Paracentral Acute Middle Maculopathy as a Major Clinical Manifestation of Adenosine Deaminase-2 Deficiency

Paracentral Acute Middle Maculopathy as a Major Clinical Manifestation of Adenosine Deaminase-2 Deficiency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Paracentral Acute Middle Maculopathy as a Major Clinical Manifestation of Adenosine Deaminase-2 Deficiency Leonardo Eleuterio Ariello, Thais Souza Andrade, Rodrigo D. Fernandes, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5263201/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jul, 2025 Read the published version in BMC Ophthalmology → Version 1 posted 4 You are reading this latest preprint version Abstract BACKGROUND Adenosine deaminase-2 (ADA2) deficiency is a rare autosomal recessive autoinflammatory syndrome, typically presenting in young patients with a broad spectrum of phenotypes. These phenotypes may include primary immune deficiencies, livedo reticularis, and various hematological abnormalities. Visual loss associated with ADA2 deficiency is uncommon and, when it does occur, is often linked to major vascular involvement, such as occlusion of the ophthalmic arteries. CASE PRESENTATION: A 31-year-old woman with a presumptive diagnosis of common variable immunodeficiency and livedo reticularis presented with sudden onset severe visual loss in the left eye due to paracentral acute middle maculopathy (PAMM) followed a few weeks later by a lacunar stroke. An extensive laboratory investigation including genetic testing led to the diagnosis of ADA2 deficiency, a rare autoinflammatory syndrome. Treatment regimen was switched to anti-TNF-α inhibitors, leading to disease remission with no further vascular events over a two-year follow-up period. CONCLUSION This case serves to emphasize the importance of considering ADA2 deficiency in patients with PAMM, particularly when it occurs in young patients with a history of strokes and/or immunological abnormalities. Adenosine deaminase-2 deficiency paracentral acute middle maculopathy early-onset stroke immunodeficiency Figures Figure 1 Figure 2 BACKGROUND Adenosine deaminase-2 (ADA2) deficiency is a rare autosomal recessive autoinflammatory syndrome described in 2014. 1 Early reports described patients with fever, recurrent strokes, livedo racemosa and polyarteritis nodosa (PAN)-like features. 1 , 2 Clinical manifestations have since been categorized into three main phenotypes: systemic vasculitis; hematological abnormalities; and immunodeficiency. However, more recently, additional phenotypes were described, many of which overlap with other known diseases. 3 , 4 The wide range of clinical manifestations, combined with variable ages of disease onset, often leads to significant diagnostic challenges and treatment delay. Ocular involvement in ADA2 deficiency has been previously reported, ranging from red eyes to more disabling manifestations, such as diplopia and visual loss from optic neuropathies and major retinal vascular occlusions. Paracentral acute middle maculopathy (PAMM) is a disease characterized by ischemia at the inner retinal capillary complex rather than the major retinal vessels. 5 PAMM has been previous associated with a variety of conditions including systemic diseases such as giant cell arteritis and sickle cell anemia, infectious agents and febrile illness, vascular insufficiency due to hypercoagulable states, central venous and partial retinal arterial occlusion and drugs side-effects. 6 The aim of this paper is to first describe PAMM as a manifestation of ADA2 deficiency in a patient who presented with severe visual loss. The finding of the retinal followed by brain ischemic event raised the suspicion of ADA2 deficiency that was genetically confirmed and properly treated with anti-TNF- \(\:\alpha\:\) inhibitor. This case shows that ADA2 deficiency should be included in the differential diagnosis of young patients with PAMM, particularly with history of stoke and immune deficiency. CASE PRESENTATION A 31-year-old woman, previously diagnosed with common variable immunodeficiency (CVID) and livedo reticularis during childhood, presented to the emergency department (ED) with a two-day history of acute, painless and severe visual loss in her left eye (LE). This was preceded by multiple episodes of transient visual loss lasting around 20 seconds. The patient also reported experiencing horizontal diplopia 12 years earlier, which had resolved after a short course of intravenous steroids, with no underlying cause identified. On examination, her best-corrected visual acuity (BCVA) was 20/20 in her right eye (RE) and counting fingers at 1 meter in the LE. Pupils were equal in size and photoreactive with a mild relative afferent defect in the LE. Extraocular motility, slit lamp examination of the anterior segment and intraocular pressure measurements werenormal. Fundus examination of the RE was unremarkable, while in the LE,the optic disc appeared normal, but a grayish aspect of the macula could be noticed, especially under a red-free filter exam (Fig. 1 ), along with a single cotton-wool spot. Magnetic resonance imaging (MRI) of the orbits was unremarkable. Brain MRI showed lacunar spaces in the deep gray matter and brainstem without contrast enhancement or restricted diffusion, suggestive of previous lacunar infarcts. Laboratory investigation for inflammatory