Newborn Screening for X-Linked Adrenoleukodystrophy in Georgia: Experiences from a Pilot Study Screening of 51,081 Newborns

Hall, Patricia; Li, Hong; Hagar, Arthur F.; Jerris, S Caleb; Wittenauer, Angela; Wilcox, William R.

doi:10.3390/ijns6040081

Cited by 20 publications

(27 citation statements)

References 14 publications

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“…After our adjusted second tier cutoff, California observed an ALD birth prevalence of 1 in 14,397 males. This compares to a birth prevalence of 1 in 18,783 found in New York state [ 16 ], 1 in 3878 in Minnesota [ 31 ], 1 in 8717 in South Carolina [ 32 ], and 1 in 51,081 in Georgia [ 33 ]. Differences between screening cutoffs, case definitions, and ABCD1 carrier frequencies in our population samples are likely leading to the reported variations in birth prevalence between states.…”

Section: Discussionmentioning

confidence: 75%

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

Matteson

Sciortino

Feuchtbaum

et al. 2021

IJNS

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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.

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Section: Discussionmentioning

confidence: 75%

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

Matteson

Sciortino

Feuchtbaum

et al. 2021

IJNS

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“…Finally, we compared our X-ALD NBS practices and outcomes with those of six other U.S. states with published experiences: California, Georgia, Illinois, New York, North Carolina, and Minnesota [ 2 , 40 , 41 , 42 , 43 , 44 ]. Screening practices universally utilized tiered MS/MS approaches to quantify VLCFAs or C26:0-LPC ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

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

Priestley

Adang

Williams

et al. 2022

IJNS

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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.

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“…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 ].…”

Section: Abcd1 Variant Interpretation In the Era Of Ald Newborn Screeningmentioning

confidence: 99%

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

Mallack

Gao

Engelen

et al. 2022

Cells

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The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.

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Newborn Screening for X-Linked Adrenoleukodystrophy in Georgia: Experiences from a Pilot Study Screening of 51,081 Newborns

Cited by 20 publications

References 14 publications

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

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

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

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

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