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, which 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).
Figure 1: Map showing the states in the US that have initiated adrenoleukodystrophy newborn screening (green), states that will start in 2019 (red), are running a pilot (yellow), 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.
- 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.
- 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 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.
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 mutation.
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 first criterion for newborn screening inclusion, which dictates that early diagnosis must be directly advantageous to the newborn, may be cause for ethical concerns. In adrenoleukodystrophy, about one third of boys will develop cerebral ALD between the age of 3 and 18 years. However, the remaining two thirds of adrenoleukodystrophy males will develop adrenomyeloneuropathy (AMN) in adulthood, which is characterized by limb spasticity, gait dysfunction, and incontinence. Adrenomyeloneuropathy is treated symptomatically. The absence of laboratory markers or other biological tools makes predicting health outcomes for individuals difficult and may therefore increase the risk of unnecessary medical interventions.
- Newborn screening also identifies girls carrying a defective adrenoleukodystrophy gene. Females with adrenoleukodystrophy have a <<1% chance for developing adrenal insufficiency or cerebral ALD, and thus there is no direct health benefit for a newborn girl with adrenoleukodystrophy since she cannot be treated with HSCT or adrenal hormone therapy. About 80% of the females with adrenoleukodystrophy will develop a myelopathy by the age of 60 years.
- In various countries there is a growing debate within the scientific community and among patient organizations regarding the inclusion of certain untreatable conditions in newborn programs. As mentioned previously, early diagnosis must ultimately result in providing a direct health benefit to the newborn him or herself. This may not be evident in the case of a disease that is diagnosed, and yet is not treatable.
- Sometimes newborn screening identifies diseases beyond the scope of the intended test (a secondary finding). The newborn screening assay of C26:0-LPC also identifies untreatable disease that are associated with increased levels of C26:0-LPC (Fig 2). These include: the Zellweger spectrum disorders, the peroxisomal fatty acid oxidation disorders caused by a defect in either the peroxisomal acyl-CoA oxidase 1 (ACOX1) or the multifunctional protein (HSD17B4), the “contiguous ABCD1 DXS1357E deletion syndrome” (CADDS), acyl-CoA binding domain containing protein 5 (ACBD5) deficiency, and Aicardi Goutières Syndrome.
- In some scenarios, other advantages, beyond those that are clearly intended to improve the health of the newborn may be considered. Some of these may benefit the newborn, like the faster diagnostic process. But most advantages are of clear benefit for the family. The possibility for extended family screening to identify additional family members at risk, and adjustment of family life to deal with the consequences of the disease. In addition, parents may also benefit from screening for a condition for which there is no effective treatment since this knowledge provides parents with information they can apply for making future reproductive choices. However, there are also clear disadvantages. The diagnosis of an untreatable disease may cast a shadow or stigma over the newborn’s early life and childhood.
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 mutation. 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. 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 (https://scanstudie.nl/) etc., clinical care pathway and secondary findings, psychosocial aspects and a concise analysis of healthcare costs.
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 | 2019-10-09