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Last updated: 2/19/2025
Years published: 2021, 2025
NORD gratefully acknowledges Zbigniew K. Wszolek, MD, Consultant, Department of Neurology, Haworth Family Professor in Neurodegenerative Diseases, Professor of Neurology and Tomasz Chmiela, MD, Research Fellow, Department of Neurology, Mayo Clinic Florida and Neurologist, Department of Neurology, Faculty of Medical Science, Medical University of Silesia for assistance in the preparation of this report.
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Summary
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a term that refers to the characteristic brain tissue findings in affected people. People with ALSP present with a rare and progressive neurological disease in which the brain tissue known as white matter wastes away (leukodystrophy) forming lesions in certain brain areas. Most cases are due to disease-causing variants in the CSF1R (colony-stimulating factor-1 receptor) gene.
The brains of people with ALSP show characteristic microscopic changes and patterns of atrophy on brain imaging that distinguish ALSP from other neurological conditions. Symptoms can vary considerably from one person to the next (even in the same family). Currently, brain biopsy is not necessary for diagnosis because genetic testing is available.
There is no cure yet. Treatment is directed to improve the specific symptoms that the affected person has
Introduction
ALSP was previously known as two separate disorders: hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). These were grouped together because the brains of affected people had similar findings under the microscope (pathologic findings) and because both were linked to CSF1R gene variants. Recently, researchers have suggested grouping CSF1R– ALSP as well as any disease caused by CSF1R gene variants under the term CSF1R-related disorder (NORD has a separate report on this group of conditions), as CSF1R variants might also cause an early-onset form of disease. In addition, ALSP might be caused by variants in other genes like AARS1 or AARS2.
There are four clinical types of ALSP caused by variants in different genes: CSF1R-related disorder, AARS2-related leukoencephalopathy (AARS2-L), Swedish type hereditary diffuse leukoencephalopathy with spheroids (HDLS-S) associated with AARS1 gene variants and ALSP without CSF1R, AARS1 or AARS2 variants (caused by unknown gene variants).
Most cases of ALSP are caused by CSF1R gene variants (CSF1R- ALSP).
ALSP caused by CSF1R variants often starts with mild psychological or cognitive changes. Some people may develop difficulty walking, fall easily or have slower movements, though this is less common. Over time, the disease affects thinking, emotions and movement. Symptoms can vary even among family members.
People with ALSP may develop:
ALSP affects nerve pathways that control movement leading to:
Seizures occur in about 30% of people with ALSP, often early in the disease. As the condition worsens, individuals lose the ability to walk, speak, and control bladder or bowel function, requiring full-time care. The main cause of death for people with ALSP is pneumonia, a common complication.
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) is 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. Some affected people had digestive issues as well. Some Individuals decline quickly die shortly after they are diagnosed, and others have a longer disease course. Another family with AARS1-rekated leukoencephalopathy was recently reported.
AARS2-related leukoencephalopathy is a rare, inherited brain disease that affects thinking, behavior, coordination and movement. Unlike CSF1R-related disorder, it usually does not cause small calcium deposits (calcification) in the brain and affects the corpus callosum (a structure connecting the brain’s hemispheres) less severely. There are two main forms, the infantile-onset cardiomyopathy (heart disease in infants) form and the neurodegeneration with or without leukoencephalopathy (a brain and nervous system disease) which can cause ALSP when associated with leukoencephalopathy. In females, it can also cause early menopause due to ovarian failure. This can be an indicator that the condition is related to AARS2 gene variants as opposed to CSF1 gene variants. For a more detailed information of AARS2-related leukoencephalopathy please see the GeneReview article for this condition entitled AARS2-related disorders.
The forms of ALSP that are inherited in an autosomal recessive pattern tend to appear earlier in life and affected individuals often have vision problems and damage to certain parts of the brain (cerebellum and brainstem). Calcification in the brain has only been found in two specific types: CSF1R-ALSP and AARS1-AR-ALSP. Patients with AARS1-AR-ALSP also tend to have brain changes that mainly affect the back part of the brain, milder overall damage and inflammation and low levels of albumin in the blood, which may be linked to malnutrition.
Most cases of ALSP are caused by changes (variants) in the CSF1R gene which plays a role in brain cell function and repair. The CSF1R gene codes for the protein colony stimulating factor-1 receptor found in many cell membranes, including those in the central nervous system (brain and spinal cord). CSF1R gene variants lead to damage in nerve cells by affecting myelin (the protective coating around nerves made of white matter) especially the axons, the portions of the neurons that transmit signals among the nerves. The formation of swellings (spheroids) within axons causes the immune cells known as macrophages and microglia to further destroy the brain’s white matter. Over time, this leads to progressive brain degeneration and worsening symptoms.
ALSP can also be caused by variants in other genes like AARS1 or AARS2 or genes not yet identified.
ALSP caused by variants in the CSF1R gene is autosomal dominant. 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.
ALSP caused by variants in the AARS2 gene is inherited in an autosomal recessive pattern. 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.
