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Newborn screening for Cerebrotendinous Xanthomatosis: A retrospective biomarker study using both flow-injection and
Frédéric M Vaz1, Youssra Jamal2, Rob Barto2
1Amsterdam UMC Location University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands; United for Metabolic Diseases, the Netherlands.
Insights
Newborn screening for Cerebrotendinous Xanthomatosis (CTX) is feasible using metabolite ratios. This study demonstrates that measuring specific biomarkers in dried blood spots can effectively identify potential CTX cases in newborns.
Area of Science:
- Biochemistry
- Genetics
- Neonatal Medicine
Background:
- Cerebrotendinous Xanthomatosis (CTX) is a treatable genetic disorder of bile acid synthesis.
- It results from a deficiency in 27-sterol hydroxylase (CYP27A1), leading to gastrointestinal and neuropsychiatric symptoms.
- Biochemical hallmarks include elevated cholestanetetrol glucuronide (GlcA-tetrol) and reduced tauro-chenodeoxycholic acid (t-CDCA) and tauro-trihydroxycholestanoic acid (t-THCA).
Purpose of the Study:
- To evaluate the feasibility of implementing newborn screening (NBS) for Cerebrotendinous Xanthomatosis (CTX).
- To assess the utility of specific bile acid metabolite ratios as biomarkers for CTX in newborns.
- To determine the effectiveness of mass spectrometry techniques for CTX detection in dried blood spots.
Main Methods:
- Analyzed 20,076 deidentified Dutch newborn dried blood spots (DBS).
- Employed flow-injection analysis (FIA)-MS/MS and ultra-performance liquid chromatography (UPLC)-MS/MS.
- Measured GlcA-tetrol concentration and calculated metabolite ratios (GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol).
Main Results:
- UPLC-MS/MS analysis showed that GlcA-tetrol concentration and the GlcA-tetrol/t-CDCA ratio are informative biomarkers.
- Newborn DBS results using these markers did not overlap with those from CTX patients.
- FIA-MS/MS also identified GlcA-tetrol as a strong marker, and metabolite ratios showed no false positives.
Conclusions:
- Newborn screening for CTX is achievable using metabolite ratios and three key biomarkers.
- Both FIA-MS/MS and UPLC-MS/MS are suitable analytical methods for CTX NBS.
- These findings support the potential introduction of CTX newborn screening programs.
Background And Aims:
Cerebrotendinous Xanthomatosis (CTX) is a treatable disorder of bile acid synthesis caused by deficiency of 27-sterol hydroxylase -encoded by CYP27A1- leading to gastrointestinal and progressive neuropsychiatric symptoms. Biochemically, CTX is characterized by accumulation of the bile alcohol cholestanetetrol glucuronide (GlcA-tetrol) and the deficiency of tauro-chenodeoxycholic acid (t-CDCA) and tauro-trihydroxycholestanoic acid (t-THCA).
Materials And Methods:
To ascertain the feasibility of CTX newborn screening (NBS) we performed a study with deidentified Dutch dried blood spots using reagents and equipment that is frequently used in NBS laboratories. 20,076 deidentified newborn blood spots were subjected to flow-injection (FIA)-MS/MS and UPLC-MS/MS analysis to determine the concentration of GlcA-tetrol and calculate the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios.
Results:
Using UPLC-MS/MS analysis both GlcA-tetrol concentration and/or metabolite ratios GlcA-tetrol/t-CDCA proved to be informative biomarkers; newborn DBS results did not overlap with those of the CTX patients. For FIA-MS/MS, GlcA-tetrol also was an excellent marker but when using the combination of the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios also did not yield any screen positives.
Conclusion:
Newborn screening for CTX using only metabolite ratios following the measurement of three CTX biomarkers is possible using either FIA-MS/MS or UPLC-MS/MS, which paves the way for introduction of CTX NBS.
