CoChat
Sign Up
Cited by 60Metabolism and Genetic DisordersGenomics and Rare DiseasesLysosomal Storage Disorders Research

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

Open access
Mallack, Eric J., Gao, Kerry, Engelen, Marc, Kemp, Stephan·2022·Cells
DOI 10.3390/cells11020283PMC PMC8773697
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This paper updates the ABCD1 Variant Database after 20 years, reporting 3401 ALD cases and 948 unique likely pathogenic variants as of December 2021. It confirms known pathogenic variant clustering in exons 1–2 and 6–9 and highlights high-density missense hotspots in exons 1, 2, 6, 8, and 9, while emphasizing the database’s role in variant interpretation during newborn screening.

Key findings

  • As of December 2021, the ABCD1 Variant Database contained 3401 cases, 948 non-recurrent unique (likely) pathogenic variants, 40 benign variants, and 249 variants of uncertain significance (VUS). Missense pathogenic variants were most frequent (61.4%), followed by frameshift (17.2%), nonsense (9.9%), splice site (4.3%), small amino acid insertions/deletions (3.5%), large deletions (2.6%), and benign variants (1.2%).
  • Pathogenic variants clustered most often in the transmembrane domain (46%, exons 1–2), followed by the ATP-binding domain (35%, exons 6–9), exons 3–4 (9%), and exon 5 (7%). The most frequent pathogenic variant remained p.Gln472Argfs*83 (n = 170, 5.0% of all pathogenic variants), followed by p.Arg554His (n = 70, 2.1%), p.Arg660Trp (n = 60, 1.8%), p.Arg617His (n = 57, 1.7%), and p.Arg518Gln (n = 54, 1.6%).
  • Novel insights included nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9, whereas benign, synonymous, and VUS variants were homogenously distributed. The exon 6 and 9 hotspots map to Walker A and B motifs and the ABC signature within the ATP-binding domain.
  • The 2017 database rebuild added case counts and experimental pathogenicity data; for example, p.Ser606Leu was reported in 37 ALD cases and reduced detectable ALD protein to 25% of control cells, while p.Gly608Asp was reclassified as benign based on a gnomAD frequency of 124/162246 alleles. Website visits increased from an annual average of 30,000 before 2014 to over 150,000 since 2019.

Methods

  • Updated analysis of ABCD1 variant data as of December 2021, annotated in RStudio (v.1.2.5033) using the Bioconductor package trackViewer; dandelion plots depicted variant distribution and density by chromosome position across ABCD1 according to GRCh37 (hg19).
  • A multiple sequence alignment of ABCD1 proteins from 54 species (from Danio rerio to human) was created using ClustalW, and WebLogo was used to represent evolutionary conservation of each amino acid. Variants were reported per HGVS nomenclature using Alamut Visual with transcript NM_000033.3 on GRCh37.
  • The paper compares the 2001 initial database analysis with the 2021 update, including variant type frequencies, clustering by domain/exon, and high-density missense hotspots.

Limitations

  • Stated: the database is maintained without funding, and translation into other languages depends on collaborators with biology/medical training, making expansion slow. Early studies used two nucleotide numbering systems that differ by 386, which may complicate alignment of newly identified variants with early reported cases.
  • Stated: ALD has no established genotype–phenotype correlation, limiting prediction of disease course from ABCD1 variants.
  • Evident: as a voluntary curated registry, variant and case counts depend on reporting completeness and accuracy, and the distribution analyses are descriptive without formal statistical testing or confidence intervals.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/cells11020283

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 53 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Study design and conductcitation

    The ABCD1 Variant Database reports all (likely) pathogenic and benign variants in conformity with the nomenclature recommended by the Human Genome Variation Society (HGVS).

    “The ABCD1 Variant Database reports all (likely) pathogenic and benign variants in conformity with the nomenclature recommended by the Human Genome Variation Society (HGVS; https://varnomen.hgvs.org/) [20].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Higgins, 2021, Verifying nomenclature of DNA variants in submitted manuscripts: Guidance for journals, Hum. Mutat. source

      The Recommended Guidelines section says variant descriptions should follow HGVS recommendations. Neither that section nor the passages retrieved for “ABCD1 Variant Database” and “pathogenic and benign variants” establishes that the ABCD1 Variant Database reports all such variants or that its entries conform to HGVS nomenclature. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    The first iteration of the ALD Mutation Database reported four polymorphisms and 406 total mutations.