markers, syphilis, autoimmune markers and hematologic parameters was normal. Optical coherence tomography (OCT) B-scans images of the RE were normal, while in the LE, a diffuse hyperreflective band of the inner nuclear layer (INL) of the macula was evident (Fig. 2 A), with a corresponding “fern-like” pattern on en-face OCT middle retina slab. OCT angiography demonstrated reduced density in the deep vascular complex of the left macula (Fig. 2 B). Based on these findings, the patient was diagnosed with unilateral PAMM. During an outpatient follow-up, the patient returned to the hospital, reporting acute onset dizziness and weakness in her left arm and leg. She was admitted, and an MRI of the brain revealed restricted diffusion surrounding the middle portion of the left medulla and cerebral peduncle, suggesting an acute ischemic lacunar infarct. Given the patient’s history of CVID, livedo reticularis, and the new onset of vascular events such as PAMM and lacunar stroke, a deficiency of ADA2 was suspected. Whole exome sequencing revealed a homozygous mutation positive for the variant c.973-2A > G in the ADA2 gene transcriptions site on chromosome 22. Anti-TNF- \(\:\alpha\:\) inhibitor was initiated as main therapy. She has been followed for the past two years without any new vascular event. DISCUSSION AND CONCLUSIONS ADA2 is an enzyme normally expressed at low levels in myeloid precursor cells, with its expression increasing during periods of stress. 7 The enzyme catalyzes the conversion of adenosine to deoxyadenosine, a key process in normal metabolism Insufficient ADA2 activity results in the accumulation of adenosine, which alters the function of various cells, including macrophages, endothelial cells, and neutrophils. 8 In vascular pathology, disfunction of these cells due to reduced ADA2 production compromises endothelial integrity and promotes inflammation, characterized by elevated levels of TNF- \(\:\alpha\:\) , predisposing individuals to systemic inflammatory vasculopathic processes. Clinically, ADA2 deficiency presents as a multi-phenotypic disease, posing significant diagnostic challenges. First, vascular manifestations often mimic primary vasculitis conditions, such as granulomatosis with polyangiitis, polyarteritis nodosa (PAN), and Raynaud’s syndrome, among others. ADA2 deficiency is particularly considered in the differential diagnosis of patients presenting with small and medium vessels vasculitis, particularly PAN-like, especially during the first decade of life. 9 The disease usually presents with cutaneous and central nervous system manifestations; however, major organ vasculopathy (e.g., coronary arteries, liver, gastrointestinal) is also commonly observed as the disease progresses. 10 Second, although neurological involvement is estimated to occur in 42–77% of patients, the manifestations vary, affecting both the peripheral or central nervous system (CNS). 11 , 12 The most common neurological presentation is lacunar strokes, particularly in young patients, where conventional investigations often yield negative results. A Turkish cohort found that 75% of CNS lesions were located in the deep gray matter and brainstem, with up to 50% of patients experiencing recurrent strokes. 13 Third, ADS2 deficiency may be misdiagnosed as bone marrow aplasia or, more commonly, as primary immunodeficiencies. This is particularly true in the first decade of life when recurrent infections or hypogammaglobulinemia are the primary presenting symptoms. Ocular involvement, although uncommon, has been reported and includes coditions such as episcleritis, uveitis, diplopia from nuclear, internuclear and infra-nuclear cranial nerve palsies, and visual loss from optic neuropathies or major retinal vascular occlusions. 11 , 13 – 18 Central retinal artery occlusion (CRAO) is the main cause of visual loss in these patients and one of the most frequently reported 1 , 3 , 19 , 20 . However, our case is unusual as the visual loss was caused by PAMM, an ischemic event that differs from CRAO (which affects the major superficial retinal vessels) by causing ischemia restricted to involvement of the deep vascular complex (DVC) of the retina. PAMM was first described in 2013 by Sarraf et al. 5 It results from ischemia in the deep capillary system rather than in the major superficial retinal vessels and is often overlooked during ophthalmoscopy or fluorescein angiography. However, PAMM is readily identifiable on OCT B-scans, which shows hyperreflectivity in the inner nuclear layer. En -face OCT, particularly when segmented, is also especially useful, by showing a characteristic hyperreflective perivenular ‘fern-like’ pattern with periarterial sparring. 