Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia (ALSP)

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:

• Cognitive symptoms include issues with language, memory, attention, problem solving, and impulse control, and can progress to mental decline and dementia.
• Motor symptoms include overactive reflexes, muscle stiffness, muscle spasms or tremors, weakness, slow movements, and problems with coordination, vision, and speech. These symptoms can make it difficult to walk, swallow, and speak.
• Psychological symptoms include changes in personality and mood, depression, anxiety, irritability, and issues with social behaviors.

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.