    “The first iteration of the ALD Mutation Database [16] reported four polymorphisms and 406 total mutations.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. source

      The “Mutations in the ABCD1 Gene” section reports 406 database mutations as of June 2001, and “Polymorphisms in the ABCD1 Gene” identifies four polymorphisms. But “Mutation Database for X-ALD” says the database was first released in November 1999; the paper does not attribute either count to that first iteration, and two of the four polymorphisms were described in 2001. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim3 of 10 sources checked
    • cites [7] Moser, A.B., Jones, R.O., Hubbard, W.C., Tortorelli, S., Orsini, J., Caggana, M., Vogel, B.H., and Raymond, G.V. (2016). Newborn screening for X-linked adrenoleukodystrophy. Int. J. Neonatal Screen., 2. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [38] Raymond, 2019, Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation, Biol. Blood Marrow Transpl. source
    • cites [43] Peters, 2004, Cerebral X-linked adrenoleukodystrophy: The international hematopoietic cell transplantation experience from 1982 to 1999, Blood source
    • cites [44] Moser, 1992, Adrenoleukodystrophy: Phenotypic variability and implications for therapy, J. Inherit. Metab. Dis. source
    • cites [45] Bezman, 2001, Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy, Ann. Neurol. source
    • cites [46] Shapiro, 2000, Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy, Lancet source
    • cites [47] Pierpont, 2017, Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy, JAMA Neurol. source
    • cites [48] Eichler, 2017, Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy, N. Engl. J. Med. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [49] Moser, 2018, Newborn Screening and Emerging Therapies for X-Linked Adrenoleukodystrophy, JAMA Neurol. source
    • cites [50] Cartier, 2009, Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy, Science source
  • Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [59] van de Stadt, S.I.W., Mooyer, P.A.W., Dijkstra, I.M.E., Dekker, C.J.M., Vats, D., Vera, M., Ruzhnikov, M.R.Z., van Haren, K., Tang, N., and Koop, K. (2021). Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene. Genes, 12. source

      The Discussion reports that biochemical and functional studies of fibroblasts helped classify variants as (likely) pathogenic or benign. The study concerns VUS in the ABCD1 gene, however, so it does not establish the claim for VUS generally. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    The majority of women with ALD are not merely carriers but may develop some degree of myeloneuropathy leading to gait, bowel, and bladder dysfunction.

    “It is becoming increasingly recognized that the majority of women are not merely carriers, but may develop some degree of myeloneuropathy leading to gait, bowel, and bladder dysfunction [14,15,63].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [14] Engelen, 2014, X-linked adrenoleukodystrophy in women: A cross-sectional cohort study, Brain source
    • cites [15] Huffnagel, 2019, Disease progression in women with X-linked adrenoleukodystrophy is slow, Orphanet J. Rare Dis. source
    • cites [63] Corre, 2021, Beyond gait and balance: Urinary and bowel dysfunction in X-linked adrenoleukodystrophy, Orphanet J. Rare Dis. source

      The Results (Study population; Cross-sectional symptom prevalence and age of onset) report neurological signs or symptoms in 91.5% of females in the cohort, urinary symptoms in 78.8%, and bowel symptoms in 67.3%. This supports the point that women with ALD can be symptomatic rather than merely carriers. The Discussion cautions that a cohort largely drawn from patients seeking neurological evaluation may overestimate prevalence in the broader ALD population, so the paper does not establish that the majority of all women with ALD develop this combination of problems. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Premisecitation

    In the first iteration, missense mutations constituted the most frequent pathogenic variants (55.9%), followed by frame shift (27.1%), nonsense (9.1%), small amino acid insertions/deletions (3.9%), and large deletions (3.9%).

    “Missense mutations constituted the most frequent pathogenic variants (55.9%), followed by frame shift (27.1%), nonsense (9.1%), small amino acid insertions/deletions (3.9%), and large deletions (3.9%).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. source

  • May combine two claims.

