Newborn screening
Introduction
Babies born with adrenoleukodystrophy (ALD) are neurologically normal at birth. However, early diagnosis of boys with ALD can lead to life-saving interventions. These include the timely initiation of adrenal steroid replacement therapy after identification of adrenal insufficiency and the provision of allogeneic hematopoietic stem cell transplantation (HSCT) as a means of treating cerebral ALD. HSCT can halt the often fatal progression of cerebral demyelination, provided the procedure is performed at a very early stage of the disease. Unfortunately, this can only be effective during a narrow therapeutic window that is often missed. Newborn screening provides access to this “window of opportunity” and allows timely initiation of these established therapies.
In February 2016, ALD was added to the US Recommended Uniform Screening Panel (RUSP). This is the federal list of all genetic conditions recommended for state newborn screening programs. New York State initiated newborn screening for ALD on December 30, 2013. Since then, other states have initiated newborn screening for ALD (Fig 1). Legislative approval is pending in several additional states that have not yet started screening. It is expected that these states will begin newborn screening for ALD once the budgetary resources, testing procedures and follow-up protocols are in place.
Outside the Unites States, Taiwan initiated newborn screening for ALD in November 2016 (Chen et al. 2022) and a pilot projects are underway in Japan (Shimozawa et al. 2021), Israel, Italy (Bonaventura et al. 2023) and Spain. In the Netherlands, the Health Council of the Netherlands has recommended that only male newborns be screened for ALD. The novelty of sex-specific newborn screening and the lack of an example of a screening algorithm for boys only required a pilot study before ALD could be included in the national screening program. A one-year pilot study was conducted in 2021 (see below).
Figure 1: Map showing the states in the US that have initiated ALD newborn screening.
Criteria for inclusion in the screening program
There is broad international consensus on the criteria for inclusion of a condition in a newborn screening program.
- Early diagnosis must be of direct benefit to the newborn. There must be a substantial health benefit to be gained from early intervention in serious diseases with a known natural history.
- The screening test must be of good quality. The test must have high specificity and sensitivity, i.e. a very low rate of false positive and false negative results.
History
In 2004, at a meeting of the National Advisory Committee for Newborn Screening, Dr. Hugo Moser suggested that ALD be added to the U.S. RUSP. The only problem was that there was no valid test for newborn screening. 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). In the following years, scientists continued to improve the analysis (Hubbard et al. 2009; Theda et al. 2014). Then, in collaboration with researchers at the Mayo Clinic (Rochester, Minnesota), a high-throughput method for the analysis of C26:0-LPC was developed (Haynes and De Jesús 2012; Turgeon et al. 2015). In 2013, this method was validated using 100,000 anonymous dried blood spots.
Aidan’s Law
In April 2012, after 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 New York State. The bill passed in February 2013 and became law in March 2013. On December 30, 2013, the New York State Newborn Screening Laboratory began testing babies for ALD.
New York State
In the first three years, New York State screened over 700,000 newborns and identified 45 babies with ALD: 22 boys and 23 girls (Moser et al. 2016). Based on these numbers, the birth incidence of ALD is 1 in 15,000. When a newborn with ALD is identified, the family is referred to a clinical geneticist for confirmation of the diagnosis, along with genetic counseling for support services and screening of other family members at risk for ALD (extended family screening).
In males, it is imperative to initiate serial monitoring with brain MRI to detect the earliest signs of onset of cerebral ALD and to initiate adrenal function testing to detect adrenal insufficiency. A comprehensive evaluation of neurological, neuropsychological, neuroradiological, and adrenal function is necessary because there is no test to predict the clinical outcome of an individual child born with an ALD pathogenic variant.
The newborn screening test
The details of the C26:0-LPC test may vary slightly from laboratory to laboratory. In general, the diagnosis of ALD is made using a three-step (tier) algorithm (Fig 2). The first step is a high-throughput standard MS/MS analysis of C26:0-LPC. Samples with elevated levels of C26:0-LPC are then screened in the second step using HPLC-MS/MS. This test is more sensitive, but also a little more time consuming. For those samples that still show elevated C26:0-LPC, sequencing of the ABCD1 gene is performed in the third step.
Figure 2: The principles of ALD 3-tier screening.
