NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

CSF1R-Related Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia

Synonym: CSF1R-Related ALSP

, MD, PhD and , MD.

Author Information

Initial Posting: ; Last Update: October 5, 2017.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is characterized by executive dysfunction, memory decline, personality changes, motor impairments, and seizures. A frontal lobe syndrome (e.g., loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course. The mean age of onset is usually in the fourth decade. Affected individuals eventually become bedridden with spasticity and rigidity. The disease course ranges from two to 30 or more years (mean: 8 years).

Diagnosis/testing.

The diagnosis is suspected in individuals with characteristic clinical and brain MRI findings and is confirmed by identification of a heterozygous pathogenic variant in CSF1R.

Management.

Treatment of manifestations: Supportive management includes: attention to general care and nutritional requirements; antiepileptic drugs for seizures; and antibiotic treatment for general and recurrent infections.

Prevention of secondary complications: Information about and support systems for the social problems and suicidal tendencies often associated with disease progression.

Surveillance: Periodic brain MRI and clinical evaluation to monitor disease progression.

Agents/circumstances to avoid: Use of first-generation neuroleptics due to increased seizure risk and risk of additional parkinsonian signs; medications used to treat multiple sclerosis as they are of no benefit and have major side effects.

Genetic counseling.

CSF1R-related ALSP is inherited in an autosomal dominant manner. Individuals with CSF1R-related ALSP usually have an affected parent; de novo mutation can occur. Each child of an individual with CSF1R-related ALSP has a 50% chance of inheriting the pathogenic variant. Prenatal testing is possible if the pathogenic variant in a family is known.

Diagnosis

Suggestive Findings

CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) should be suspected in individuals with the following clinical and brain findings.

Clinical

  • Progressive neurologic decline; presenting signs may include the following:
    • Personality changes, cognitive impairments, memory decline, and depression
    • Motor impairments including paresis, gait dysfunction, bradykinesia, rigidity, and tremor
    • On rare occasions, seizures
    Later signs usually include dementia, seizures, and pyramidal and extrapyramidal signs.
  • Family history consistent with autosomal dominant inheritance

Brain

    • The white matter lesions are hyperintense on T2-weighted and FLAIR images, and hypointense on T1-weighted images.
    • Bifrontal or bifrontoparietal T2-weighted/FLAIR hyperintensities in the deep, subcortical, and periventricular areas are typical. The white matter lesions are often asymmetric, especially in the early stages of the disease. Early lesions are patchy and focal, but with time become confluent. T2-weighted and FLAIR hyperintensities are present in other areas, including the corpus callosum and corticospinal tracts.
    • Cerebral atrophy manifesting as enlarged ventricles is typical, as is cerebral atrophy corresponding to the white matter lesions.
    • The following are absent:
      • Significant gray matter pathology
      • Brain stem atrophy
      • Contrast uptake in the parenchyma
    • Cerebellar abnormalities are minimal.
  • On CT. Brain calcifications in the white matter are seen in up to half of individuals. Frequently they have a characteristic pattern of “stepping stone appearance” in the frontal pericallosal area, and punctate appearance in the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter [Konno et al 2017].

Establishing the Diagnosis

The diagnosis of CSF1R-related ALSP is established in a proband by identification of a heterozygous pathogenic variant in CSF1R by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of CSF1R is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes CSF1R and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in CSF1R-Related ALSP

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
CSF1RSequence analysis 3~100% 4
Gene targeted deletion/duplication analysis 5None detected
1.
2.

See Molecular Genetics for information on allelic variants.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

To date more than 50 pathogenic variants have been reported, including deletions and missense, frameshift, nonsense, and splice site variants. Almost all pathogenic variants are located in the intracellular tyrosine kinase domain of exons 12-22 of CSF1R (see Molecular Genetics).

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is characterized by a constellation of findings including executive dysfunction, memory decline, personality changes, motor impairments, and seizures. A frontal lobe syndrome (including loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course.