21 , 22 This is the first description of PAMM associated with ADA2 deficiency, and we hypothesize two mechanisms that may explain this ocular finding. Given that the DCP operates under lower perfusion pressure compared to the more superficial retinal plexuses, it is more vulnerable to ischemia caused by global insufficiency of the retinal vascular system, as seen in variants of central retinal vein occlusion or CRAO. 23 One hypothesis is that a vasculitic process involving the central retinal vein may have occurred. Althought this process may not have been severe or prolonged enough to cause retinal venous congestion and hemorrhages, it may have benn sufficient to increase hydrostatic outflow pressure in the terminal venules, thereby impeding arterial inflow. The second, and more plausible mechanism, is that of an incomplete form of CRAO. In this scenario superficial retinal arterial ischemia would not occur, but the reduction tension within the DCP could lead to PAMM. This hypothesis is clinically supported by the patient’s episodes of transient visual loss prior to permanent visual loss. It is also supported by the literature, as most cases of visual loss in ADA2 deficiency are related to CRAO. In conclusion, our patient demonstrates that ADA2 deficiency should be conisdered in the differential diagnosis of PAMM, particularly in individual with a history of lacunar strokes, immunodeficiency, and hematological abnormalities. Recognizing this association can aid in early diagnosis and timely initiation of appropriate treatment, potentially preventing further severe complications. Abbreviations ADA2: Adenosine deaminase-2 PAN: polyarteritis nodosa CVID: Common Variable Immunodeficiency PAMM: Paracentral Acute Middle Maculopathy CRAO: Central Retinal Arterial Occlusion MRI: Magnetic Resonance Imaging Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The study was approved by the Research Ethics Committee of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Written informed consent was obtained from the patient for publication of this case report and accompanying images. CONSENT FOR PUBLICATION The patient consented with the publication of this case report, including images and clinical data base. AVALIABILITY OF DATA EM MATERIALS: All data and materials are in possessions of the corresponding author and can be requested any time through this email: [email protected] ACKNOWLEDGEMENT : Not applicable DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST: None of the authors have any potential conflicts of interest to disclose. FUNDING: This study received no specific financial support. AUTHORS' CONTRIBUTION: Leonardo Eleuterio Ariello made substantial contributions to conceptualization, design, the acquisition of data and writing the manuscript. Thais de Souza Andrade contributed by writing up the manuscript. Rodrigo Dahia Fernandes made substantial contributions to acquisition of data and writing the manuscript. Leonardo Provetti Cunha and Mario Luiz Ribeiro Monteiro analyzed and interpreted the data and critically reviewed the manuscript. All authors read and approved the final manuscript. References Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med . Mar 6 2014;370(10):911-20. doi:10.1056/NEJMoa1307361 Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med . Mar 6 2014;370(10):921-31. doi:10.1056/NEJMoa1307362 Li GM, Han X, Wu Y, et al. A Cohort Study on Deficiency of ADA2 from China. J Clin Immunol . May 2023;43(4):835-845. doi:10.1007/s10875-023-01432-8 Kendall JL, Springer JM. The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency. Curr Rheumatol Rep . Aug 26 2020;22(10):64. doi:10.1007/s11926-020-00944-1 Sarraf D, Rahimy E, Fawzi AA, et al. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia. JAMA Ophthalmol . Oct 2013;131(10):1275-87. doi:10.1001/jamaophthalmol.2013.4056 Moura-Coelho N, Gaspar T, Ferreira JT, Dutra-Medeiros M, Cunha JP. Paracentral acute middle maculopathy-review of the literature. Graefes Arch Clin Exp Ophthalmol . Dec 2020;258(12):2583-2596. doi:10.1007/s00417-020-04826-1 Zavialov AV, Engstrom A. Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity. Biochem J . Oct 1 2005;391(Pt 1):51-7. doi:10.1042/BJ20050683 Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J Leukoc Biol . Aug 2010;88(2):279-90. doi:10.1189/jlb.1109764 Kasap Cuceoglu M, Sener S, Batu ED, et al. Systematic review of childhood-onset polyarteritis nodosa and DADA2. Semin Arthritis Rheum . Jun 2021;51(3):559-564. doi:10.1016/j.semarthrit.2021.04.009 Ben-Ami T, Revel-Vilk S, Brooks R, et al. Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency. J Pediatr . Oct 2016;177:316-320. doi:10.1016/j.jpeds.2016.06.058 Batu ED, Karadag O, Taskiran EZ, et al. A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations. J Rheumatol . Aug 2015;42(8):1532-4. doi:10.3899/jrheum.150024 Sahin S, Adrovic A, Barut K, et al. Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency. Rheumatol Int . Jan 2018;38(1):129-136. doi:10.1007/s00296-017-3740-3 Bulut E, Erden A, Karadag O, Oguz KK, Ozen S. Deficiency of adenosine deaminase 2; special focus on central nervous system imaging. J Neuroradiol . May 2019;46(3):193-198. doi:10.1016/j.neurad.2018.05.002 Caorsi R, Penco F, Grossi A, et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis . Oct 2017;76(10):1648-1656. doi:10.1136/annrheumdis-2016-210802 Xu Y, Shan Y, Hu Y, et al. Case Report: An Adult Patient With Deficiency of Adenosine Deaminase 2 Resembled Unilateral Frosted Branch Angiitis. Front Med (Lausanne) . 2021;8:642454. doi:10.3389/fmed.2021.642454 Veryser E, Meyts I, Casteels I, Demaerel P, De Somer L, Cassiman C. Two Cases Presenting With Unilateral Adduction Deficit Associated With Human Adenosine Deaminase 2 Deficiency. J Pediatr Ophthalmol Strabismus . Jul-Aug 2021;58(4):e22-e26. doi:10.3928/01913913-20210416-02 Celikel E, Aydin F, Tekin ZE, et al. Deficiency of adenosine deaminase 2 as an unrecognized cause of early-onset stroke and cranial nerve palsy. North Clin Istanb . 