Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees With X‐linked Adrenoleukodystrophy and Review of the Literatures

Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees With X‐linked Adrenoleukodystrophy and Review of the Literatures | 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 Research Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees With X‐linked Adrenoleukodystrophy and Review of the Literatures Bingzi Dong, Wenshan Lv, Lili Xu, Yuhang Zhao, Xiaofang Sun, Bingfei Cheng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-179763/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Feb, 2022 Read the published version in International Journal of Endocrinology → Version 1 posted You are reading this latest preprint version Abstract Background X-linked adrenoleukodysrophy (ALD) is an inherited peroxisomal metabolism disorder, results from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 ( ABCD1 ) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long chain fatty acids (VLCFAs) accumulation in organs including brain, spine and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency. Results In this study, we reported two cases of X-ALD, which were firstly diagnosed as adrenal insufficiency (Addison’s disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, c.874_876delGAG (p.Glu292del) and c.96_97delCT (p.Tyr33Profs*161) in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband’s mother of the first case was hemizygous carrying the same variant. Adrenal insufficiency-only type is very rare, however, it may be the starting performance of X-ALD. In addition, we summarized reported mutation sites and clinical manifestations to investigate the correlationship of phenotype-genotype of X-ALD. Conclusions The early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD. Internal Medicine X-linked adrenoleukodystrophy (ALD) ABCD1 very long chain fatty acids (VLCFAs) adrenal insufficiency Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Cite Share Download PDF Status: Published Journal Publication published 06 Feb, 2022 Read the published version in International Journal of Endocrinology → Version 1 posted 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-179763","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":10665382,"identity":"3861272d-949d-4d1e-a64e-0774d057ebec","order_by":0,"name":"Bingzi Dong","email":"","orcid":"","institution":"The Affiliated Hospital of Qingdao University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bingzi","middleName":"","lastName":"Dong","suffix":""},{"id":10665383,"identity":"ca8d8d2a-cfce-490b-9574-b68b49922920","order_by":1,"name":"Wenshan Lv","email":"","orcid":"","institution":"The Affiliated Hospital of Qingdao University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wenshan","middleName":"","lastName":"Lv","suffix":""},{"id":10665384,"identity":"d1c1b769-7d04-4ab1-ad54-1c9282846d82","order_by":2,"name":"Lili Xu","email":"","orcid":"","institution":"The Affiliated Hospital of Qingdao University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lili","middleName":"","lastName":"Xu","suffix":""},{"id":10665385,"identity":"3e6b2a52-2fe8-4948-977a-a0b3109155c9","order_by":3,"name":"Yuhang Zhao","email":"","orcid":"","institution":"The Affiliated Hospital of Qingdao University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuhang","middleName":"","lastName":"Zhao","suffix":""},{"id":10665386,"identity":"5fb88c54-c278-417b-add4-f369392f3b64","order_by":4,"name":"Xiaofang Sun","email":"","orcid":"","institution":"The Affiliated Hospital of Qingdao University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaofang","middleName":"","lastName":"Sun","suffix":""},{"id":10665387,"identity":"27615b40-b3e6-4840-946d-ceddbe47032f","order_by":5,"name":"Bingfei Cheng","email":"","orcid":"","institution":"The Affiliated Hospital of Qingdao University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bingfei","middleName":"","lastName":"Cheng","suffix":""},{"id":10665388,"identity":"257eac1c-7e43-4a42-9267-c74d53d9182e","order_by":6,"name":"Yangang Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYPACCTl+9uYDBz5UEK/Fwliy51jiwRlniNdSkbhhho/xYd4WItQaHD97+DXPL4nEDRI8Hw7wNjDI84sdIKDlTF6aNW+fhPF26d4NByR3MBjOnJ2AX4vZgRwzY94eCdmdc85uOGB4hiHB4DYhLeffgLUwbriR8+BAYhsxWm7kGD/m+SGhCNTCcOAgMVrsb7wxY5zbIAEKZIODDWckCPtFsj/H+MObP3WgqHz8+U+FjTy/NAEtQMAmxdsG50gQVA4CzB9//CFK4SgYBaNgFIxUAACsyE+ZutLRawAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3411-4025","institution":"The