Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor.

Rinse W Barendsen,Ingrid Metgod,Yorrick R J Jaspers,Ellen Elsinghorst,Henk Van Lenthe,Elise H C Van Der Sluijs,Frits A Wijburg,Christiaan F Mooij,Stephan Kemp,Marelle J Bouva,Ankie G M Van Gorp,Hans R Waterham,Eugènie Dekkers,Marc Engelen,Mariëlle Alders,Annemieke C Heijboer,Saskia N Van Der Crabben,Jet Bliek,Frédéric M Vaz,Anita Boelen,Inge M E Dijkstra,W J Visser ,Rendelien K Verschoof-Puite ,A S Paul Van Trotsenburg ,M.c.j.f Jansen

doi:10.3389/fcell.2020.00499

Abstract

X-linked adrenoleukodystrophy (ALD) is a devastating metabolic disorder affecting the adrenal glands, brain and spinal cord. Males with ALD are at high risk for developing adrenal insufficiency or progressive cerebral white matter lesions (cerebral ALD) at an early age. If untreated, cerebral ALD is often fatal. Women with ALD are not at risk for adrenal insufficiency or cerebral ALD. Newborn screening for ALD in males enables prospective monitoring and timely therapeutic intervention, thereby preventing irreparable damage and saving lives. 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. The recommendation made by the Dutch Health Council to only screen boys, without gathering any unsolicited findings, posed a challenge. We were invited to set up a prospective pilot study that became known as the SCAN study (SCreening for ALD in the Netherlands). 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 successfully developed and validated a screening algorithm that can be integrated into the Dutch newborn screening program. 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. The X-counter is integrated as second tier in our 4-tier screening algorithm. Furthermore, we ensured that our screening algorithm does not result in unsolicited findings. Finally, we developed a patient- and parent-friendly, multidisciplinary, centralized follow-up protocol. 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. For ALD, this alternative boys-only screening algorithm may result in a more rapid inclusion of ALD in newborn screening programs worldwide.

Highlights

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)
Approval of the Institutional Review Board for the analysis of C26:0 lysophosphatidylcholine (C26):0-LPC in dried blood spots (DBS) cards was not required, since all measurements were performed as part of diagnostic procedures or standard patient care and data were anonymized for the purpose of further analysis
The folder was inserted in the existing information folder about the newborn screening program and was distributed to the relevant healthcare providers

Summary

Introduction

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). Hematopoietic stem cell transplantation (HSCT) can stop the progression of cerebral ALD, provided the procedure is performed at an early stage of the disease (Aubourg et al, 1990; Raymond et al, 2019). This therapeutic window is narrow and often missed because of delayed diagnosis (Polgreen et al, 2011; Engelen et al, 2012)

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