Clinical characteristics.

The spectrum of CSF1R-related disorder ranges from early-onset disease (age <18 years) to late-onset disease (age ≥18 years). Early-onset disease is associated with hypotonia, delayed acquisition of developmental milestones, and non-neurologic manifestations (such as skeletal abnormalities); both early- and late-onset disease have similar neurodegenerative involvement. Most affected individuals eventually become bedridden with spasticity, rigidity, and loss of the ability to walk. They lose speech and voluntary movement and appear to be generally unaware of their surroundings. The last stage of disease progresses to a vegetative state with presence of primitive reflexes, such as visual and tactile grasp, mouth-opening reflex, and sucking reflex. Death most commonly results from pneumonia or other infections. About 500 individuals with CSF1R-related disorder have been reported to date.

Diagnosis/testing.

The diagnosis of CSF1R-related disorder is established in a proband with suggestive findings and a heterozygous CSF1R pathogenic variant or biallelic CSF1R pathogenic variants identified by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary care by specialists in neurology, psychotherapy, neuropsychological rehabilitation, physical therapy, occupational therapy, speech-language therapy, social services for family support, and genetic counseling.

Surveillance: Monitoring of existing manifestations, the individual's response to supportive care, and the emergence of new manifestations as specified by the multidisciplinary care providers.

Agents/circumstances to avoid: For individuals with gait problems and cognitive decline, sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously.

Genetic counseling.

Early-onset CSF1R-related disorder is typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner; rarely, early-onset CSF1R-related disorder may be caused by a heterozygous pathogenic variant. Late-onset CSF1R-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner; rarely, late-onset CSF1R-related disorder may be caused by biallelic CSF1R pathogenic variants. While biallelic pathogenic variants are usually associated with early-onset disease and heterozygous pathogenic variants are usually associated with late-onset disease, definitive prediction of phenotype based on CSF1R genotype is not possible at this time.

Autosomal recessive inheritance: The parents of an individual with CSF1R-related disorder caused by biallelic pathogenic variants are presumed to be heterozygous for a CSF1R pathogenic variant. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial CSF1R pathogenic variants. Sibs who inherit the same biallelic CSF1R pathogenic variants do not necessarily have the same clinical manifestations early in the disease course; however, in the end stage, all individuals with CSF1R-related disorder typically have devastating neurologic involvement. The heterozygous sibs of an individual with CSF1R-related disorder caused by biallelic pathogenic variants are typically asymptomatic.

Autosomal dominant inheritance: Many individuals with CSF1R-related disorder caused by a heterozygous pathogenic variant have an affected parent. Some individuals with CSF1R-related disorder caused by a heterozygous pathogenic variant represent a simplex case; such individuals may have the disorder as the result of a pathogenic variant that occurred de novo in the proband; a pathogenic variant inherited from a mosaic parent; or a pathogenic variant inherited from an asymptomatic heterozygous parent. Each child of an individual with a heterozygous CSF1R pathogenic variant has a 50% chance of inheriting the pathogenic variant. Family members who are heterozygous for the same CSF1R pathogenic variant do not necessarily have the same clinical manifestations early in the disease course; however, in the end stage, all individuals with CSF1R-related disorder typically have devastating neurologic involvement.

Once the CSF1R pathogenic variant(s) have been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for CSF1R-related disorder are possible.

Suggestive Findings

CSF1R-related disorder should be suspected in a proband with the following clinical and neuroimaging findings (that present in an age-dependent manner) and family history [Konno et al 2017, Dulski et al 2023c, Dulski et al 2024].

Establishing the Diagnosis

The diagnosis of CSF1R-related disorder is established in a proband with suggestive findings and a heterozygous CSF1R pathogenic (or likely pathogenic) variant or biallelic CSF1R pathogenic (or likely pathogenic) variants identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous or biallelic CSF1R variant(s) of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of CSF1R, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

The spectrum of CSF1R-related disorder ranges from early-onset disease (age <18 years) to late-onset disease (age ≥18 years). Early-onset disease is more often associated with non-neurologic manifestations (such as skeletal abnormalities), whereas both early- and late-onset disease have similar neurodegenerative involvement.

Information on about 500 affected individuals has been reported to date. The following description of the phenotypic features associated with CSF1R-related disorder is based on reports of about 150 individuals (most of whom have late-onset disease) [Konno et al 2017, Dulski et al 2023c, Dulski et al 2024]. See Table 2 for a summary of the frequency of select features by age of onset.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified to date.

