
==== Front
Neurol Genet
Neurol Genet
nng
NNG
Neurology: Genetics
2376-7839
Wolters Kluwer Baltimore

NXG-2024-100065
10.1212/NXG.0000000000200187
3
155
161
91
Clinical/Scientific Note
Global Presence and Penetrance of CSF1R-Related Disorder
https://orcid.org/0000-0002-5517-9875
Dulski Jaroslaw MD, PhD
https://orcid.org/0009-0001-2691-5757
Baker Matthew BSc
https://orcid.org/0000-0002-5856-1367
Banks Samantha A. MD
https://orcid.org/0000-0003-1793-390X
Bayat Michael MD
https://orcid.org/0000-0002-2631-9234
Bruffaerts Rose MD, PhD
Ortiz Cruz Gabriela MD
https://orcid.org/0000-0001-7568-0897
Disserol Caio C. MD
Fisher Kristen S. DO
Jose Jainy N. MD
Kalman Bernadette MD, PhD, DSc
Kantarci Orhun H. MD
Maltsev Dmytro MD
Middleton Catherine MD
Novotni Gabriela MD
Plaseska-Karanfilska Dijana MD
https://orcid.org/0000-0002-7191-0592
Raskin Salmo MD, PhD
Souza Josiane PhD
https://orcid.org/0000-0003-2305-1073
Teive Helio A. MD, PhD
https://orcid.org/0000-0001-5487-1053
Wszolek Zbigniew K. MD
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.
Correspondence Dr. Wszolek wszolek.zbigniew@mayo.edu
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

The Article Processing Charge was funded by the authors.

Submitted and externally peer reviewed. The handling editor was Associate Editor Raymond P. Roos, MD, FAAN.

10 2024
13 9 2024
13 9 2024
10 5 e20018711 3 2024
17 7 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
2024
American Academy of Neurology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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.

OPEN-ACCESSTRUE
==== Body
pmcIntroduction

CSF1R-related disorder (CSF1R-RD) is a rare hereditary neurodegenerative disease with growing global recognition as genetic testing becomes more widely available.1 The disorder was first reported in 1936 as pigmentary orthochromatic leukodystrophy (POLD).2 Subsequently, different terminologies reflecting the contemporary state of understanding of the disease have been used, including “hereditary diffuse leukoencephalopathy with spheroids (HDLS),” “adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP),” “CSF1R-related leukoencephalopathy,” and “brain abnormalities, neurodegeneration, and dysosteosclerosis.”1,3-5 Owing to advances in research, a unified nomenclature has been proposed and the term “CSF1R-RD” was introduced with patients subdivided into early-onset (younger than 18 years) and late-onset (18 years and older) CSF1R-RD.1

The causative role of CSF1R variants was identified in 2011.6 Over the next 7 years, 70 different CSF1R variants were reported in families from Asia (China, Japan, Saudi Arabia, South Korea, Taiwan), Europe (Croatia, France, Germany, Greece, Ireland, Italy, Netherlands, Norway, Sweden, United Kingdom), and North America (Canada, United States).3 Since then, the number of reported variants has almost tripled, with 199 pathogenic or likely pathogenic CSF1R variants recognized as of February 2024, per Human Gene Mutation Database (HGMD) Professional 2023.4.7 CSF1R-RD has been reported in Australia, Belgium, Brazil, Denmark, Hungary, India, Poland, Singapore, Spain, and Turkey (eAppendix 1).8

Despite the logarithmical growth in identified CSF1R pathogenic variants, little is known about their penetrance and other genotype-phenotype correlations. This gap may stem from the fact that most of the CSF1R variants are unique to specific families. Among ∼200 families with CSF1R-RD followed by Mayo Clinic Florida (Z.K.W.), biological material was collected from 50 families. Within this subset, only a few CSF1R variants occur in more than 1 family, with the most common being the CSF1R p.Ile794Thr (c.2381T>C), which is present in 3 distinct families.

In this article, we report new patients with the disease around the world, providing the first haplotype analysis of families with CSF1R p.Ile794Thr variant and discussing the penetrance of the disease and related aspects important for genetic counseling and routine clinical settings.

Methods

The study originated from the senior author's (Z.K.W.) communication with international medical professionals who expressed interest in the CSF1R-RD. This interaction prompted the collection of epidemiologic data on new patients with CSF1R-RD globally. The gathered data included the country of origin, specific CSF1R variant(s), genotype, self-reported sex and ethnicity, family history, current age, clinical status, age at which the disease first manifested, and age at death.