Affiliated Hospital of Qingdao Univerisity","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yangang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2021-01-28 20:26:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-179763/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-179763/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1155/2022/5479781","type":"published","date":"2022-02-07T03:20:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":5801137,"identity":"6690b245-fdf1-4c65-a2b2-2802bbcdf314","added_by":"auto","created_at":"2021-02-09 21:32:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":83242,"visible":true,"origin":"","legend":"Brain magnetic resonance imaging (MRI) scan of patients. A.\nSymmetric bands with high T2 low T1 abnormal signal in bilateral genu of the corpus\ncallosum detected in case one. B. MRI scan of case two revealed long T1 and long T2\nsignals in white matter of bilateral frontal lobes, and around the anterior of lateral\nventricle, and splenium of the corpus callosum. C. Computed tomography (CT) scan\nof the adrenal gland of case one, to show bilateral adrenal atrophy. Red narrow to\nshow lesions.","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1/0f179cef4e0ad0f96830f5b9.jpg"},{"id":5801141,"identity":"b9beed34-b1dd-47dc-90d6-58282bac3d4a","added_by":"auto","created_at":"2021-02-09 21:32:28","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":108421,"visible":true,"origin":"","legend":"Pedigree diagrams and genetic analysis of two cases. A and C. Pedigree\ndiagrams of the case one and case two with X-linked ALD, respectively. Empty\nsquare and circle to show health male and female. Dark square represents patients\nwith X-ALD. Diagonal stripes to show hemizygous carrier. Arrow represents proband.\nB. Genetic analysis revealed novel mutation of c.874_876delGAG (p.Glu292del) of ABCD1 gene in patient one (proband III-7) and his mother (II-10). D. Novel mutation\nc.96_97delCT (p.Tyr33Profs*161) was detected in patient two (Proband III-4).","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1/eb6db8c34c0d3d32978b8d21.jpg"},{"id":5801207,"identity":"cd7eda81-0dc9-44d1-a8ef-484a537ff773","added_by":"auto","created_at":"2021-02-09 21:35:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":122432,"visible":true,"origin":"","legend":"Three-dimensional structure prediction of adrenoleukodystrophy (ALD)\nprotein. A. The modeled structure of health control. The visible alteration of ALD\nprotein structure induced by mutations B. c.874_876delGAG (p.Glu292del) and C.\nc.96_97delCT (p.Tyr33Profs*161) were indicated in circles. It indicated that those\nmutations might lead to alteration of the protein structure and potential dysfunction.","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1/f23651f633e5f52fe54d0463.jpg"},{"id":5801140,"identity":"721a0305-6df3-4d82-bb6e-aeba6b0b42c2","added_by":"auto","created_at":"2021-02-09 21:32:28","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":83113,"visible":true,"origin":"","legend":"ABCD1 gene reported from ALD mutation database. A. Types of\nvariants of ABCD1 gene, including pathogenic, synonymous, benign, variants of\nundetermined significance (VUS) and screening of newborns state of unknown (UN).\nB. The content of ABCD1mutations, including points mutations, deletion, delinsertion,\ninsertion, and duplication. (http://www.x-ald.nl/). C. The distribution of mutations, including point mutation, deletion, del-insertion, insertion, and duplication.\nMost of the mutations harboring in the Exon 1. The lower panel shows the mutation\nrate in each exon. Bold to show the location of two novel mutations indicated in this\nstudy.","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1/b28229fceda14b4bb8178407.jpg"},{"id":5801360,"identity":"9cb7de51-d249-4027-8179-809120e9a9aa","added_by":"auto","created_at":"2021-02-09 21:38:28","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":109315,"visible":true,"origin":"","legend":"Summary of the reported mutation sites and clinical manifestations from the\ndatabase of Uniprot (https://www.uniprot.org/uniprot/) and X-ALD Mutation\n(https://adrenoleukodystrophy.info/). The