Evaluating the feasibility and diagnostic performance of a multi-tier newborn screening algorithm for X-linked adrenoleukodystrophy in Denmark

ABCD1

Dried blood spot C26:0-lysophosphatidylcholine measurement, followed by targeted NGS of ABCD1 and X-chromosome copy number

This retrospective Danish study evaluates a three-tier newborn screening algorithm for X-linked adrenoleukodystrophy (ALD): C26:0-LPC by FIA-MS/MS, then by LC-MS/MS, then targeted NGS of ABCD1 and X-chromosome copy number. It included 61,431 newborns, 22 ALD patients and 20 patients with other peroxisomal disorders. With cut-offs of 0.33 and 0.15 µmol/L, 21 of 22 ALD patients were identified (the missed case was a female), as well as one previously undiagnosed male with ALD from the newborn cohort. In males, sensitivity was 100% at both first and second tiers, with positive predictive value rising from 4.8% to 82.4% after the second tier; NGS identified the new case and all known cases.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Second-tier LC-MS/MS does most of the work by bringing PPV to a level compatible with a national program, and NGS-based X-chromosome copy number analysis settles the question of genetic sex. Sensitivity is estimated on a small number of known cases, and the missed female case is a reminder that screening primarily targets males. The retrospective design calls for prospective validation before wider rollout.

Analysis by Dr Thibaut Benquey