In the haplotype analysis, we investigated polymorphisms of short tandem repeats (STRPs) in representative samples from our 3 distinct families, all of whom are affected by a CSF1R-RD due to CSF1R p.Ile794Thr (c.2381T>C) variant. The examined STRPs covered approximately 10-Mb region, encompassing genetic markers located upstream (D5S436, D5S434), within (D5S1469), and downstream (D5S410, D5S820) of CSF1R.

Standard Protocol Approvals, Registrations, and Patient Consents

The patient's data were collected under IRB 19-011016. The study data are available from the corresponding author on reasonable request.

Results

We collected data on 19 patients (9 men) from 14 families with a mean age of 38.7 years, ranging from 11 to 74 years, of White (n = 14), Latino (n = 2), Asian (n = 1), Black (n = 1), and Native American (n = 1) ethnicity (Table). They were from Asia (India), Australia, Europe (Belgium, Denmark, Hungary, North Macedonia, Ukraine), and North and South America (Brazil, Canada, Mexico, United States) (Figure). A Hungarian family, with neuropathologic confirmation of POLD, was included in the study, given the consistent observation of CSF1R variants in all previously documented patients with POLD. In the other patients (n = 15), 15 CSF1R variants were found, 8 of which were not reported previously. Three individuals were compound heterozygotes for CSF1R variants, with symptomatic disease onset (AOO) at age 1, 4, and 22 years, respectively. In the group with heterozygous CSF1R variants, the mean AOO was 39.0 years (range 8–71 years), with 1 individual remaining free of symptoms at 54 years. Four patients died at a mean of 3.3 years from onset (range 2–5 years). A negative family history for CSF1R-RD was noted in 5 patients with heterozygous and 2 with compound heterozygous CSF1R variants.

Table Characteristics of the Newly Reported Patients With CSF1R-Related Disorder

Family	Country	Ethnicity	CSF1R variant(s)	CSF1R genotype	
1	Australia	White	c.1991_2005del p.Glu664_Tyr668del	Heterozygous	
White	c.1991_2005del p.Glu664_Tyr668del	Heterozygous	
2	Belgium	White	c.2329 C>T (p.Arg777Trp)	Heterozygous	
3	Brazil	White	c.880C>T (p.Arg294Trp	Heterozygous	
4	Brazil	Native American	c.2345G>A (p. Arg782His);
c.592+5G>A	Compound heterozygous	
5	Brazil	White	c.1441C>T (p.Gln481*);
c.592+5G>A	Compound heterozygous	
6	Canada	White	c.1735C>T (p.Arg579Trp)	Heterozygous	
7	Denmark	White	c.2392 G>A (p.Gly798Arg)	Heterozygous	
8	Hungary	White	N/A*	N/A	
White	N/A	N/A	
White	N/A	N/A	
White	N/A	N/A	
		
9	India	Asian	c.322_329delinsG (p.Trp108GlyfsTer2)	Heterozygous	
10	Mexico	Latino	c.1047del (p.Lys350Serfs*22)	Heterozygous	
Latino	c.1047del (p.Lys350Serfs*22)	Heterozygous	
11	North Macedonia	White	c.2381T>C (p.Ile794Thr)	Heterozygous	
12	Ukraine	White	c. 1765 G>A (p.Gly589Arg)	Heterozygous	
13	United States	White	c.2455G>T (p.Val819Leu);
c.368C>A (p.Ala123Glu)	Compound heterozygous	
14	United States	Black	c.1772G>A (p.Gly591Glu)	Heterozygous	
N/A = not applied; *neuropathologic confirmation of pigmentary orthochromatic leukodystrophy.

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.

In haplotype analysis, 2 families exhibited a shared haplotype in the D5S1469, D5S410, and D5S820 markers, encompassing ∼6-Mb region downstream of the CSF1R p.Ile794Thr variant. By contrast, the third family displayed a unique haplotype in this region.

