{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T09:24:20Z","timestamp":1778750660512,"version":"3.51.4"},"reference-count":45,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["\"Ricerca Corrente\u201d to Istituto Besta \/ N\/A"],"award-info":[{"award-number":["\"Ricerca Corrente\u201d to Istituto Besta \/ N\/A"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2026,1,26]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Adult adrenoleukodystrophy is a rare X linked disorder with heterogeneous phenotypes, complicating prognosis and trial design. We characterised phenotype and natural history in a large single-centre nationwide cohort and contextualised findings with prior reports.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a combined retrospective-prospective observational study of adults (\u226518 years) with confirmed\n                      <jats:italic>ABCD1<\/jats:italic>\n                      variants evaluated at Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (January 2004\u2013June 2023), with reassessments between July and December 2023. Clinical, genetic, biochemical, MRI and neurophysiological data were analysed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The cohort comprised 140 patients (64 males, 76 females) from 58 families, carrying 50\n                      <jats:italic>ABCD1<\/jats:italic>\n                      variants, including 11 novel mutations. Adrenomyeloneuropathy (AMN) predominated in males, with low mortality (&lt;10%) and rare cerebral progression (7%) across 18 years, suggesting protective factors. An intermediate phenotype, adrenoleukomyeloneuropathy (ALMN), showed earlier onset, demyelinating MRI changes without cerebral symptoms at baseline and higher mortality than AMN (HR 4.75, 95% CI 1.60 to 14.11). In females, symptom prevalence increases with age, affecting 57% over 60, although only 37% required walking aids. Males had higher very long-chain fatty acid (VLCFA) levels than females, but intrasex correlations with phenotype were absent. Brainstem auditory evoked potentials (BAEPs) were consistently abnormal, whereas nerve conduction studies were abnormal in ~half of male patients (less often in females).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Adult adrenoleukodystrophy comprises distinct phenotypes with variable prognosis. Recognition of ALMN as an intermediate form and the low cerebral progression rate in Italian AMN refine disease classification. Sex-related VLCFA differences may influence severity, although standard assays lack sensitivity. Neurophysiological testing, particularly BAEPs, can support differential diagnosis in patients with hereditary spastic paraplegias.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04880356\">NCT04880356<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jnnp-2025-337540","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:25:57Z","timestamp":1770747957000},"page":"483-492","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Adrenoleukodystrophy in adults: phenotypic characterisation and natural history in a large cohort"],"prefix":"10.1136","volume":"97","clinical-trial-number":[{"clinical-trial-number":"nct04880356","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8801-9114","authenticated-orcid":false,"given":"Chiara","family":"Benzoni","sequence":"first","affiliation":[{"name":"Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"},{"name":"Translational Medicine PhD Programme, University of Milan, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6745-474X","authenticated-orcid":false,"given":"Marco","family":"Moscatelli","sequence":"additional","affiliation":[{"name":"Unit of Neuroradiology, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"},{"name":"Department of Biomedical Sciences for Health, University of Milan, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7561-7724","authenticated-orcid":false,"given":"Paola","family":"Lanteri","sequence":"additional","affiliation":[{"name":"Unit of Neurophysiology, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viviana","family":"Pensato","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Cal\u00f2","sequence":"additional","affiliation":[{"name":"Unit of Neurophysiology, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Allievi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cinzia","family":"Gellera","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1969-0147","authenticated-orcid":false,"given":"Anna","family":"Ardissone","sequence":"additional","affiliation":[{"name":"Unit of Child Neurology, Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3322-1681","authenticated-orcid":false,"given":"Isabella","family":"Moroni","sequence":"additional","affiliation":[{"name":"Unit of Child Neurology, Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5233-6580","authenticated-orcid":false,"given":"Silvia","family":"Fenu","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Cavalca","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6854-765X","authenticated-orcid":false,"given":"Davide","family":"Pareyson","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9167-1878","authenticated-orcid":false,"given":"Ettore","family":"Salsano","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"2026051402050514000_97.6.483.1","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-7-51","article-title":"X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management","volume":"7","author":"Engelen","year":"2012","journal-title":"Orphanet J Rare Dis"},{"key":"2026051402050514000_97.6.483.2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.101"},{"key":"2026051402050514000_97.6.483.3","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/brain\/awt361","article-title":"X-linked adrenoleukodystrophy in women: a cross-sectional cohort study","volume":"137","author":"Engelen","year":"2014","journal-title":"Brain (Bacau)"},{"key":"2026051402050514000_97.6.483.