2023;10(4):411-417. doi:10.14744/nci.2022.45380 van Well GTJ, Kant B, van Nistelrooij A, et al. Phenotypic variability including Behcet's disease-like manifestations in DADA2 patients due to a homozygous c.973-2A>G splice site mutation. Clin Exp Rheumatol . Nov-Dec 2019;37 Suppl 121(6):142-146. Sharabati I, Ayesh BM, Qafesha RM, et al. Central retinal artery occlusion in a child with ADA2 deficiency: a case report. Ann Med Surg (Lond) . Apr 2024;86(4):2343-2347. doi:10.1097/MS9.0000000000001857 Sharma A, Naidu G, Sharma V, et al. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India. Arthritis Rheumatol . Feb 2021;73(2):276-285. doi:10.1002/art.41500 Garrity ST, Tseng VL, Sarraf D. Paracentral Acute Middle Maculopathy in a Perivenular Fern-Like Distribution with En Face Optical Coherence Tomography. Retin Cases Brief Rep . Fall 2018;12 Suppl 1:S25-S28. doi:10.1097/ICB.0000000000000657 Ghasemi Falavarjani K, Phasukkijwatana N, Freund KB, et al. En Face Optical Coherence Tomography Analysis to Assess the Spectrum of Perivenular Ischemia and Paracentral Acute Middle Maculopathy in Retinal Vein Occlusion. Am J Ophthalmol . May 2017;177:131-138. doi:10.1016/j.ajo.2017.02.015 Linsenmeier RA, Zhang HF. Retinal oxygen: from animals to humans. Prog Retin Eye Res . May 2017;58:115-151. doi:10.1016/j.preteyeres.2017.01.003 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 07 Jul, 2025 Read the published version in BMC Ophthalmology → Version 1 posted Editorial decision: Revision requested 15 Oct, 2024 Editor assigned by journal 14 Oct, 2024 Submission checks completed at journal 14 Oct, 2024 First submitted to journal 14 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5263201","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":366276633,"identity":"1abf88c5-8722-463e-8d51-db28b9855992","order_by":0,"name":"Leonardo Eleuterio Ariello","email":"data:image/png;base64,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","orcid":"","institution":"University of São Paulo Medical School","correspondingAuthor":true,"prefix":"","firstName":"Leonardo","middleName":"Eleuterio","lastName":"Ariello","suffix":""},{"id":366276637,"identity":"96baea4e-8414-4810-9a60-993b88936d3d","order_by":1,"name":"Thais Souza Andrade","email":"","orcid":"","institution":"University of São Paulo Medical School","correspondingAuthor":false,"prefix":"","firstName":"Thais","middleName":"Souza","lastName":"Andrade","suffix":""},{"id":366276638,"identity":"c694b32b-5850-40cc-8548-0a216ce26af6","order_by":2,"name":"Rodrigo D. Fernandes","email":"","orcid":"","institution":"Obras Sociais Irmã Dulce","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"D.","lastName":"Fernandes","suffix":""},{"id":366276639,"identity":"b897481d-1428-4793-8eef-b49d822e6d38","order_by":3,"name":"Leonardo P. Cunha","email":"","orcid":"","institution":"Federal University of Juiz de Fora Medical School","correspondingAuthor":false,"prefix":"","firstName":"Leonardo","middleName":"P.","lastName":"Cunha","suffix":""},{"id":366276640,"identity":"d7773fac-fb5e-43a4-9b72-95759c48072f","order_by":4,"name":"Mário L. R. Monteiro","email":"","orcid":"","institution":"University of São Paulo Medical School","correspondingAuthor":false,"prefix":"","firstName":"Mário","middleName":"L. R.","lastName":"Monteiro","suffix":""}],"badges":[],"createdAt":"2024-10-14 18:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5263201/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5263201/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12886-025-04230-5","type":"published","date":"2025-07-07T15:57:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69354552,"identity":"95cf9abe-8128-4f25-8fc6-d1110bdfcd46","added_by":"auto","created_at":"2024-11-19 13:38:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":590534,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5263201/v1/109a0a401cb62b230b709972.png"},{"id":69353739,"identity":"dde0428f-21d4-436b-906c-d08699b575dd","added_by":"auto","created_at":"2024-11-19 13:30:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1000206,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5263201/v1/6c745229a9e15f6b43861482.png"},{"id":86699468,"identity":"8d255038-ef79-448a-8ca4-6b169476f561","added_by":"auto","created_at":"2025-07-14 16:10:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1970622,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5263201/v1/a30f29aa-c567-430c-a27d-a86d3e973268.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eParacentral Acute Middle Maculopathy as a Major Clinical Manifestation of Adenosine Deaminase-2 Deficiency\u003c/p\u003e","fulltext":[{"header":"BACKGROUND","content":" \u003cp\u003eAdenosine deaminase-2 (ADA2) deficiency is a rare autosomal recessive autoinflammatory syndrome described in 2014.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Early reports described patients with fever, recurrent strokes, livedo racemosa and polyarteritis nodosa (PAN)-like features.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Clinical manifestations have since been categorized into three main phenotypes: systemic vasculitis; hematological abnormalities; and immunodeficiency. However, more recently, additional phenotypes were described, many of which overlap with other known diseases.