    Premisecitation

    In the first iteration, pathogenic variants clustered most often in the transmembrane domain (40%, exons 1 and 2), followed by the ATP-binding domain (30%, exons 6-9), and exon 5 (14%).

    “Pathogenic variants in the ABCD1 gene clustered most often in the transmembrane domain (40%, exons 1 and 2), followed by the ATP-binding domain (30%, exons 6–9), and exon 5 (14%).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. source

      In “Mutations in the ABCD1 Gene” (page unavailable), the paper reports the stated 40%, 30%, and 14% clustering, but specifies that these percentages describe non-recurrent mutations. It identifies exons 6–9 with the ATP-binding domain; its discussion of the transmembrane-region cluster points to parts of exon 1 rather than establishing the claim’s exon 1-and-2 designation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premiseown data

    Analysis of missense pathogenic variants in the first iteration revealed a non-random distribution across the gene, with higher-than-expected frequency in exon 1 (amino acids 100-300) and exons 6-9 (amino acids 497-664).

    “Analysis of missense pathogenic variants revealed a non-random distribution across the gene. Missense mutations were found at higher-than-expected frequency in exon 1 (amino acids 100–300), which code for four segments of the transmembrane domain, and at higher-than-expected frequency in exons 6–9 (amino acids 497–664), which code for the ATP-binding domain.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. source

      The “MUTATIONS IN THE ABCD1 GENE” section reports a non-random distribution, with more missense mutations than expected in exon 1b–1c (amino acids 101–300) and exons 6–9. It says the exon 1 region encompasses the second, third, and fourth transmembrane segments—three segments, not the four stated in the citing sentence. No page number is available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Further work demonstrated the role of the Walker A and B motifs in forming the ATP bindings site sandwich required for homodimerization of the ALD protein, and the subsequent power stroke of ATP-dependent substrate transport.

    “Further work demonstrated the role of the Walker A and B motifs in forming the ATP bindings site sandwich required for homodimerization of the ALD protein, and the subsequent power stroke of ATP-dependent substrate transport [36,37].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [36] Kawaguchi, 2016, ABC Transporter Subfamily D: Distinct Differences in Behavior between ABCD1-3 and ABCD4 in Subcellular Localization, Function, and Human Disease, Biomed. Res. Int. source

      Section 5.1 (page unavailable) says ABCD proteins need to dimerize and describes a nucleotide-binding-domain sandwich with ATP-binding sites containing Walker A and B motifs. The paper does not describe a subsequent power stroke or establish that this mechanism drives ATP-dependent substrate transport. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [37] Smith, 2002, ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer, Mol. Cell source

  • May combine two claims.

    Premisecitation

    Of the 406 mutations in the first iteration, 234 (58%) were non-recurrent and 47 were previously unpublished novel pathogenic variants.

    “Of the 406, 234 (58%) were non-recurrent and 47 were previously unpublished novel pathogenic variants.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. source

  • May combine two claims.

    Findingcitation

    The order of (likely) pathogenic variant frequency, overall nonrandom clustering of disease-causing variants in exons 1-2 (transmembrane domain) and exons 6-9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 on exon 5 are consistent with the initial reports of the mutation database.

    “The order of (likely) pathogenic variant frequency, overall nonrandom clustering of disease-causing variants in exons 1–2 (transmembrane domain) and exons 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 on exon 5 are consistent with the initial reports of the mutation database [16].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Kemp, 2001, ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations, Hum. Mutat. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hematopoietic stem cell transplantation is associated with its own degree of morbidity and mortality.

    “The former is associated with its own degree of morbidity and mortality [62], and both require the patient undergo chemotherapy [48].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Henig, 2014, Hematopoietic stem cell transplantation-50 years of evolution and future perspectives, Rambam Maimonides Med. J. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The accurate genetic diagnosis of ALD obligates the patient to rigorous monitoring protocols for adrenal insufficiency and cerebral ALD by MRI, requiring multiple medical subspecialty evaluations early in life.

    “The accurate genetic diagnosis of ALD obligates the patient to rigorous monitoring protocols for adrenal insufficiency [57] and cerebral ALD by MRI [58], requiring multiple medical subspecialty evaluations early in life.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [57] Regelmann, 2018, Adrenoleukodystrophy: Guidance for adrenal surveillance in males identified by newborn screen, J. Clin. Endocrinol. Metab. source
    • cites [58] Mallack, 2021, MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines, J. Inherit. Metab. Dis. source

  • May combine two claims.

