ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 8.14 | DOI: 10.1530/ey.16.8.14

A report on state-wide implementation of newborn screening for X-linked adrenoleukodystrophy

Wiens K, Berry SA, Choi H, Gaviglio A, Gupta A, Hietala A, Kenney-Jung D, Lund T, Miller W, Pierpont EI, Raymond G, Winslow H, Zierhut HA & Orchard PJ

Division of Genetics and Metabolism, Departments of Pediatrics and Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN, USA

To read the full abstract: Am J Med Genet A. 2019; 179(7):1205–1213.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an estimated incidence in the USA of ~1:17,000 all births (male and female) and 1:21,000 male births. X-ALD is caused by mutations in the X chromosome gene ABCD1, which encodes the peroxisomal membrane protein, ATP-binding cassette sub-family D member one, also known as adrenoleukodystrophy protein, or ALDP. ALDP transports very long chain fatty acids (VLCFA) from the cytosol into the peroxisome where the VLCFA are metabolized by beta-oxidation. Pathogenic mutations in ABCD1 cause absent or abnormally functioning ALDP, resulting in an accumulation of VLCFA in plasma and tissues, including the brain, spinal cord, and adrenal cortex.

The current paper describes a retrospective review of Minnesota Department of Health C26:0-LPC newborn screening results and follow-up outcomes from the first year of screening. This is one of the first reports describing outcomes of population screening of X-ALD on a newborn screening platform. It showed that over the first year of screening in Minnesota, 14 infants screened positive for X-ALD, and all were subsequently confirmed positive.

These results suggest that C26:0-LPC detection by LC-MS/MS is an effective and specific population-based screening assay for X-ALD, with a high positive predictive value with confirmation of all screen positive results. As five females were also detected, this newborn screening assay may also be a reliable test for detecting female heterozygotes and more sensitive than serum VLCFA levels. The benefits of adding X-ALD to newborn screening programs and the potential lives saved are predicted to be significant. However, there are unique challenges with adding this condition to newborn screening, including detection of variants of uncertain significance, inability to predict phenotypic severity in confirmed cases, and downstream diagnoses of numerous family members based on the X-linked inheritance pattern.