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The wide range of clinical manifestations, combined with variable ages of disease onset, often leads to significant diagnostic challenges and treatment delay.\u003c/p\u003e \u003cp\u003eOcular involvement in ADA2 deficiency has been previously reported, ranging from red eyes to more disabling manifestations, such as diplopia and visual loss from optic neuropathies and major retinal vascular occlusions. Paracentral acute middle maculopathy (PAMM) is a disease characterized by ischemia at the inner retinal capillary complex rather than the major retinal vessels.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e PAMM has been previous associated with a variety of conditions including systemic diseases such as giant cell arteritis and sickle cell anemia, infectious agents and febrile illness, vascular insufficiency due to hypercoagulable states, central venous and partial retinal arterial occlusion and drugs side-effects.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe aim of this paper is to first describe PAMM as a manifestation of ADA2 deficiency in a patient who presented with severe visual loss. The finding of the retinal followed by brain ischemic event raised the suspicion of ADA2 deficiency that was genetically confirmed and properly treated with anti-TNF-\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\alpha\\:\\)\u003c/span\u003e\u003c/span\u003e inhibitor. This case shows that ADA2 deficiency should be included in the differential diagnosis of young patients with PAMM, particularly with history of stoke and immune deficiency.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eA 31-year-old woman, previously diagnosed with common variable immunodeficiency (CVID) and livedo reticularis during childhood, presented to the emergency department (ED) with a two-day history of acute, painless and severe visual loss in her left eye (LE). This was preceded by multiple episodes of transient visual loss lasting around 20 seconds. The patient also reported experiencing horizontal diplopia 12 years earlier, which had resolved after a short course of intravenous steroids, with no underlying cause identified.\u003c/p\u003e \u003cp\u003eOn examination, her best-corrected visual acuity (BCVA) was 20/20 in her right eye (RE) and counting fingers at 1 meter in the LE. Pupils were equal in size and photoreactive with a mild relative afferent defect in the LE. Extraocular motility, slit lamp examination of the anterior segment and intraocular pressure measurements werenormal. Fundus examination of the RE was unremarkable, while in the LE,the optic disc appeared normal, but a grayish aspect of the macula could be noticed, especially under a red-free filter exam (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), along with a single cotton-wool spot. Magnetic resonance imaging (MRI) of the orbits was unremarkable. Brain MRI showed lacunar spaces in the deep gray matter and brainstem without contrast enhancement or restricted diffusion, suggestive of previous lacunar infarcts. Laboratory investigation for inflammatory markers, syphilis, autoimmune markers and hematologic parameters was normal. Optical coherence tomography (OCT) B-scans images of the RE were normal, while in the LE, a diffuse hyperreflective band of the inner nuclear layer (INL) of the macula was evident (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), with a corresponding “fern-like” pattern on \u003cem\u003een-face\u003c/em\u003e OCT middle retina slab. OCT angiography demonstrated reduced density in the deep vascular complex of the left macula (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Based on these findings, the patient was diagnosed with unilateral PAMM.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDuring an outpatient follow-up, the patient returned to the hospital, reporting acute onset dizziness and weakness in her left arm and leg. She was admitted, and an MRI of the brain revealed restricted diffusion surrounding the middle portion of the left medulla and cerebral peduncle, suggesting an acute ischemic lacunar infarct. Given the patient’s history of CVID, livedo reticularis, and the new onset of vascular events such as PAMM and lacunar stroke, a deficiency of ADA2 was suspected. Whole exome sequencing revealed a homozygous mutation positive for the variant c.973-2A \u0026gt; G in the ADA2 gene transcriptions site on chromosome 22. Anti-TNF-\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\alpha\\:\\)\u003c/span\u003e\u003c/span\u003e inhibitor was initiated as main therapy. She has been followed for the past two years without any new vascular event.\u003c/p\u003e "},{"header":"DISCUSSION AND CONCLUSIONS","content":"\u003cp\u003eADA2 is an enzyme normally expressed at low levels in myeloid precursor cells, with its expression increasing during periods of stress.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e The enzyme catalyzes the conversion of adenosine to deoxyadenosine, a key process in normal metabolism Insufficient ADA2 activity results in the accumulation of adenosine, which alters the function of various cells, including macrophages, endothelial cells, and neutrophils.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In vascular pathology, disfunction of these cells due to reduced ADA2 production compromises endothelial integrity and promotes inflammation, characterized by elevated levels of TNF-\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\alpha\\:\\)\u003c/span\u003e\u003c/span\u003e, predisposing individuals to systemic inflammatory vasculopathic processes.