Colony Stimulating Factor-1 Receptor-Related Disorder

Disease Overview

Summary

Colony stimulating factor-1 receptor (CSF1R) related disorder (RD) is a rare, progressive neurological disease that causes brain tissue known as white matter to waste away (leukodystrophy) and to form lesions in certain areas of the brain.

Lesions of this white matter lead to major changes in personality, thinking (cognition) and muscle function, eventually causing people with this disorder to develop dementia and later decline into a vegetative state.

This condition is caused by changes (disease-causing variants) in the CSF1R gene.

There are many other diseases that may have similar symptoms, making diagnosis difficult unless genetic testing is done.

There is no cure yet. Treatment is directed toward the symptoms.

Introduction

CSF1R-RD is one type of leukodystrophy disorder. It is estimated by some studies that it accounts for 10% to 25% of adult-onset leukodystrophies.

CSF1R-RD was previously known as two separate disorders: hereditary diffuse leukoencephalopathy with spheroids (HDLS)¹ and pigmentary orthochromatic leukodystrophy (POLD)². However, it was found that both disorders were linked to CSF1R gene variants ^5,6 and they became known as “adult-onset leukoencephalopathy with axonal spheroid” or “ALSP”.^3,4 More recently, researchers found that another condition, BANDDOS (brain abnormalities, neurodegeneration, and dysosteosclerosis) also known as “early-onset calcifying leukoencephalopathy-skeletal dysplasia” is also caused by CSFIR gene variants. Since these conditions have overlapping symptoms, experts now use the term CSF1R-related disorder (CSF1R-RD) to include all disorders caused by changes in CSF1R gene.⁶

There are three clinical types of ALSP , caused by variants in different genes: CSF1R-related ALSP, AARS2-related leukoencephalopathy (AARS2-L), and Swedish type hereditary diffuse leukoencephalopathy with spheroids (HDLS-S).

CSF1R-related disorder is classified in two subtypes based on when symptoms start: ^6,9

• Early-onset CSF1R-related disorder (before age 18)
• Late-onset CSF1R-related disorder (age 18 or older)

Early-onset CSF1R-RD is inherited in an autosomal recessive pattern. Late-onset CSF1R-RD is inherited in autosomal dominant pattern.

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Synonyms

• CSF1R-RD
• CSF1R-related disorder
• hereditary diffuse leukoencephalopathy with spheroids-1 (HDLS1)
• leukoencephalopathy, diffuse hereditary, with spheroids
• adult-onset leukodystrophy with neuroaxonal spheroids
• CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
• CSF1R-related ALSP

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Subdivisions

• early-onset CSF1R-related disorder (before age 18) - which includes brain abnormalities, neurodegeneration and dysosteosclerosis (BANDDOS)
• late-onset CSF1R-related disorder (age 18 or older) – which includes the diseases that were known as adult-onset leukoencephalopathy w/axonal spheroids & pigmented glia (ALSP), pigmentary orthochromatic leukodystrophy (POLD), CSF1R-related leukoencephalopathy and hereditary diffuse leukoencephalopathy w/spheroids (HDLS), except Swedish HDLS that is caused by variants in the AARS/AARS1 gene

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Signs & Symptoms

CSF1R-RD can appear at different ages, from early childhood to later in life. Despite the age of onset, the neurological symptoms are often similar.

Early-onset CSF1R-RD symptoms usually appear in childhood and may include low muscle tone (hypotonia), delayed development, skeletal abnormalities, subtle differences in facial features and brain abnormalities that are present at birth (congenital). ^10,13

Early symptoms of CSF1R-RD often include mild psychological or cognitive changes as well as movement difficulties such as walking problems, falling and slow movements. Eventually, as damage in the brain becomes more extensive, psychological, cognitive and motor symptoms exist together, but symptoms vary widely, even within the same family. Symptoms may include:^{9,14,15,16,17,18,19,20}

