Adrenoleukodystrophy Newborn Screening in California Since 2016: Programmatic Outcomes and Follow-Up

Abstract

X-linked adrenoleukodystrophy (ALD) is a recent addition to the Recommended Uniform Screening Panel, prompting many states to begin screening newborns for the disorder. We provide California’s experience with ALD newborn screening, highlighting the clinical and epidemiological outcomes observed as well as program implementation challenges. In this retrospective cohort study, we examine ALD newborn screening results and clinical outcomes for 1,854,631 newborns whose specimens were received by the California Genetic Disease Screening Program from 16 February 2016 through 15 February 2020. In the first four years of ALD newborn screening in California, 355 newborns screened positive for ALD, including 147 (41%) with an ABCD1 variant of uncertain significance (VUS) and 95 males diagnosed with ALD. After modifying cutoffs, we observed an ALD birth prevalence of 1 in 14,397 males. Long-term follow-up identified 14 males with signs of adrenal involvement. This study adds to a growing body of literature reporting on outcomes of newborn screening for ALD and offering a glimpse of what other large newborn screening programs can expect when adding ALD to their screening panel.

Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy

“…Early-stage treatment of childhood cerebral ALD with hematopoietic stem cell transplantation and, more recently, gene therapy can arrest disease progression if performed in the window of opportunity when the MRI is abnormal but neurological symptoms are not yet apparent [ 7 , 38 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. The implementation of newborn screening for ALD in the United States and the Netherlands has provided the opportunity to identify patients at birth [ 7 , 51 , 52 , 53 , 54 , 55 , 56 ]. Asymptomatic boys are monitored for adrenal insufficiency [ 57 ] and by MRI [ 58 ] to detect early cerebral lesions, with the aim of intervention in the narrow window prior to symptom onset [ 41 , 57 , 58 ].…”

Monitoring for and Management of Endocrine Dysfunction in Adrenoleukodystrophy

“…The published prevalence of ALD based on newborn screening has varied but is consistent with improved identification of those with ALD. In the largest published cohort, California State reported the prevalence of ALD was 1 in 14,397 males and 1 in 9593 females with ~1.85 million newborns screened in the first four years [ 19 ]. Minnesota, a relatively small state with potential founder effects, reported an even higher prevalence of 1:4845 in females and 1:3878 in males in the first 67,835 screened newborns [ 20 ].…”

“…The earliest reports of biochemical adrenal insufficiency are at 5 weeks and 3.5 months of age [ 21 ]. California newborn screening reported 14 patients had abnormal ACTH testing in the first three plus years of follow-up and five patients were treated with glucocorticoids [ 19 ]. These very early presentations seem to be less common, but more long-term newborn screening follow-up data are needed.…”

“…It is common for multiple family members to be identified as being at risk for ALD once an infant is diagnosed. Male family members require urgent evaluations for adrenal insufficiency, as well as the cerebral ALD [ 19 , 20 , 28 ].…”

Newborn Screening for X-Linked Adrenoleukodystrophy: Past, Present, and Future

“…Newborn screening for X-linked adrenoleukodystrophy (ALD) was added to the Recommended Uniform Screening Panel in February 2016. The implementation of this screening continues to expand in the United States and is being considered in other countries [1][2][3][4][5][6][7][8][9]. It is an opportune time to evaluate the development, performance, and the future of the endeavor.…”