    Premisecitation

    Both hematopoietic stem cell transplantation and gene therapy require the patient to undergo chemotherapy.

    “The former is associated with its own degree of morbidity and mortality [62], and both require the patient undergo chemotherapy [48].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Eichler, 2017, Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy, N. Engl. J. Med. source

      The Methods (Study Design and Investigational Therapy; page unavailable) state that patients receiving Lenti-D gene therapy were conditioned with busulfan and cyclophosphamide before infusion. The Discussion says allogeneic transplantation requires immunosuppression, but the passages found do not state that transplantation requires chemotherapy. The paper therefore supports the gene-therapy part of the claim, not the assertion that both require chemotherapy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The most frequent pathogenic variant continues to be the 2 bp deletion in exon 5 p.Gln472Argfs*83 (n = 170, 5.0% of all pathogenic variants), followed by missense pathogenic variants p.Arg554His (n = 70, 2.1%), p.Arg660Trp (n = 60, 1.8%), p.Arg617His (n = 57, 1.7%), and p.Arg518Gln (n = 54, 1.6%).

    “The most frequent pathogenic variant continues to be the 2 bp deletion in exon 5 p.Gln472Argfs*83 (n = 170, 5.0% of all pathogenic variants), followed by missense pathogenic variants p.Arg554His (n = 70, 2.1%), p.Arg660Trp (n = 60, 1.8%), p.Arg617His (n = 57, 1.7%), and p.Arg518Gln (n = 54, 1.6%).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingown data

    Missense variants cluster across chromosome segment 152991000-152991621 (exon 1, amino acids 100-300) and in chromosome segment 152994751-152994822 (exon 2, amino acids 315-346), which encodes the transmembrane domain.

    “Missense variants cluster across chromosome segment 152991000–152991621 (exon 1, amino acids 100–300, Figure 2b), and in the chromosome segment 152994751–152994822 (exon 2, amino acids 315–346, Figure 2c), which encodes the transmembrane domain.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingown data

    Overall, variant density is highest in exon 6, followed by exon 1.

    “Overall, variant density is highest in exon 6, followed by exon 1 (Figure 1a).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingcitation

    p.Gly608Asp was reported as the pathogenic variant in an ALD male patient, but gnomAD data show its frequency to be 124/162246 alleles, confirming that it is not a pathogenic variant.

    “For example, p.Gly608Asp was reported as the pathogenic variant in an ALD male patient (Database Ref 48) [26], but data from gnomAD show its frequency to be 124/162246 alleles (X:153008483 G/A), confirming that this is not a pathogenic variant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Dvorakova, 2001, Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange, Hum. Mutat. source

  • May combine two claims.

    Findingown data

    Eighty-nine large exon deletions are reported, distributed across the entire gene, the most frequent of which are exon 8-10 del (n = 21), exon 7-10 del (n = 16), and exon 3-10 del (n = 12).

    “Eighty-nine large exon deletions are reported, also distributed across the entire gene, the most frequent of which are exon 8–10 del (n = 21), exon 7–10 del (n = 16), and exon 3–10 del (n = 12).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingown data

    As of December 2021, the ABCD1 Variant Database had collected 3401 cases representing 948 non-recurrent, unique, (likely) pathogenic variants as well as 40 benign variants and 249 variants of uncertain significance (VUS).

    “As of December 2021, the ABCD1 Variant Database had collected 3401 cases representing 948 non-recurrent, unique, (likely) pathogenic variants as well as 40 benign variants and 249 variants of uncertain significance (VUS).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingown data

    Exon 1 contains the overall highest pathogenic variant burden distributed in the latter 2/3 of the exon (amino acids 100-300), studded with multiple high-density hotspots.

    “Exon 1 contains the overall highest pathogenic variant burden distributed in the latter 2/3 of the exon (amino acids 100–300), studded with multiple high-density hotspots (Figure 1c).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingown data

    Pathogenic variants in ABCD1 cluster most often in the transmembrane domain (46%, exons 1-2), followed by the ATP-binding domain (35%, exons 6-9), followed by exons 3 and 4 (9%) and exon 5 (7%).

