Newborn Screening for X-Linked Adrenoleukodystrophy: Review of Data and Outcomes in Pennsylvania

Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It results from pathogenic variants in ABCD1, which encodes the peroxisomal very-long-chain fatty acid transporter, causing a spectrum of neurodegenerative phenotypes. The childhood cerebral form of the disease is particularly devastating. Early diagnosis and intervention improve outcomes. Because newborn screening facilitates identification of at-risk individuals during their asymptomatic period, X-ALD was added to the Pennsylvania newborn screening program in 2017. We analyzed outcomes from the first four years of X-ALD newborn screening, which employed a two-tier approach and reflexive ABCD1 sequencing. There were 51 positive screens with elevated C26:0-lysophosphatidylcholine on second-tier screening. ABCD1 sequencing identified 21 hemizygous males and 24 heterozygous females, and clinical follow up identified four patients with peroxisomal biogenesis disorders. There were two false-positive cases and one false-negative case. Three unscreened individuals, two of whom were symptomatic, were diagnosed following their young siblings’ newborn screening results. Combined with experiences from six other states, this suggests a U.S. incidence of roughly 1 in 10,500, higher than had been previously reported. Many of these infants lack a known family history of X-ALD. Together, these data highlight both the achievements and challenges of newborn screening for X-ALD.

Newborn screening for X-linked adrenoleukodystrophy in Italy: Diagnostic algorithm and disease monitoring

“…The first state to introduce this screening was the state of New York in 2013 (14), and since February 2016, X-ALD has been added to the United States Recommended Uniform Screening Panel (RUSP). Since then, NBS for X-ALD has been implemented in other states of the USA (15)(16)(17)(18)(19)(20)(21). Preliminary studies have been conducted in China and India to promote its implementation (22,23).…”

“…Excluding premature infants (around 10% of newborns) and newborns from families and Neonatal Units that refuse to participate in the study, we expect to include at least 40,000 newborns each year. Given the prevalence of X-ALD (1:17.000), other peroxisomal diseases (1:50.000), direct experience with AGS (no epidemiological data available), and other published pilot studies (15)(16)(17)(18)(19)(20)(21), we expect to select 10 "non-negative patients" per year. We expect that genetic analyses will confirm the results of NBS in 80% of patients, who will be immediately recruited in the surveillance protocol.…”

Sex‐specific newborn screening for X‐linked adrenoleukodystrophy

“…Interestingly, 97 out of 98 VUS have been reported in the last 3 years. In fact, all were identified in newborn screening, often with borderline elevated C26:0‐LPC concentrations (determined by HPLC–MS/MS) and in all cases without a family history of ALD 22–27 . A functional test in skin fibroblasts may help to classify a VUS as likely benign or likely pathogenic, but it requires taking a skin biopsy from the newborn and highly specialized diagnostic testing 36 .…”

“…ALD newborn screening started in December 2013 in New York State 19,20 . At present, over 25 US states have added ALD to their screening program 19,21–27 . Outside the US, Taiwan initiated ALD newborn screening in November 2016, 28 and a pilot is ongoing in Japan 29 …”

An update on the diagnosis and treatment of adrenoleukodystrophy

“…2). Several states in the United States recently reported their data on ALD prevalence and presentation following the implementation of the NBS as summarized in Table 1 [9][10][11][12]. Interestingly, Minnesota remains the state with the highest birth prevalence…”