The presenting problems and rate of progression vary among individuals and even within a family harboring the same pathogenic variant. The mean age of onset is usually in the fourth decade, but ranges from early adulthood to the eighth decade of life [Sundal et al 2012b]. The disease course may be from two to 30 years or more with a mean of eight years.

Signs and symptoms that usually occur during the disease course include the following:

  • Personality problems, memory decline, executive dysfunction
  • Disturbances of higher cortical function such as motor aphasia, agraphia, acalculia, and apraxia
  • Depression
  • Gait disturbance
  • Pyramidal signs such as spasticity, hyperreflexia, extensor plantar response, hemiparesis, or quadriparesis
  • Sensory deficits including some impairment of vibration, position, tactile, and pain perception. The higher integrative sensory functions such as graphesthesia, stereognosis, and double simultaneous stimulation are also impaired.
  • Parkinsonian signs such as rigidity, bradykinesia, tremor (resting and/or kinetic), shuffling gait, and postural instability. Hypomimic face and hypophonic voice are common. Lack of beneficial response to levodopa defines the parkinsonian signs as atypical.
  • Bulbar/pseudobulbar signs: dysphagia, dysarthria, slurred speech, and palatal myoclonus
  • Cerebellar signs with ataxia, dysmetria, and intention tremor
  • Visual field defects such as homonymous quadrantanopsia or hemianopsia
  • Other signs of a movement disorder: dystonia, myoclonic twitches, dyskinesia, and akathisia
  • Seizures in some individuals (at times only a single episode at the onset of the illness)
  • Progressive course

Affected individuals eventually become bedridden with spasticity and rigidity. They lose speech and voluntary movements, and appear to be generally unaware of their surroundings. In the last stage of the disease, individuals lose their ability to walk and progress to a vegetative state. Primitive reflexes, such as visual and tactile grasp and mouth-opening reflex, as well as the sucking reflex, are present.

Death most commonly results from pneumonia or other infections.

Other findings. Cerebrospinal fluid (CSF):

  • Normal cell count, glucose concentration, and proteins
  • No inflammatory cells
  • Usually normal isoelectric focusing and no oligoclonal bands; however, oligoclonal bands have been demonstrated in samples from affected individuals with the pathogenic variant p.Asn854Lys or p.Val 838Leu [Karle et al 2013, Levin et al 2014, Schuberth et al 2014, Sundal et al 2015].
  • No identified CSF biomarker. The following preliminary findings in four persons with ALSP need to be interpreted cautiously and require further research [Sundal et al 2012a, Sundal et al 2015]:
    • Normal Aβ42 protein concentrations
    • Minimally increased levels of total Tau protein concentrations
    • Borderline normal phospho-Tau protein concentrations
    • Elevated neurofilament light chain (NF-L) proteins (Note that NF-L proteins are markers of neuronal death and axonal damage.)
    • Slight increase in glial fibrillary acidic protein, indicating gliosis or astroglial cell damage

Brain pathology. The following features may be seen on brain biopsy or at autopsy:

  • White matter changes that are typically vacuolated and demyelinated
  • Axonal spheroids in the white matter lesions that are immunoreactive for neurofilament, amyloid precursor protein, and ubiquitin
  • Bizarre astrocytes and lipid-laden and myelin-laden macrophages
  • Unaffected or very mildly affected basal ganglia, thalamus, hypothalamus, hippocampus, substantia nigra, raphe nucleus, reticular formation, and cerebellar gray matter
  • Absence or only traces of amyloid angiopathy in parenchymal or leptomeningeal vessels
  • Pigmented changes of either iron or lipofuscin found in macrophages and other glia cells

Genotype-Phenotype Correlations

No genotype-phenotype correlation exists: individuals from the same family harboring the same CSF1R pathogenic variant do not necessarily share the same phenotype. In the end stage all have devastating multiple neurologic impairments.

Penetrance

Penetrance appears to be incomplete [Karle et al 2013, Sundal et al 2015, Konno et al 2017]; estimates have not been calculated given the limited number of families reported to date. Although CSF1R-related ALSP is a dominantly inherited disease, de novo mutation occurs and variable expressivity in terms of the phenotype and the disease course can be found in members of the same family sharing the same pathogenic variant.

