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CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids

Synonyms: Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids, Leukoencephalopathy with Neuroaxonal Spheroids, Neuroaxonal Leukodystrophy

, MD and , MD.

Author Information
, MD
Department of Neurology
Mayo Clinic
Jacksonville, Florida
Department of Neurology
Sahlgrenska University Hospital
Sahlgrenska Academy, Gothenburg University
Gothenburg, Sweden
, MD
Department of Neurology
Mayo Clinic
Jacksonville, Florida

Initial Posting: ; Last Revision: January 17, 2013.


Disease characteristics. CSF1R-related hereditary diffuse leukoencephalopathy with spheroids (HDLS) is characterized by executive dysfunction, memory decline, personality changes, motor impairment, 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 11 or more years (mean: 6 years).

Diagnosis/testing. The diagnosis is suspected in individuals with characteristic clinical and brain MRI findings and is confirmed by identification of a heterozygous mutation in CSF1R, the only gene in which mutations are known to cause HDLS.

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 have no benefit and have major side effects.

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


CSF1R-related hereditary diffuse leukoencephalopathy with spheroids (HDLS) should be suspected in individuals with the following clinical and brain MRI findings. Definite diagnosis relies on identification of a disease-causing CSF1R mutation.

  • Progressive neurologic decline
    • Presenting signs may include:
      • Personality changes, cognitive impairments, memory decline, and depression;
      • Motor impairments including gait dysfunction, bradykinesia, rigidity and tremor;
      • In rare individuals, seizure.
    • Later signs usually include dementia, pyramidal signs, and seizures.
  • Family history consistent with autosomal dominant inheritance
    • The white matter lesions are hyperintense on T2- and FLAIR-weighted images, and hypointense on T1-weighted images.
    • Bifrontal or bifrontoparietal T2/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. Also early on they are patchy and focal, but with time become confluent. T2 and FLAIR hyperintensities are present in other areas, including the corpus callosum and corticospinal tracts.
    • Cerebral atrophy manifesting as enlarged ventricles is typical, as well as cerebral atrophy corresponding to the white matter lesions.
    • The following are absent:
      • Significant grey matter pathology
      • Brain stem atrophy
      • Contrast uptake in the parenchyma
    • Cerebellar abnormalities are minimal.


Brain pathology. Prior to the definition of the molecular basis of HDLS, the only method of definitive diagnosis was the demonstration of white matter lesions with axonal spheroids on brain biopsy or at autopsy [Axelsson et al 1984, Baba et al 2006, Sundal et al 2012b].

  • White matter changes are typically vacuolated and demyelinated.
  • The histopathologic hallmarks are axonal spheroids in the white matter lesions that are immunoreactive for neurofilament, amyloid precursor protein (APP), and ubiquitin.
  • Bizarre astrocytes and lipid-laden and myelin-laden macrophages are also observed.
  • The basal ganglia, thalamus, hypothalamus, hippocampus, substantia nigra, raphe nucleus, reticular formation, and cerebellar grey matter are usually unaffected or very mildly affected.
  • Amyloid angiopathy is not significantly present in parenchymal or leptomeningeal vessels.

Note: Molecular genetic testing practically eliminates the need for performing brain biopsy for diagnosis.

Molecular Genetic Testing

Gene. CSF1R is the only gene in which mutations are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS).

Evidence for locus heterogeneity. Families with phenotypes that suggest HDLS but without an identifiable CSF1R mutation have been observed [Authors, personal observation]. Although this finding could result from the inability of current molecular genetic testing methods to detect pathogenic CSF1R mutations, locus heterogeneity is also possible.

Table 1. Summary of Molecular Genetic Testing Used in CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
CSF1RSequence analysisSequence variants 214/14 probands 3, 4
1/1 proband 4, 5
3/4 probands 4, 6
3/3 probands 4, 7

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Rademakers et al [2011]

4. Each family has a unique CSF1R mutation that is distributed in exons 12-22 [Kinoshita et al 2012, Kleinfeld et al 2012, Mitsui et al 2012, Rademakers et al 2011].

5. Kinoshita et al [2012]

6. Mitsui et al [2012]

7. Kleinfeld et al [2012]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. Sequence analysis of CSF1R is recommended to confirm the diagnosis in a proband with suggestive clinical and brain MRI findings.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) requires prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

CSF1R-related hereditary diffuse leukoencephalopathy with spheroids (HDLS) is characterized by a constellation of findings including executive dysfunction, memory decline, personality changes, motor impairment, 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 the same family harboring the same mutation. 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 2012c]. The disease course may be from two to 11 years or more with a mean of six 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 intension tremor
  • Visual field defects such as homonymus quadrant- or hemi-anopsia
  • Other signs of a movement disorder: dystonia, myoclonic twitches, dyskinesia, and akathisia
  • Seizures in some (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
  • Normal isoelectric focusing and no oligoclonal bands
  • No identified CSF biomarker. The following preliminary findings in two persons with HDLS need to be interpreted cautiously and require further research [Sundal et al 2012a]:
    • Normal Aβ42 protein concentrations
    • Minimally increased levels of total Tau protein concentrations,
    • Borderline normal phospho-Tau protein concentrations
    • Significantly elevated neurofilament light chain (NF-L) proteins. (Note that NF-L proteins are markers of neuronal death and axonal damage.)