Penetrance

Penetrance is estimated to be high but incomplete [Karle et al 2013, Sundal et al 2015, Konno et al 2017].

Nomenclature

Pathology-based terminology. Prior to the molecular characterization of CSF1R-related disorder, pathology-based terminology – pigmentary orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with spheroids (HDLS) – was used to describe what appeared to be distinct disorders [Dulski et al 2024]. These terms were later consolidated under a single pathology-based designation, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Gene-based terminology. The molecular characterization of CSF1R allowed gene-based terminology to be established, i.e., CSF1R-related leukoencephalopathy/leukodystrophy and CSF1R-related ALSP.

Unified terminology. In recognition of the shared molecular etiology and significant phenotype overlap between CSF1R-related leukoencephalopathy and brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS), Dulski et al [2024] proposed the designation CSF1R-related disorder – subdivided into early onset (age <18 years) and late onset (age ≥18 years) – as a unifying diagnostic term encompassing both entities.

Prevalence

Based on a few screening studies in cohorts with leukoencephalopathies/leukodystrophies, the total worldwide prevalence of CSF1R-related disorder to date is estimated to be 0.5-1.5:100,000 [Papapetropoulos et al 2022].

Early-Onset CSF1R-Related Disorder

Hereditary disorders that primarily affect the central nervous system and manifest with glial and/or myelin abnormalities may mimic early-onset CSF1R-related disorder (see Table 3) [Sarret 2020, Davies et al 2023, Jańczewska et al 2023].

Late-Onset CSF1R-Related Disorder

Primary progressive multiple sclerosis. Before the discovery of the molecular genetic cause of the disorder, CSF1R-related disorder was frequently misdiagnosed as multiple sclerosis, particularly primary progressive multiple sclerosis (PPMS). There is significant clinical overlap between PPMS (average age of onset: 32 years) and late-onset CSF1R-related disorder [Tutuncu et al 2013, Aharony et al 2017, Saitoh et al 2019]. White matter lesions are seen in both PPMS and CSF1R-related disorder; however, confluent white matter lesions in frontoparietal areas are more consistent with CSF1R-related disorder than with PPMS [Sundal et al 2015]. PPMS is also associated with callosomarginal lesions and later onset of cognitive decline than CSF1R-related disorder. Incontinence appears later in the disease course and correlates with the overall disability in PPMS [Aharony et al 2017]. In contrast to CSF1R-related disorder, oligoclonal bands are often present in PPMS and can be used as a discriminative marker [Saitoh et al 2019].

Genetic disorders. CSF1R-related disorder may also phenotypically mimic genetic motor neuron disease and other neurodegenerative disorders featuring spasticity, parkinsonism, ataxia, and cognitive decline [Baba et al 2006, Aharony et al 2017, Souza et al 2020]. These disorders can be distinguished by brain MRI findings characterized mainly by cerebral atrophy without the characteristic white matter lesions found in CSF1R-related disorder. However, molecular genetic testing or neuropathologic examination are needed to make the ultimate distinction.

• AARS1-related leukoencephalopathy or Swedish hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult-onset autosomal dominant progressive neurodegenerative disorder that clinically and pathologically mimics the late-onset form of CSF1R-related disorder [Sundal et al 2019]. However, affected individuals show a unique neuroimaging pattern, with a centrifugally expanding rim of decreased diffusion evidenced by MRI diffusion-weighted/tensor imaging through the white matter around anterior ventricular horns [Sundal et al 2014, Sundal et al 2019].
• AARS2-related leukoencephalopathy is an autosomal recessive progressive neurodegenerative disease with cognitive decline, neurobehavioral/psychiatric manifestations, cerebellar ataxia, and pyramidal and extrapyramidal features. In addition, most affected women develop premature ovarian insufficiency. The age of onset usually occurs between the second and fifth decades of life. Compared to CSF1R-related disorder, AARS2-related leukoencephalopathy has less corpus callosum involvement and usually no brain calcifications [Papapetropoulos et al 2022, Muthusamy et al 2023].
• A CSF1R-related disorder mimic with an autosomal dominant pattern of inheritance of unknown genetic cause was reported in a single family with typical clinical, radiologic, and neuropathologic features of late-onset CSF1R-related disorder, but without pathogenic variants in CSF1R, AARS1, AARS2, or other genes known to be associated with neurodegenerative disorders [Dulski et al 2023b].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CSF1R-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The limited data available to date suggest that hematopoietic stem cell transplantation (HSCT) could modify disease progression in symptomatic individuals with early neurologic findings of CSF1R-related disorder [Tipton et al 2021, Dulski et al 2022a, Dulski et al 2024] and could be more beneficial in individuals with motor involvement (i.e., gait problems) as the initial and predominant disease manifestation, in contrast to individuals initially experiencing non-motor manifestations (i.e., cognitive impairment) [Dulski et al 2022a]. However, before conclusions can be drawn about the role of HSCT in the treatment of individuals with CSF1R-related disorder, more data are needed.

