Newborn Screening for Adrenoleukodystrophy

present the results from the follow-up of all patients identified during the first 5 years of newborn screening (NBS) for adrenoleukodystrophy (ALD) in Minnesota.They identified 43 individuals (32 male and 11 female) of whom 7 males have, so far, developed a leukodystrophy and/or adrenal failure.The study suggests that the level of C26:0lysophosphatidylcholine (LPC) at screening predicts early complications and has important implications for further improvement of ALD NBS screening protocols in the future.ALD is a neurometabolic disorder caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal transporter of saturated very long-chain fatty acids (VLCFA) (≥C22:0) into peroxisomes for degradation by β-oxidation.ABCD1 dysfunction leads to accumulation of VLCFA in tissues. 2 Patients with ALD are asymptomatic at birth.In childhood, male patients are at high risk of developing adrenocortical failure and/or leukodystrophy, also known as cerebral ALD, with a prevalence of approximately 50% and 35%, respectively, before the age of 10 years. 3In adulthood, all males and more than 80% of females develop spinal cord disease and peripheral neuropathy, 4,5 for which there is no diseasemodifying therapy.Untreated adrenal insufficiency can lead to significant morbidity and untreated leukodystrophy is usually progressive, often leading to severe disability or death within a few years of symptom onset. 6Adrenal insufficiency can be effectively treated with corticosteroid replacement therapy.Hematopoietic stem cell transplant halts the progression of leukodystrophy, but good outcome is only achieved if performed when patients have lesions on magnetic resonance imaging of the brain but are still asymptomatic. 7BS for ALD identifies male newborns at the asymptomatic stage, allowing monitoring and timely therapeutic intervention, preventing irreversible damage, and saving lives. 8NBS for ALD was first implemented in New York state in 2013 8,9 and is now implemented in nearly every US state.Outside of the US, Taiwan and the Netherlands have added ALD to their NBS program 9,10 and regional pilots are ongoing in Israel, Italy, and Japan. 11,12Although early identification of boys with ALD undoubtedly reduces morbidity and mortality, it comes at a price.Many of the newborns currently identified have levels of C26: 0-LPC above the cutoff but not in the range of patients identified on the basis of symptoms, also referred to as the grey zone.In many of these cases, the missense variants identified in the ABCD1 gene have not been identified in known patients and reported in the ABCD1 Variant Registry 13,14 and, therefore, are classified as variants of unknown significance