Genotype-Phenotype Correlations

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


Penetrance seems to be high; however, estimates have not been calculated given the limited number of families reported to date.


Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is probably closely related to or 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).’ One family with POLD has a CSF1R mutation [Authors’ personal observation, unpublished data], providing evidence that HDLS and POLD may both be caused by mutation of CSF1R.


HDLS is thought to be rare; actual prevalence figures have not been reported.

Differential Diagnosis

The clinical presentation of hereditary diffuse leukoencephalopathy with spheroids (HDLS) often overlaps with other neurologic disorders. HDLS 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.

Familial pigmentary orthochromatic leukodystrophy (POLD) is phenotypically and radiologically similar to HDLS [Wider et al 2009]. See Nomenclature.

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

Autosomal Dominant Disorders

The adult form of Alexander disease has extensive cerebral white matter abnormalities with a frontal predominance and a periventricular rim of decreased T2 and increased T1 signal intensities. Additionally, there are abnormalities in the basal ganglia, thalamus, and brain stem with contrast enhancement of the cerebrum or brain stem [Van der Knaap et al 2005, Sawaishi 2009].

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms is characterized by white matter changes in a frontoparietal distribution involving the corticospinal tracts from the supratentorial regions to the spinal cord. Additionally, it involves the superior and middle cerebellar peduncles [Sundblom et al 2009].

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has multiple cerebral infarcts and white matter lesions including the characteristic temporal pools [Tikka et al 2009].

Frontotemporal dementia typically demonstrates frontal and/or temporal atrophy with far fewer white matter lesions than are seen in HDLS [Seelaar et al 2011].

  • A study comparing the pattern of cerebral atrophy suggests that the pattern of atrophy is more widespread in persons with mutations in GRN (encoding progranulin) than in persons with mutations in MAPT (encoding microtubule-associated protein tau).
  • C9ORF72-related FTD is associated with symmetric atrophy predominantly involving dorsolateral, medial, and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes, and cerebellum. In contrast, striking anteromedial temporal atrophy is associated with MAPT mutations and temporoparietal atrophy was associated with GRN mutations.
  • The sporadic frontotemporal dementia group is associated with frontal and anterior temporal atrophy [Whitwell et al 2012].

Early-onset Alzheimer disease (EOAD) typically begins with subtle memory failure which becomes more severe leading to disability. Common findings include confusion, poor judgment, language disturbance, agitation, hallucinations, withdrawal, and mutism. Seizures, parkinsonism, myoclonus, and urinary incontinence can occur. The significant overlap in clinical presentation of EOAD with HDLS includes similar age of onset. The predominant finding of EOAD on brain MRI is evolving cortical atrophy; white matter changes are present, but much less pronounced than those of HDLS. CSF biomarker examination reveals elevated total-Tau and phosphorylated Tau protein concentrations and reduced Aβ42 concentrations. Heterozygosity for mutation of APP, PSEN 1, or PSEN 2 is causative [Andreasen et al 2003, Lopez et al 2011, Cohn-Hokke et al 2012].

Autosomal Recessive Disorders

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola disease) is characterized by sclerosing leukoencephalopathy with progressive cerebral atrophy, cerebellar atrophy, or both. White matter lesions are diffuse and usually centrally located, with sparing of the arcuate fibers. Basal ganglia atrophy and calcifications are often present. Lytic foci are also often evident on bone radiographs [Paloneva et al 2001, Kaneko et al 2010].

Vanishing white matter (VWM) and metachromatic leukodystrophy (MLD) both have more wide-spread and diffuse white matter changes and atrophy than HDLS [Eichler et al 2009, Bugiani et al 2010].

Lysosomal storage diseases that can present in adult life with white matter lesions include the adult form of Krabbe disease. Although it can present with parieto-occipital white matter [Loes et al 1999] and can be unilaterally diffuse [Lemmens et al 2011], upper corticospinal tract involvement can also be the first presenting change [Wang et al 2007].

Leukoencephalopathy with brain stem and spinal cord involvement (LBSL) diagnostic MRI findings are white matter lesions that are either non-homogeneous/spotty or homogeneous and confluent [Scheper et al 2007]. Signal abnormalities are evident in the medullary pyramids, dorsal columns, and lateral corticospinal tracts. Additionally, signal abnormalities may be present in the splenium of the corpus callosum, superior/inferior cerebellar peduncles, and cerebellum.