Supportive treatment is recommended to improve quality of life, maximize function, and reduce complications. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

As many individuals with CSF1R-related disorder have gait problems and cognitive decline, sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In a retrospective cohort study, it was observed that glucocorticoids might protect against symptomatic disease onset in individuals at risk for late-onset CSF1R-related disorder (i.e., asymptomatic individuals with a heterozygous CSF1R pathogenic variant) [Dulski et al 2023a]. This effect was also observed in a mouse model of the disease [Chitu et al 2023]. For a detailed discussion on the optimal dose, route of administration, type of glucocorticoid, and timing of therapy, see Dulski et al [2023d]. Note that glucocorticoids are not beneficial in individuals with advanced disease [Dulski et al 2023d].

Currently, one interventional clinical trial is in progress, enrolling individuals age 18 years and older with the late-onset CSF1R-related disorder commonly known as adult-onset leukoencephalopathy w/axonal spheroids & pigmented glia (ALSP) (NCT05677659). It is a Phase II multicenter, open-label study investigating the safety and tolerability of VGL101 (Vigil Neuroscience, Inc), a humanized monoclonal antibody acting as an agonist for the triggering receptor expressed on myeloid cells 2 (TREM2) receptor. Since TREM2 and macrophage colony-stimulating factor 1 receptor (CSF1R; encoded by CSF1R) share common signaling pathways, it is hypothesized that activation of TREM2 may compensate for deficiency in CSF1R.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Early-onset CSF1R-related disorder is typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner. Rarely, early-onset CSF1R-related disorder may be caused by a heterozygous pathogenic variant [Breningstall & Asis 2020; Sriram et al 2022; Dulski et al 2024; J Dulski, unpublished data].

Late-onset CSF1R-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner. Rarely, late-onset CSF1R-related disorder may be caused by biallelic CSF1R pathogenic variants [Guo et al 2019; Dulski et al 2024; J Dulski, unpublished data].

Note: While biallelic pathogenic variants are typically associated with early-onset disease and heterozygous pathogenic variants are typically associated with late-onset disease, definitive prediction of phenotype based on CSF1R genotype is not possible at this time [Dulski et al 2024].

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an individual with CSF1R-related disorder caused by biallelic CSF1R pathogenic variants are presumed to be heterozygous for a CSF1R pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CSF1R pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of an individual with early-onset CSF1R-related disorder caused by biallelic pathogenic variants are typically asymptomatic; however, definitive prediction of phenotype based on CSF1R genotype is not possible at this time [Dulski et al 2024].

Sibs of a proband

• If both parents are known to be heterozygous for a CSF1R pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial CSF1R pathogenic variants.
• Sibs who inherit the same biallelic CSF1R pathogenic variants do not necessarily have the same clinical manifestations early in the disease course; however, in the end stage, all individuals with CSF1R-related disorder typically have devastating neurologic involvement.
• The heterozygous sibs of an individual with CSF1R-related disorder caused by biallelic pathogenic variants are typically asymptomatic; however, definitive prediction of phenotype based on CSF1R genotype is not possible at this time [Dulski et al 2024].