Nomenclature

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is within the same disease spectrum as familial pigmentary orthochromatic leukodystrophy (POLD) [Wider et al 2009]. Because of the phenotypic and radiologic similarities of the two disorders, Wider et al [2009] proposed the following terminology for the combined entity: "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)." Families with POLD have recently been found to have CSF1R pathogenic variants [Nicholson et al 2013], providing evidence that HDLS and POLD are a single disease entity. Because a similar phenotype has been reported in individuals with biallelic AARS2 pathogenic variants, the authors propose new nomenclature: CSF1R-related ALSP.

Prevalence

CSF1R-related ALSP was previously thought to be a rare disease. However, recent expanded publications in this field have demonstrated that it is more common than previously recognized: it is now estimated to be responsible for 10%-25% of adult-onset leukodystrophy. However, actual prevalence figures have not been reported [Lynch et al 2016].

Differential Diagnosis

The clinical presentation of CSF1R-related ALSP often overlaps with other neurologic disorders. CSF1R-related ALSP should be considered in previously healthy individuals who develop cognitive decline, memory problems, and personality changes in midlife with a progressive course and white matter lesions evident on brain MRI.

Because the signs and symptoms in the early stages of CSF1R-related ALSP are nonspecific, ALSP can often be confused with the inherited and sporadic disorders listed below. In individuals with CSF1R-related ALSP, laboratory and/or genetic testing for these other disorders are normal.

Table 2.

Disorders to Consider in the Differential Diagnosis of CSF1R-Related Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)