X-Linked Disorders

X-linked adrenoleukodystrophy (X-ALD) rarely develops into a cerebral form; when it does, it may demonstrate symmetric, increased T2 signal intensities usually in the parieto-occipital region with contrast enhancement at the periphery of the demyelination zone [Eichler et al 2007].

Fabry disease can present with white matter lesions together with grey matter pathology [Reisin et al 2011]; however, the clinical presentation is different from that of HDLS [Meschia et al 2011].

Mitochondrial Disorders

White matter lesions (WML) may also be present in adult mitochondrial diseases [Saneto et al 2008].

In Leigh syndrome the WML may involve the deep white matter, posterior centrum semiovale and corpus callosum. The progression of WML is from posterior to anterior [Lerman-Sagie et al 2005].

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) occasionally presents with diffuse WML involving the periventricular white matter, centrum semiovale, and corpus callosum [Apostolova et al 2005].

Alpers syndrome may show T2 hyperintensities in the occipital lobe, deep cerebellar nuclei, thalamus, and basal ganglia.

MNGIE (mitochondrial neuro-gastro-intestinal encephalopathy) has diffuse WML (typically sparing the corpus callosum) and supratentorial cortical atrophy [Barragan-Campos et al 2005].

In contrast to HDLS, the cranial MRI in mitochondrial diseases may demonstrate symmetric T1 hypointense and T2 hyperintense signal abnormalities in deep grey matter. These abnormalities are not restricted to vascular territories and the lesions often fluctuate over the course of the disease. Additionally, varying degrees of cerebral and cerebellar atrophy may be present [Saneto et al 2008].


Primary progressive multiple sclerosis (PPMS) is initially dominated by progressive central paraparesis. With advanced disease the clinical picture is more multifocal with multiple sclerosis (MS) typical symptomatology including internuclear ophthalmoplegia (INO) and optic neuropathy. Cerebrospinal fluid enriched oligoclonal IgG bands support the diagnosis. MRI lesions tend to be periventricular with characteristic MS “right-angle lesions.” Diagnostic PPMS criteria are based on one year of steady clinical progression and MRI and CSF findings [Polman et al 2011]. Although HDLS can mimic MS, it does not fulfill the diagnostic criteria for MS [Keegan et al 2008].

Susac’s syndrome typically presents with the triad of retino-cochleo-cerebral vasculopathy. MRI demonstrates centrally located lesions of the corpus callosum of varying shapes and sizes (without atrophy) that usually evolve into pathognomic central callosal “holes” [Saenz et al 2005]. Most affected individuals improve with immunosuppressive therapy [Mateen et al 2012].

Frontotemporal lobar degeneration (FTLD) ranges from behavioral and executive impairments to language disorders and motor dysfunction. The clinical findings of FTLD differ from those of HDLS. Although the combination of FTD with atypical parkinsonism has features such as multisystem atrophy (MSA) and progressive supranuclear palsy (PSP), and the addition of amyotrophic lateral sclerosis (ALS) can mimic clinical HDLS, the neuroimaging is different. MRI demonstrates mainly cerebral atrophy without the characteristic white matter lesions found in HDLS.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with hereditary diffuse leukoencephalopathy with spheroids (HDLS), the following evaluations are recommended:

  • 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 patient 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 system
  • Medical genetics consultation

Treatment of Manifestations

No specific therapy is currently available for HDLS.

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


  • L-dopa or other dopaminergic therapies have not been beneficial in individuals with HDLS or in those with an atypical parkinsonian phenotype, but may be worth trying.
  • Antidepressant medications can be tested for depression but reports so far 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 individuals 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.


The following are appropriate:

  • Periodic clinical evaluation to monitor for:
    • 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 can potentially help with prognosis as during the disease course the more rapid the confluence of patchy or focal T2 hyperintensities and the progression of cortical atrophy, the poorer the prognosis appears to be [Van Gerpen et al 2008, Sundal et al 2012c].

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 have 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.

Therapies Under Investigation

Search ClinicalTrials.gov 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 hereditary diffuse leukoencephalopathy with spheroids (HDLS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Individuals with CSF1R-related HDLS usually have an affected parent, albeit de novo mutations can occur [Kinoshita et al 2012, Rademakers et al 2011].
  • A proband with CSF1R-related HDLS may have the disorder as the result of a de novo mutation. In 14 families with CSF1R-related HDLS, one set of monozygotic (MZ) twins was identified with a de novo mutation [Rademakers et al 2011].
  • If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include the following:
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with CSF1R-related HDLS have an affected parent, the family history 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, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred she/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

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 affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for CSF1R-related HDLS because of the possibility of reduced penetrance in one parent.
  • If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to the sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with CSF1R-related HDLS has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

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

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.