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2010.00392.x"},{"key":"2026051402050514000_97.6.483.5","doi-asserted-by":"publisher","DOI":"10.1007\/s11373-004-8177-5"},{"key":"2026051402050514000_97.6.483.6","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1002\/(SICI)1096-8628(19980413)76:5<424::AID-AJMG11>3.0.CO;2-O","article-title":"X-linked adrenoleukodystrophy: phenotype distribution and expression of ALDP in Spanish kindreds","volume":"76","author":"Ruiz","year":"1998","journal-title":"Am J Med Genet"},{"key":"2026051402050514000_97.6.483.7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/BF00713859","article-title":"X-linked adrenoleukodystrophy: first report of the Italian Study Group","volume":"19","author":"Di Biase","year":"1998","journal-title":"Ital J Neurol Sci"},{"key":"2026051402050514000_97.6.483.8","doi-asserted-by":"publisher","DOI":"10.1055\/s-2000-9236"},{"key":"2026051402050514000_97.6.483.9","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1007\/s100380200090","article-title":"Epidemiology of X-linked adrenoleukodystrophy in Japan","volume":"47","author":"Takemoto","year":"2002","journal-title":"J Hum Genet"},{"key":"2026051402050514000_97.6.483.10","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.braindev.2004.09.008","article-title":"Natural history of X-linked adrenoleukodystrophy in Japan","volume":"27","author":"Suzuki","year":"2005","journal-title":"Brain Dev"},{"key":"2026051402050514000_97.6.483.11","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0034195","article-title":"Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy","volume":"7","author":"Pereira","year":"2012","journal-title":"PLoS One"},{"key":"2026051402050514000_97.6.483.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2012.12.007"},{"key":"2026051402050514000_97.6.483.13","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1007\/s11011-015-9717-6","article-title":"Clinical, biochemical, neuroimaging and molecular findings of X-linked Adrenoleukodystrophy patients in South China","volume":"30","author":"Jiang","year":"2015","journal-title":"Metab Brain Dis"},{"key":"2026051402050514000_97.6.483.14","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.ejpn.2017.02.006","article-title":"Long-term outcome of patients with X-linked adrenoleukodystrophy: A retrospective cohort study","volume":"21","author":"Tran","year":"2017","journal-title":"Eur J Paediatr Neurol"},{"key":"2026051402050514000_97.6.483.15","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1590\/1984-0462\/;2019;37;4;00015","article-title":"X-LINKED ADRENOLEUKODYSTROPHY IN BRAZIL: A CASE SERIES","volume":"37","author":"Furlan","year":"2019","journal-title":"Rev Paul Pediatr"},{"key":"2026051402050514000_97.6.483.16","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(20010201)49:2<186::AID-ANA38>3.0.CO;2-R"},{"key":"2026051402050514000_97.6.483.17","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1212\/WNL.0000000000001074","article-title":"Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy","volume":"83","author":"de Beer","year":"2014","journal-title":"Neurology (ECronicon)"},{"key":"2026051402050514000_97.6.483.18","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/ene.13816","article-title":"Natural history of a cohort of ABCD1 variant female carriers","volume":"26","author":"Schirinzi","year":"2019","journal-title":"Eur J Neurol"},{"key":"2026051402050514000_97.6.483.19","doi-asserted-by":"crossref","DOI":"10.1002\/jimd.12845","article-title":"Progression of Spinal Cord Disease in Adult Men With Adrenoleukodystrophy","volume":"48","author":"Yska","year":"2025","journal-title":"J Inherit Metab Dis"},{"key":"2026051402050514000_97.6.483.20","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S1474-4422(22)00495-1","article-title":"Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial","volume":"22","author":"K\u00f6hler","year":"2023","journal-title":"Lancet Neurol"},{"key":"2026051402050514000_97.6.483.21","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:13:3:247"},{"key":"2026051402050514000_97.6.483.22","first-page":"e2499","article-title":"Clinical and radiographic course of arrested cerebral adrenoleukodystrophy","volume":"94","author":"Mallack","year":"2020","journal-title":"Neurology (ECronicon)"},{"key":"2026051402050514000_97.6.483.23","doi-asserted-by":"crossref","DOI":"10.3390\/cells11020283","article-title":"Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy","volume":"11","author":"Mallack","year":"2022","journal-title":"Cells"},{"key":"2026051402050514000_97.6.483.24","doi-asserted-by":"crossref","first-page":"690","DOI":"10.3389\/fcell.2020.00690","article-title":"Comparison of the Diagnostic Performance of C26:0-Lysophosphatidylcholine and Very Long-Chain Fatty Acids Analysis for Peroxisomal Disorders","volume":"8","author":"Jaspers","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"2026051402050514000_97.6.483.25","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ymgme.2017.10.012","article-title":"Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy","volume":"122","author":"Huffnagel","year":"2017","journal-title":"Mol Genet Metab"},{"key":"2026051402050514000_97.6.483.26","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(80)91182-1"},{"key":"2026051402050514000_97.6.483.