DisorderGene(s)Clinical Features of This Disorder
Overlapping w/CSF1R-Related ALSPDistinguishing from CSF1R-Related ALSP
Autosomal dominant disorders
Alexander diseaseGFAPBulbar/pseudobulbar signs, ataxia, spasticityPalatal myoclonus; cognitive function in adults frequently normal; infratentorial atrophy on MRI
Adult-onset autosomal dominant leukodystrophy (OMIM 169500)LMNB1Cognitive impairment, pyramidal & cerebellar signsEarly autonomic dysfunction; a periventricular normal rim on MRI
CADASILNOTCH3Frontal lobe syndrome, WMLStroke-like clinical signs; multiple cerebral infarcts & WML incl the characteristic temporal pools
MAPT-related disorders (OMIM 157140)MAPTProgresses over a few years into profound dementia w/mutismFrontal &/or temporal atrophy w/far fewer WML
Frontotemporal dementia, chromosome 3-linkedCHMP2BFrontal lobe affected; pyramidal &/or extrapyramidal signsFrontal &/or temporal atrophy w/far fewer WML
GRN-related frontotemporal dementiaGRNFrontal lobe affected; pyramidal/extrapyramidal signsFrontal &/or temporal atrophy w/far fewer WML
C9orf72-related FTDC9orf72Frontal lobe affected; pyramidal/extrapyramidal signsFrontal &/or temporal atrophy w/far fewer WML
Early-onset Alzheimer diseaseAPP, PSEN1, PSEN2Executive dysfunction & personality changes; similar onset ageEpisodic memory loss; WM changes present but much less pronounced
Autosomal recessive disorders
PLOSL (Nasu-Hakola disease)TREM2, TYROBPInsidious personality changes, frontal lobe syndrome, motor impairments, dementia & progression to vegetative stagePain/tenderness of feet/wrists, polycystic osseous lesions, pathologic fractures; U-fibers partially affected
Vanishing white matterEIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5Cognitive decline, spastic paraparesis, cerebellar ataxiaStress-induced deterioration w/minor trauma or infections; more widespread & diffuse WM changes & atrophy than in ALSP; cystic breakdown of the WM
Adult type of metachromatic leukodystrophyARSAExecutive dysfunction, personality changes, memory problems, pyramidal signs and seizuresPeripheral neuropathy; spread of WML into the cerebellar region & WM myelin breakdown w/low-density tigroid stripes
Adult form of Krabbe diseaseGALCPyramidal signs, developing into para- or tetraparesisPeripheral neuropathy; MRI w/predominance in the posterior part of the WM. MRI detects demyelination in the brain stem & cerebellum. T2-weighted value is progressively prolonged in the occipital deep WM and posterior part of central semiovale in late-onset disease.
LBSLDARS2Slowly progressive pyramidal, cerebellar, & dorsal column dysfunction; deterioration of motor skillsPeripheral neuropathy; WML are either non-homogeneous/spotty or homogeneous & confluent. Signal abnormalities are evident in the medullary pyramids, dorsal columns, & lateral corticospinal tracts.
AARS2-related ALSPAARS2Cognitive, neuropsychiatric, & upper motor neuron signs; symmetric leukoencephalopathy w/punctate regions of restricted diffusionEarlier age of onset of symptoms (mean age 26 yrs); ovarian failure in all women. WM demonstrates rarefaction [Lakshmanan et al 2017].
X-linked disorders
X-linked adrenoleukodystrophyABCD1Cognitive decline, dementia, spastic paraparesisNeuropathy & slowly spastic paraparesis. WML are contrast enhancing. Corticospinal tracts are involved from cranial to medulla.
Fabry diseaseGLAWMLGray matter pathology
Mitochondrial disorders (caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA)
Leigh syndromemtDNA deletionPsychomotor regression; WML may be present in adult mt diseasesStrikingly different clinical presentation; brain MRI in mt diseases may demonstrate symmetric T1-weighted hypointense & T2-weighted hyperintense signal abnormalities in deep gray matter; abnormalities are not restricted to vascular territories; lesions often fluctuate over the course of the disease. Varying degrees of cerebral & cerebellar atrophy may also be present.
MELASMT-TL1 or other mtDNA genes
Alpers-Huttenlocher syndromePOLG 1
MNGIETYMP 1
Other (complex multifactorial inheritance/sporadic)
Primary progressive multiple sclerosis (PPMS)WMLCognitive decline occurs later; callosomarginal lesions occur.
Confluent WML in frontoparietal areas are more consistent w/CSF1R-related ALSP than w/PPMS 2.
Susac syndromeCognitive impairment, behavioral changesBranch retinal artery inclusions, tinnitus, hearing loss, vertigo; gray matter lesions
Frontotemporal lobar degenerationThe combination of FTD & atypical parkinsonism is characterized by multisystem atrophy & progressive supranuclear palsy; the addition of ALS can mimic clinical ALSP.MRI demonstrates mainly cerebral atrophy w/out the characteristic WML found in CSF1R-related ALSP.

ALS = amyotrophic lateral sclerosis; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; FTD = frontotemporal dementia; LBSL = leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MNGIE = mitochondrial neurogastrointestinal encephalopathy; PLOSL = polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy; WM = white matter; WML = white matter lesions

1.

Alpers-Huttenlocher syndrome and MNGIE are inherited in an autosomal recessive manner.

2.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), the following evaluations are recommended if they have not already been completed:

  • Complete neurologic assessment
  • Psychological and psychiatric assessments
  • Brain MRI to determine the extent and localization of white matter changes, presence of cortical atrophy, and involvement of the corpus callosum and corticospinal tracts
  • Assessment of feeding/eating, digestive problems (constipation, incontinence), and nutrition based on clinical history
  • EEG or video EEG if a seizure disorder is suspected; evaluation of the need for antiepileptic drugs
  • Lumbar puncture to measure neurofilament light protein (NFL) in the cerebrospinal fluid (CSF) to follow the disease progression. An increased level of NFL on repeat CSF examinations may suggest faster disease course and thus worse prognosis.
  • Assessment of family and social structure to determine the availability of adequate support systems
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific therapy is currently available for ALSP. However, as CSF1R-related ALSP is a microglia-associated neurodegenerative disease it is suggested that hematopoietic stem cell transplantation may have a therapeutic role for this disease [Eichler et al 2016].