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.

  • Australian Leukodystrophy Support Group, Inc.
    Nerve Centre
    54 Railway Road
    Blackburn Victoria 3130
    Phone: 1800-141-400 (toll free); +61 3 98452831
    Fax: +61 3 95834379
    Email: mail@alds.org.au
  • European Leukodystrophy Association (ELA)
    2, rue Mi-les-Vignes
    B.P. 61024
    Laxou Cedex 54521
    Phone: 03833093 34
    Fax: 03833000 68
    Email: ela@ela-asso.com
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    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 Hereditary Diffuse Leukoencephalopathy with Spheroids: Genes and Databases

Gene SymbolChromosomal LocusProtein NameHGMD
CSF1R5q32Macrophage colony-stimulating factor 1 receptorCSF1R

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids (View All in OMIM)


Normal allelic variants. CSF1R comprises 22 exons. No normal allelic variants have been reported.

Pathologic allelic variants. To identify the genetic basis of HDLS, an international consortium was established and one large kindred with clear autosomal dominant inheritance was selected for linkage analyses. Evidence for linkage was identified at loci on chromosome 5. Whole-exome sequencing identified CSF1R as the gene in which mutation is causative. Additional mutations were demonstrated in 13 probands with neuropathologically proven HDLS. CSF1R mutations cosegregated with the disease phenotype in all families with HDLS. Ten missense mutations, one single codon deletion, and three splice site mutations were identified in exons 12 to 22.The CSF1R mutation was absent in all 660 controls [Rademakers et al 2011].

Table 2 shows the 18 CSF1R mutations reported to date [Kinoshita et al 2012, Kleinfeld et al 2012, Mitsui et al 2012, Rademakers et al 2011].

Table 2. Selected CSF1R Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.1754-2A>Gp.Gly585_Lys619delinsAla 2NM_005211​.3
c.1766G>Ap.Gly589Glu 2
c.1897G>Ap.Glu663Lys 2
c.2297T>Cp.Met766Thr 2
c.2308G>Cp.Ala770Pro 2
c.2320-2A>Gp.Cys774_Asp814del 2
c.2324T>Ap.Ile775Asn 2
c.2381T>Cp.Ile794Thr 2, 3, 4
c.2442+5G>Cp.Cys774_Asp814delinsGlnGlyLeuGlnSerHisVal GlyProSerLeuProSerSerSerProGlnAlaGln 2
c.2345G>Ap.Arg782His 5
c.2329C>Tp.Arg777Trp 3
c.1958G>Ap.Cys653Tyr 3
p.Phe828Ser 4

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Rademakers et al [2011]

3. Mitsui et al [2012]

4. Kleinfeld et al [2012]

5. Kinoshita et al [2012]

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 mutations in CSF1R and the neuronal/ glial dysfunction remains to be elucidated.

Abnormal gene product. The CSF1R mutations that cause HDLS affect the kinase activity and potentially the phosphorylation of downstream targets.


Literature Cited

  1. Andreasen N, Vanmechelen E, Vanderstichele H, Davidsson P, Blennow K. Cerebrospinal fluid levels of total-tau, phospho-tau and A beta 42 predicts development of Alzheimer's disease in patients with mild cognitive impairment. Acta Neurol Scand Suppl. 2003;179:47–51. [PubMed: 12603251]
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Suggested Reading

  1. Grant E, Sessa M, Biffi A, Bley A, Kohlschuetter A, Loes DJ, Kraegeloh-Mann I. Metachromatic leukodystrophy: a scoring system for brain MR imaging observations. AJNR Am J Neuroradiol. 2009;30:1893–7. [PubMed: 19797797]
  2. Farina L, Pareyson D, Minati L, Ceccherini I, Chiapparini L, Romano S, Gambaro P, Fancellu R, Savoiardo M. Can MR imaging diagnose adult-onset Alexander disease? AJNR Am J Neuroradiol. 2008;29:1190–6. [PubMed: 18388212]
  3. Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology. 2011;259:659–81. [PubMed: 21602503]
  4. Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72:750–9. [PMC free article: PMC2677542] [PubMed: 19237705]
  5. Tian R, Wu X, Hagemann TL, Sosunov AA, Messing A, McKhann GM, Goldman JE. Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes. J Neuropathol Exp Neurol. 2010;69:335–45. [PMC free article: PMC3342699] [PubMed: 20448479]

Chapter Notes


Dr. Wszolek was partially supported by National Institute of Health/National Institute of Neurological Disorders and Stroke [P50-NS072187-01S2] and the National Institute of Health/National Institute of Neurological Disorders and Stroke [1RC2-NS070276, R01-NS057567], and the Dystonia Medical Research Foundation.

Dr. Sundal is supported by the American Scandinavian Foundation: Haakon Styri Fund.

Revision History

  • 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
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