of CCM gene polymorphisms for clinical management of sporadic cerebral cavernous malformations. J Neurol Sci 380:31–37CrossRefPubMedGoogle Scholar
  71. 71.
    Ge M, Du C, Li Z, Liu Y, Xu S, Zhang L, Pang Q (2017) Association of ACVRL1 genetic polymorphisms with arteriovenous malformations: a case-control study and meta-analysis. World Neurosurg 108:690–697CrossRefPubMedGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2018

Authors and Affiliations

  1. 1.Department of Biomedical and Dental Science and Morphological and Functional ImagesUniversity of MessinaMessinaItaly
  2. 2.Department of Vanguard Medicine and Therapies, Biomolecular Strategies and NeuroscienceI.E.ME.S.TPalermoItaly
  3. 3.IRCSS Centro Neurolesi “Bonino-Pulejo”MessinaItaly

Personalised recommendations