Offspring of a proband. The offspring of an individual with biallelic CSF1R pathogenic variants are obligate heterozygotes for a pathogenic variant in CSF1R.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a CSF1R pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives requires prior identification of the CSF1R pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Many individuals with CSF1R-related disorder caused by a heterozygous CSF1R pathogenic variant have an affected parent [Rademakers et al 2011, Kinoshita et al 2012, Stabile et al 2016, Dulski et al 2024].
• Some individuals with CSF1R-related disorder caused by a heterozygous CSF1R pathogenic variant represent a simplex case (i.e., the only family member known to be affected). Such individuals may have the disorder as the result of:
  • A pathogenic variant that occurred de novo in the proband;
  • A pathogenic variant inherited from a mosaic parent; or
  • A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of CSF1R-related disorder is estimated to be high but incomplete [Karle et al 2013, Sundal et al 2015, Konno et al 2017].)
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and provide insight into familial genotype-phenotype correlations.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset CSF1R-related disorder [Eichler et al 2016]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The family history of some individuals diagnosed with CSF1R-related disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or incomplete penetrance [Dulski et al 2024]. Therefore, a negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to be heterozygous for the CSF1R pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • Sibs who are heterozygous for the same CSF1R pathogenic variant do not necessarily have the same clinical manifestations early in the disease course; however, in the end stage, all individuals with CSF1R-related disorder typically have devastating neurologic involvement.
  • On average, women develop the first manifestations of late-onset CSF1R-related disorder earlier (age 40 years) than men (age 47 years).
• If the CSF1R pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Eichler et al 2016].
• If the parents have not been tested for the CSF1R pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for CSF1R-related disorder because of possible incomplete penetrance in a parent and the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a heterozygous CSF1R pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CSF1R pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the causative CSF1R pathogenic variant(s) have been identified in an affected family member. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• Predictive testing of minors for adult-onset disorders for which no treatment exists is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of CSF1R-related disorder, it is appropriate to consider testing symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the CSF1R pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for CSF1R-related disorder are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Pathogenesis

CSF1R encodes macrophage colony-stimulating factor 1 receptor (CSF1R), a cell surface receptor primarily for cytokine colony-stimulating factor 1 (CSF-1) that regulates the survival, proliferation, differentiation, and function of mononuclear phagocytic cells, including microglia of the central nervous system . CSF1R comprises a highly glycosylated extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Binding of CSF-1 to its receptor, CSF1R, results in the formation of receptor homodimers and subsequent autophosphorylation of several important proteins, including the phosphatase SHP-1 and the kinases Src, PLC-γ, PI(3)K, Akt, and Erk [Rademakers et al 2011]. In the brain, CSF1R is predominately expressed in microglial cells [Papapetropoulos et al 2022].

To date, most reported CSF1R pathogenic variants that cause CSF1R-related disorder affect kinase activity and potentially phosphorylation of downstream targets. However, the mechanisms of neuronal/glial dysfunction underlying CSF1R-related disorder remain to be fully elucidated [Papapetropoulos et al 2022].

Mechanism of disease causation. The mechanisms of disease causation are not fully understood and likely differ depending on the CSF1R pathogenic variant(s) and possible interplay with other genetic and non-genetic factors [Dulski et al 2024].

CSF1R-specific laboratory technical considerations. While most pathogenic variants underlying CSF1R-related disorder are within coding or canonical splice site regions, several splicing variants beyond the canonical splice site have been identified that may be detected by genome sequencing [Rademakers et al 2011, Konno et al 2017, Wu et al 2022].

Author Notes

Dr Wszolek (ude.oyam@weingibz.kelozsw) and Dr Dulski (ude.oyam@walsoraj.ikslud; lp.ude.demug@ikslud.walsoraj) are actively involved in clinical research regarding individuals with CSF1R-related disorder. They would be happy to communicate with patients and their families, patient organizations, and clinicians treating patients with the disorder.

Contact Drs Wszolek and Dulski to inquire about review of CSF1R variants of uncertain significance.

Acknowledgments

We thank the patients, their families, and the Sisters' Hope and My Complex Genes Foundations for their never-ending support, encouragement, and inspiration.

Jaroslaw 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).

Zbigniew 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, the Albertson Parkinson's Research Foundation, and the 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.

Revision History

• 4 April 2024 (bp) Comprehensive update posted live
• 5 October 2017 (sw) Comprehensive update posted live
• 18 December 2014 (me) Comprehensive update posted live
• 30 August 2012 (me) Review posted live
• 23 May 2012 (zkw) Original submission

