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-O-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 CYP27A1 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.
Highlights
Cerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy
Three CTX-positive dried bloodspot (DBS) from Druze newborns known to be homozygous for the pathogenic founder c.355delC CYP27A1 gene variant [27], as well as known carrier newborn DBSs, were retrieved from the Israeli Newborn Screening Laboratory archives
The newborn DBSs had been stored for 3–8 years refrigerated (4°C) and were from children previously identified as being affected with CTX or as carriers through prenatal genetic testing, performed as part of a community-wide screening program for genetic diseases established and overseen in the region by Falik-Zaccai et al [15]
Summary
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. 5 -cholestane3 ,7 ,12 ,25-tetrol-3-O- -D-glucuronide was identified as the predominant bile-alcohol disease marker present in CTXpositive newborn DBSs. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC CYP27A1 gene variant, providing an estimated disease prevalence of 1:3,600 in this population. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC CYP27A1 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.— DeBarber, A. Cholestatic jaundice can be a presenting symptom of CTX in neonates [6,7,8,9] This may be self-limiting or progress to severe liver disease that can result in death from liver failure [8, 9].
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