Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, progressive brain disease. ALSP damages white matter (tissue in the brain), which can lead to changes in personality, thinking and cognitive function, and muscle function. As the disease progresses, people with ALSP can develop dementia and lose the ability to walk, talk, or complete daily tasks.
Percentage of adult-onset leukodystrophies that are ALSP
Average age of diagnosis
Average life expectancy after symptoms start
ALSP is caused by a mutation in the CSF1R (colony-stimulating factor-1 receptor) gene. This gene plays an important role in cell growth and is found throughout the central nervous system. When the CSF1R gene does not function normally, it changes the structure of nerve cells (neurons), damaging nerve cell function and causing problems with movement and thinking.
These structural changes in neurons are what give ALSP its name:
– The CSF1R mutation causes harmful bulges called spheroids to develop on the nerve fibers (called axons) that send signals to neurons throughout the brain.
– Spheroids cause damage to the myelin sheath, the protective coating around nerve fibers. This is a key characteristic of all leukoencephalopathy disorders.
– The CSF1R mutation also reduces the ability of microglia—a type of immune cell—to protect neurons.
– Microglia appear pigmented in brain biopsies of people with ALSP.
The combination of spheroids, damage to myelin, and underactive microglia cause the symptoms of ALSP.
The altered CSF1R gene that causes ALSP can be passed down from one parent (inherited) or may be the result of a new genetic mutation (sporadic). There is a 50% chance that a person with the altered gene will pass it to their child. The exact number of ALSP cases are unknown, but it’s estimated that 10,000 people in the United States have the disease.
Initial symptoms and the rate of disease progression can vary, even from person to person within a single family. People with ALSP begin experiencing symptoms before age 60 in 95% of cases. In some rare instances, people have reported symptoms starting as young as 18 years old. Both men and women can develop ALSP, but women generally show symptoms earlier—around age 40, compared to age 47 for men.
Early symptoms of ALSP typically involve psychological and cognitive changes, but in rare cases, they can appear as motor problems, such as trouble with walking or slow movements. Seizures are reported by around 30% of people with ALSP, usually as an early symptom.
As the disease progresses, people with ALSP often experience a combination of cognitive, motor, and psychological symptoms:
Eventually, people with ALSP lose the ability to walk and speak, lose control of most other bodily functions, and require daily care. The average life expectancy for someone with ALSP is 8 years after symptoms begin, though actual life expectancy can range from anywhere between 2 and 30+ years depending on the individual case.
ALSP used to be classified as two separate disorders: hereditary diffuse leukoencephalopathy with spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD). Both diseases cause damage to white matter and present with similar signs and symptoms, but after both were linked to the abnormal CSF1R gene, researchers re-classified them collectively as ALSP.
Because the disease is linked to an abnormal gene, genetic testing to identify the CSF1R gene variant can provide a diagnosis for ALSP. The average age of diagnosis is 43 years old.
Signs that can point to ALSP and may lead doctors to order genetic testing include family history, cognitive and movement-related symptoms before age 60, and brain imaging that shows white matter lesions and other deterioration.
ALSP is often initially misdiagnosed because many symptoms overlap with other types of leukodystrophies and other neurological disorders, such as frontotemporal dementias, multiple sclerosis, and Parkinson’s disease. Genetic testing can clarify symptoms and provide a diagnosis in many of these cases.
There are no cures or FDA-approved treatments for ALSP, but there are some options available to help manage symptoms and slow disease progression. These treatments include anti-seizure medication for people who experience ALSP-linked seizures, muscle relaxers to help with muscle tightness and stiffness, and antidepressants to manage psychological symptoms. Nutritional supplements and physical therapy are also often recommended to promote better range of movement and overall health.
Because ALSP is caused by an abnormal gene, genetic counseling can be helpful for individuals and families to better understand the disease and receive additional support.
Research efforts are focused on understanding how ALSP begins and progresses in order to develop more effective treatments. Among current clinical trials, researchers are studying whether bone marrow transplants may be effective as the first potential treatment to modify the disease itself. In these cases, bone marrow transplants provide new, healthy immune cells from people without the abnormal CSF1R gene mutation, which researchers think may be able to increase microglia in the brain and slow symptom progression.
Sisters’ Hope Foundation for ALSP
National Organization for Rare Disorders: ALSP
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