New metabolic screening

developed for newborns

Published August 01 2017


Researchers in the Netherlands used dried blood spots from infants to screen for Cerebrotendinous xanthomatosis, known as CTX.Photo courtesy of Frédéric Vaz

Newborn screening programs are used worldwide for detecting and treating hereditary diseases. Many of these diseases, if left untreated, will cause complications that later become life-threatening. In a recent paper in the Journal of Lipid Research, Frédéric Vaz and colleagues from the Academic Medical Center, Amsterdam, and the Erasmus Medical Center, Rotterdam, describe the development of a new screen for Cerebrotendinous xanthomatosis, known as CTX.

CTX is estimated to occur in about one out of every 40,000 to 200,000 people and is caused by a deficiency of 27-sterol hydroxylase, an enzyme encoded by the CYP27A1 gene. Lack of this enzyme causes a metabolic block in bile acid synthesis. This block results in deficiency of primary bile acids cholic acid and chenodeoxycholic acid and accumulation of bile alcohols and cholestanol. The buildup of bile alcohols — which consist primarily of a tetrol named cholestenol — as well as cholesterol is thought to contribute to pathology seen in CTX patients.

Symptoms of CTX can present during infancy or in childhood and include neonatal cholestasis due to the bile acid production block, bilateral cataract and developmental delay. CTX often is diagnosed in adulthood and is characterized by both neurological and non-neurological symptoms. Supplementation with chenodeoxycholic acid starting at an early age can prevent CTX symptoms. “It is hard to swallow that an effective treatment for this severe disease is already available, but no validated newborn screening method is yet available,” senior author Hidde Huidekoper stated. “The disease causes irreversible neurological damage, and diagnostic delay greatly affects the outcome of patients with CTX.”

The method developed by Vaz and his team primarily relies on quantification of sugar-conjugated tetrols and amino acid-conjugated chenodeoxycholic acids from dried blood spots using negative ion electrospray mass spectrometry. This technology selects the ions based on their mass and, after fragmentation, detects specific fragments characteristic of the metabolites of interest. Importantly, using the researchers’ new workflow, the samples do not have to undergo expensive and time-consuming derivatization steps. Removing the need for these steps allows for expansion of newborn screening programs and fast turnaround times for newborn diagnosis. Using their methodology, the researchers were able reliably to distinguish CTX newborn samples from other bile acid-synthesis disorders using metabolite ratios of the sugar-conjugated tetrol to amino acid-conjugated chenodeoxycholic acid. Furthermore, their work easily can be integrated into current newborn screening programs at hospitals.

The identification of a consistent metabolic biomarker for CTX paves the way for a larger pilot study. “We think that the method we have now developed has the potential of being used as a one-tier screening method for CTX and can be implemented into newborn screening laboratories worldwide after conducting a successful pilot study,” Huidekoper stated. Although Vaz and his team screened a total of 150 term and 50 preterm newborns, a much larger study is planned to include at least 100,000 newborn dried blood spots to validate their new technique on a grander scale. “We hope to really speed up the development of a suitable newborn screening method for CTX,” Huidekoper stated, “and have established a collaboration with Andrea DeBarber at Oregon Health and Sciences University, and other international partners who are actively pursuing the introduction of CTX into newborn screening programs.” It seems a better prognosis is on the horizon for CTX patients.


Alexandra Nail Alexandra Nail is a Ph.D. candidate at the University of Kentucky.