• Psychiatric symptoms:
  • Personality changes
  • Anxiety, depression and apathy (lack of interest in activities)
  • Irritability and distractibility
  • Socially inappropriate behavior (disinhibition)
  • Unusual food cravings (for example, wanting to eat only ice cream)
• Cognitive symptoms:
  • Dementia (progressive memory loss and confusion)
  • Difficulty finding words and forming sentences (aphasia)
  • Trouble planning and carrying out movements (apraxia)
  • Poor attention, judgment and impulse control
• Motor symptoms (caused by the brain degeneration occurring in CSF1R-RD)
  • Movement disorders due to the damage of the pyramidal system (nerve tracts controlling movement):
    • Overactive reflexes (hyperreflexia)
    • Increased muscle stiffness (hypertonicity)
    • Spastic movements and muscle spasms
    • Weakness on one side of the body (hemiparesis) or in all four limbs (quadriparesis)
  • Other movement symptoms:
    • Poor coordination
    • Vision changes
    • Walking and swallowing difficulties
    • Slurred speech
    • Inappropriate laughing or crying due to a disorder known as pseudobulbar palsy that causes a loss of control over facial muscles and develop alongside various causes of brain damage
• Parkinsonism features, which are similar to Parkinson’s disease (note that unlike Parkinson’s disease, these symptoms do not improve with typical Parkinson’s medications):
  • Stiff muscles (rigidity)
  • Tremors
  • Slow movements (bradykinesia)
  • Shuffling gait
  • Reduced facial expressions (masked face)
• Sensory changes:
  • Reduced ability to feel pain, touch and vibration
  • Difficulty recognizing right vs. left side of the body
• Seizures:
  • Occur in about 30% of affected people
  • May happen early or in later stages of the disease

Late-Onset CSF1R-RD typically affects only the nervous system. It is caused by one disease-causing variant of the CSF1R gene (autosomal dominant inheritance).^14-16

Early-onset CSF1R-RD can appear as early as infancy.¹⁰ Late-onset CSF1R-RD symptoms usually start around age 40 but can appear as early as 18. About 95% of affected people develop symptoms before age 60. Males and females are equally affected, though some studies suggest females may develop symptoms earlier.^14,16

As CSF1R-RD worsens, affected people lose the ability to walk and speak and need care with all daily living functions. They also lose control of bladder and bowel sphincter functions with involuntary leaking of urine and stools (double incontinent). Many people affected with CSF1R-RD may die from pneumonia.⁹ Life expectancy ranges from 2 to over 30 years, with an average survival of 6.8 years after symptom onset.^14-15

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Causes

CSF1R-RD is caused by changes (variants) in the CSF1R gene. This gene codes for the protein colony-stimulating factor-1 receptor, which is found on many cell membranes, including those in the central nervous system, or CNS (consisting of the brain and spinal cord).^6,21 The CSF1 receptor plays a role in cell growth and cell specialization where cells take on specific functions in the body. Without a normally functioning CSF-1 receptor, structural changes to the nerve cells (neurons) eventually occur. Axons, the portions of neurons that transmit signals to the next neuron, are covered in a myelin sheath, the protective coating around nerves made of white matter, that is destroyed in CSF1R-RD and other leukodystrophies.^22,23

In CSF1R-RD, there is a formation of swellings within the axons that are known as “spheroids”. This causes immune cells known as macrophages to destroy the myelin sheathing, further damaging nerve cell function. Microglia, another type of macrophage immune cell of the CNS that’s responsible for maintaining brain tissue, is highly dependent on the CSF-1 receptor.^22,23 When the receptor is inhibited, microglia become underactive and is destroyed. When a brain biopsy is done in people with CSF1R-RD, the macrophages and microglia take on a pigmented appearance.^9,14

People with early-onset CSF1R-RD usually have two CSF1R gene variants, one inherited from each parent. People with late-onset CSF1R-RD have one disease-causing CSF1R gene variant that can be inherited from either parent or can be the result of a new variant in the affected individual (known as a “de novo” variant) where the variant is not inherited and has never before been present in the family.²⁴ These are referred to as a sporadic cases rather than inherited cases of CSF1R-RD.⁹

Therefore, early-onset CSF1R-RD is inherited as an autosomal recessive condition (inherited from both parents) and late-onset CSF1R-RD is inherited as an autosomal dominant condition (inherited from one parent or occurs due to a new variant).^9,24

Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

The exact number of people with CSF1R-RD is unknown. Many affected people are misdiagnosed as multiple sclerosis, dementia, or other neurological diseases.^9,25

About 10,000 people in the U.S. are estimated to have CSF1R-RD, but new studies suggest the number may be 10 times higher.

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Disorders with Similar Symptoms

Many symptoms of CSF1R-RD overlap with other neurological disorders including other types of leukodystrophies. Genetic testing is required for accurate diagnosis. Based on symptoms, CSF1R-RD can be similar to the following disorders.^9,25

Frontotemporal degeneration (FTD) is a group of neurodegenerative disorders associated with shrinking of the frontal and temporal lobes of the brain. Symptoms include marked changes in social behavior and personality and/or problems with language. Some people with FTD also develop a motor syndrome such as Parkinsonism or motor neuron disease which result in  additional symptoms. Both CSF1R-RD and FTD affect the frontal lobes, causing behavioral and cognitive changes, but CSF1R-RD also causes significant motor symptoms, including muscle stiffness (spasticity), difficulty walking (gait disturbances), and seizures, which are not common in FTD. Brain imaging can also help differentiate the two conditions.