Discussion

In this study, we present 15 patients with CSF1R-RD and 4 from a family with POLD, revealing 8 novel variants in CSF1R, and report, for the first time, patients from Mexico, North Macedonia, and Ukraine, highlighting the global distribution of this disease. Of interest, despite showing symptoms, 7 individuals had no family history of the disease. This observation suggests incomplete penetrance of some CSF1R variants. Our previous research has shown that glucocorticoid exposure can protect against the development of symptomatic disease in individuals carrying CSF1R variants, as demonstrated in a retrospective cohort study and a mouse model study.9-11 This finding opened the possibility that other environmental factors may also play a role in the penetrance of CSF1R variants. Moreover, similar to other disorders, individual genetic architecture may also affect the penetrance of CSF1R variants. Therefore, the AOO and penetrance are most likely modulated by a combination of environmental factors, including but not limited to glucocorticoid exposure and genetic factors.

The haplotype analysis in our families with CSF1R p.Ile794Thr variant indicated a possible common ancestral origin for the variant in the 2 families, whereas the variant in the third family seems to be of independent origin. The 2 families with shared haplotype could not be genealogically linked in recent generations, indicating that the CSF1R p.Ile794Thr variant likely originated at least several generations before. The independent haplotype in the third family evidences the recurrence of de novo mutations in the CSF1R. This observation was first made in our original article on CSF1R variant discovery, in which both parents of the 2 affected Norwegian twins with CSF1R p.G585_K619delinsA variant tested negative for the variants.6 Thus, a negative family history in some individuals affected by CSF1R-RD may be explained by the de novo variants. Another possible explanation is mosaicism, i.e., the presence of 2 or more populations of cells with different genotypes in 1 individual, which can arise from variants occurring during development. Mosaic parents may not show symptoms of a CSF1R-RD due to a limited distribution of mutant cells but can still pass on the CSF1R variant to offspring.12

To date, most of the pathogenic CSF1R variants are missense/nonsense (75%, n = 149/199), followed by structural (small and gross deletions, insertion, indels, complex rearrangements) (16%, n = 32/199) and splicing variants (9%, n = 18/199), per HGMD Professional 2023.47. The advent of next-generation sequencing technologies (multigene panels, exome and genome sequencing) has made genetic testing more accessible, leading to a significant increase in the detection of CSF1R variants.13,14 Many of the newly identified CSF1R variants are labeled as variants of unknown significance (VUSs), posing a challenge to interpret them in a clinical context, particularly in patients with negative family history. To better understand the clinical relevance of VUS, we suggest a review of the up-to-date literature, segregation studies, and in silico predictions. However, the functional studies in cellular and animal models remain the gold standard for elucidating the pathogenicity of these variants.

In conclusion, as genetic testing for CSF1R variants becomes more widespread, the identification of VUS is expected to increase, emphasizing the need for more research to elucidate these variants. Further research is required, including the investigation of asymptomatic and symptomatic carriers of CSF1R variants, to better understand the penetrance of variants and the influence of environmental and genetic modifiers on the disease phenotype. This information is important for enhancing genetic counseling, guiding the development of prophylactic interventions, and improving risk prediction for disease onset.

Acknowledgment

The authors thank the patients and their families for participating in this study. R.B. is a member of the European Reference Network for Rare Neurological Diseases-Project ID No. 101085584.

Study Funding

The authors report no targeted funding.

Disclosure

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.