Literature Cited

• Aharony SM, Lam O, Corcos J. Evaluation of lower urinary tract symptoms in multiple sclerosis patients: review of the literature and current guidelines. Can Urol Assoc J. 2017;11:61-4. [PMC free article: PMC5403674] [PubMed: 28443147]
• Ahmed A, Simmons Z. Pseudobulbar affect: prevalence and management. Ther Clin Risk Manag. 2013;9:483-9. [PMC free article: PMC3849173] [PubMed: 24348042]
• Baba Y, Ghetti B, Baker MC, Uitti RJ, Hutton ML, Yamaguchi K, Bird T, Lin W, DeLucia MW, Dickson DW, Wszolek ZK. Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. Acta Neuropathol. 2006;111:300-11. [PubMed: 16523341]
• Bender B, Klose U, Lindig T, Biskup S, Nägele T, Schöls L, Karle KN. Imaging features in conventional MRI, spectroscopy and diffusion weighted images of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). J Neurol. 2014;261:2351-9. [PubMed: 25239393]
• Breningstall GN, Asis M. Bone disease associated with hereditary diffuse leukoencephalopathy with spheroids. Pediatr Neurol. 2020;112:44-6. [PubMed: 32911262]
• Chitu V, Biundo F, Oppong-Asare J, Gökhan Ş, Aguilan JT, Dulski J, Wszolek ZK, Sidoli S, Stanley ER. Prophylactic effect of chronic immunosuppression in a mouse model of CSF-1 receptor-related leukoencephalopathy. Glia. 2023;71:2664-78. [PMC free article: PMC10529087] [PubMed: 37519044]
• Daida K, Nishioka K, Li Y, Nakajima S, Tanaka R, Hattori N. CSF1R mutation p.G589R and the distribution pattern of brain calcification. Intern Med. 2017;56:2507-12. [PMC free article: PMC5643183] [PubMed: 28824062]
• Davies A, Tolliday A, Craven I, Connolly DJA. An approach to reporting paediatric leukoencephalopathy and leukodystrophies. Clin Radiol. 2023;78:401-11. [PubMed: 36990927]
• Dulski J, Heckman MG, Nowak JM, Wszolek ZK. Protective effect of glucocorticoids against symptomatic disease in CSF1R variant carriers. Mov Disord. 2023a;38:1545-9. [PubMed: 37309919]
• Dulski J, Heckman MG, White LJ, Żur-Wyrozumska K, Lund TC, Wszolek ZK. Hematopoietic stem cell transplantation in CSF1R-related leukoencephalopathy: retrospective study on predictors of outcomes. Pharmaceutics. 2022a;14:2778. [PMC free article: PMC9788080] [PubMed: 36559271]
• Dulski J, Koga S, Dickson DW, Wszolek ZK. Report of a family with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) without mutations in CSF1R, AARS1 or AARS2. Mov Disord Clin Pract. 2023b;10:307-12. [PMC free article: PMC9941916] [PubMed: 36825047]
• Dulski J, Middlebrooks EH, Wszolek ZK. Novel application of 7T MRI in CSF1R-related leukoencephalopathy. Neurology. 2022b;99:1110-1111. [PubMed: 36180242]
• Dulski J, Muthusamy K, Lund T, Wszolek Z. CSF1R-related disorder: state of the art, challenges, and proposition of a new terminology. Parkinsonism Relat Disord. 2024;121:105894. [PubMed: 37839910]
• 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. 2023c;18:160. [PMC free article: PMC10288773] [PubMed: 37349768]
• Dulski J, Stanley ER, Chitu V, Wszolek ZK. Potential use of glucocorticosteroids in CSF1R mutation carriers - current evidence and future directions. Neurol Neurochir Pol. 2023d;57:444-9. [PubMed: 37889001]
• Eichler FS, Li J, Guo Y, Caruso PA, Bjonnes AC, Pan J, Booker JK, Lane JM, Tare A, Vlasac I, Hakonarson H, Gusella JF, Zhang J, Keating BJ, Saxena R. CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids. Brain. 2016;139:1666-72. [PMC free article: PMC4892751] [PubMed: 27190017]
