{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:17:13Z","timestamp":1785428233166,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82271459"],"award-info":[{"award-number":["82271459"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82571426"],"award-info":[{"award-number":["82571426"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82020108012"],"award-info":[{"award-number":["82020108012"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82071422"],"award-info":[{"award-number":["82071422"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82271459"],"award-info":[{"award-number":["82271459"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82571426"],"award-info":[{"award-number":["82571426"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82020108012"],"award-info":[{"award-number":["82020108012"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82071422"],"award-info":[{"award-number":["82071422"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction: Adult-onset Alexander disease (AOAD) is a rare astrocytopathy linked to the glial fibrillary acidic protein (GFAP) gene, which is known for its clinical heterogeneity and common misdiagnosis. In adults, it may present with bulbar dysfunction, pyramidal signs, ataxia, dysautonomia, cognitive decline, or parkinsonism, which often mimics atypical parkinsonian syndromes like multiple system atrophy (MSA). The purpose of this case series was to define practical clinical, radiological, and genetic cues for suspecting AOAD in adults with atypical parkinsonism, autonomic dysfunction, or paroxysmal focal symptoms, particularly when genetic findings are inconclusive. Case Presentation: Four patients, aged 40 to 59 years, had progressive and varied neurological symptoms, like gait disturbance, lower limb weakness, dysarthria, dysphagia, autonomic dysfunction, parkinsonism, cognitive decline, and paroxysmal focal deficits. Initial diagnoses were parkinsonian syndrome, stroke, transient ischemic attack (TIA), and MSA. Diagnostic Assessment and Intervention: Brain magnetic resonance imaging (MRI) in all patients showed characteristic lower brainstem abnormalities, particularly atrophy of the medulla oblongata and upper cervical spinal cord, consistent with the \u201ctadpole sign.\u201d GFAP sequencing identified one likely pathogenic variant (p.Arg70Trp) and three variants of uncertain significance: p.Glu122_Arg124del, p.Met415Ile, and p.Glu195Val. Management was mainly symptomatic; one patient showed significant motor improvement after repetitive transcranial magnetic stimulation (rTMS). Conclusions: AOAD should be considered in adults with parkinsonism-plus syndromes or unexplained combinations of bulbar symptoms, pyramidal signs, autonomic dysfunction, and cognitive decline. Recognizing the tadpole sign on MRI may improve diagnostic accuracy, particularly when genetic results are inconclusive.<\/jats:p>","DOI":"10.3390\/jcm15145677","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"5677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adult-Onset Alexander Disease Presenting as Atypical Parkinsonism and Autonomic Dysfunction: A Case Series"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1205-7181","authenticated-orcid":false,"given":"Jinping","family":"Fang","sequence":"first","affiliation":[{"name":"Parkinson Medical Center, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6712-2286","authenticated-orcid":false,"given":"Zhan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Feng","sequence":"additional","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7486-7203","authenticated-orcid":false,"given":"Ying","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/bpa.12601","article-title":"Alexander disease: An astrocytopathy that produces a leukodystrophy","volume":"28","author":"Sosunov","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.4103\/1673-5374.369097","article-title":"Alexander disease: The road ahead","volume":"18","author":"Pajares","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1523\/JNEUROSCI.5384-11.2012","article-title":"Alexander Disease","volume":"32","author":"Messing","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1086\/504411","article-title":"The Alexander Disease-Causing Glial Fibrillary Acidic Protein Mutant, R416W, Accumulates into Rosenthal Fibers by a Pathway That Involves Filament Aggregation and the Association of aB-Crystallin and HSP27","volume":"79","author":"Perng","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1242\/jcs.02339","article-title":"Alexander-disease mutation of GFAP causes filament disorganization and decreased solubility of GFAP","volume":"118","author":"Hsiao","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ana.25118","article-title":"Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease","volume":"83","author":"Hagemann","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15010","DOI":"10.1007\/s12035-025-05083-1","article-title":"Alexander\u2019s Disease: Potential Drug Targets and Future Directions","volume":"62","author":"Zavala","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"325","DOI":"10.2217\/nmt-2020-0022","article-title":"Clinical Characteristics of Alexander Disease","volume":"10","author":"Yoshida","year":"2020","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"24341","DOI":"10.1038\/s41598-024-75383-4","article-title":"A systematic review and meta-analysis of GFAP gene variants in Alexander disease","volume":"14","author":"Grossi","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1007\/s00415-010-5706-1","article-title":"The clinical spectrum of late-onset Alexander disease: A systematic literature review","volume":"257","author":"Balbi","year":"2010","journal-title":"J. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1136\/pn-2024-004490","article-title":"Diagnosing Alexander disease in adults","volume":"25","author":"Lynch","year":"2025","journal-title":"Pract. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Park, J., Park, S.-T., Kim, J., and Kwon, K.-Y. (2020). A case report of adult-onset Alexander disease clinically presenting as Parkinson\u2019s disease: Is the comorbidity associated with genetic susceptibility?. BMC Neurol., 20.","DOI":"10.1186\/s12883-020-1616-8"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jocn.2021.03.001","article-title":"Adult-onset Alexander disease mimicking multiple system atrophy predominant cerebellar ataxia","volume":"87","author":"Watanabe","year":"2021","journal-title":"J. Clin. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1093\/brain\/awn178","article-title":"Adult-onset Alexander disease: A series of eleven unrelated cases with review of the literature","volume":"131","author":"Pareyson","year":"2008","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1212\/01.wnl.0000438230.33223.bc","article-title":"Neuroimaging and clinical features in type II (late-onset) Alexander disease","volume":"82","author":"Schwartz","year":"2014","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"738","DOI":"10.4103\/aian.aian_402_24","article-title":"Tadpole Brainstem Atrophy in Adult-Onset Alexander Disease: A Case Report and Review of Literature","volume":"27","author":"Kota","year":"2024","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1136\/jnnp-2024-335089","article-title":"Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease","volume":"96","author":"Gagliardi","year":"2025","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s10286-013-0205-y","article-title":"Autonomic dysfunction in adult-onset alexander disease: A case report and review of the literature","volume":"23","author":"Spritzer","year":"2013","journal-title":"Clin. Auton. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Namekawa, M., Takiyama, Y., Honda, J., Shimazaki, H., Sakoe, K., and Nakano, I. (2010). Adult-onset Alexander disease with typical \u201ctadpole\u201d brainstem atrophy and unusual bilateral basal ganglia involvement: A case report and review of the literature. BMC Neurol., 10.","DOI":"10.1186\/1471-2377-10-21"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.3174\/ajnr.A1060","article-title":"Can MR Imaging Diagnose Adult-Onset Alexander Disease?","volume":"29","author":"Farina","year":"2008","journal-title":"Am. J. Neuroradiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kang, Y.-R., Nam, T.-S., Kim, J.-M., Kang, K.W., Lee, S.-H., Choi, S.-M., and Kim, M.-K. (2023). Older adult-onset Alexander disease with atypical clinicoradiological features: A case report. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1139047"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1111\/ene.15017","article-title":"Clinical and radiological characteristics of older-adult-onset Alexander disease","volume":"28","author":"Yoshida","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1212\/WNL.0b013e3182309f72","article-title":"GFAP mutations, age at onset, and clinical subtypes in Alexander disease","volume":"77","author":"Prust","year":"2011","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1159\/000475661","article-title":"Quantitative Evaluation of Brain Stem Atrophy Using Magnetic Resonance Imaging in Adult Patients with Alexander Disease","volume":"77","author":"Yoshida","year":"2017","journal-title":"Eur. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41431-022-01073-2","article-title":"A novel in-frame GFAP p.E138_L148del mutation in Type II Alexander disease with atypical phenotypes","volume":"30","author":"Kang","year":"2022","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/83679","article-title":"Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease","volume":"27","author":"Brenner","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1016\/j.yexcr.2011.06.017","article-title":"Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability","volume":"317","author":"Chen","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e681","DOI":"10.1212\/NXG.0000000000000681","article-title":"Adult-Onset Alexander Disease: New Causal Sequence Variant in the GFAP Gene","volume":"8","author":"Goerttler","year":"2022","journal-title":"Neurol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1016\/j.yexcr.2007.04.004","article-title":"GFAP and its role in Alexander disease","volume":"313","author":"Quinlan","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Muthusamy, K., Sivadasan, A., Dixon, L., Sudhakar, S., Thomas, M., Danda, S., Wszolek, Z.K., Wierenga, K., Dhamija, R., and Gavrilova, R. (2023). Adult-onset leukodystrophies: A practical guide, recent treatment updates, and future directions. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1219324"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12927","DOI":"10.1111\/nan.12927","article-title":"Adult-onset Alexander disease with unusual inflammatory features and a novel GFAP mutation in two patients","volume":"49","author":"Ziad","year":"2023","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103","DOI":"10.21037\/atm.2016.03.24","article-title":"Increased cerebellar activation after repetitive transcranial magnetic stimulation over the primary motor cortex in patients with multiple system atrophy","volume":"4","author":"Wang","year":"2016","journal-title":"Ann. Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zhang, M., He, T., and Wang, Q. (2021). Effects of Non-invasive Brain Stimulation on Multiple System Atrophy: A Systematic Review. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.771090"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, M., Zhang, W., and Zang, W. (2024). Repetitive transcranial magnetic stimulation improves cognition, depression, and walking ability in patients with Parkinson\u2019s disease: A meta-analysis. BMC Neurol., 24.","DOI":"10.1186\/s12883-024-03990-9"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"bcr2013201554","DOI":"10.1136\/bcr-2013-201554","article-title":"The CARE guidelines: Consensus-based clinical case reporting guideline development","volume":"2013","author":"Gagnier","year":"2013","journal-title":"BMJ Case Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.jclinepi.2017.04.026","article-title":"CARE guidelines for case reports: Explanation and elaboration document","volume":"89","author":"Riley","year":"2017","journal-title":"J. Clin. Epidemiol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/14\/5677\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:24:08Z","timestamp":1784694248000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/14\/5677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":36,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["jcm15145677"],"URL":"https:\/\/doi.org\/10.3390\/jcm15145677","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}