    “Pathogenic variants in ABCD1 cluster most often in the transmembrane domain (46%, exons 1–2), followed by the ATP-binding domain (35%, exons 6–9), followed by exons 3 and 4 (9%) and exon 5 (7%).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingown data

    The highest density of pathogenic variants occurs in exon 1 followed by exon 6, with comparable densities in exons 2, 8, and 9.

    “The highest density of pathogenic variants occurs in exon 1 followed by exon 6, with comparable densities in exons 2, 8, and 9 (Figure 1b).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The pathogenic variant p.Ser606Leu has been reported in 37 ALD cases.

    “For example, the pathogenic variant p.Ser606Leu has been reported in 37 ALD cases.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • May combine two claims.

    Findingown data

    Missense pathogenic variants continue to account for the most frequent variants in the entire dataset (61.4%), followed by frame shift (17.2%), nonsense (9.9%), splice site (4.3%), small amino acid insertions/deletions (3.5%), large deletions (2.6%), and benign variants (1.2%).

    “Missense pathogenic variants continue to account for the most frequent variants in the entire dataset (61.4%), followed by frame shift (17.2%), nonsense (9.9%), splice site (4.3%), small amino acid insertions/deletions (3.5%), large deletions (2.6%), and benign variants (1.2%).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    All pathogenic variant types are homogenously distributed spatially across ABCD1.

    “All pathogenic variant types are homogenously distributed spatially across ABCD1.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Benign variants and variants of uncertain significance (VUS) are homogenously distributed across ABCD1 with no variation in density.

    “Benign variants and variants of uncertain significance (VUS) are homogenously distributed across ABCD1 with no variation in density (data not shown).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Parallel to the expansion of ALD newborn screening, website visits increased from an annual average of 30,000 before 2014 to over 150,000 since 2019.

    “Parallel to the expansion of ALD newborn screening, there has been a steady increase in visitors with an annual average of 30,000 visits before 2014 to over 150,000 since 2019.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient with the VUS c.970C > T (p.Arg324Cys) developed elevated VLCFAs and an elevated ACTH, was diagnosed with partial adrenal insufficiency before 2 years old, and is now proactively treated with stress dose steroids.

    “The patient developed elevated VLCFAs and an elevated ACTH, was diagnosed with partial adrenal insufficiency before 2 years old, and is now proactively treated with stress dose steroids.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pathogenic variants in the ABCD1 gene lead to the accumulation of VLCFAs in plasma and tissues, including adrenal glands, testes, the central nervous system, and the subsequent development of X-linked adrenoleukodystrophy (ALD).

    “Pathogenic variants in the ABCD1 gene lead to the accumulation of VLCFAs in plasma and tissues, including adrenal glands, testes, the central nervous system, and the subsequent development of X-linked adrenoleukodystrophy (ALD) [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Moser, 1999, Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls, Ann. Neurol. source

  • May combine two claims.

    Premisecitation

    The pathogenic variant p.Ser606Leu affects ATP-binding capacity and results in deficient VLCFA beta-oxidation.

    “Studies using experimental cell lines showed that the pathogenic variant affects ATP-binding capacity (Database Refs 194 and 244) [22,23], resulting in deficient VLCFA beta-oxidation (Database Ref 261) [24].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Dehmel, 2002, Functional characterization of the adrenoleukodystrophy protein (ALDP) and disease pathogenesis, Endocr. Res. source
    • cites [23] Roerig, 2001, Characterization and functional analysis of the nucleotide binding fold in human peroxisomal ATP binding cassette transporters, FEBS Lett. source
    • cites [24] Takahashi, 2007, Adrenoleukodystrophy: Subcellular localization and degradation of adrenoleukodystrophy protein (ALDP/ABCD1) with naturally occurring missense mutations, J. Neurochem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ABCD1 gene is located on Xq28, covers 19.9 kb and contains 10 exons.