• Guo L, Bertola DR, Takanohashi A, Saito A, Segawa Y, Yokota T, Ishibashi S, Nishida Y, Yamamoto GL, Franco J, Honjo RS, Kim CA, Musso CM, Timmons M, Pizzino A, Taft RJ, Lajoie B, Knight MA, Fischbeck KH, Singleton AB, Ferreira CR, Wang Z, Yan L, Garbern JY, Simsek-Kiper PO, Ohashi H, Robey PG, Boyde A, Matsumoto N, Miyake N, Spranger J, Schiffmann R, Vanderver A, Nishimura G, Passos-Bueno M, Simons C, Ishikawa K, Ikegawa S. Bi-allelic CSF1R mutations cause skeletal dysplasia of dysosteosclerosis-pyle disease spectrum and degenerative encephalopathy with brain malformation. Am J Hum Genet. 2019;104:925-35. [PMC free article: PMC6507048] [PubMed: 30982609]
• Ishiguro T, Konno T, Hara N, Zhu B, Okada S, Shibata M, Saika R, Kitano T, Toko M, Nezu T, Hama Y, Kawazoe T, Takahashi-Iwata I, Yabe I, Sato K, Takeda H, Toda S, Nishimiya J, Teduka T, Nozaki H, Kasuga K, Miyashita A, Onodera O, Ikeuchi T. Novel partial deletions, frameshift and missense mutations of CSF1R in patents with CSF1R-related leukoencephalopathy. Eur J Neurol. 2023;30:1861-70. [PubMed: 36943150]
• Jańczewska I, Preis-Orlikowska J, Domżalska-Popadiuk I, Preis K, Jańczewska A. Children with corpus callosum anomalies: clinical characteristics and developmental outcomes. Neurol Neurochir Pol. 2023;57:269-81. [PubMed: 37078131]
• Jiang J, Li W, Wang X, Du Z, Chen J, Liu Y, Li W, Lu Z, Wang Y, Xu J. Two novel intronic mutations in the CSF1R gene in two families with CSF1R-microglial encephalopathy. Front Cell Dev Biol. 2022;10:902067. [PMC free article: PMC9198639] [PubMed: 35721475]
• Kaler J, Hussain A, Patel S, Majhi S. Neuromuscular junction disorders and floppy infant syndrome: a comprehensive review. Cureus. 2020;12:e6922. [PMC free article: PMC7008760] [PubMed: 32071826]
• Karle KN, Biskup S, Schüle R, Schweitzer KJ, Krüger R, Bauer P, Bender B, Nägele T, Schöls L. De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). Neurology 2013;81:2039-44. [PubMed: 24198292]
• Kındış E, Simsek-Kiper P, Koşukcu C, Taşkıran EZ, Göçmen R, Utine E, Haliloğlu G, Boduroğlu K, Alikaşifoğlu M. Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: a rare disorder with neurologic regression and skeletal features. Am J Med Genet Part A. 2021;185:1888–96. [PubMed: 33749994]
• Kinoshita M, Yoshida K, Oyanagi K, Hashimoto T, Ikeda S. Hereditary diffuse leukoencephalopathy with axonal spheroids caused by R782H mutation in CSF1R: case report. J Neurol Sci. 2012;318:115–8. [PubMed: 22503135]
• Konno T, Tada M, Tada M, Koyama A, Nozaki H, Harigaya Y, Nishimiya J, Matsunaga A, Yoshikura N, Ishihara K, Arakawa M, Isami A, Okazaki K, Yokoo H, Itoh K, Yoneda M, Kawamura M, Inuzuka T, Takahashi H, Nishizawa M, Onodera O, Kakita A, Ikeuchi T. Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS. Neurology. 2014;82:139-48. [PMC free article: PMC3937843] [PubMed: 24336230]
• Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda SI, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T. 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. [PMC free article: PMC5215554] [PubMed: 27680516]
• Konno T, Yoshida K, Mizuta I, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda SI, Onodera O, Wszolek ZK, Ikeuchi T. Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. Eur J Neurol. 2018;25:142-7. [PMC free article: PMC5741468] [PubMed: 28921817]
• Lee D, Yun JY, Jeong JH, Yoshida K, Nagasaki S, Ahn TB. Clinical evolution, neuroimaging, and volumetric analysis of a patient with a CSF1R mutation who presented with progressive nonfluent aphasia. Parkinsonism Relat Disord. 2015;21:817-20. [PubMed: 25934184]
• McCormick EM, Zolkipli-Cunningham Z, Falk MJ. Mitochondrial disease genetics update: recent insights into the molecular diagnosis and expanding phenotype of primary mitochondrial disease. Curr Opin Pediatr. 2018;30:714-24. [PMC free article: PMC6467265] [PubMed: 30199403]
