Cholesterol as a novel biomarker for Fragile X syndrome

Fragile X syndrome, or FXS, is the most common inherited cause of intellectual disability in the U.S. Each year, thousands of people are diagnosed with the condition. Many patients’ families may be told their child will have the condition, with no real knowledge of what life will look like for their child.

While the cause of the disease is known — a mutation in the FMR1 gene — there is a wide range of symptoms among those with the trinucleotide repeat. Tests may catch the disease, but they do not give parents much guidance about what degree of learning disability to expect when raising their kids.

At the University of Sherbrooke in Quebec, Asma Laroui Artuela Çaku and Jean–Francois Lepage sought to identify better biomarkers of FXS function. Their work was published in the Journal of Lipid Research.

“We have access to the FXS clinic, which regroups patients from all around the province, so we can do a lot of associations between the lipid profile and the clinical phenotype,” Çaku said.

The team discovered that levels of 24S-hydroxycholesterol, or 24-OHC — a downstream metabolite of brain cholesterol — decreased in patients with FXS compared with controls. Cholesterol is synthesized in the brain by astrocytes, and excess amounts are converted to 24-OHC before being transported into peripheral circulation. Thus, a drop in 24-OHC in the blood offers a practical way to measure brain cholesterol metabolism in patients with FXS.

The researchers also found that 24-OHC levels were inversely correlated with several neurologic measures. Patients with lower 24-OHC showed slower motor evoked potentials, meaning their motor neurons fired less efficiently when stimulated by transcranial magnetic stimulation. On behavioral and cognitive questionnaires, patients with lower levels of 24-OHC reported greater difficulties with social communication as well as more symptoms of anxiety and depression.

Taken together, these results suggest that 24-OHC could serve as a useful biomarker to help clinicians give families a clearer picture of what to expect after an FXS diagnosis.

“We try to develop techniques that are not invasive,” Çaku said. “In a simple blood collection, you can have information about the brain.” These lipid profiles may help patients and their families better understand their neurologic development.

Laroui added that the findings also shed light on brain cholesterol biology more broadly.

“There is a lot of research from the peripheral, but comparatively fewer studies on brain cholesterol,” she said. “However, we found that in diseases where brain cholesterol is dysregulated, this imbalance can affect the phenotype. We are giving importance to research on brain cholesterol.”

The team now hopes to uncover the source of the abnormal cholesterol metabolism in FXS.

“Maybe it’s the enzyme that’s dysregulated, or maybe the astrocytes cannot produce enough cholesterol,” Laroui said.

Despite these unknowns, the researchers are optimistic that their work will deepen understanding of brain lipid metabolism and open the door to new tools for patient care.