Management is supportive and includes attention to general care and nutritional requirements, antiepileptic drugs for seizures, and antibiotic treatment for general and recurrent infections such as pneumonia or urinary tract infections.

Other:

  • L-dopa or other dopaminergic therapies have not been beneficial in individuals with ALSP or in those with an atypical parkinsonian phenotype, but may be worth trying.
  • Antidepressant medications may be prescribed for depression, although reports to date have demonstrated no long-term benefit.
  • Antipsychotics are in general not recommended due to extrapyramidal side effects, but may be used in aggressive individuals.
  • Anti-seizure medications should be initiated in any individual with seizures and are reported to be beneficial.

Prevention of Secondary Complications

Social problems (unemployment, divorce, financial troubles, and alcoholism) and suicidal tendencies are often associated with the progression of the disease. Some of the social consequences may be avoided if family members are informed early about the nature of the disorder.

Surveillance

Periodic clinical evaluation to monitor for the following is appropriate:

  • Changes in mobility, communication, and behavior, which could indicate a need to alter care and support systems (wheelchair / personal assistance)
  • Onset of seizures and need for antiepileptic therapy
  • Contractures, which could indicate a need to change medical management and physical therapy
  • Behavioral changes, inappropriate emotions and actions, problems following directions, memory loss, incontinence, which indicate curtailing of independence
  • Difficulties in swallowing or weight loss, which trigger consideration for gastrostomy
  • Need for physical therapy to minimize contractures and maintain locomotion

Longitudinal MRI studies every year can potentially help with prognosis, as during the disease course the more rapid the confluence of patchy or focal T2-weighted hyperintensities and the progression of cortical atrophy, the poorer the prognosis appears to be [Van Gerpen et al 2008, Sundal et al 2012b].

Agents/Circumstances to Avoid

The following should be avoided:

  • Use of first-generation neuroleptics, which increase seizure risk and risk of additional parkinsonian signs
  • Treatment agents for multiple sclerosis, as these medications are of no benefit and have major side effects

Evaluation of Relatives at Risk

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

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. Each child of an individual with CSF1R-related ALSP 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, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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

  • Predictive testing for at-risk relatives is possible once a CSF1R pathogenic variant has 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 ALSP, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CSF1R pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CSF1R-related ALSP are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • European Leukodystrophy Association (ELA)
    2, rue Mi-les-Vignes
    B.P. 61024
    Laxou Cedex 54521
    France
    Phone: 03833093 34
    Fax: 03833000 68
    Email: ela@ela-asso.com
  • Leukodystrophy Australia
    P O Box 2550
    Mount Waverley Victoria 3149
    Australia
    Phone: 1800-141-400 (toll free)
    Email: info@leuko.org.au
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CSF1R-Related Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CSF1R-Related Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (View All in OMIM)

164770COLONY-STIMULATING FACTOR 1 RECEPTOR; CSF1R
221820LEUKOENCEPHALOPATHY, HEREDITARY DIFFUSE, WITH SPHEROIDS; HDLS

Gene structure. CSF1R comprises 22 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. No normal variants have been reported.

Pathogenic variants. To date, more than 50 different CSF1R pathogenic variants including missense variants, in-frame deletions, and splice site variants have been reported. All identified pathogenic variants are located in exons 12 to 22, which encode the intracellular tyrosine kinase domain of the receptor [Rademakers et al 2011, Stabile et al 2016, Konno et al 2017].

Table 3.

CSF1R Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.2512G>Cp.Val838LeuNM_005211​.3
NP_005202​.2
c.2562T>Ap.Asn854Lys

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The CSF1R protein is a cell-surface receptor primarily for the cytokine CSF-1, which 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 tyrosine residues in the cytoplasmic domain. CSF1R autophosphorylation precedes CSF1R-dependent phosphorylation of several 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. The link between pathogenic variants in CSF1R and the neuronal/glial dysfunction remains to be elucidated.

Abnormal gene product. The CSF1R pathogenic variants that cause ALSP affect the kinase activity and potentially the phosphorylation of downstream targets.

