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Toward newborn screening of cerebrotendinous xanthomatosis: results of a biomarker research study using 32,000 newborn dried blood spots.

ABSTRACT: Purpose: Cerebrotendinous xanthomatosis (CTX) is a treatable hereditary disorder caused by the deficiency of sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. Different newborn screening biomarkers for CTX have been described, including 7?,12?-dihydroxy-4-cholesten-3-one (7?12?C4), 5?-cholestane-3?,7?,12?,25-tetrol glucuronide (GlcA-tetrol), the ratio of GlcA-tetrol to tauro-chenodeoxycholic acid (t-CDCA) (GlcA-tetrol/t-CDCA), and the ratio of tauro-trihydroxycholestanoic acid (t-THCA) to GlcA-tetrol (t-THCA/GlcA-tetrol). We set out to evaluate these screening methods in a research study using over 32,000 newborn dried blood spots (DBS).

Methods: Metabolites were extracted from DBS with methanol containing internal standard, which was then quantified by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).

Results: The measurement of 7?12?C4 was complicated by isobaric interferences and was discontinued. A total of 32,737 newborns were screened based on the GlcA-tetrol concentration in DBS. GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios were also calculated. Newborns displaying both elevated GlcA-tetrol and GlcA-tetrol/t-CDCA ratio were considered to be screen positives. The t-THCA/GlcA-tetrol ratio was used to further distinguish CTX screen positives from Zellweger Spectrum Disorder (ZSD) screen positives. Only one newborn displayed both elevated GlcA-tetrol concentration in DBS and a typical CTX biochemical profile. This newborn was interpreted as a CTX-affected patient as CYP27A1 gene sequencing identified two known pathogenic variants.

Conclusion: The results indicate that both GlcA-tetrol and the GlcA-tetrol/t-CDCA ratio are excellent CTX biomarkers suitable for newborn screening. By characterizing the relationship of GlcA-tetrol, t-CDCA, and t-THCA as secondary markers, 100% assay specificity can be achieved.

SUBMITTER: Hong X

PROVIDER: S-EPMC7529987 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Toward newborn screening of cerebrotendinous xanthomatosis: results of a biomarker research study using 32,000 newborn dried blood spots.

Hong Xinying X Daiker Jessica J Sadilek Martin M DeBarber Andrea E AE Chiang John J Duan Jie J Bootsma Albert H AH Huidekoper Hidde H HH Vaz Frédéric M FM Gelb Michael H MH

Genetics in medicine : official journal of the American College of Medical Genetics 20200610 10

<h4>Purpose</h4>Cerebrotendinous xanthomatosis (CTX) is a treatable hereditary disorder caused by the deficiency of sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. Different newborn screening biomarkers for CTX have been described, including 7α,12α-dihydroxy-4-cholesten-3-one (7α12αC4), 5β-cholestane-3α,7α,12α,25-tetrol glucuronide (GlcA-tetrol), the ratio of GlcA-tetrol to tauro-chenodeoxycholic acid (t-CDCA) (GlcA-tetrol/t-CDCA), and the ratio of tauro-trihydroxycholestanoic acid ...[more]

PMID: 32523054

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Project description:ImportanceResearch clearly indicates that current approaches to newborn blood spot screening (NBS) education are ineffective. Incorporating NBS education into prenatal care is broadly supported by lay and professional opinion.ObjectiveTo determine the efficacy and effect of prenatal education about newborn screening and use of residual dried blood spots (DBS) in research on parental knowledge, attitudes, and behaviors.Design, setting, and participantsA randomized clinical trial of prenatal educational interventions, with outcomes measured by survey at 2 to 4 weeks postpartum. Participants were recruited from obstetric clinics in Salt Lake City, Utah; San Francisco, California; and the Bronx, New York. Eligible women were English- or Spanish-speaking adults and did not have a high-risk pregnancy. A total of 901 women were enrolled. Participants who completed the follow-up survey included 212 women in the usual care group (70% retention), 231 in the NBS group (77% retention), and 221 women in the NBS?+?DBS group (75% retention). Those who completed the survey were similar across the 3 groups with respect to age, ethnicity, race, education, marital status, income, obstetric history, and language.InterventionsParticipants were randomized into 1 of 3 groups: usual care (n?=?305), those viewing an NBS movie and brochure (n?=?300), and those viewing both the NBS and DBS movies and brochures (n?=?296).Main outcomes and measuresTwo to four weeks postpartum, women completed a 91-item survey by telephone, addressing knowledge, attitudes, and behavior with respect to opting out of NBS or DBS for their child.ResultsA total of 901 women (mean age, 31 years) were randomized and 664 completed the follow-up survey. The total correct responses on the knowledge instrument in regard to NBS were 69% in the usual care group, 79% in the NBS group, and 75% in the NBS?+?DBS group, a significant between-group difference (P?<?.05). Although all groups showed strong support for NBS, the percentage of women who were "very supportive" was highest in the NBS group (94%), followed by the NBS + DBS group (86%) and was lowest in the usual care group (73%) (P < .001). The interventions were not associated with decisions to decline newborn screening or withdraw residual DBS. Nine women stated that they had declined NBS (all the usual care group; P < .001). With respect to DBS, 5 participants indicated that they contacted the health department to have their child's sample withdrawn after testing: 3 in the NBS + DBS group and 2 in the usual care group (P = .25).Conclusions and relevanceEducational interventions can be implemented in the prenatal clinic, using multimedia tools and electronic platforms. Prenatal education is effective in increasing postnatal knowledge and support for these programs. These results are relevant to other contexts in which residual clinical specimens and data are used for research purposes.Clinical trial registrationclinicaltrials.gov Identifier: NCT02676245.

Dataset Information

Toward newborn screening of cerebrotendinous xanthomatosis: results of a biomarker research study using 32,000 newborn dried blood spots.

Publications

Toward newborn screening of cerebrotendinous xanthomatosis: results of a biomarker research study using 32,000 newborn dried blood spots.

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