clinical types include childhood and\nadolescent cerebral ALD (CCALD and adoles ALD), adult ALD, AMN\n(adrenomyeloneuropathy), adrenal insufficiency-only (AIO), complicated ALD which\ncannot be classified, and asymptomatic or pre-symptomatic types.","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1/86868083b3c9a0a98f0bdac0.jpg"},{"id":18016742,"identity":"217c0bec-e1c0-4a34-aa54-e8ba345a68ce","added_by":"auto","created_at":"2022-02-08 03:20:30","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1042015,"visible":true,"origin":"","legend":"","description":"","filename":"2noveladrenoleukodystrophyandreview20210125.pdf","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1_covered.pdf"},{"id":13582602,"identity":"7daf5926-34e9-4040-9cd2-a64b8cfbe6d8","added_by":"auto","created_at":"2021-09-17 04:31:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1036911,"visible":true,"origin":"","legend":"","description":"","filename":"2noveladrenoleukodystrophyandreview20210125.pdf","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1_covered.pdf"},{"id":5801516,"identity":"0c09a43a-137f-4356-bf4f-d032902dc61d","added_by":"auto","created_at":"2021-02-09 21:41:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1097259,"visible":true,"origin":"","legend":"","description":"","filename":"2noveladrenoleukodystrophyandreview20210125.pdf","url":"https://assets-eu.researchsquare.com/files/rs-179763/v1_stamped.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eIdentification of Two Novel Mutations of ABCD1\u0026nbsp;Gene in Pedigrees With X‐linked Adrenoleukodystrophy and Review of the Literatures\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-179763/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"X-linked adrenoleukodystrophy (ALD), ABCD1, very long chain fatty acids (VLCFAs), adrenal insufficiency","lastPublishedDoi":"10.21203/rs.3.rs-179763/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-179763/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eX-linked adrenoleukodysrophy (ALD) is an inherited peroxisomal metabolism disorder, results from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 ( ABCD1 ) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long chain fatty acids (VLCFAs) accumulation in organs including brain, spine and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency. \u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eIn this study, we reported two cases of X-ALD, which were firstly diagnosed as adrenal insufficiency (Addison’s disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, c.874_876delGAG (p.Glu292del) and c.96_97delCT (p.Tyr33Profs*161) in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband’s mother of the first case was hemizygous carrying the same variant. Adrenal insufficiency-only type is very rare, however, it may be the starting performance of X-ALD. In addition, we summarized reported mutation sites and clinical manifestations to investigate the correlationship of phenotype-genotype of X-ALD. \u003c/p\u003e\u003cp\u003eConclusions\u003c/p\u003e\u003cp\u003eThe early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD.\u003c/p\u003e","manuscriptTitle":"Identification of Two Novel Mutations of ABCD1\u0026nbsp;Gene in Pedigrees With X‐linked Adrenoleukodystrophy and Review of the Literatures","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-02-09 21:32:27","doi":"10.21203/rs.3.rs-179763/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a9bb03b-990a-4b1c-a0ab-d9c4068b5119","owner":[],"postedDate":"February 9th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":2334674,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2022-02-08T03:20:24+00:00","versionOfRecord":{"articleIdentity":"rs-179763","link":"https://doi.org/10.1155/2022/5479781","journal":{"identity":"international-journal-of-endocrinology","isVorOnly":true,"title":"International Journal of Endocrinology"},"publishedOn":"2022-02-07 03:20:24","publishedOnDateReadable":"February 7th, 2022"},"versionCreatedAt":"2021-02-09 21:32:27","video":"","vorDoi":"10.1155/2022/5479781","vorDoiUrl":"https://doi.org/10.1155/2022/5479781","workflowStages":[]},"version":"v1","identity":"rs-179763","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-179763","identity":"rs-179763","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}