High incidence of null variants identified from newborn screening of X-linked adrenoleukodystrophy in Taiwan

Mol Genet Metab Rep. 2022 Jul 28;32:100902. doi: 10.1016/j.ymgmr.2022.100902. eCollection 2022 Sep.

Abstract

Background: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by variants in the ABCD1 gene and can lead to Addison disease, childhood cerebral ALD, or adrenomyeloneuropathy. Presymptomatic hematopoietic stem cell transplantation is the only curative treatment for the disease and requires early detection through newborn screening (NBS) and close follow-up.

Methods: An NBS program for ALD was performed by a two-tiered dried blood spot (DBS) lysophosphatidylcholine C26:0 (C26:0-LPC) concentration analysis. ABCD1 sequencing was eventually added as a third-tier test, and whole exome sequencing was used to confirm the diagnosis of all peroxisomal diseases. Affected newborns were followed-up for adrenal insufficiency and cerebral white matter abnormalities.

Results: We identified 12 males and 10 females with ABCD1 variants, and 3 patients with Zellweger syndrome from 320,528 newborns. Eight (36.4%) ABCD1 variants identified in the current study were null variants, but there were no hotspots or founder effect. During a median follow-up period of 2.28 years, two (16.7%) male patients with ABCD1 variants developed Addison's disease. Extended family screening revealed one 28-year-old asymptomatic hemizygous father of a null variant (c.678delC). Among the three with Zellweger syndrome, one died at the age of 3 months, one showed developmental delay at the age of 1 year, and one was lost to follow-up.

Conclusion: Screening for ALD has been added to the NBS program in Taiwan with a high degree of success. The screening algorithm revealed a high proportion of null variants in cases found by NBS in Taiwan, a subset of patients who may have earlier disease onset. We also demonstrate the feasibility of combining the diagnosis of ALD and other peroxisomal disorders into one screening algorithm.

Keywords: ABCD1; ALD, adrenoleukodystrophy; AMN, adrenomyeloneuropathy; Adrenoleukodystrophy; C26:0-LPC; C26:0-LPC, Lysophosphatidylcholine C26:0; DBS, dried-blood spot; FIA-MS/MS, flow injection-tandem mass spectrometry; HPLC-MS/MS, High-performance liquid chromatography-tandem mass spectrometry analysis; HSCT, hematopoietic stem cell transplantation; NBS, newborn screening; Newborn screening; Null variant; Tandem mass analysis; VLCFA, very long-chain fatty acids; ZSD, Zellweger spectrum disorder.