Multiple sclerosis (MS) is a chronic neurologic and immunologic disorder of the central nervous system involving the brain, spinal cord and optic nerves, as well as the myelin that covers the nerve. There is characteristic scarring (plaques or patches) of the myelin sheath due to inflammatory attacks occurring unpredictability, and varying in intensity, and at many sites thus the name, multiple sclerosis. The randomness of the location of damage can result in a wide range of neurological symptoms. MS typically follows a relapsing-remitting course (symptoms come and go), whereas CSF1R-RD is a progressively worsening disorder. Brain imaging findings are distinct as in MS. Lesions tend to appear in specific areas of the brain, such as the periventricular white matter, brainstem and spinal cord, whereas in CSF1R-RD, lesions are more widespread. The people with MS test positive for oligoclonal bands in cerebrospinal fluid (CSF), a hallmark of MS that is not found in CSF1R-RD.

Parkinson’s disease is a slowly progressive neurologic condition characterized by involuntary trembling (resting tremor), muscular stiffness or inflexibility (rigidity), slowness of movement (bradykinesia) and difficulty carrying out voluntary movements (akinesia). CSF1R-RD does not typically cause resting tremors. Instead, CSF1R-RD presents with spasticity, cognitive decline and white matter damage, which are not classic features of Parkinson’s. Parkinson’s disease affects dopamine-producing neurons in the substantia nigra, whereas CSF1R-RD causes widespread white matter lesions. While Parkinson’s disease can cause dementia (especially in advanced stages), cognitive decline is often an early symptom of CSF1R-RD.

The following conditions can also look similar to CSF1R-related disorder:

• AARS1-related leukoencephalopathy (also known as Swedish HDLS, as it was reported in a Swedish family that was initially diagnosed as leukoencephalopathy and hereditary diffuse leukoencephalopathy w/spheroids-HDLS): A progressive brain disease that starts in adulthood and closely resembles late-onset CSF1R-related disorder. However, brain scans show a unique pattern of damage in the white matter near the front of the brain.
• AARS2-related leukoencephalopathy: A rare, inherited brain disease that affects thinking, behavior, coordination and movement. Unlike CSF1R-related disorder, it usually does not cause brain calcifications and affects the corpus callosum (a key brain structure) less severely. In females, it can also cause early menopause.
• Unknown Genetic Cause: In one family, doctors found a condition identical to CSF1R-related disorder but without variants in known related genes (CSF1R, AARS1, or AARS2). This suggests that other, yet undiscovered genes may also cause similar disorders.

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Diagnosis

The diagnosis of CSF1R-RD should be done by a neurologist. Since symptoms of CSF1R-RD can resemble other neurological conditions, genetic testing is required to confirm the presence of a CSF1R gene variant.⁹

Doctors suspect CSF1R-RD based in a family history, along with clinical symptoms affecting cognition, movement, or seizures before age 60. Cognitive testing by a psychiatrist, neurologist, or psychologist can help detect subtle behavioral changes linked to frontal lobe dysfunction, such as reduced impulse control.

Brain scans can reveal specific patterns of deterioration associated with CSF1R-RD. These include:^14,27-29

• Lesions in the white matter on both sides of the brain, which are often asymmetric in early stages but become symmetric and widespread as the disease progresses
• Lesions that are most common in the frontal and parietal lobes and the white matter around the lateral ventricles, causing enlarged ventricles on imaging
• Thinning of the corpus callosum, which is a structure that connects the right and left sides of the brain, allowing them to communicate
• Small calcium deposits (calcifications) in the white matter of the frontal and parietal lobes

To help doctors recognize and diagnose late-onset CSF1R-RD, diagnostic criteria were established in 2018.³⁰ These criteria state that a person with late-onset CSF1R-RD generally has:

• An age of symptom onset before 60 years old
• More than two clinical symptoms, which may include cognitive or psychiatric symptoms, movement problems (pyramidal signs), Parkinsonism, or epilepsy
• A family history suggests that inheriting one gene variant from either parent is enough to cause the disease
• Typical findings on brain imaging match the patterns seen in CSF1R-RD

Some features that are not typically associated with late-onset CSF1R-RD include symptom onset before age 10, epileptic seizure-like episodes as the primary symptom, and severe peripheral nerve damage.

While these criteria help doctors identify probable or possible CSF1R-RD, genetic testing is essential for a definitive diagnosis. Additionally, other leukodystrophies must be ruled out before confirming CSF1R-RD.

