Measuring the levels of three biomarkers in the blood may help identify newborns at risk of X-linked adrenoleukodystrophy (X-ALD), a Chinese study suggests.
The study, “Evaluation of a panel of very long-chain lysophosphatidylcholines and acylcarnitines for screening of X-linked adrenoleukodystrophy in China,” was published in the journal Clinica Chimica Acta.
X-ALD is a neurodegenerative disease caused by mutations in the ABCD1 gene, which lead to the accumulation of a type of fat, called saturated very long-chain fatty acids (VLCFA), in tissues, including the brain and spinal cord.
Although at birth patients with X-ALD show no symptoms, a subgroup of male patients has a higher risk of developing a fast and severe brain demyelinating disease known as cerebral ALD (cALD). Estimates show that male newborns with X-ALD have a 35% increased risk of developing cALD later in life (from age 2.5 to 10 years).
Hematopoietic (blood) stem cell transplant is the most effective treatment for these cases, but it can only be done in a short time window at early stages of the disease.
Currently, X-ALD is diagnosed through tests measuring VLCFA, and genetic analysis of ABCD1 mutations. Yet, “because these methods are time-consuming and laborious, it is difficult to use them as screening methods to effectively identify patients with higher risk before their clinical symptoms appear,” the researchers wrote.
Newborn screening using reliable biomarkers could improve the outcome and prognosis of these patients.
Recently, elevated blood levels of three markers — called C24:0 carnitine, C26:0 carnitine, and lysophosphadylchilines (LPCs) — have been suggested as diagnostic biomarkers for X-ALD. Carnitines are derivatives from amino acids (the building blocks of proteins), and LPCs are a type of fat linked to inflammation.
In the new study, a group of Chinese researchers investigated the threshold limits and reference values for VLC acylcarnitines (C20, C22, C24, C26) and LPCs (C20:0-, C22:0-, C24:0-, C26:0-LPC) to determine those that could help identify children at risk for X-ALD.
The team used a technique called “flow injection analysis tandem mass spectrometry” to quantify these biomarkers in dry blood spots from seven boys with X-ALD, and 396 healthy age-matched boys.
Results showed that a cut-off value of 0.05 umol/L for C24, 0.046 umol/L for C26, and the ratios between C24/C22 and C26/C22 were able to correctly distinguish X-ALD patients from healthy controls.
From this analysis, the team also showed that C24, C26, and their ratio had a 100% sensitivity and specificity for detecting X-ALD. A test’s sensitivity indicates its ability to correctly identify those with a given disease, while specificity refers to correctly identifying those without it.
Then, to establish reference intervals suitable for the screening of newborns, the researchers quantified these biomarkers in 3,078 apparently healthy newborns. The results showed that newborns had significantly different biomarker levels compared to children.
Specifically, cut-off values for C26 and C22 were lower in newborns — C26 was 0.02 umol/L in newborns (versus 0.046 umol/L in children), and the C26/C22 ratio was 2 (versus 4 in children).
In contrast, the upper limits for C26:0-LPC, C26:0/C22:0-LPC, and C24:0/C22:0-LPC ratios were significantly higher in newborns than in children (C26:0-LPC was 0.34 versus 0.3 umol/L in children; C26:0/C22:0-LPC was 3 versus 2.12 in children; and C24:0/C22:0-LPC was 5.15 versus 4 in children).
Overall, “we found that C26:0-LPC, C24, and C26 are three most valuable biomarkers for screening X-ALD in children,” the researchers wrote, adding that “the reference intervals of C26 and C26:0-LPC are significantly different between newborns and children.”
“We anticipate that this preliminary study can promote the implementation of screening for X-ALD in China as a national public health project,” the researchers said.