Adrenoleukodystrophy (ALD)
https://pmc.ncbi.nlm.nih.gov/articles/PMC12886174
X-linked adrenoleukodystrophy (ALD) is an inherited neurometabolic disorder caused by pathogenic variants in the ABCD1 gene. The gene encodes the peroxisomal transporter ALDP, which is required for the degradation of very-long-chain fatty acids (VLCFAs). Loss of ALDP function leads to VLCFA accumulation in tissues such as the adrenal cortex, spinal cord, and brain. In males, this can result in adrenal insufficiency and the inflammatory brain disease cerebral ALD (CALD), which can be halted if treated early. Newborn screening programs detect ALD by measuring the biomarker C26:0 lysophosphatidylcholine (LPC(26:0)) in dried blood spots, followed by sequencing of the ABCD1 gene. However, screening frequently identifies variants of uncertain significance (VUS), many of these cases present with only borderline elevations of LPC(26:0), creating a diagnostic “grey zone” in which the risk of developing paediatric disease is unclear. The Grey Zone Project was established to address this uncertainty by integrating biochemical measurements with longitudinal clinical data (data collected from the same subject over time). Using receiver operating characteristic (ROC) analyses of LPC(26:0) concentrations from 1,627 control individuals and 196 males with confirmed ALD, researchers were able to see the differences between normal and disease samples and define clinically actionable thresholds. LPC(26:0) levels below 110 nmol/L were classified as “no ALD”, levels between 110 and 177 nmol/L as “lower-risk AI/CALD”, and levels above 177 nmol/L as “at-risk AI/CALD.” Applying this framework to 108 individuals carrying 51 unique ABCD1 VUSs enabled reclassification of many variants based on their biochemical risk profile. Importantly, the project uses standardised dried blood spot sampling after 100 days of age to avoid elevated neonatal red blood cell counts impacting the samples. By combining genetic, biochemical, and clinical evidence, the Grey Zone Project provides a scalable risk-stratification model (system to categorise people into risk groups) that improves interpretation of uncertain variants, refines newborn screening specificity, and enables more personalised clinical follow-up in ALD.