{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T14:46:11Z","timestamp":1782225971376,"version":"3.54.5"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Fabry disease (FD) is a rare X-linked, lysosomal storage disorder caused by mutations in the alpha-galactosidase gene and characterized by neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and ocular manifestations. The aim of this study is to characterize morphological, functional and autophagy-lysosome pathway alterations of the ocular surface in FD patients.\n<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Eleven subjects with a diagnosis of FD and fifteen healthy control subjects were examined. All patients underwent ocular surface slit lamp examination, corneal aesthesiometry and in vivo confocal laser-scanning microscopy (CCM). Conjunctival impression cytology was performed in six FD patients and six controls, to assess for expression of two markers of the autophagy-lysosome pathway: the microtubule-associated protein light chain 3 (LC3) and lysosome-associated membrane protein 2 (LAMP2).\n<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Cornea verticillata and increased conjunctival vessel tortuosity were detected respectively in 67% and 33% of patients with FD. Compared with healthy subjects, patients affected by FD showed a significant reduction in corneal nerve fiber length, density and nerve branching on CCM and a significantly increased expression of LC3 on conjunctival impression cytology (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). No changes were observed in the conjunctival expression of LAMP2 between the two groups.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study shows that FD is associated with ocular surface alterations including corneal and conjunctival morphology, innervation and vascularization changes. Our data demonstrate an increased expression of LC3 protein in patients with FD, suggesting that alteration of the autophagy-lysosome pathway may play a role in the occurrence of ocular manifestations.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-022-02441-3","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T11:02:43Z","timestamp":1658574163000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Autophagy-lysosome pathway alteration in ocular surface manifestations in Fabry disease patients"],"prefix":"10.1186","volume":"17","author":[{"given":"Marco","family":"Marenco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Segatto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5569-778X","authenticated-orcid":false,"given":"Marta","family":"Sacchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Mangiantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Giovannetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Plateroti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,23]]},"reference":[{"issue":"33","key":"2441_CR1","doi-asserted-by":"publisher","first-page":"5974","DOI":"10.2174\/13816128113199990352","volume":"19","author":"A Tuttolomondo","year":"2013","unstructured":"Tuttolomondo A, Pecoraro R, Simonetta I, Miceli S, Pinto A, Licata G. Anderson-Fabry disease: a multiorgan disease. Curr Pharm Des. 2013;19(33):5974\u201396.","journal-title":"Curr Pharm Des"},{"issue":"4","key":"2441_CR2","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.ymgme.2018.02.014","volume":"123","author":"A Ortiz","year":"2018","unstructured":"Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416\u201327.","journal-title":"Mol Genet Metab"},{"issue":"2","key":"2441_CR3","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1111\/j.1442-9071.2005.00990.x","volume":"33","author":"TT Nguyen","year":"2005","unstructured":"Nguyen TT, Gin T, Nicholls K, Low M, Galanos J, Crawford A. Ophthalmological manifestations of Fabry disease: a survey of patients at the Royal Melbourne Fabry Disease Treatment Centre. Clin Exp Ophthalmol. 2005;33(2):164\u20138.","journal-title":"Clin Exp Ophthalmol"},{"issue":"4","key":"2441_CR4","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.ajo.2005.11.053","volume":"141","author":"L Mastropasqua","year":"2006","unstructured":"Mastropasqua L, Nubile M, Lanzini M, Carpineto P, Toto L, Ciancaglini M. Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study. Am J Ophthalmol. 2006;141(4):709\u201318.","journal-title":"Am J Ophthalmol"},{"issue":"2","key":"2441_CR5","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1136\/bjo.2006.100602","volume":"91","author":"A Sodi","year":"2007","unstructured":"Sodi A, Ioannidis AS, Mehta A, Davey C, Beck M, Pitz S. Ocular manifestations of Fabry\u2019s disease: data from the Fabry outcome survey. Br J Ophthalmol. 2007;91(2):210\u20134.","journal-title":"Br J Ophthalmol"},{"issue":"3","key":"2441_CR6","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1111\/j.1365-2362.2004.01309.x","volume":"34","author":"A Mehta","year":"2004","unstructured":"Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry outcome survey. Eur J Clin Invest. 2004;34(3):236\u201342.","journal-title":"Eur J Clin Invest"},{"key":"2441_CR7","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1097\/GIM.0b013e3181bb05bb","volume":"11","author":"S Waldek","year":"2009","unstructured":"Waldek S, Patel M, Banikazemi M, et al. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry registry. Genet Med. 2009;11:790\u20136.","journal-title":"Genet Med"},{"key":"2441_CR8","first-page":"3733","volume-title":"The metabolic and molecular bases of inherited disease","author":"RJ Desnick","year":"2001","unstructured":"Desnick RJ, Ioannou YA, Eng CM. \u03b1-Galactosidase a deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw Hill; 2001. p. 3733\u201374.","edition":"8"},{"key":"2441_CR9","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1001\/jama.281.3.249","volume":"281","author":"PJ Meikle","year":"1999","unstructured":"Meikle PJ, Hopwood JJ, Clague AE, et al. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249\u201354.","journal-title":"JAMA"},{"issue":"2","key":"2441_CR10","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1051\/jbio\/2002196020161","volume":"196","author":"DP Germain","year":"2002","unstructured":"Germain DP. Maladie de Fabry (d\u00e9ficit en alpha-galactosidase A): physiopathologie, signes cliniques et aspects g\u00e9n\u00e9tiques [Fabry\u2019s disease (alpha-galactosidase-A deficiency): physiopathology, clinical signs, and genetic aspects]. J Soc Biol. 2002;196(2):161\u201373.","journal-title":"J Soc Biol"},{"issue":"6","key":"2441_CR11","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1111\/j.1365-2796.2004.01300.x","volume":"255","author":"AC Hauser","year":"2004","unstructured":"Hauser AC, Lorenz M, Sunder-Plassmann G. The expanding clinical spectrum of Anderson-Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy. J Intern Med. 2004;255(6):629\u201336.","journal-title":"J Intern Med"},{"issue":"5","key":"2441_CR12","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.jbspin.2003.10.015","volume":"71","author":"C Masson","year":"2004","unstructured":"Masson C, Ciss\u00e9 I, Simon V, Insalaco P, Audran M. Fabry disease: a review. Joint Bone Spine. 2004;71(5):381\u20133.","journal-title":"Joint Bone Spine"},{"issue":"11","key":"2441_CR13","first-page":"625","volume":"3","author":"JL Dufier","year":"1980","unstructured":"Dufier JL, Gubler MC, Dhermy P, Lenoir G, Paupe J, Haye C. La maladie de Fabry et ses manifestations ophtalmologiques [Fabry\u2019s disease in ophthalmology (author\u2019s transl)]. J Fr Ophtalmol. 1980;3(11):625\u201330.","journal-title":"J Fr Ophtalmol"},{"issue":"4","key":"2441_CR14","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1111\/j.1442-9071.1984.tb01174.x","volume":"12","author":"T Roussel","year":"1984","unstructured":"Roussel T, Grutzmacher R, Coster D. Patterns of superficial keratopathy. Aust J Ophthalmol. 1984;12(4):301\u201316.","journal-title":"Aust J Ophthalmol"},{"issue":"4","key":"2441_CR15","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1001\/archopht.1979.01020010327008","volume":"97","author":"NA Sher","year":"1979","unstructured":"Sher NA, Letson RD, Desnick RJ. The ocular manifestations in Fabry\u2019s disease. Arch Ophthalmol. 1979;97(4):671\u20136.","journal-title":"Arch Ophthalmol"},{"issue":"5","key":"2441_CR16","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1111\/j.1755-3768.1981.tb08733.x","volume":"59","author":"K Tuppurainen","year":"1981","unstructured":"Tuppurainen K, Collan Y, Rantanen T, Hollmen A. Fabry\u2019s disease and cornea verticillata. A report of 3 cases. Acta Ophthalmol (Copenh). 1981;59(5):674\u201382.","journal-title":"Acta Ophthalmol (Copenh)"},{"issue":"3","key":"2441_CR17","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3109\/13816818509006132","volume":"5","author":"WG Macrae","year":"1985","unstructured":"Macrae WG, Ghosh M, McCulloch C. Corneal changes in Fabry\u2019s disease: a clinico-pathologic case report of a heterozygote. Ophthalmic Paediatr Genet. 1985;5(3):185\u201390.","journal-title":"Ophthalmic Paediatr Genet"},{"issue":"6","key":"2441_CR18","first-page":"347","volume":"18","author":"J Libert","year":"1982","unstructured":"Libert J, Toussaint D. Tortuosities of retinal and conjunctival vessels in lysosomal storage diseases. Birth Defects Orig Artic Ser. 1982;18(6):347\u201358.","journal-title":"Birth Defects Orig Artic Ser"},{"issue":"4","key":"2441_CR19","first-page":"192","volume":"19","author":"C McCulloch","year":"1984","unstructured":"McCulloch C, Ghosh M. Ultrastructural changes in the cornea and conjunctiva of a heterozygous woman with Fabry\u2019s disease. Can J Ophthalmol. 1984;19(4):192\u20138.","journal-title":"Can J Ophthalmol"},{"issue":"5","key":"2441_CR20","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0039-6257(82)90159-X","volume":"26","author":"EM Riegel","year":"1982","unstructured":"Riegel EM, Pokorny KS, Friedman AH, Suhan J, Ritch RH, Desnick RJ. Ocular pathology of Fabry\u2019s disease in a hemizygous male following renal transplantation. Surv Ophthalmol. 1982;26(5):247\u201352.","journal-title":"Surv Ophthalmol"},{"issue":"1","key":"2441_CR21","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1097\/00006982-200102000-00024","volume":"21","author":"MA Dantas","year":"2001","unstructured":"Dantas MA, Fonseca RA, Kaga T, Yannuzzi LA, Spaide RF. Retinal and choroidal vascular changes in heterozygous Fabry disease. Retina. 