If left untreated, cerebral ALD is often fatal ( Moser et al., 2007). About 35% of boys with ALD develop progressive cerebral white matter lesions (cerebral ALD) between the 3rd and 10th year of life, and it is well documented that this type of brain pathology frequently occurs in adulthood, as well ( Moser et al., 2000 van Geel et al., 2001 de Beer et al., 2014 Huffnagel et al., 2019b). ALD has an estimated prevalence of 1 in 15.000–17.000 births ( Bezman and Moser, 1998 Moser et al., 2016). ALD can affect the brain, adrenal glands and the spinal cord ( Kemp et al., 2016). A defect in ABCD1 results in impaired VLCFA beta-oxidation and consequently an accumulation of VLCFA in plasma and tissues ( Singh et al., 1984 Moser et al., 1998 Huffnagel et al., 2017). The ABCD1 gene codes for the peroxisomal transmembrane protein (ABCD1 protein) that transports very long-chain fatty acids (VLCFA, ≥C22:0) into the peroxisome. X-linked adrenoleukodystrophy (ALD) is a severe inborn error of metabolism caused by a mutation in the ABCD1 gene located on the X chromosome ( Mosser et al., 1993). For ALD, this alternative boys-only screening algorithm may result in a more rapid inclusion of ALD in newborn screening programs worldwide. Our boys-only ALD screening algorithm offers a solution for countries that encounter similar ethical considerations, for ALD as well as for other X-linked diseases. Finally, we developed a patient- and parent-friendly, multidisciplinary, centralized follow-up protocol. Furthermore, we ensured that our screening algorithm does not result in unsolicited findings. The X-counter is integrated as second tier in our 4-tier screening algorithm. The core of this algorithm is the “X-counter.” The X-counter determines the number of X chromosomes without assessing the presence of a Y chromosome. We successfully developed and validated a screening algorithm that can be integrated into the Dutch newborn screening program. The objectives of the SCAN study are: (1) designing a boys-only screening algorithm that identifies males with ALD and without unsolicited findings (2) integrating this algorithm into the structure of the Dutch newborn screening program without harming the current newborn screening (3) assessing the practical and ethical implications of screening only boys for ALD and (4) setting up a comprehensive follow-up that is both patient- and parent-friendly. We were invited to set up a prospective pilot study that became known as the SCAN study (SCreening for ALD in the Netherlands). The recommendation made by the Dutch Health Council to only screen boys, without gathering any unsolicited findings, posed a challenge. The Dutch Ministry of Health adopted the advice of the Dutch Health Council to add a boys-only screen for ALD to the newborn screening panel. Newborn screening for ALD in males enables prospective monitoring and timely therapeutic intervention, thereby preventing irreparable damage and saving lives. Women with ALD are not at risk for adrenal insufficiency or cerebral ALD. If untreated, cerebral ALD is often fatal. Males with ALD are at high risk for developing adrenal insufficiency or progressive cerebral white matter lesions (cerebral ALD) at an early age. X-linked adrenoleukodystrophy (ALD) is a devastating metabolic disorder affecting the adrenal glands, brain and spinal cord.
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