Newborn screening

Authors: Rachel Salzman, DVM (CSO, The Stop ALD Foundation) and Stephan Kemp, Ph.D.


Babies born with adrenoleukodystrophy (ALD) are neurologically normal at birth. However, early diagnosis of boys with adrenoleukodystrophy can lead to life-saving interventions. These include initiating timely adrenal steroid replacement therapy following detection of adrenal insufficiency, and for providing allogeneic hematopoietic stem cell transplantation (HSCT) as a means of treating cerebral ALD. HSCT can arrest the often fatal progression of cerebral demyelination provided that the procedure is performed at a very early stage of the disease. Unfortunately, this can only be effective during a narrow therapeutic window, which is often missed. Newborn screening provides access to this “window of opportunity” and allows for timely initiation of these established therapies.

In February 2016, adrenoleukodystrophy was added to the Recommended Uniform Screening Panel (RUSP) in the USA. This is the federal list of all genetic diseases recommended for state newborn screening programs. The state of New York initiated screening for adrenoleukodystrophy in newborns on December 30, 2013. Since then other states began adrenoleukodystrophy newborn screening (Fig 1). In the US, several additional states have legislative approval. It is expected that adrenoleukodystrophy newborn screening will commence in these states as soon as budgetary resources, testing procedures and follow-up protocols are in place.

Outside the US, the Minister of Health in the Netherlands has approved the addition of adrenoleukodystrophy to the newborn screening program. A pilot will start in 2019 (see below).

Newborn Screening Map showing US states that have included ALD in their newborn screening programFigure 1: Map showing the states in the US that have initiated adrenoleukodystrophy newborn screening.

Criteria for inclusion in the screening program

There is broad international consensus on the criteria for inclusion of a disease in a newborn screening program.


In 2004, at the National Advisory Committee for Newborn Screening meeting, Dr. Hugo Moser suggested adding adrenoleukodystrophy to the United States’ RUSP. The only problem was that a valid test for newborn screening was not available. To overcome this, he raised funds and recruited a team of researchers at the Kennedy Krieger Institute (Baltimore, MD) to identify a suitable biomarker and develop a test using tandem mass spectrometry (MS/MS). In 2006, the team reported the identification of C26:0-lysophosphatidylcholine (C26:0-LPC) in postnatal venous dried blood spots (DBS) from adrenoleukodystrophy males (Hubbard et al. 2006). Over the ensuing years scientists continued to improve the analysis (Hubbard et al. 2009; Theda et al. 2014). Together with investigators at the Mayo Clinic (Rochester, Minnesota), a high-throughput method for the analysis of C26:0-LPC was then developed (Haynes and De Jesús 2012; Turgeon et al. 2015). In 2013, this method was validated using a 100,000 anonymous dried blood spots.

Aidan’s Law

In April 2012, following the death of their son, Aidan, who had cerebral ALD, but was diagnosed too late, the Seeger family drafted and supported the passage of Aidan’s Law in the State of New York. The bill was approved in February 2013 and became law in March 2013. On 30 December 2013, New York State’s newborn screening laboratory began testing babies for adrenoleukodystrophy.

New York State

During the first three years, New York State has screened over 700,000 newborns and identified 45 babies with adrenoleukodystrophy: 22 boys and 23 girls. Based on these numbers, the birth-incidence of adrenoleukodystrophy is 1 in 15,000. When a newborn with adrenoleukodystrophy is identified, the family’s primary physician is notified and a referral is made to a clinical geneticist for confirmation of the diagnosis, along with genetic counseling for support services and screening of other family members at risk of adrenoleukodystrophy (extended family screening).

For males, it is imperative to initiate serial monitoring by brain MRI to detect the earliest evidence of onset of cerebral ALD; and to initiate adrenal function testing to detect adrenal insufficiency. Comprehensive evaluation of neurologic, neuropsychological, neuroradiology, and adrenal function is necessary because there is no test to predict the clinical outcome of an individual baby born with an adrenoleukodystrophy pathogenic variant.

The newborn screening test

The details of the C26:0-LPC test may differ slightly across laboratories. In general, the adrenoleukodystrophy diagnosis is accomplished using a three-tier algorithm (Fig 2). The first tier is a high-throughput standard MS/MS analysis of C26:0-LPC. Samples that have an elevated C26:0-LPC concentration are then screened in the second tier, using HPLC–MS/MS. This test is more sensitive, but it is also somewhat more time-consuming. In those samples that still show elevated C26:0-LPC, the third-tier sequencing of the ABCD1 gene is performed.

Figure 2: The principles of adrenoleukodystrophy 3-tier screening.


In different countries there are significant challenges and ongoing ethical discussions with respect to the implementation of adrenoleukodystrophy newborn screening.

The Netherlands

In 2015, the Dutch Ministry of Health adopted the advice of the Dutch Health Council (‘Neonatal screening: new recommendations’) to add adrenoleukodystrophy to the neonatal screening panel. The Dutch Health Council advised that the screening for adrenoleukodystrophy should be setup to only identify boys with adrenoleukodystrophy. This requires the addition of a sex-determination step to the screening process. Boys with adrenoleukodystrophy can be identified by the combination of: 1) elevated C26:0-lysoPC, 2) sex-determination and 3) an ABCD1 pathogenetic variant.

The SCAN study

World-wide there is no example of a newborn screening program that screens either only boys or only girls. Therefore, adrenoleukodystrophy newborn screening will start with a pilot study (performed in 2021). This pilot is referred to as the SCAN study (Screening for ALD in the Netherlands). The aim of the SCAN study is to enable an optimal implementation of newborn screening for adrenoleukodystrophy by examining the test characteristics and practical implications of the C26:0-lysoPC, the sex-determination and the final diagnosis of adrenoleukodystrophy. This concerns logistical implications (both ICT and analytical), information dissemination e.g. brochures and a website for parents and health professionals ( etc., clinical care pathway and secondary findings, psychosocial aspects and a concise analysis of healthcare costs. The publication covering the Dutch NBS process, the boys-only ALD screening algorithm as well as the multidisciplinary, centralized follow up protocol and a flowchart to confirm the diagnosis is freely accessible at: Barendsen et al 2020

As a result of being added to the RUSP, it is expected that adrenoleukodystrophy newborn screening will be initiated in a growing number of states in the US in the coming years, and that other countries will follow. These measures will significantly improve the clinical outcome of hundreds of adrenoleukodystrophy babies, their biological relatives, and their loved ones.

Last modified | 2022-06-15