Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment

Abstract

Cerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy. Early identification and treatment from birth onward effectively provides a functional cure, but diagnosis is often delayed. We conducted a pilot study using a two-tier test for CTX to screen archived newborn dried bloodspots (DBSs) or samples collected prospectively from a high-risk Israeli newborn population. All DBS samples were analyzed with flow injection analysis (FIA)-MS/MS, and 5% of samples were analyzed with LC-MS/MS. Consecutively collected samples were analyzed to identify CTX-causing founder genetic variants common among Druze and Moroccan Jewish populations. First-tier analysis with FIA-MS/MS provided 100% sensitivity to detect CTX-positive newborn DBSs, with a low false-positive rate (0.1-0.5%). LC-MS/MS, as a second-tier test, provided 100% sensitivity to detect CTX-positive newborn DBSs with a false-positive rate of 0% (100% specificity). In addition, 5β-cholestane-3α,7α,12α,25-tetrol-3--β-D-glucuronide was identified as the predominant bile-alcohol disease marker present in CTX-positive newborn DBSs. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC gene variant, providing an estimated disease prevalence of 1:3,600 in this population. These data support the feasibility of two-tier DBS screening for CTX in newborns and set the stage for large-scale prospective pilot studies.

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

“…We did not investigate the stability of GlcA-tetrol in DBS, as previous studies demonstrated that GlcA-tetrol is stable for at least 3 weeks in DBS stored at room temperature. 7 , 10 This stability study is adequate for our studies since the DBS were stored for up to 1–2 months at room temperature prior to analysis. No external calibration was used in our routine analysis; the GlcA-tetrol concentration in DBS was calculated using the internal standard.…”

“… 6 Since an early start of therapy can prevent the neurological phenotype completely, and patients are expected to remain symptom-free if treatment is started immediately after neonatal diagnosis, CTX is considered to be an excellent candidate disease for newborn screening programs. 3 , 5 , 7 , 8 …”

“… 9 Quantification of 7α12αC4 was performed with a derivatization step to improve LC-MS/MS method sensitivity, or more recently, without derivatization but using a more sensitive LC-MS/MS instrument. 7 , 9 The second CTX newborn screening method was described by Vaz et al and is based on measuring the amount of a bile alcohol, 5β-cholestane-3α,7α,12α,25-tetrol glucuronide (GlcA-tetrol), as well as the ratio of GlcA-tetrol to tauro-chenodeoxycholic acid (t-CDCA) in DBS using flow-injection MS/MS. 10 It was also recommended to measure the tauro-trihydroxycholestanoic acid (t-THCA) level and calculate the t-THCA/GlcA-tetrol ratio as a secondary disease indicator to distinguish CTX patients from cholestasis and Zellweger patients.…”

Case Report: Early Treatment With Chenodeoxycholic Acid in Cerebrotendinous Xanthomatosis Presenting as Neonatal Cholestasis

“…It has been previously demonstrated that starting treatment as early as possible can improve and even avoid the onset of neurological involvement ( 10 , 29 ). Taking into account this observation, some authors suggest to include CTX in newborn screening ( 30 , 31 ).…”

Harmonizing Newborn Screening Laboratory Proficiency Test Results Using the CDC NSQAP Reference Materials

“…Since laboratory testing methodologies that establish cutoffs vary, it is difficult to directly compare metabolite results and cutoffs between NBS laboratories. Variability between NBS results and cutoffs may also occur for the following reasons: not accounting for metabolite recovery, the use of additional metabolites or metabolite ratios per screening disorder [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ], differences in mass spectrometer vendor and model, differences in internal standard surrogates [ 12 , 13 ], and varying use of calibration curves.…”