\u003c/p\u003e\u003cp\u003eClinically, ADA2 deficiency presents as a multi-phenotypic disease, posing significant diagnostic challenges. First, vascular manifestations often mimic primary vasculitis conditions, such as granulomatosis with polyangiitis, polyarteritis nodosa (PAN), and Raynaud’s syndrome, among others. ADA2 deficiency is particularly considered in the differential diagnosis of patients presenting with small and medium vessels vasculitis, particularly PAN-like, especially during the first decade of life.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The disease usually presents with cutaneous and central nervous system manifestations; however, major organ vasculopathy (e.g., coronary arteries, liver, gastrointestinal) is also commonly observed as the disease progresses.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Second, although neurological involvement is estimated to occur in 42–77% of patients, the manifestations vary, affecting both the peripheral or central nervous system (CNS).\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e The most common neurological presentation is lacunar strokes, particularly in young patients, where conventional investigations often yield negative results. A Turkish cohort found that 75% of CNS lesions were located in the deep gray matter and brainstem, with up to 50% of patients experiencing recurrent strokes.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Third, ADS2 deficiency may be misdiagnosed as bone marrow aplasia or, more commonly, as primary immunodeficiencies. This is particularly true in the first decade of life when recurrent infections or hypogammaglobulinemia are the primary presenting symptoms.\u003c/p\u003e\u003cp\u003eOcular involvement, although uncommon, has been reported and includes coditions such as episcleritis, uveitis, diplopia from nuclear, internuclear and infra-nuclear cranial nerve palsies, and visual loss from optic neuropathies or major retinal vascular occlusions.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e–\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Central retinal artery occlusion (CRAO) is the main cause of visual loss in these patients and one of the most frequently reported\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. However, our case is unusual as the visual loss was caused by PAMM, an ischemic event that differs from CRAO (which affects the major superficial retinal vessels) by causing ischemia restricted to involvement of the deep vascular complex (DVC) of the retina. PAMM was first described in 2013 by Sarraf et al.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e It results from ischemia in the deep capillary system rather than in the major superficial retinal vessels and is often overlooked during ophthalmoscopy or fluorescein angiography. However, PAMM is readily identifiable on OCT B-scans, which shows hyperreflectivity in the inner nuclear layer. \u003cem\u003eEn\u003c/em\u003e-face OCT, particularly when segmented, is also especially useful, by showing a characteristic hyperreflective perivenular ‘fern-like’ pattern with periarterial sparring. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis is the first description of PAMM associated with ADA2 deficiency, and we hypothesize two mechanisms that may explain this ocular finding. Given that the DCP operates under lower perfusion pressure compared to the more superficial retinal plexuses, it is more vulnerable to ischemia caused by global insufficiency of the retinal vascular system, as seen in variants of central retinal vein occlusion or CRAO.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e One hypothesis is that a vasculitic process involving the central retinal vein may have occurred. Althought this process may not have been severe or prolonged enough to cause retinal venous congestion and hemorrhages, it may have benn sufficient to increase hydrostatic outflow pressure in the terminal venules, thereby impeding arterial inflow. The second, and more plausible mechanism, is that of an incomplete form of CRAO. In this scenario superficial retinal arterial ischemia would not occur, but the reduction tension within the DCP could lead to PAMM. This hypothesis is clinically supported by the patient’s episodes of transient visual loss prior to permanent visual loss. It is also supported by the literature, as most cases of visual loss in ADA2 deficiency are related to CRAO.\u003c/p\u003e\u003cp\u003eIn conclusion, our patient demonstrates that ADA2 deficiency should be conisdered in the differential diagnosis of PAMM, particularly in individual with a history of lacunar strokes, immunodeficiency, and hematological abnormalities. Recognizing this association can aid in early diagnosis and timely initiation of appropriate treatment, potentially preventing further severe complications.