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(06)80013-2"},{"key":"2026051402050514000_97.6.483.28","first-page":"164","article-title":"Adrenoleukodystrophy: effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids","volume":"151","author":"Brown","year":"1982","journal-title":"Johns Hopkins Med J"},{"key":"2026051402050514000_97.6.483.29","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1001\/jamapediatrics.2024.6774","article-title":"Prognostication and Biomarker Potential of C26:0 Lysophosphatidylcholine in Adrenoleukodystrophy","volume":"179","author":"Billington","year":"2025","journal-title":"JAMA Pediatr"},{"key":"2026051402050514000_97.6.483.30","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M044586"},{"key":"2026051402050514000_97.6.483.31","doi-asserted-by":"crossref","DOI":"10.1172\/JCI142500","article-title":"Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy","volume":"131","author":"Raas","year":"2021","journal-title":"J Clin Invest"},{"key":"2026051402050514000_97.6.483.32","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh323"},{"key":"2026051402050514000_97.6.483.33","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199309093291101"},{"key":"2026051402050514000_97.6.483.34","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1212\/WNL.0000000000000770","article-title":"Brain fluorodeoxyglucose PET in adrenoleukodystrophy","volume":"83","author":"Salsano","year":"2014","journal-title":"Neurology (ECronicon)"},{"key":"2026051402050514000_97.6.483.35","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2019.20356","article-title":"Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina","volume":"3","author":"Lee","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2026051402050514000_97.6.483.36","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-01307"},{"key":"2026051402050514000_97.6.483.37","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000200061","article-title":"A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy","volume":"9","author":"Van Haren","year":"2023","journal-title":"Neurol Genet"},{"key":"2026051402050514000_97.6.483.38","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.2337\/db22-1050","article-title":"Association of Serum Very-Long-Chain Saturated Fatty Acids With Changes in Insulin Sensitivity and \u03b2-Cell Function: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) Cohort","volume":"72","author":"Lai","year":"2023","journal-title":"Diabetes"},{"key":"2026051402050514000_97.6.483.39","doi-asserted-by":"crossref","DOI":"10.3390\/nu16193341","article-title":"Nutritional Counseling and Mediterranean Diet in Adrenoleukodystrophy: A Real-Life Experience","volume":"16","author":"Spreghini","year":"2024","journal-title":"Nutrients"},{"key":"2026051402050514000_97.6.483.40","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000213370","article-title":"Disease Burden in Female Patients With X-Linked Adrenoleukodystrophy","volume":"104","author":"Grant","year":"2025","journal-title":"Neurology (ECronicon)"},{"key":"2026051402050514000_97.6.483.41","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1212\/01.WNL.0000079050.91337.83","article-title":"Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy","volume":"61","author":"Loes","year":"2003","journal-title":"Neurology (ECronicon)"},{"key":"2026051402050514000_97.6.483.42","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1055\/s-0041-1730937","article-title":"Imaging in X-Linked Adrenoleukodystrophy","volume":"52","author":"van de Stadt","year":"2021","journal-title":"Neuropediatrics"},{"key":"2026051402050514000_97.6.483.43","doi-asserted-by":"crossref","DOI":"10.1186\/s41747-023-00373-6","article-title":"Interval between contrast administration and T1-weighted MRI for cerebral adrenoleukodystrophy: a single-case observation","volume":"7","author":"Moscatelli","year":"2023","journal-title":"Eur Radiol Exp"},{"key":"2026051402050514000_97.6.483.44","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.61.2.181"},{"key":"2026051402050514000_97.6.483.45","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1212\/WNL.46.1.112","article-title":"Peripheral nerve abnormalities in adrenomyeloneuropathy: a clinical and electrodiagnostic study","volume":"46","author":"van Geel","year":"1996","journal-title":"Neurology (ECronicon)"}],"container-title":["Journal of Neurology, Neurosurgery &amp; Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jnnp-2025-337540","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T09:05:45Z","timestamp":1778749545000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnnp.bmj.com\/lookup\/doi\/10.1136\/jnnp-2025-337540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,10]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,5,14]]},"published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1136\/jnnp-2025-337540"],"URL":"https:\/\/doi.org\/10.1136\/jnnp-2025-337540","relation":{},"ISSN":["0022-3050","1468-330X"],"issn-type":[{"value":"0022-3050","type":"print"},{"value":"1468-330X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,10]]}}}