Global Presence and Penetrance of CSF1R-Related Disorder

Jaroslaw Dulski¹, Matthew Baker¹, Samantha A Banks¹, Michael Bayat¹, Rose Bruffaerts¹, Gabriela Ortiz Cruz¹, Caio C Disserol¹, Kristen S Fisher¹, Jainy N Jose¹, Bernadette Kalman¹, Orhun H Kantarci¹, Dmytro Maltsev¹, Catherine Middleton¹, Gabriela Novotni¹, Dijana Plaseska-Karanfilska¹, Salmo Raskin¹, Josiane Souza¹, Helio A Teive¹, Zbigniew K Wszolek¹

Affiliations

Affiliation

¹ From the Department of Neurology (J.D., Z.K.W.), Mayo Clinic, Jacksonville, FL; Division of Neurological and Psychiatric Nursing (J.D.), Faculty of Health Sciences, Medical University of Gdansk; Neurology Department (J.D.), St Adalbert Hospital, Copernicus PL Ltd., Gdansk, Poland; Department of Neuroscience (M. Baker), Mayo Clinic, Jacksonville, FL; Department of Neurology (S.A.B., O.H.K.), Mayo Clinic, Rochester, MN; Department of Neurology (M. Bayat); Centre for Rare Diseases (M. Bayat), Aarhus University Hospital, Aarhus, Denmark; Experimental Neurobiology Unit (R.B.), Department of Biomedical Sciences, University of Antwerp; Department of Neurology, Antwerp University Hospital, Belgium; Center for Research in Genetics and Genomics (CIGEN) (G.O.C.), Autonomous University of Coahuila, México; Universidade Federal do Paraná (C.C.D.), Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Curitiba, Brazil; Department of Pediatrics (K.S.F.), Section of Neurology and Developmental Neuroscience, Baylor College of Medicine (BCM), Houston, TX; Department of Paediatrics (J.N.J.), St. Johns Medical College, Bangalore, Karnataka, India; Office of the Dean (B.K.), University of Pécs, School of Medicine; Molecular Medicine (B.K.), Markusovszky University Teaching Hospital, Szombathely, Hungary; Immunology and Molecular Biology Laboratory of Experimental and Clinical Medicine Institute at the O'Bogomolets National Medical University (D.M.), Kyiv, Ukraine; General Practice (C.M.), Brisbane, Queensland, Australia; Department of Cognitive Neurology and Neurodegenerative Diseases (G.N.), University Clinic of Neurology, Medical Faculty, University "Ss. Cyril and Methodius", Institute for Alzheimer's Disease and Neuroscience-Skopje; Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov" (D.P.-K.), Macedonian Academy of Sciences and Arts, Skopje, North Macedonia; Postgraduate Program in Child and Adolescent (S.R.), Department of Pediatrics, Federal University of Paraná, Curitiba; School of Medicine (J.S.), Pontificia Universidade Católica do Paraná (PUCPR); Department of Genetics (J.S.), Hospital Infantil Pequeno Príncipe; and Universidade Federal do Paraná (H.A.T.), Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Setor de Distúrbios do Movimento, Curitiba, Brazil.

PMID: 39280886
PMCID: PMC11398975
DOI: 10.1212/NXG.0000000000200187

Global Presence and Penetrance of CSF1R-Related Disorder

Jaroslaw Dulski et al. Neurol Genet. 2024.

. 2024 Sep 13;10(5):e200187.

doi: 10.1212/NXG.0000000000200187. eCollection 2024 Oct.

Authors

Affiliation

¹ From the Department of Neurology (J.D., Z.K.W.), Mayo Clinic, Jacksonville, FL; Division of Neurological and Psychiatric Nursing (J.D.), Faculty of Health Sciences, Medical University of Gdansk; Neurology Department (J.D.), St Adalbert Hospital, Copernicus PL Ltd., Gdansk, Poland; Department of Neuroscience (M. Baker), Mayo Clinic, Jacksonville, FL; Department of Neurology (S.A.B., O.H.K.), Mayo Clinic, Rochester, MN; Department of Neurology (M. Bayat); Centre for Rare Diseases (M. Bayat), Aarhus University Hospital, Aarhus, Denmark; Experimental Neurobiology Unit (R.B.), Department of Biomedical Sciences, University of Antwerp; Department of Neurology, Antwerp University Hospital, Belgium; Center for Research in Genetics and Genomics (CIGEN) (G.O.C.), Autonomous University of Coahuila, México; Universidade Federal do Paraná (C.C.D.), Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Curitiba, Brazil; Department of Pediatrics (K.S.F.), Section of Neurology and Developmental Neuroscience, Baylor College of Medicine (BCM), Houston, TX; Department of Paediatrics (J.N.J.), St. Johns Medical College, Bangalore, Karnataka, India; Office of the Dean (B.K.), University of Pécs, School of Medicine; Molecular Medicine (B.K.), Markusovszky University Teaching Hospital, Szombathely, Hungary; Immunology and Molecular Biology Laboratory of Experimental and Clinical Medicine Institute at the O'Bogomolets National Medical University (D.M.), Kyiv, Ukraine; General Practice (C.M.), Brisbane, Queensland, Australia; Department of Cognitive Neurology and Neurodegenerative Diseases (G.N.), University Clinic of Neurology, Medical Faculty, University "Ss. Cyril and Methodius", Institute for Alzheimer's Disease and Neuroscience-Skopje; Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov" (D.P.-K.), Macedonian Academy of Sciences and Arts, Skopje, North Macedonia; Postgraduate Program in Child and Adolescent (S.R.), Department of Pediatrics, Federal University of Paraná, Curitiba; School of Medicine (J.S.), Pontificia Universidade Católica do Paraná (PUCPR); Department of Genetics (J.S.), Hospital Infantil Pequeno Príncipe; and Universidade Federal do Paraná (H.A.T.), Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Setor de Distúrbios do Movimento, Curitiba, Brazil.

