Abstract
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal genetic disorder in which an accumulation of very long-chain fatty acids leads to inflammatory demyelination in the central nervous system and to adrenal cortex atrophy. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel. To evaluate the performance of a single-tier newborn screening assay for X-ALD in North Carolina. This diagnostic screening study was of all newborn dried blood spot specimens received in the North Carolina State Laboratory of Public Health between January 2 and June 1, 2018, excluding specimens of insufficient quantity or quality. A total of 52 301 specimens were screened for X-ALD using negative ionization high-performance liquid chromatography tandem mass spectrometry to measure C24:0- and C26:0-lysophosphatidylcholine concentrations. Sanger sequencing of the adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene was performed on screen-positive specimens. A medical and family history, newborn physical examination, sequencing of ABCD1 on dried blood spot samples, and plasma analysis of very long-chain fatty acids were obtained for all infants with screen-positive results. The prevalence of X-ALD in North Carolina and the positive predictive value and false-positive rate for the first-tier assay were determined. Of 52 301 infants tested (47.8% female, 50.6% male, and 1.7% other or unknown sex), 12 received screen-positive results. Of these 12 infants, 8 were confirmed with a genetic disorder: 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, 1 female infant with a peroxisome biogenesis disorder, and 1 female infant with Aicardi-Goutières syndrome. Four infants were initially classified as having false-positives results, including 3 female infants who were deemed unaffected and 1 male infant with indeterminate results on confirmatory testing. The positive predictive value for X-ALD or other genetic disorders for the first-tier assay was 67%, with a false-positive rate of 0.0057%. This newborn screening pilot study reported results on 2 lysophosphatidylcholine analytes, identifying 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, and 3 infants with other disorders associated with increased very long-chain fatty acids. These results showed successful implementation in a public health program with minimal risk to the population. The findings will support other state laboratories planning to implement newborn screening for X-ALD and related disorders.
Highlights
The X-linked adrenoleukodystrophy (X-ALD) disorder is a peroxisomal disorder caused by a deficiency of adenosine triphosphate–binding cassette transporter protein encoded by the adenosine triphosphate–binding cassette subfamily D member 1 (ABCD1) gene (OMIM 300371).[1,2]
A 3.2-mm-diameter circle from dried blood spot (DBS) specimens was extracted in 96-well plates with 100 μL of methanol containing the internal standard, 1-hexacosanoyl-d4-2-hydroxy-sn-glycero-3-phosphocholine (d4-C26:0-LPC)
In positive ion mode, an isobaric interference increases the false-positive rate of these flow injection analysis methods, necessitating the use of a more specific second-tier test, such as the negative-ion HPLC-MS/MS method used in our pilot study
Summary
The X-linked adrenoleukodystrophy (X-ALD) disorder is a peroxisomal disorder caused by a deficiency of adenosine triphosphate–binding cassette transporter protein (adrenoleukodystrophy protein) encoded by the adenosine triphosphate–binding cassette subfamily D member 1 (ABCD1) gene (OMIM 300371).[1,2] The protein transports very long-chain acyl-CoA esters into peroxisomes, the site of very long-chain fatty acid (VLCFA) beta-oxidation.[3]. Patients with childhood CALD rapidly decline, and death typically occurs 2 to 4 years after onset of symptoms.[4]
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