Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Mar 11:15:1320663.
doi: 10.3389/fneur.2024.1320663. eCollection 2024.

Clinical presentation and diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: a literature analysis of case studies

Spyros Papapetropoulos  1 , Jeffrey M Gelfand  2 , Takuya Konno  3 , Takeshi Ikeuchi  3 , Angela Pontius  1 , Andreas Meier  1 , Farid Foroutan  4 , Zbigniew K Wszolek  5
Affiliations

Clinical presentation and diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: a literature analysis of case studies

Spyros Papapetropoulos et al. Front Neurol. .

Abstract

Introduction: Because adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive, debilitating, and ultimately fatal neurodegenerative disease, a rapid and accurate diagnosis is critical. This analysis examined the frequency of initial misdiagnosis of ALSP via comprehensive review of peer-reviewed published cases.

Methods: Data were extracted from a MEDLINE search via PubMed (January 1, 1980, through March 22, 2022) from eligible published case reports/series for patients with an ALSP diagnosis that had been confirmed by testing for the colony-stimulating factor-1 receptor gene (CSF1R) mutation. Patient demographics, clinical symptoms, brain imaging, and initial diagnosis data were summarized descriptively. Categorical data for patient demographics, symptoms, and brain imaging were stratified by initial diagnosis category to test for differences in initial diagnosis based on each variable.

Results: Data were extracted from a cohort of 291 patients with ALSP from 93 published case reports and case series. Mean (standard deviation) age of symptom onset was 43.2 (11.6) years. A family history of ALSP was observed in 59.1% of patients. Cognitive impairment (47.1%) and behavioral and psychiatric abnormalities (26.8%) were the most frequently reported initial symptoms. Of 291 total cases, an accurate initial diagnosis of ALSP was made in 72 cases (24.7%) and the most frequent initial misdiagnosis categories were frontotemporal dementia (28 [9.6%]) and multiple sclerosis (21 [7.2%]). Of the 219 cases (75.3%) that were initially mis- or undiagnosed, 206 cases (94.1%) were later confirmed as ALSP by immunohistology, imaging, and/or genetic testing; for the remaining 13 cases, no final diagnosis was reported. Initial diagnosis category varied based on age, family history, geographic region, mode of inheritance, and presenting symptoms of pyramidal or extrapyramidal motor dysfunction, behavioral and psychiatric abnormalities, cognitive impairment, and speech difficulty. Brain imaging abnormalities were common, and initial diagnosis category was significantly associated with white matter hyperintensities, white matter calcifications, and ventricular enlargement.

Discussion: In this literature analysis, ALSP was frequently misdiagnosed. Improving awareness of this condition and distinguishing it from other conditions with overlapping presenting symptoms is important for timely management of a rapidly progressive disease such as ALSP.

Keywords: ALSP; CSF1R-related leukoencephalopathy; adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; diagnosis; misdiagnosis.

PubMed Disclaimer

Conflict of interest statement

SP and AP are former full-time employees of Vigil Neuroscience, Inc. JG receives research support to his institution from Vigil Neuroscience, Inc. for clinical trials, from Genentech/Roche for clinical trials, and personal fees for consulting from Arialys. TK and TI are funded by AMED JP23dk0207060, a public grant from the Japanese government to support research on ALSP. FF is a consultant for Vigil Neuroscience, Inc. ZW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson’s Research Foundation; he serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206) and Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, CSF1R biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants; he serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research, as an external advisory board member for Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilly and Company. AM is a full-time employee of Vigil Neuroscience, Inc. This study received funding from Vigil Neuroscience, Inc. The funder had the following involvement with the study: study design; data collection, analysis, and interpretation; and drafting, revising, and submitting this article for publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Summary of initial and final diagnosis categories. a14 cases from 7 publications were published prior to the identification of CSF1R mutation as the genetic basis of ALSP. bAll, c2, or d1 cases published prior to the identification of CSF1R mutation as the genetic basis of ALSP.
See this image and copyright information in PMC

References

    1. Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, et al. . Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation. Eur J Neurol. (2017) 24:37–45. doi: 10.1111/ene.13125, PMID: - DOI - PMC - PubMed
    1. Sundal C, Van Gerpen JA, Nicholson AM, Wider C, Shuster EA, Aasly J, et al. . MRI characteristics and scoring in HDLS due to CSF1R gene mutations. Neurology. (2012) 79:566–74. doi: 10.1212/WNL.0b013e318263575a, PMID: - DOI - PMC - PubMed
    1. Papapetropoulos S, Pontius A, Finger E, Karrenbauer V, Lynch DS, Brennan M, et al. . Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: review of clinical manifestations as foundations for therapeutic development. Front Neurol. (2022) 12:788168. doi: 10.3389/fneur.2021.788168, PMID: - DOI - PMC - PubMed
    1. Sundal C, Wszolek ZK. CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews®. Seattle, WA: University of Washington, Seattle; (2017). 1993–2023. - PubMed
    1. NORD . Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. (2021). Available at: https://rarediseases.org/rare-diseases/adult-onset-leukoencephalopathy-w... (Accessed January 23, 2024) - PubMed