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cu\u003eADA2:\u003c/u\u003e Adenosine deaminase-2\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePAN:\u003c/u\u003e polyarteritis nodosa\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCVID:\u003c/u\u003e Common Variable Immunodeficiency\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePAMM:\u003c/u\u003e Paracentral Acute Middle Maculopathy\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCRAO:\u003c/u\u003e Central Retinal Arterial Occlusion\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMRI:\u003c/u\u003e Magnetic Resonance Imaging\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Research Ethics Committee of the \u003cem\u003eHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. \u003c/em\u003eWritten informed consent was obtained from the patient for publication of this case report and accompanying images. \u003c/p\u003e\n\n\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient consented with the publication of this case report, including images and clinical data base. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAVALIABILITY OF DATA EM MATERIALS: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data and materials are in possessions of the corresponding author and can be requested any time through this email: [email protected] \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u003c/strong\u003e: Not applicable \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors have any potential conflicts of interest to disclose. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFUNDING: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received no specific financial support. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAUTHORS\u0026apos; CONTRIBUTION: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLeonardo Eleuterio Ariello made substantial contributions to conceptualization, design, the acquisition of data and writing the manuscript. Thais de Souza Andrade contributed by writing up the manuscript. Rodrigo Dahia Fernandes made substantial contributions to acquisition of data and writing the manuscript. Leonardo Provetti Cunha and Mario Luiz Ribeiro Monteiro analyzed and interpreted the data and critically reviewed the manuscript. All authors read and approved the final manuscript. \u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. \u003cem\u003eN Engl J Med\u003c/em\u003e. Mar 6 2014;370(10):911-20. doi:10.1056/NEJMoa1307361\u003c/li\u003e\n\u003cli\u003eNavon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. \u003cem\u003eN Engl J Med\u003c/em\u003e. Mar 6 2014;370(10):921-31. doi:10.1056/NEJMoa1307362\u003c/li\u003e\n\u003cli\u003eLi GM, Han X, Wu Y, et al. A Cohort Study on Deficiency of ADA2 from China. \u003cem\u003eJ Clin Immunol\u003c/em\u003e. May 2023;43(4):835-845. doi:10.1007/s10875-023-01432-8\u003c/li\u003e\n\u003cli\u003eKendall JL, Springer JM. The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency. \u003cem\u003eCurr Rheumatol Rep\u003c/em\u003e. Aug 26 2020;22(10):64. doi:10.1007/s11926-020-00944-1\u003c/li\u003e\n\u003cli\u003eSarraf D, Rahimy E, Fawzi AA, et al. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia. \u003cem\u003eJAMA Ophthalmol\u003c/em\u003e. Oct 2013;131(10):1275-87. doi:10.1001/jamaophthalmol.2013.4056\u003c/li\u003e\n\u003cli\u003eMoura-Coelho N, Gaspar T, Ferreira JT, Dutra-Medeiros M, Cunha JP. Paracentral acute middle maculopathy-review of the literature. \u003cem\u003eGraefes Arch Clin Exp Ophthalmol\u003c/em\u003e. Dec 2020;258(12):2583-2596. doi:10.1007/s00417-020-04826-1\u003c/li\u003e\n\u003cli\u003eZavialov AV, Engstrom A. Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity. \u003cem\u003eBiochem J\u003c/em\u003e. Oct 1 2005;391(Pt 1):51-7. doi:10.1042/BJ20050683\u003c/li\u003e\n\u003cli\u003eZavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. \u003cem\u003eJ Leukoc Biol\u003c/em\u003e. Aug 2010;88(2):279-90. doi:10.1189/jlb.1109764\u003c/li\u003e\n\u003cli\u003eKasap Cuceoglu M, Sener S, Batu ED, et al. Systematic review of childhood-onset polyarteritis nodosa and DADA2. \u003cem\u003eSemin Arthritis Rheum\u003c/em\u003e. Jun 2021;51(3):559-564. doi:10.1016/j.semarthrit.2021.04.009\u003c/li\u003e\n\u003cli\u003eBen-Ami T, Revel-Vilk S, Brooks R, et al. Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency. \u003cem\u003eJ Pediatr\u003c/em\u003e. Oct 2016;177:316-320. doi:10.1016/j.jpeds.2016.06.058\u003c/li\u003e\n\u003cli\u003eBatu ED, Karadag O, Taskiran EZ, et al. A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations. \u003cem\u003eJ Rheumatol\u003c/em\u003e. Aug 2015;42(8):1532-4. doi:10.3899/jrheum.150024\u003c/li\u003e\n\u003cli\u003eSahin S, Adrovic A, Barut K, et al. Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency. \u003cem\u003eRheumatol Int\u003c/em\u003e. Jan 2018;38(1):129-136. doi:10.1007/s00296-017-3740-3\u003c/li\u003e\n\u003cli\u003eBulut E, Erden A, Karadag O, Oguz KK, Ozen S. Deficiency of adenosine deaminase 2; special focus on central nervous system imaging. \u003cem\u003eJ Neuroradiol\u003c/em\u003e. May 2019;46(3):193-198. doi:10.1016/j.neurad.2018.05.002\u003c/li\u003e\n\u003cli\u003eCaorsi R, Penco F, Grossi A, et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. \u003cem\u003eAnn Rheum Dis\u003c/em\u003e. Oct 2017;76(10):1648-1656. doi:10.1136/annrheumdis-2016-210802\u003c/li\u003e\n\u003cli\u003eXu Y, Shan Y, Hu Y, et al. Case Report: An Adult Patient With Deficiency of Adenosine Deaminase 2 Resembled Unilateral Frosted Branch Angiitis. \u003cem\u003eFront Med (Lausanne)\u003c/em\u003e. 2021;8:642454. doi:10.3389/fmed.2021.642454\u003c/li\u003e\n\u003cli\u003eVeryser E, Meyts