Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene

Stadt, Stephanie I. W. van de; Mooyer, Petra; Dijkstra, Inge M. E.; Dekker, C.; Vats, Divya; Vera, Moin; Ruzhnikov, Maura R.Z.; Haren, Keith Van; Tang, Nelson L.S.; Koop, Klaas; Willemsen, M.A.A.P.; Hui, Joannie; Vaz, Frédéric M.; Ebberink, Merel S.; Engelen, Marc; Kemp, Stephan; Ferdinandusse, Sacha

doi:10.3390/genes12121930

Cited by 8 publications

(9 citation statements)

References 31 publications

(36 reference statements)

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“…The diagnosis of index cases identified by newborn screening requires the demonstration of elevated VLCFAs and an accurate interpretation of the genetic variant in ABCD1 . In the case of a VUS, biochemical and functional analyses of patient fibroblasts can aid the interpretation of the variant as either a (likely) benign or pathogenic change [ 59 ].…”

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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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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“…A skin biopsy was taken for functional testing of VLCFA metabolism in fibroblasts with the aim to (re)classify these variants as likely benign or likely pathogenic. 36 Compared to control fibroblasts, all three cell lines showed abnormal VLCFA metabolism: C26:0‐LPC and total C26:0 levels were elevated with an increased C26:0/C22:0 ratio, d3‐C26:0 synthesis was increased and d3‐C22:0 beta‐oxidation was reduced (Table 2 ). Therefore, all three variants were reclassified as likely pathogenic, yielding a positive predictive value (PPV) of 100% for the ALD pilot screening algorithm (4/4).…”

Section: Resultsmentioning

confidence: 99%

“…The tests to assess the effect of a variant of uncertain significance (VUS) identified in ABCD1 on VLCFA metabolism in skin fibroblasts, that is, C26:0‐LPC and C26:0 levels, the C26:0/C22:0 ratio, peroxisomal beta‐oxidation and de novo VLCFA synthesis, have been described in detail by van de Stadt and coworkers. 36 Of note, this functional testing of VLCFA metabolism is not part of the newborn screening algorithm. It is performed as part of the follow‐up protocol after referral to the pediatric neurologist.…”

Section: Methodsmentioning

confidence: 99%

Sex‐specific newborn screening for X‐linked adrenoleukodystrophy

Albersen

Beek

Dijkstra

et al. 2022

J of Inher Metab Disea

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Males with X-linked adrenoleukodystrophy (ALD) are at high risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age. Pathogenic variants in ABCD1 result in elevated levels of very longchain fatty acids (VLCFA), including C26:0-lysophosphatidylcholine (C26:0-LPC). Newborn screening for ALD enables prospective monitoring and timely therapeutic intervention, thereby preventing irreversible damage and saving lives. The Dutch Health Council recommended to screen only male newborns for ALD without identifying untreatable conditions associated with elevated C26:0-LPC, like Zellweger spectrum disorders and single peroxisomal enzyme defects. Here, we Click here to access the podcast for this paper.

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“…However, an MRI of the brain is relatively costly and for young children invasive because of the need for general anesthesia. As a predictive marker to identify individuals at high risk for cerebral ALD before its onset, particularly with respect to newborn screening positives [ 20 , 21 ]. Currently, all male ALD patients undergo the same intensive follow-up [ 22 , 23 , 24 ].…”

Section: Molecular Biomarkers For Ald: An Unmet Needmentioning

confidence: 99%

“…As a predictive marker to identify individuals at high risk for cerebral ALD before its onset, particularly with respect to newborn screening positives [ 20 , 21 ]. Currently, all male ALD patients undergo the same intensive follow-up [ 22 , 23 , 24 ].…”

Section: Molecular Biomarkers For Ald: An Unmet Needmentioning

confidence: 99%

Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need

Honey

Jaspers

Engelen

et al. 2021

Cells

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X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories (‘biobanking’) as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research.

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Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene

Cited by 8 publications

References 31 publications

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

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

Sex‐specific newborn screening for X‐linked adrenoleukodystrophy

Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need

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