Recent research has explored biomarkers (biological indicators of disease) to improve diagnostic accuracy. One potential biomarker is neurofilament light chain, a protein that signals nerve damage and can be detected in blood or cerebrospinal fluid.³¹ However elevated neurofilament levels are not specific to CSF1R-RD and can also be seen in other diseases such as multiple sclerosis. Also, in early stages of CSF1R-RD, neurofilament levels may not yet be elevated.³¹^, ³²

Another biomarker under study is chitinase, an enzyme linked to brain inflammation.³³ However, like neurofilament, it is not exclusive to CSF1R-RD and is found in other neurological diseases.

The brains of people with CSF1R-RD show characteristic features under a microscope. However, brain biopsy is not necessary for diagnosis because genetic testing is available.

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Standard Therapies

There are currently no cures or FDA-approved treatments for CSF1R-RD. Researchers are continuing to study the disease to develop effective therapies.

Symptomatic treatment options do not reverse brain damage but instead are meant to manage symptoms and improve quality of life.

• Epilepsy can be controlled with standard seizure medications
• Infections that can develop as the disease progresses, such as pneumonia or urinary tract infections can be treated with antibiotics
• Muscle stiffness (spasticity) can be reduced with muscle relaxers
• Psychological symptoms may be improved with antidepressants, though they are not always effective
• Aggressive behavior can be reduced with antipsychotic medications, but they often have significant side effects that can be difficult for patients to tolerate

Physical therapy and nutritional support can help slow disease progression and maintain overall health for as long as possible.⁹

Genetic counseling is recommended to help patients and families understand the genetics and progression of CSF1R-RD and to provide psychosocial support.

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Clinical Trials and Studies

Bone marrow transplantation is the most promising and first potential treatment to modify the course of CSF1R-RD. Results vary from person to person, but in some people, bone marrow transplants have slowed the progression of motor and cognitive symptoms of the disease. Bone marrow transplants are thought to be beneficial for some people with CSF1R-RD by providing new immune cells from donors with normal CSF-1 receptors that develop into microglia and increase the number of microglia in the brain.^34,35

There are clinical trials involving modulators of the TREM2 pathway.³⁶ The goal of this intervention is to compensate for CSF1R gene’s lost function. The TREM2 gene is expressed in brain microglia, which are a line of defense against pathogenic insults and are also involved in physiological functions essential for correct CNS development. The TREM2 protein is essential for good communication between microglia and neurons during early development and variants in the TREM2 gene are associated with neurodegenerative diseases, including Alzheimer’s disease.

Another potential option for people who have CSF1R variants but do not have symptoms might be chronic use of steroids. There are promising observations of asymptomatic variant carriers who chronically took steroids and developed symptoms of CSF1R-RD later or not at all, compared to their affected relatives.^37,38 This observation was confirmed in an animal model.³⁹ Nevertheless, further research into this strategy is needed.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

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35. 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. 2022;14(12):2778. Published 2022 Dec 12. doi:10.3390/pharmaceutics14122778
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39. Chitu V, Biundo F, Oppong-Asare J, et al. Prophylactic effect of chronic immunosuppression in a mouse model of CSF-1 receptor-related leukoencephalopathy. Glia. 2023;71(11):2664-2678. doi:10.1002/glia.24446

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Programs & Resources

• Assistance Programs
• Patient Organizations

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Learn more about Patient Assistance Programs >

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Patient Organizations

United Leukodystrophy Foundation

NORD Member

Email: [email protected]

Related Rare Diseases: Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia, Cerebral Folate Deficiency, Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation, ...

https://rarediseases.org/organizations/united-leukodystrophy-foundation/

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Sisters’ Hope Foundation

NORD Member

Phone: 717-202-9103 Email: [email protected]

Related Rare Diseases: Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia, Leucoencefalopatía de inicio en el adulto con esferoides axonales y células gliales pigmentadas, Colony Stimulating Factor-1 Receptor-Related Disorder ...

https://rarediseases.org/organizations/sisters-hope-foundation/

View Profile >

Leukodystrophy Australia

Email: [email protected]

Related Rare Diseases: Cerebrotendinous Xanthomatosis, Leukodystrophy, Metachromatic Leukodystrophy, ...

https://rarediseases.org/organizations/leukodystrophy-australia/

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Myelin Disorders Bioregistry Project (MDBP)

Phone: 202-476-6230 Email: [email protected] Fax: 202-476-5226

Related Rare Diseases: Leukodystrophy, Leucodistrofia, Colony Stimulating Factor-1 Receptor-Related Disorder ...

https://rarediseases.org/organizations/myelin-disorders-bioregistry-project-mdbp/

View Profile >

Learn more about Patient Organization & Membership >

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