I, Casteels I, Demaerel P, De Somer L, Cassiman C. Two Cases Presenting With Unilateral Adduction Deficit Associated With Human Adenosine Deaminase 2 Deficiency. \u003cem\u003eJ Pediatr Ophthalmol Strabismus\u003c/em\u003e. Jul-Aug 2021;58(4):e22-e26. doi:10.3928/01913913-20210416-02\u003c/li\u003e\n\u003cli\u003eCelikel E, Aydin F, Tekin ZE, et al. Deficiency of adenosine deaminase 2 as an unrecognized cause of early-onset stroke and cranial nerve palsy. \u003cem\u003eNorth Clin Istanb\u003c/em\u003e. 2023;10(4):411-417. doi:10.14744/nci.2022.45380\u003c/li\u003e\n\u003cli\u003evan Well GTJ, Kant B, van Nistelrooij A, et al. Phenotypic variability including Behcet\u0026apos;s disease-like manifestations in DADA2 patients due to a homozygous c.973-2A\u0026gt;G splice site mutation. \u003cem\u003eClin Exp Rheumatol\u003c/em\u003e. Nov-Dec 2019;37 Suppl 121(6):142-146. \u003c/li\u003e\n\u003cli\u003eSharabati I, Ayesh BM, Qafesha RM, et al. Central retinal artery occlusion in a child with ADA2 deficiency: a case report. \u003cem\u003eAnn Med Surg (Lond)\u003c/em\u003e. Apr 2024;86(4):2343-2347. doi:10.1097/MS9.0000000000001857\u003c/li\u003e\n\u003cli\u003eSharma A, Naidu G, Sharma V, et al. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India. \u003cem\u003eArthritis Rheumatol\u003c/em\u003e. Feb 2021;73(2):276-285. doi:10.1002/art.41500\u003c/li\u003e\n\u003cli\u003eGarrity ST, Tseng VL, Sarraf D. Paracentral Acute Middle Maculopathy in a Perivenular Fern-Like Distribution with En Face Optical Coherence Tomography. \u003cem\u003eRetin Cases Brief Rep\u003c/em\u003e. Fall 2018;12 Suppl 1:S25-S28. doi:10.1097/ICB.0000000000000657\u003c/li\u003e\n\u003cli\u003eGhasemi Falavarjani K, Phasukkijwatana N, Freund KB, et al. En Face Optical Coherence Tomography Analysis to Assess the Spectrum of Perivenular Ischemia and Paracentral Acute Middle Maculopathy in Retinal Vein Occlusion. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. May 2017;177:131-138. doi:10.1016/j.ajo.2017.02.015\u003c/li\u003e\n\u003cli\u003eLinsenmeier RA, Zhang HF. Retinal oxygen: from animals to humans. \u003cem\u003eProg Retin Eye Res\u003c/em\u003e. May 2017;58:115-151. doi:10.1016/j.preteyeres.2017.01.003\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Adenosine deaminase-2 deficiency, paracentral acute middle maculopathy, early-onset stroke, immunodeficiency","lastPublishedDoi":"10.21203/rs.3.rs-5263201/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5263201/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBACKGROUND\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAdenosine deaminase-2 (ADA2) deficiency is a rare autosomal recessive autoinflammatory syndrome, typically presenting in young patients with a broad spectrum of phenotypes. These phenotypes may include primary immune deficiencies, livedo reticularis, and various hematological abnormalities. Visual loss associated with ADA2 deficiency is uncommon and, when it does occur, is often linked to major vascular involvement, such as occlusion of the ophthalmic arteries.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCASE PRESENTATION:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA 31-year-old woman with a presumptive diagnosis of common variable immunodeficiency and livedo reticularis presented with sudden onset severe visual loss in the left eye due to paracentral acute middle maculopathy (PAMM) followed a few weeks later by a lacunar stroke. An extensive laboratory investigation including genetic testing led to the diagnosis of ADA2 deficiency, a rare autoinflammatory syndrome. Treatment regimen was switched to anti-TNF-α inhibitors, leading to disease remission with no further vascular events over a two-year follow-up period.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCONCLUSION\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis case serves to emphasize the importance of considering ADA2 deficiency in patients with PAMM, particularly when it occurs in young patients with a history of strokes and/or immunological abnormalities.\u003c/p\u003e","manuscriptTitle":"Paracentral Acute Middle Maculopathy as a Major Clinical Manifestation of Adenosine Deaminase-2 Deficiency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-19 13:30:18","doi":"10.21203/rs.3.rs-5263201/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-15T11:37:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-15T03:45:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-15T03:43:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2024-10-14T18:15:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e578d7b8-d8de-46dc-a073-9e8b797a635e","owner":[],"postedDate":"November 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:04:54+00:00","versionOfRecord":{"articleIdentity":"rs-5263201","link":"https://doi.org/10.1186/s12886-025-04230-5","journal":{"identity":"bmc-ophthalmology","isVorOnly":false,"title":"BMC Ophthalmology"},"publishedOn":"2025-07-07 15:57:14","publishedOnDateReadable":"July 7th, 2025"},"versionCreatedAt":"2024-11-19 13:30:18","video":"","vorDoi":"10.1186/s12886-025-04230-5","vorDoiUrl":"https://doi.org/10.1186/s12886-025-04230-5","workflowStages":[]},"version":"v1","identity":"rs-5263201","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5263201","identity":"rs-5263201","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}