The original report of the Swedish family with ALSP caused by changes in the AARS1 gene showed an autosomal dominant inheritance pattern. However, a more recent case report described a person with ALSP caused by AARS1 gene variants with an autosomal recessive inheritance pattern.
The estimated number of people in the U.S. thought to have ALSP due to variants in the CSF1R gene is 10,000 with similar estimates in Europe and Japan. More recent data suggest that this number is an underestimate. The average age of diagnosis of CSF1R-ALSP is 43 years old but symptoms have been reported to occur in people as young as 18, and 95% of people with ALSP start having symptoms before age 60. Males and females are equally affected but symptoms usually appear earlier in females, at age 40 versus 47 for males. Life expectancy ranges from 2 to over 30 years, with an average life expectancy of 8 years after symptom onset.
AARS2-related disorder is an ultrarare disorder with fewer than 70 affected individuals reported to date.
ALSP caused by variants in the AARS1 gene has been reported in a multigenerational family of 19 individuals.
There are only a few reports of people with ALSP who do not have variants in the CSF1R, AARS1 or AARS2 genes.
ALSP is diagnosed by a neurologist using genetic testing to identify changes in the CSF1R gene or other related genes. However, doctors first look for warning signs before ordering genetic tests. These include family history, cognitive changes, movement difficulties and brain scan results.
If a person under age 60 has a combination of cognitive (thinking) problems, movement difficulties and seizures, doctors may suspect ALSP. Neurologists, psychiatrists or psychologists can perform cognitive tests to check for signs of frontal lobe dysfunction, such as trouble controlling impulses (reduced inhibition). The presence of premature ovarian failure may provide a clue that ALSP is related to AARS2 gene variants, but no such clue exists for males.
Brain scans (MRI and CT) can reveal patterns of white matter damage that are common in ALSP. Early on, these changes may be uneven, but as the disease progresses, they become more widespread and symmetrical. Affected areas are usually in the frontal and parietal lobes and near the brain’s fluid-filled spaces (ventricles), making them appear enlarged. Other findings include thinning of the corpus callosum (which connects the brain’s two halves) and small calcium deposits in the white matter. In cases of ALSP related to AARS1 gene variants, brain scans show a unique pattern of damage mainly in the white matter near the front of the brain. In AARS2-related leukoencephalopathy the corpus callosum is less severely affected compared with ALSP-CSF1R.
A blood or spinal fluid test measuring neurofilament light chain, a protein linked to axonal nerve damage, can also be part of the diagnostic work-up. It should be noted that this is a non-specific marker, and elevated levels of this protein are detected in many different diseases characterized by rapidly progressing neurological deficit. The measurement of this biomarker is, therefore, used more for monitoring disease progression than in the diagnostic process itself.
There are currently no FDA-approved treatments for ALSP. Researchers are studying underlying disease mechanisms and symptom progression to develop more effective treatment options. Current treatment options do not reverse brain damage but instead are meant to manage symptoms. For patients with ALSP who have seizures, anti-epileptic medications are useful for controlling seizures. Antibiotics may be prescribed to help control infections such as pneumonia or urinary tract infections that may arise as individuals grow progressively weaker. Muscle relaxers may be recommended to target spasticity. Anti-depressants are often prescribed to treat psychological symptoms of ALSP but are not especially effective. Anti-psychotic medications may be used to control aggression in ALSP, but side effects are generally not well-tolerated. Nutritional supplements and physical therapy are often recommended to slow overall decline and maintain the most optimal overall health possible.
Genetic counseling is recommended to help patients and families understand the genetics and progression of ALSP and to provide psychosocial support.
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:
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Some current clinical trials also are posted on the following page on the NORD website:
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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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Tipton PW, Kenney-Jung D, Rush BK, et al. Treatment of CSF1R-related leukoencephalopathy: Breaking New Ground. Mov Disord. 2021 Jul 30. https://pubmed.ncbi.nlm.nih.gov/34329526/
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Han J, Sarlus H, Wszolek ZK, Karrenbauer VD, Harris RA. Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy. Acta Neuropathol Commun. 2020;8(1):217. Published 2020 Dec 7. doi:10.1186/s40478-020-01093-3
Konno T, Yoshida K, Mizuta I, et al. Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. Eur J Neurol. 2018 Jan; 25(1): 142–147. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741468/
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Lynch D, Jaunmuktane Z, Sheerin U, et al. Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series. Journal of Neurology, Neurosurgery & Psychiatry. 2016; 87:512-519. https://jnnp.bmj.com/content/87/5/512.info
Lynch DS, Zhang WJ, Lakshmanan R, et al. Analysis of mutations in AARS2 in a series of CSF1R-negative patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. JAMA Neurol. 2016;73(12):1433-1439. doi:10.1001/jamaneurol.2016.2229
INTERNET
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Chmiela T, Wszolek ZK. AARS2-Related Disorder. 2024 Oct 31. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK608563/ Accessed Feb 18, 2025.
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