Challenges
There are significant challenges and ongoing ethical discussions in different countries regarding the implementation of newborn screening for ALD.
- The first criterion for inclusion in newborn screening that early diagnosis must be of direct benefit to the newborn, may raise ethical concerns. In ALD, approximately one third of boys will develop cerebral ALD between the ages of 3 and 18 years. However, the remaining two-thirds of ALD males will develop myeloneuropathy in adulthood, which is characterized by limb spasticity, gait dysfunction, and incontinence. Myeloneuropathy is treated symptomatically. The lack of laboratory markers or other biological tools makes it difficult to predict individual health outcomes and may increase the risk of unnecessary medical intervention.
- Newborn screening also identifies girls who carry a defective ALD gene. Females with ALD have a <1% chance of developing adrenal insufficiency or cerebral ALD, so there is no direct health benefit for a newborn girl with ALD, as she cannot be treated with HSCT or adrenal hormone therapy. Approximately 80% of women with ALD will develop myelopathy by the age of 60.
- In various countries, there is a growing debate within the scientific community and among patient organizations regarding the inclusion of certain untreatable diseases in neonatal programs. As noted above, early diagnosis must ultimately result in a direct health benefit to the newborn. This may not be obvious in the case of a diagnosed but untreatable condition.
- Sometimes, newborn screening identifies conditions outside the scope of the intended test (a secondary finding). Newborn screening for C26:0-LPC also identifies untreatable conditions associated with elevated levels of C26:0-LPC (Fig 2). These include: Zellweger spectrum disorders, peroxisomal fatty acid oxidation disorders caused by a defect in either the peroxisomal acyl-CoA oxidase 1 (ACOX1) or multifunctional protein (HSD17B4), “contiguous ABCD1 DXS1357E deletion syndrome” (CADDS), acyl-CoA binding domain containing protein 5 (ACBD5) deficiency, and Aicardi Goutières syndrome.
- In some scenarios, other benefits, beyond those clearly intended to improve neonatal health may be considered. Some of these may benefit the newborn, such as faster diagnosis. But most of the benefits are clearly for the family. The possibility of extended family screening to identify additional family members at risk, and the 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, as this knowledge provides parents with information that they can use to make future reproductive decisions. However, there are also clear disadvantages. The diagnosis of an untreatable condition may cast a shadow or stigma over the newborn’s early life and childhood.
The Netherlands
In 2015, the Dutch Ministry of Health adopted the advice of the Dutch Health Council (‘Neonatal screening: new recommendations’) to include ALD in the newborn screening panel. The Health Council of the Netherlands followed the Wilson and Jungner criteria and recommended that only male newborns be screened for ALD, as boys are at high risk of developing adrenal insufficiency and/or cerebral ALD and will therefore directly benefit from newborn screening. This required the addition of a sex determination step to the screening process. Boys with ALD can be identified by the combination of 1) elevated C26:0-lysoPC, 2) sex determination and 3) an ABCD1 pathogenetic variant.
The SCAN study
Worldwide there was no example of a newborn screening program that screened either only boys or only girls. Therefore, ALD newborn screening started with a pilot study (conducted in 2021). This pilot study was called the SCAN study (Screening for ALD in the Netherlands). The aim of the SCAN study was to enable an optimal implementation of newborn screening for ALD by investigating the test characteristics and practical implications of the C26:0-lysoPC, the sex determination and final diagnosis of ALD. This includes 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 outcomes, psychosocial aspects and a concise analysis of health care costs. The publication on the Dutch NBS process, the boys-only ALD screening algorithm, the multidisciplinary centralized follow-up protocol and a flow chart to confirm the diagnosis is freely available at: (Barendsen et al. 2020).
In the pilot study, 71,208 newborns were screened for ALD. This resulted in the identification of four boys with ALD who, after referral to the pediatric neurologist and confirmation of the diagnosis, were enrolled in a long-term follow-up program at the Amsterdam Leukodystrophy Center of the Amsterdam UMC. The results of the pilot study demonstrate the feasibility of using a boys-only screening algorithm to identify males with ALD. The results have been published and are freely available at (Albersen et al. 2022).
As of October 1, 2023, newborn boys in the Netherlands are screened for ALD.
Last modified | 2024-11-15