Appendix Authors

Name	Location	Contribution	
Jaroslaw Dulski, MD, PhD	Department of Neurology, Mayo Clinic, Jacksonville, FL; Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk; Neurology Department, St Adalbert Hospital, Copernicus PL Ltd., Gdansk, Poland	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Matthew Baker, BSc	Department of Neuroscience, Mayo Clinic, Jacksonville, FL	Analysis or interpretation of data	
Samantha A Banks, MD	Department of Neurology, Mayo Clinic, Rochester, MN	Major role in the acquisition of data	
Michael Bayat, MD	Department of Neurology; Centre for Rare Diseases, Aarhus University Hospital, Denmark	Major role in the acquisition of data	
Rose Bruffaerts, MD, PhD	Experimental Neurobiology Unit, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Belgium	Major role in the acquisition of data	
Gabriela Ortiz Cruz, MD	Center for Research in Genetics and Genomics (CIGEN), Autonomous University of Coahuila, México	Major role in the acquisition of data	
Caio César Diniz Disserol, MD	Universidade Federal do Paraná, Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Curitiba, Brazil	Major role in the acquisition of data	
Kristen S. Fisher, DO	Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine (BCM), Houston, TX	Major role in the acquisition of data	
Jainy N. Jose, MD	Department of Paediatrics, St. Johns Medical College, Bangalore, Karnataka, India	Major role in the acquisition of data	
Bernadette Kalman, MD, PhD, DSc	Office of the Dean, University of Pécs, School of Medicine; Molecular Medicine, Markusovszky University Teaching Hospital, Szombathely, Hungary	Major role in the acquisition of data	
Orhun H. Kantarci, MD	Department of Neurology, Mayo Clinic, Rochester, MN	Major role in the acquisition of data	
Dmytro Maltsev, MD	Immunology and Molecular Biology Laboratory of Experimental and Clinical Medicine Institute at the O'Bogomolets National Medical University, Kyiv, Ukraine	Major role in the acquisition of data	
Catherine Middleton, MD	General Practice, Brisbane, Queensland, Australia	Major role in the acquisition of data	
Gabriela Novotni, MD	Department of Cognitive Neurology and Neurodegenerative Diseases, University Clinic of Neurology, Medical Faculty, University “Ss. Cyril and Methodius”, Institute for Alzheimer's Disease and Neuroscience-Skopje, North Macedonia	Major role in the acquisition of data	
Dijana Plaseska-Karanfilska, MD	Research Center for Genetic Engineering and Biotechnology “Georgi D. Efremov”, Macedonian Academy of Sciences and Arts, Skopje, North Macedonia	Major role in the acquisition of data	
Salmo Raskin, MD, PhD	Postgraduate Program in Child and Adolescent, Department of Pediatrics, Federal University of Paraná, Curitiba, Brazil	Major role in the acquisition of data	
Josiane Souza, PhD	School of Medicine, Pontificia Universidade Católica do Paraná (PUCPR); Department of Genetics, Hospital Infantil Pequeno Príncipe, Curitiba, Paraná, Brazil	Major role in the acquisition of data	
Helio A. Teive, MD	Universidade Federal do Paraná, Hospital de Clínicas, Departamento de Medicina Interna, Serviço de Neurologia, Setor de Distúrbios do Movimento, Curitiba, Brazil	Major role in the acquisition of data	
Zbigniew K. Wszolek, MD	Department of Neurology, Mayo Clinic, Jacksonville, FL	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design
==== Refs
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 37839910
2. Bogaert V. Le type tardif de la leucodystrophie progressive familiale. Rev Neurol. 1936;65 :21.
3. 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 30429277
4. 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 35185751
5. 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 37349768
6. Rademakers R, Baker M, Nicholson AM, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2011;44 (2 ):200-205. doi:10.1038/ng.1027 22197934
7. Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database (HGMD(®)): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139 (10 ):1197-1207. doi:10.1007/s00439-020-02199-3 32596782
8. Wszolek ZK. First Polish case of CSF1R-related leukoencephalopathy. Neurol Neurochir Pol. 2021;55 (3 ):239-240. doi:10.5603/PJNNS.a2021.0022 34096015
9. Dulski J, Heckman MG, Nowak JM, Wszolek ZK. Protective effect of glucocorticoids against symptomatic disease in CSF1R variant carriers. Mov Disord. 2023;38 (8 ):1545-1549. doi:10.1002/mds.29504 37309919
10. Chitu V, Biundo F, Oppong-Asare J, et al. Prophylactic effect of chronic immunosuppression in a mouse model of CSF-1 receptor-related leukoencephalopathy. Glia. 2023;71 (11 ):2664-2678. doi:10.1002/glia.24446 37519044
11. Dulski J, Stanley ER, Chitu V, Wszolek ZK. Potential use of glucocorticosteroids in CSF1R mutation carriers - current evidence and future directions. Neurol Neurochir Pol. 2023;57 (5 ):444-449. doi:10.5603/pjnns.97373 37889001
12. Eichler FS, Li J, Guo Y, et al. CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids. Brain. 2016;139 (Pt 6 ):1666-1672. doi:10.1093/brain/aww066 27190017
13. Ayrignac X, Carra-Dallière C, Codjia P, et al. Evaluation of CSF1R-related adult onset leukoencephalopathy with axonal spheroids and pigmented glia diagnostic criteria. Eur J Neurol. 2022;29 (1 ):329-334. doi:10.1111/ene.15115 34541732
14. Ishiguro T, Konno T, Hara N, et al. Novel partial deletions, frameshift and missense mutations of CSF1R in patents with CSF1R-related leukoencephalopathy. Eur J Neurol. 2023;30 (7 ):1861-1870. doi:10.1111/ene.15796 36943150
