A report on state‐wide implementation of newborn screening for X‐linked Adrenoleukodystrophy

Abstract

Minnesota became the fourth state to begin newborn screening (NBS) for X‐linked adrenoleukodystrophy (X‐ALD) in 2017. As there is limited retrospective data available on NBS for X‐ALD, we analyzed Minnesota's NBS results from the first year of screening. C26:0 lysophosphatidylcholine (C26:0‐LPC) screening results of 67,836 infants and confirmatory testing ( ABCD1 gene and serum VLCFA analysis) for screen positives were obtained. Fourteen infants (nine males, five females) screened positive for X‐ALD and all were subsequently confirmed to have X‐ALD, with zero false positives. The birth prevalence of X‐ALD in screened infants was 1 in 4,845 and 1 in 3,878 males, more than five times previous reported incidences. Pedigrees of affected infants were analyzed, and 17 male (mean age of 17) and 24 female relatives were subsequently diagnosed with X‐ALD. Phenotypes of these family members included self‐reported mild neuropathy symptoms in two males and seven females, and childhood cerebral disease (ccALD) and adrenal insufficiency in one male. We observed fewer cases of ccALD and adrenal insufficiency than expected in male family members (5.9% of males for both) compared to previous observations. Together, these findings suggest that the spectrum of X‐ALD may be broader than previously described and that milder cases may previously have been underrepresented. Other challenges included a high frequency of variants of uncertain significance in ABCD1 and an inability to predict phenotypic severity. We posit that thoughtful planning to address these novel challenges and coordination by dedicated specialists will be imperative for successful implementation of population‐based screening for X‐ALD.

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

“…As the number of analytes scales to hundreds or thousands, the requirement for automated methods of supervised classification provides an opportunity to gather additional information, with the whole being more significant than the sum of the individual parts. These circumstances have been long-established in NBS with incremental improvements to existing methods [15,16,[18][19][20]57]. As has been described, by switching the diagnostic method for the single disorder, PKU, over to mass spectrometry, dozens of other of conditions have been able to be simultaneously tested in the NBS, enabling early-and pre-symptomatic detection of these conditions, affording better health outcomes.…”

“…NBS has advanced substantially over the past ten years. Numerous applications of metabolomic-based NBS have been piloted, introduced or proposed in recent years [15,16]. The US Health Resources and Services Administration Recommended Uniform Screening Panel has currently mandated 57 conditions amenable to mass screening of neonates, including some lysosomal, peroxisomal as well as non-metabolic genetic disorders, such as spinal muscular atrophy and severe combined immunodeficiency [13].…”

The Clinical Impact of CLIR Tools toward Rapid Resolution of Post-Newborn Screening Confirmatory Testing for X-Linked Adrenoleukodystrophy in California

“…The reduction could be extended to over 60% if a more aggressive informative threshold was used. Without any reduction in diagnosed ALD cases with VUS, the prevalence of ALD in California screening population was about 1 in 10,000, higher than that reported in the earlier literature (1 in 21,000) and in New York (1 in 16,074) [ 2 , 28 ], although significantly lower than that reported by Minnesota [ 21 ]. With a more aggressive interpretation algorithm when using the CLIR POX tool, the reduction in ALD cases would lead to a prevalence that was similar to the prevalence reported by the New York newborn screening program.…”

“…Since the start of ALD newborn screening in California, a larger proportion of screen positive infant boys have been found to have a VUS on the ABCD1 gene, compared to the reports from other state programs [ 21 , 28 ]. They have been considered to have ALD if the plasma VLCFA confirmatory test is positive, which is the case for most of them.…”

“…Once the results of variant analysis are available, the California Genetic Disease Screening Program (GDSP) refers all ALD-positive cases to one of fourteen metabolic Special Care Centers (SCCs) across the state for clinical follow-up, which includes a diagnostic process based on screening results and other confirmatory testing. Plasma very long-chain fatty acid (VLCFA) analysis is the main confirmatory measure for ALD diagnosis [ 18 , 19 , 20 ], and has been integrated in other state ALD screening programs [ 14 , 21 ]. For the majority of ALD positive cases in California, the SCC will order plasma VLCFA to confirm the elevated C26:0-LPC found on newborn screening; they may also order additional confirmatory testing to differentiate an ALD diagnosis from other peroxisomal disorders (such as Zellweger spectrum disorder) or from a false positive.…”