PMID: 39280886
PMCID: PMC11398975
DOI: 10.1212/NXG.0000000000200187

Abstract

Objectives: To highlight the worldwide presence of CSF1R-related disorder (CSF1R-RD), discuss its penetrance, and provide the first haplotype analysis.

Methods: Data on patients worldwide were collected, including demographics, genotype, family history, and clinical status. For haplotype analysis, polymorphisms of short tandem repeats in 3 distinct families with CSF1R p.Ile794Thr variant were examined.

Results: Nineteen new patients were included, at a mean age of 38.7 years (ranging from 11 to 74 years), from 14 families from the Americas, Asia, Australia, and Europe, including the first from Mexico, North Macedonia, and Ukraine. Fifteen CSF1R variants were found, including 8 novel. Three patients were compound heterozygotes with disease onset at 1, 4, and 22 years. Patients with heterozygous CSF1R variants developed symptoms at a mean of 39.0 years (range 8-71 years). Four patients died at a mean of 3.3 years from onset (range 2-5 years). Negative family history was noted in 7 patients. In haplotype analysis, 2 families exhibited shared haplotype encompassing ∼6-Mb region downstream of the CSF1R while the third family displayed a different haplotype.

Discussion: CSF1R-RD has a global prevalence. The reasons for negative family history include de novo variants (as shown by the haplotype analysis), mosaicism, and incomplete penetrance, which are possibly modulated by environmental and genetic factors.

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Conflict of interest statement

J. Dulski is partially supported by the Haworth Family Professorship in Neurodegenerative Diseases fund (90052067). He serves as an editorial board member of Neurologia i Neurochirurgia Polska. He received speakers' bureau honoraria from VM Media Ltd., Radosław Lipiński 90 Consulting, Ipsen. He has intellectual property rights for “Application of Hydrogen Peroxide and 17β-Estradiol and its Metabolites as Biomarkers in a Method of Diagnosing Neurodegenerative Diseases In Vitro” (WO/2023/234790); R. Bruffaerts received consulting fees (advisory board) from Eisai; Z. K. Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the 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, and PPND Family 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 and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. Go to Neurology.org/NG for full disclosures.

Figures

**Figure. Global Presence of *CSF1R*-Related Disorder as of February 2024**
The countries where the disease was reported by 2018 are shown in blue. The countries where the disease was reported between 2018 and 2023 are shown in yellow. The newly reported countries are shown in red.

See this image and copyright information in PMC

References

1. Dulski J, Muthusamy K, Lund TC, Wszolek ZK. CSF1R-related disorder: state of the art, challenges, and proposition of a new terminology. Parkinsonism Relat Disord. 2024;121:105894. doi: 10.1016/j.parkreldis.2023.105894 - DOI - PubMed
1. Bogaert V. Le type tardif de la leucodystrophie progressive familiale. Rev Neurol. 1936;65:21.
1. Konno T, Kasanuki K, Ikeuchi T, Dickson DW, Wszolek ZK. CSF1R-related leukoencephalopathy: a major player in primary microgliopathies. Neurology. 2018;91(24):1092-1104. doi: 10.1212/WNL.0000000000006642 - DOI - PMC - PubMed
1. Papapetropoulos S, Pontius A, Finger E, et al. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: review of clinical manifestations as foundations for therapeutic development. Front Neurol. 2021;12:788168. doi: 10.3389/fneur.2021.788168 - DOI - PMC - PubMed
1. Dulski J, Souza J, Santos ML, Wszolek ZK. Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP. Orphanet J Rare Dis. 2023;18(1):160. doi: 10.1186/s13023-023-02772-9 - DOI - PMC - PubMed

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Global Presence and Penetrance of CSF1R-Related Disorder

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Global Presence and Penetrance of CSF1R-Related Disorder

Authors

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Conflict of interest statement

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