Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, inherited neurodegenerative disorder that primarily affects the brain’s white matter. This condition is progressive, meaning symptoms worsen over time, and it typically strikes individuals between their 30s and 50s. A hallmark of ALSP is the destruction of white matter (leukoencephalopathy), which impairs the brain’s ability to transmit signals efficiently. ALSP is now understood to be part of a spectrum of disorders caused by a single genetic defect, collectively referred to as CSF1R-related leukoencephalopathy.
Genetic Origin and Neurological Impact
ALSP is caused by a mutation in the CSF1R gene, which provides instructions for making the Colony Stimulating Factor 1 Receptor protein. This receptor is heavily expressed on microglia, the brain’s resident immune cells. Microglia are responsible for protecting and maintaining neurons by acting as scavengers, clearing cellular debris, and regulating inflammation.
The CSF1R mutation typically results in a dysfunctional receptor protein, impairing the signaling pathways necessary for normal microglial function. This failure to properly support the brain environment classifies ALSP as a primary microgliopathy. The dysfunctional microglia become abnormally pigmented and fail to maintain the health of the nerve fibers.
The failure of microglial support leads to the characteristic pathological features that give the disease its name. Axonal spheroids are focal swellings of the nerve cell extensions (axons), signifying severe damage to the white matter tracts. Damage to the axons and the protective myelin sheath results in the widespread white matter lesions seen in the brain. This neurodegeneration is typically inherited in an autosomal dominant pattern, meaning a person needs only one copy of the altered gene to develop the disorder.
Manifestations of ALSP
The onset of ALSP is highly variable, even among family members carrying the same mutation. The mean age of symptom onset is around 43 years, with the disease duration averaging about six to eight years. Initial clinical presentation is often nonspecific, frequently leading to misdiagnosis as conditions like multiple sclerosis or frontotemporal dementia.
Cognitive impairment is one of the most frequently reported initial symptoms, affecting nearly half of all patients. This involves a progressive decline in mental abilities, starting with difficulties in executive function, such as planning, problem-solving, and impulse control. As the condition advances, these cognitive deficits worsen, culminating in severe dementia.
Behavioral and psychiatric changes are also common early indicators of the disease. Individuals may experience significant shifts in personality, including depression, anxiety, and a loss of social inhibitions. These neuropsychiatric complications can manifest as apathy or changes in mood, reflecting damage in the frontal and temporal lobes.
Motor symptoms usually emerge as the disease progresses, eventually leading to severe physical disability. Patients often develop problems with gait, balance, and muscle stiffness, which can resemble parkinsonism. These motor abnormalities include slow movement, involuntary trembling, and rigidity, severely impacting the ability to walk and perform daily activities.
Establishing a Diagnosis
Diagnosing ALSP is challenging because its symptoms overlap with many common neurological disorders. The diagnostic process begins when a physician notes a combination of progressive cognitive, psychiatric, and motor symptoms in an adult, especially if a family history of a similar disorder exists. A comprehensive evaluation often involves ruling out infectious, inflammatory, and other genetic causes of leukoencephalopathy.
Magnetic Resonance Imaging (MRI) of the brain is a fundamental step in the diagnostic workup, revealing characteristic patterns of white matter lesions. These lesions, which appear as areas of damage and demyelination, are often asymmetrical or predominantly affect the frontal and parietal regions. Specific findings, such as thinning of the corpus callosum and small punctate calcifications, can strongly suggest ALSP.
Despite suggestive clinical and imaging findings, the definitive diagnosis of ALSP relies on genetic sequencing. This test identifies a pathogenic mutation in the CSF1R gene, confirming the underlying molecular cause. Genetic testing is important because it provides diagnostic certainty even when the clinical presentation is unusual or the family history is negative due to a spontaneous new mutation.
Treatment Approaches and Ongoing Research
Currently, there is no approved cure or specific disease-modifying treatment that can halt or reverse the progression of ALSP. The standard of care focuses on symptomatic and supportive management to improve the quality of life. This involves a multidisciplinary approach, using neurological and psychiatric medications to manage specific symptoms like depression, anxiety, and motor rigidity.
Physical, occupational, and speech therapy are often employed to help patients maintain function and mobility. Management strategies are tailored to the individual’s most debilitating symptoms, adapting to the rapid and variable nature of the disease progression. This supportive care is currently the only available option.
One promising investigational therapy is Hematopoietic Stem Cell Transplantation (HSCT). HSCT aims to replace the patient’s faulty microglia with healthy, donor-derived immune cells. Case reports suggest HSCT can stabilize disease progression, particularly when performed early, by providing a supply of functional microglia. However, this procedure carries substantial risks, including high mortality and complication rates, and its long-term efficacy is still under evaluation.
Researchers are also exploring gene editing and gene therapy approaches that directly target the CSF1R mutation. Since overexpression of the CSF1R protein can be problematic, simple gene addition is not feasible, driving interest toward more complex gene editing techniques. These efforts focus on correcting the genetic defect within the patient’s own stem cells, offering an alternative to traditional transplantation and its associated immunological risks.