Axonal Spheroids and Pigmented Glia (ALSP)

Dr. La Piana, MD, PhD, Professor in McGill’s Department of Neurology and Neurosurgery, defines ALSP and its diagnostic process.

Transcription:
ALSP is… well, first of all, let's start with the name. It's an acronym which stands for a very long name for a disease which is adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

The name is so complex and long to remember that with a community of experts, we are working towards establishing whether it's more convenient to change it into CSF1R-related disorders. Currently, in the literature, you can find these two terms as actually synonyms. ALSP or CSF1R-related disorders are the same entity. This is a genetic leukoencephalopathy, so a genetic white matter disorder, caused by mutations in a gene called CSF1R, which stands for colony-stimulating factor.

This gene is crucial for the proliferation function of microglia. Microglia are the resident immune cells in the brain in the central nervous system. In this way, ALSP is unique in the landscape of genetic white matter disorders, because it's one of the very few primary microgliopathies. While all other genetic white matter disorders are caused by a mutation and malfunctioning of oligodendrocytes or astrocytes, ALSP is a microgliopathy.

In this sense, I can start anticipating why it is so important, the right diagnosis, because microgliopathy being involved in immunity in general, we understand how this is often misdiagnosed as multiple sclerosis.

First of all, ALSP is still worldwide, highly underdiagnosed. The number of patients known worldwide is really low in comparison to what the prediction of the real prevalence of the diseases are. This is because ALSP is frequently misdiagnosed with other disorders. Why is that? Well, because the onset is usually in the fourth to fifth decade of life, and usually it starts very insidiously with mild cognitive problems, mild psychiatric disturbances such as apathetic features, depression, anxiety, behavioral disturbances that become more important over time.

Sometimes it can also present, or these symptoms can be accompanied by motor deficits like walking difficulties or Parkinsonism. These are the classical presentations of the disease. When the patients are investigated, usually white matter abnormalities are found in the brain. Usually, these white matter abnormalities are mainly located… They have a frontal predominance.

We see the majority of the white matter abnormalities in the frontal regions of the brain, but they can be multifocal. Hence, the misdiagnosis with acquired myelin disorders, such as multiple sclerosis or frontotemporal dementia, because frontotemporal dementia has an involvement of the frontal regions of the brain, of the frontal lobes, and that's why often the two disorders are also misdiagnosed.

To answer your question, with regard to how we can improve the diagnosis, well, first of all, awareness. We really need to increase education and awareness among the medical community. The disorder is still very much ignored by many neurologists, family physicians, but also neurologists. We really need to spread awareness about the disorder, because these patients will not present immediately to white matter experts.

They will present more classically to either movement disorder experts, and then they can be misdiagnosed as Parkinson's disease or to dementia and cognitive neurocognitive specialists, MS physicians. All these categories, they need to keep in mind ALSP and to keep that disorder in the differential diagnosis of these patients, especially when white matter abnormalities are disclosed by MRI.