Changes in Cell Lipids May Help Explain Symptom Severity in X-ALD, Study Suggests

Changes in Cell Lipids May Help Explain Symptom Severity in X-ALD, Study Suggests

People with X-linked adrenoleukodystrophy (X-ALD) have an imbalance in the production of important fat molecules, or lipids, in their cells that may influence the symptoms and severity of the disease, a study reports.

The levels of two lipid types — triglycerides and ceramides — distinguishes adrenomyeloneuropathy (a milder form of X-ALD) from childhood cerebral X-ALD (a severe disease form starting early in life), the results suggest.

The study, “Integrative lipidomic and transcriptomic analysis of X-linked adrenoleukodystrophy reveals distinct lipidome signatures between adrenomyeloneuropathy and childhood cerebral adrenoleukodystrophy,” was published in the journal Biochemical and Biophysical Research Communications.

X-ALD is caused by mutations in the ABCD1 gene, and is inherited in an X-linked manner. The disease is a lipid metabolism disorder, marked by the buildup of a type of lipids called very long-chain fatty acids (VLCFA) particularly in the brain, adrenal glands, testis, and skin cells of patients.

X-ALD can manifest in multiple forms, varying in onset age and severity. But the defects in the ABCD1 gene alone cannot explain the molecular basis behind this variability.

Now, a team of researchers at the Seoul National University and the Yonsei University College of Medicine in South Korea are suggesting a more comprehensive approach to identify lipid alterations beyond VLCFAs, to better understand the mechanisms behind X-ALD.

The team compared the lipidomes — the whole lipid content of cells — between healthy people and patients with two types of X-ALD — adrenomyeloneuropathy (AMN) and childhood cerebral adrenoleukodystrophy (CCALD).

CCALD is a more severe form of ALD that typically starts during childhood, between the ages of 4 and 8. It normally involves the brain, where the white matter, especially myelin, a fatty sheath that protects nerve fibers, gets progressively damaged, leading to the worsening of symptoms over time.

AMN is a milder form of ALD, which usually begins in early to mid-adulthood. It progresses slowly, and patients have symptoms such as leg stiffness, pain in the hands and feet, and bladder and bowel problems. It is the most common presentation of the disease.

Researchers quantified the major lipid classes (e.g., phospholipids, glycerolipids, and sphingolipids) in skin cell samples (dermal fibroblasts) of healthy individuals (14 samples), AMN patients (21 samples), and CCALD patients (26 samples).

To determine the lipid profile of cells, they used two standard techniques called chromatography and mass spectrometry.

Results showed there were significant changes in the abundance of some groups of lipids between healthy individuals and the two X-ALD groups.

The team saw that a lipid pathway referred to as the sphingolipid metabolism is more active in AMN cells, resulting in higher levels of a group of lipids called ceramidesAdditionally, the metabolic reactions involved in the production of triglycerides, the most common type of fat in our body, are more active in AMN.

In contrast, CCALD cells are deficient for these two types of lipids.

The difference in triglyceride levels between AMN and CCALD cells was seen specifically for triglycerides with shorter fatty acid chains — the ones that typically exist and are used by healthy cells. Triglycerides are made of glycerol and three fatty acid molecules that may vary in the length of their chains, depending on the number of carbon atoms they contain.

Researchers also measured the activity of genes involved in the metabolism of lipids in the healthy, AMN, and CCALD samples.

They observed changes in gene expression that supported the trends observed in lipid levels.

These results suggest that, in people with X-ALD, there is a “collapse of the lipid homeostasis [physiological balance], especially in typical lipids that are physiologically essential for healthy control,” the researchers concluded.

According to the team, the results also suggest that ceramides and the related sphingolipid metabolism “may be the highly relevant signatures” responsible for the disease variations in X-ALD, and that the dysfunction of typical triglycerides “might biochemically be associated with [disease] severity in CCALD patients.”

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