References

Published Guidelines/Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 10-16-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 10-16-18.

Literature Cited

  • 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]
  • 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]
  • 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]
  • 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]
  • Lakshmanan R, Adams ME, Lynch DS, Kinsella JA, Phadke R, Schott JM, Murphy E, Rohrer JD, Chataway J, Houlden H, Fox NC, Davagnanam I. Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy. Neurol Genet. 2017;3:e135. [PMC free article: PMC5312114] [PubMed: 28243630]
  • Levin J, Tiedt S, Arzberger T, Biskup S, Schuberth M, Stenglein-Krapf G, Kreth FW, Högen T, la Fougère C, Linn J, van der Knaap MS, Giese A, Kretzschmar HA, Danek A. Diffuse leukoencephalopathy with spheroids: biopsy findings and a novel mutation. Clin Neurol Neurosurg. 2014;122:113–5. [PubMed: 24908228]
  • Lynch DS, Jaunmuktane Z, Sheerin UM, Phadke R, Brandner S, Milonas I, Dean A, Bajaj N, McNicholas N, Costello D, Cronin S, McGuigan C, Rossor M, Fox N, Murphy E, Chataway J, Houlden H. Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series. J Neurol Neurosurg Psychiatry. 2016;87:512–9. [PMC free article: PMC4853550] [PubMed: 25935893]
  • Nicholson AM, Baker MC, Finch NA, Rutherford NJ, Wider C, Graff-Radford NR, Nelson PT, Clark HB, Wszolek ZK, Dickson DW, Knopman DS, Rademakers R. CSF1R mutations link POLD and HDLS as a single disease entity. Neurology. 2013;80:1033–40. [PMC free article: PMC3653204] [PubMed: 23408870]
  • 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]
  • Sarma AK, Khandker N, Kurczewski L, Brophy GM. Medical management of epileptic seizures: challenges and solutions. Neuropsychiatr Dis Treat. 2016;12:467–85. [PMC free article: PMC4771397] [PubMed: 26966367]
  • Schuberth M, Levin J, Sawalhe D, Schwarzkopf R, von Baumgarten L, Ertl-Wagner B, Rominger A, Arzberger T, Kretzschmar HA, Froböse T, Diehl-Schmid J, Biskup S, Danek A. Hereditary diffuse leukencephalopathy with spheroids: a microgliopathy due to CSF1 receptor impairment. Nervenarzt. 2014;85:465–70. [PubMed: 24706185]
  • 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, Ekholm S, Nordborg C, Jönsson L, Börjesson-Hanson A, Lindén T, Zetterberg H, Viitanen M, Andersen O. Update of the original HDLS kindred: divergent clinical courses. Acta Neurol Scand. 2012a;126:67–75. [PubMed: 22098561]
  • 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. 2012b;79:566–74. [PMC free article: PMC3413763] [PubMed: 22843259]
  • 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]
  • Wider C, Van Gerpen JA, Dearmond S, Shuster EA, Dickson DW, Wszolek ZK. Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD): a single entity? Neurology. 2009;72:1953–9. [PMC free article: PMC2843560] [PubMed: 19487654]

Chapter Notes

Acknowledgments

Dr Wszolek was partially supported by National Institute of Health/National Institute of Neurological Disorders and Stroke [P50-NS072187] , Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida) and philanthropic gifts from Carl Edward Bolch, Jr., and Susan Bass Bolch, The Sol Goldman Charitable Trust, and Donald G and Jodi P Heeringa.

Dr Sundal is partially supported by a grant from NHR (Society of the Neurologically Handicapped), Stockholm and Gothenburg, Sweden.

Revision History

  • 5 October 2017 (sw) Comprehensive update posted live
  • 18 December 2014 (me) Comprehensive update posted live
  • 17 January 2013 (cd) Revision: sequence analysis and prenatal diagnosis for CSF1R available clinically
  • 30 August 2012 (me) Review posted live
  • 23 May 2012 (zkw) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK100239PMID: 22934315

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...