• Mickeviciute GC, Valiuskyte M, Plattén M, Wszolek ZK, Andersen O, Danylaité Karrenbauer V, Ineichen BV, Granberg T. Neuroimaging phenotypes of CSF1R-related leukoencephalopathy: Systematic review, meta-analysis, and imaging recommendations. J Intern Med. 2022;291:269-82. [PubMed: 34875121]
• Monies D, Maddirevula S, Kurdi W, Alanazy MH, Alkhalidi H, Al-Owain M, Sulaiman RA, Faqeih E, Goljan E, Ibrahim N, Abdulwahab F, Hashem M, Abouelhoda M, Shaheen R, Arold ST, Alkuraya FS. Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation. Genet Med. 2017;19:1144–50. [PubMed: 28383543]
• Muthusamy K, Sivadasan A, Dixon L, Sudhakar S, Thomas M, Danda S, Wszolek ZK, Wierenga K, Dhamija R, Gavrilova R. Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions. Front Neurol. 2023;14:1219324. [PMC free article: PMC10410460] [PubMed: 37564735]
• Oosterhof N, Chang IJ, Karimiani EG, Kuil LE, Jensen DM, Daza R, Young E, Astle L, van der Linde HC, Shivaram GM, Demmers J, Latimer CS, Keene CD, Loter E, Maroofian R, van Ham TJ, Hevner RF, Bennett JT. Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia. Am J Hum Genet. 2019;104:936-47. [PMC free article: PMC6506793] [PubMed: 30982608]
• Papapetropoulos S, Pontius A, Finger E, Karrenbauer V, Lynch DS, Brennan M, Zappia S, Koehler W, Schoels L, Hayer SN, Konno T, Ikeuchi T, Lund T, Orthmann-Murphy J, Eichler F, Wszolek ZK. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: review of clinical manifestations as foundations for therapeutic development. Front Neurol. 2022;12:788168. [PMC free article: PMC8850408] [PubMed: 35185751]
• Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2011;44:200-5. [PMC free article: PMC3267847] [PubMed: 22197934]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Robinson JL, Suh E, Wood EM, Lee EB, Coslett HB, Raible K, Lee VMY, Trojanowski JQ, Van Deerlin VM. Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His. Acta Neuropathologica Communications. 2015;3:42. [PMC free article: PMC4491242] [PubMed: 26141825]
• Rosenstein I, Andersen O, Victor D, Englund E, Granberg T, Hedberg-Oldfors C, Jood K, Fitrah YA, Ikeuchi T, Danylaité Karrenbauer V. Four Swedish cases of CSF1R-related leukoencephalopathy: visualization of clinical phenotypes. Acta Neurol Scand. 2022;145:599-609. [PMC free article: PMC9304267] [PubMed: 35119108]
• Rush BK, Tipton PW, Strongosky A, Wszolek ZK. Neuropsychological profile of CSF1R-related leukoencephalopathy. Front Neurol. 2023;14:1155387. [PMC free article: PMC10272847] [PubMed: 37333006]
• Saitoh BY, Yamasaki R, Hiwatashi A, Matsushita T, Hayashi S, Mitsunaga Y, Maeda Y, Isobe N, Yoshida K, Ikeda SI, Kira JI. Discriminative clinical and neuroimaging features of motor-predominant hereditary diffuse leukoencephalopathy with axonal spheroids and primary progressive multiple sclerosis: a preliminary cross-sectional study. Mult Scler Relat Disord. 2019;31:22-31. [PubMed: 30901701]
• Sarret C. Leukodystrophies and genetic leukoencephalopathies in children. Revue Neurologique. 2020;176:10-9. [PubMed: 31174885]
• Shu Y, Long L, Liao S, Yang J, Li J, Qiu W, Yang Y, Bao J, Wu A, Hu X, Lu Z. Involvement of the optic nerve in mutated CSF1R-induced hereditary diffuse leukoencephalopathy with axonal spheroids. BMC Neurology. 2016;16:171. [PMC free article: PMC5020510] [PubMed: 27619214]
• Souza PVS, Badia BML, Silva LHL, Farias IB, Pinto W, Oliveira ASB. Motor neuron disease with leukodystrophy due to CSF1R mutation. Rev Neurol (Paris). 2020;176:219-21. [PubMed: 31522743]
• Sriram N, Padmanabha H, Chandra SR, Mahale R, Nandeesh B, Bhat MD, Christopher R, Gupta M, Udupi GA, Mailankody P, Mathuranath PS. CSF1R related leukoencephalopathy - rare childhood presentation of an autosomal dominant microgliopathy! Ann Indian Acad Neurol. 2022;25:311-4. [PMC free article: PMC9175392] [PubMed: 35693676]
