Overview

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, progressive neurological condition characterized by changes to the white matter of the brain. White matter contains nerve cells (neurons) and their nerve fibers (axons) which are surrounded by a protective myelin sheath covering as well as glial cells which protect and maintain the neurons. In ALSP, the axons have bubble-like spheroids and damaged microglia which lead to loss of the myelin covering. These alterations can cause changes in personality, behavior, motor control, thinking and cognitive function. The presenting symptoms and disease progression of ALSP can vary greatly from person to person, making diagnosis difficult. As the disease advances, there is a severe decline in thinking and reasoning abilities leading to the inability to walk, talk or provide self care. There is currently no cure for ALSP.

ALSP may also be referred to by the following terms:

  • POLD (Pigmented Orthochromatic Leukodystrophy)

  • HDLS (Hereditary Diffuse Leukoencephalopathy with Spheroids)

  • CSF1R-ALSP

  • CSF1R Related Leukoencephalopathy

  • CSF1R Related Disease

CSF1R-ALSP

Causes

ALSP can be caused by mutations in various genes, the most common being a colony-stimulating factor-1 receptor (CSF1R) gene mutation on chromosome 5. The CSF1R mutation is autosomal dominant, meaning only one copy of the gene is needed to cause the condition (see diagram). This gene provides instructions to make the CSF-1 receptor protein which stimulates signaling pathways needed for cell growth, division and differentiation. The mutation prevents these signaling pathways from being stimulated.

An autosomal dominant disease means that each child born to someone who has the CSF1R gene mutation has a 50% chance of also having this mutation. Because ALSP is often diagnosed after the childbearing years, most individuals have already had children by the time they are aware they have the disease. Currently there is no newborn genetic testing for the CSF1R gene mutation that causes ALSP.

The CSF1R mutation affects cells within the body that are part of the immune system. These cells are called macrophages and microglia. The mutation causes neurons to be misshapen due to the presence of spheroids in part of the cell. Macrophages take myelin away from the misshaped neurons which causes further damage. The CSF1R mutation also leads to underactive microglia, cells that are normally protective for neurons. The combination of neuron spheroids, lack of myelin, and underactive microglia are what cause the symptoms of ALSP.

There are other less common causes of ALSP.

BANDDOS (brain abnormalities, neurodegeneration, and dysosteosclerosis) is caused by autosomal recessive mutations in the CSF1R gene, meaning two copies of the mutated CSF1R gene (one from each parent) are needed to cause the disorder. Learn more here.

A less common cause of ALSP is a mutation in the AARS1 or AARS2 genes. Autosomal recessive mutations in the AARS2 (alanyl-transfer tRNA synthetase 2) gene can cause two different phenotypes. Some mutations can cause fatal, early-onset cardiomyopathy in infants, while others can cause late-onset leukoencephalopathy as seen in ALSP. Learn more here.

ALSP can also be caused by an undermined genetic mutation where patients show brain changes and characteristics associated with ALSP, but they test negative for the CSF1R and AARS1/AARS2 gene mutations, meaning there is a new, unknown mutation causing their ALSP.

Symptoms of ALSP vary from person to person. Symptoms depend on what part of the brain is affected.

Symptoms

Risk Factors

Established risk factors for ALSP include:

Genetics. A mutation in the CSF1R gene can cause ALSP. Each child of an affected parent has a 50/50 chance of inheriting the mutation.

Age. ALSP disease onset is generally between 30-50 years of age.

Sex. Each sex is at equal risk of inheriting the mutated gene. Women tend to exhibit symptoms an average of 7 years before men.

There are no known environmental factors.