Newborn screening

March 1st, 2017 |

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


Babies born with ALD are neurologically normal at birth. However, early diagnosis of boys with ALD 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, ALD was added to the Recommended Uniform Screening Panel (RUSP) in the USA, which is the federal list of all genetic diseases recommended for state newborn screening programs. The state of New York initiated screening for ALD in newborns on December 30, 2013. Since then other states (Connecticut, California and Minnesota) began ALD newborn screening (Fig 1). In the US, several additional states have legislative approval. Outside the US, the Minister of Health in the Netherlands has approved the addition of ALD to the newborn screening program. It is expected that ALD newborn screening will commence in these states and countries as soon as budgetary resources, testing procedures and follow-up protocols are in place.


Figure 1: Map showing the states in the US that have initiated ALD newborn screening (green), states that will start in 2017 (orange) and states that are mobilizing (blue).


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.

  1. Early diagnosis must be directly advantageous to the newborn. There must be substantial health gains, achieved as a result of early intervention in severe diseases with a known natural course.
  2. The screening test must be of good quality. The assay must have high specificity and sensitivity, which means it has a very low rate of both false positive and false negative results.



In 2004, at the National Advisory Committee for Newborn Screening meeting, Dr. Hugo Moser suggested adding ALD 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 ALD 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 ALD.


New York State

During the first three years, New York State has screened over 700,000 newborns and identified 45 babies with ALD: 22 boys and 23 girls. Based on these numbers, the birth-incidence of ALD is 1 in 15,000. When a newborn with ALD 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 ALD (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 ALD mutation.


The newborn screening test

The C26:0-LPC test and its associated reagents may differ slightly across laboratories. However, in all cases the ALD 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 specific, 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 ALD 3-tier screening


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

As a result of being added to the RUSP, it is expected that ALD 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 ALD babies, their biological relatives, and their loved ones.

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