• Stabile C, Taglia I, Battisti C, Bianchi S, Federico A. Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): update on molecular genetics. Neurol Sci. 2016;37:1565-9. [PubMed: 27338940]
• Sundal C, Baker M, Karrenbauer V, Gustavsen M, Bedri S, Glaser A, Myhr KM, Haugarvoll K, Zetterberg H, Harbo H, Kockum I, Hillert J, Wszolek Z, Rademakers R, Andersen O. Hereditary diffuse leukoencephalopathy with spheroids with phenotype of primary progressive multiple sclerosis. Eur J Neurol. 2015;22:328-33. [PMC free article: PMC4289423] [PubMed: 25311247]
• Sundal C, Carmona S, Yhr M, Almström O, Ljungberg M, Hardy J, Hedberg-Oldfors C, Fred Å, Brás J, Oldfors A, Andersen O, Guerreiro R. An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids. Acta Neuropathol Commun. 2019;7:188. [PMC free article: PMC6880494] [PubMed: 31775912]
• Sundal C, Fujioka S, Van Gerpen JA, Wider C, Nicholson AM, Baker M, Shuster EA, Aasly J, Spina S, Ghetti B, Roeber S, Garbern J, Tselis A, Swerdlow RH, Miller BB, Borjesson-Hanson A, Uitti RJ, Ross OA, Stoessl AJ, Rademakers R, Josephs KA, Dickson DW, Broderick D, Wszolek ZK. Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations. Parkinsonism Relat Disord. 2013;19:869-77. [PMC free article: PMC3977389] [PubMed: 23787135]
• Sundal C, Jönsson L, Ljungberg M, Zhong J, Tian W, Zhu T, Linden T, Börjesson-Hanson A, Andersen O, Ekholm S. Different stages of white matter changes in the original HDLS family revealed by advanced MRI techniques. J Neuroimaging. 2014;24:444-52. [PubMed: 23751174]
• Sundal C, Van Gerpen JA, Nicholson AM, Wider C, Shuster EA, Aasly J, Spina S, Ghetti B, Roeber S, Garbern J, Borjesson-Hanson A, Tselis A, Swerdlow RH, Miller BB, Fujioka S, Heckman MG, Uitti RJ, Josephs KA, Baker M, Andersen O, Rademakers R, Dickson DW, Broderick D, Wszolek ZK. MRI characteristics and scoring in HDLS due to CSF1R gene mutations. Neurology. 2012;79:566–74. [PMC free article: PMC3413763] [PubMed: 22843259]
• Tamhankar PM, Zhu B, Tamhankar VP, Mithbawkar S, Seabra L, Livingston JH, Ikeuchi T, Crow YJ. A novel hypomorphic CSF1R gene mutation in the biallelic state leading to fatal childhood neurodegeneration. Neuropediatrics. 2020;51:302–6. [PubMed: 32464672]
• Tipton PW, Kenney-Jung D, Rush BK, Middlebrooks EH, Nascene D, Singh B, Holtan S, Ayala E, Broderick DF, Lund T, Wszolek ZK. Treatment of CSF1R-related leukoencephalopathy: breaking new ground. Mov Disord. 2021;36:2901-9. [PubMed: 34329526]
• Tutuncu M, Tang J, Zeid NA, Kale N, Crusan DJ, Atkinson EJ, Siva A, Pittock SJ, Pirko I, Keegan BM, Lucchinetti CF, Noseworthy JH, Rodriguez M, Weinshenker BG, Kantarci OH. Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler. 2013;19:188-98. [PMC free article: PMC4029334] [PubMed: 22736750]
• van der Knaap MS, Naidu S, Kleinschmidt-Demasters BK, Kamphorst W, Weinstein HC. Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids. Neurology. 2000;54:463-8. [PubMed: 10668715]
• Van Gerpen JA, Wider C, Broderick DF, Dickson DW, Brown LA, Wszolek ZK. Insights into the dynamics of hereditary diffuse leukoencephalopathy with axonal spheroids. Neurology. 2008;71:925–9. [PMC free article: PMC2843529] [PubMed: 18794495]
• Wu J, Cheng X, Ji D, Niu H, Yao S, Lv X, Wang J, Li Z, Zheng H, Cao Y, Zhan F, Zhang M, Tian W, Huang X, Luan X, Cao L. The phenotypic and genotypic spectrum of CSF1R-related disorder in China. Mov Disord. 2024. Epub ahead of print. [PubMed: 38465843]
• Wu X, Sun C, Wang X, Liu Y, Wu W, Jia G. Identification of a de novo splicing mutation in the CSF1R gene in a Chinese patient with hereditary diffuse leukoencephalopathy with spheroids. Neurol Sci. 2022;43:3265-72. [PMC free article: PMC9018673] [PubMed: 34791569]