2001;21(1):87\u20139.","journal-title":"Retina"},{"issue":"6","key":"2441_CR22","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1002\/mus.21383","volume":"40","author":"M Tavakoli","year":"2009","unstructured":"Tavakoli M, Marshall A, Thompson L, et al. Corneal confocal microscopy: a novel noninvasive means to diagnose neuropathy in patients with Fabry disease. Muscle Nerve. 2009;40(6):976\u201384.","journal-title":"Muscle Nerve"},{"issue":"1","key":"2441_CR23","doi-asserted-by":"publisher","first-page":"12244","DOI":"10.1038\/s41598-018-30688-z","volume":"8","author":"G Bitirgen","year":"2018","unstructured":"Bitirgen G, Turkmen K, Malik RA, Ozkagnici A, Zengin N. Corneal confocal microscopy detects corneal nerve damage and increased dendritic cells in Fabry disease. Sci Rep. 2018;8(1):12244.","journal-title":"Sci Rep"},{"issue":"11","key":"2441_CR24","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1007\/s00431-003-1299-3","volume":"162","author":"M Ries","year":"2003","unstructured":"Ries M, Ramaswami U, Parini R, et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr. 2003;162(11):767\u201372.","journal-title":"Eur J Pediatr"},{"issue":"2\u20133","key":"2441_CR25","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s10545-006-0265-4","volume":"29","author":"MH Gelb","year":"2006","unstructured":"Gelb MH, Turecek F, Scott CR, Chamoles NA. Direct multiplex assay of enzymes in dried blood spots by tandem mass spectrometry for the newborn screening of lysosomal storage disorders. J Inherit Metab Dis. 2006;29(2\u20133):397\u2013404.","journal-title":"J Inherit Metab Dis"},{"issue":"3","key":"2441_CR26","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1046\/j.1365-2133.2004.05813.x","volume":"150","author":"GE Linthorst","year":"2004","unstructured":"Linthorst GE, De Rie MA, Tjiam KH, Aerts JM, Dingemans KP, Hollak CE. Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical or pathological suspicion. Br J Dermatol. 2004;150(3):575\u20137.","journal-title":"Br J Dermatol"},{"issue":"2","key":"2441_CR27","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/2051-5960-2-20","volume":"14","author":"MP Nelson","year":"2014","unstructured":"Nelson MP, Tse TE, O\u2019Quinn DB, Percival SM, Jaimes EA, Warnock DG, Shacka JJ. Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice. Acta Neuropathol Commun. 2014;14(2):20.","journal-title":"Acta Neuropathol Commun"},{"issue":"2","key":"2441_CR28","doi-asserted-by":"publisher","first-page":"208","DOI":"10.23876\/j.krcp.20.264","volume":"40","author":"S Chung","year":"2021","unstructured":"Chung S, Son M, Chae Y, Oh S, Koh ES, Kim YK, Shin SJ, Park CW, Jung SC, Kim HS. Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis. Kidney Res Clin Pract. 2021;40(2):208\u201319.","journal-title":"Kidney Res Clin Pract"},{"key":"2441_CR29","first-page":"571","volume":"8","author":"M Sacchetti","year":"2014","unstructured":"Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571\u20139.","journal-title":"Clin Ophthalmol"},{"issue":"8","key":"2441_CR30","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1007\/s00417-020-04717-5","volume":"258","author":"A Moramarco","year":"2020","unstructured":"Moramarco A, Sacchetti M, Franzone F, Segatto M, Cecchetti D, Miraglia E, Roberti V, Iacovino C, Giustini S. Ocular surface involvement in patients with neurofibromatosis type 1 syndrome. Graefes Arch Clin Exp Ophthalmol. 2020;258(8):1757\u201362.","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"5","key":"2441_CR31","doi-asserted-by":"publisher","first-page":"589","DOI":"10.4161\/auto.6.5.11943","volume":"6","author":"M Ch\u00e9vrier","year":"2010","unstructured":"Ch\u00e9vrier M, Brakch N, C\u00e9line L, et al. Autophagosome maturation is impaired in FABY disease. Autophagy. 2010;6(5):589\u201399.","journal-title":"Autophagy"},{"issue":"1","key":"2441_CR32","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.gene.2013.11.063","volume":"536","author":"EM Pereira","year":"2014","unstructured":"Pereira EM, do Monte SJ, do Nascimento FF, et al. Lysosome-associated protein 1 (LAMP-1) and lysosome-associated protein 2 (LAMP-2) in a larger family carrier of Fabry disease. Gene. 2014;536(1):118\u201322.","journal-title":"Gene"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-022-02441-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-022-02441-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-022-02441-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T11:09:25Z","timestamp":1658574565000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-022-02441-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,23]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["2441"],"URL":"https:\/\/doi.org\/10.1186\/s13023-022-02441-3","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,23]]},"assertion":[{"value":"24 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 July 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent for publication was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"291"}}