    “The ABCD1 gene is located on Xq28, covers 19.9 kb and contains 10 exons [1,2].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Mosser, 1993, Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters, Nature source
    • cites [2] Sarde, 1994, Genomic organization of the adrenoleukodystrophy gene, Genomics source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Combined deletion or dysfunction of both ABCD1 and BCAP31 causes contiguous ABCD1 DXS1357E deletion syndrome (CADDS).

    “The combined deletion or dysfunction of both ABCD1 and BCAP31 (initial name DXS1375E [32]) causes contiguous ABCD1 DXS1357E deletion syndrome (CADDS).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Mosser, 1994, A new human gene (DXS1357E) with ubiquitous expression, located in Xq28 adjacent to the adrenoleukodystrophy gene, Genomics source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ABCD1 gene encodes the ABCD1/ALD protein of 745 amino acids, an ATP-binding cassette transmembrane half-transporter required for the import of coenzyme A-activated very-long-chain fatty acids (VLCFAs; >C22:0) into peroxisomes for degradation.

    “It encodes the ABCD1/ALD protein of 745 amino acids, an ATP-binding cassette transmembrane half-transporter required for the import of coenzyme A-activated very-long-chain fatty acids (VLCFAs; >C22:0) into peroxisomes for degradation [3,4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Mosser, 1994, The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein, Hum. Mol. Genet. source
    • cites [4] Kemp, 2011, Mammalian peroxisomal ABC transporters: From endogenous substrates to pathology and clinical significance Correspondence, Br. J. Pharmacol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data

    Some of the most visited website pages are in Spanish, indicating an unmet need for information written by experts in other languages.

    “Interestingly, some of the most visited pages are in Spanish, which indicates that there is an unmet need for information written by experts in other languages.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Early experimental data revealed that the helical domain between the Walker A and B motifs undergoes conformational change when bound to ADP, indicating their role in the transduction of free energy during ATP-hydrolysis in the ALD protein.

    “Early experimental data revealed that the helical domain between the Walker A and B motifs undergoes conformational change when bound to ADP, indicating their role in the transduction of free energy during ATP-hydrolysis in the ALD protein [34,35].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Morita, 2006, ATP-binding and -hydrolysis activities of ALDP (ABCD1) and ALDRP (ABCD2), human peroxisomal ABC proteins, overexpressed in Sf21 cells, Biol. Pharm. Bull. source
    • cites [35] Kashiwayama, 2002, Nucleotide-induced conformational changes of PMP70, an ATP binding cassette transporter on rat liver peroxisomal membranes, Biochem. Biophys. Res. Commun. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    If an early-stage cerebral lesion is identified in a boy with neurologically asymptomatic ALD, he will be referred for hematopoietic stem cell transplantation or gene therapy, if applicable.

    “If an early-stage cerebral lesion is identified in a boy with neurologically asymptomatic ALD [61], he will be referred for hematopoietic stem cell transplantation or gene therapy, if applicable.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Liberato, 2019, MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy, Neurology source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Taken together, the ABCD1 Variant Database, open collaboration, and the results of this study serve as a platform to aid in the resolution of VUSs identified during newborn screening.

    “Taken together, the ABCD1 Variant Database, open collaboration, and the results of this study serve as a platform to aid in the resolution of VUSs identified during newborn screening.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The ABCD1 Variant Database provides a resource for the integration of experimental data and large datasets.

    “From a scientific perspective, the database provides a backbone for realignment of older reported variants, a resource for the integration of experimental data and large datasets, a platform for variant classification, and a way to shed light on functionally important segments of the protein.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The ABCD1 variant database has allowed families to take an active part in their child's care by being a resource for researching their child's variant and learning about ALD through well-curated information.

    “Lastly, the database has allowed families to take an active part in their child’s care by being a resource for researching their child’s variant and learning about ALD through well-curated information.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    For the ALD community, the ABCD1 Variant Database provides an opportunity to collaborate, translate, and transmit well-curated disease information to both non-expert physicians and families affected by ALD.

    “For the ALD community, the database provides an opportunity to collaborate, translate, and transmit well-curated disease information to both non-expert physicians and families affected by ALD.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The ABCD1 Variant Database provides a way to shed light on functionally important segments of the protein.

    “From a scientific perspective, the database provides a backbone for realignment of older reported variants, a resource for the integration of experimental data and large datasets, a platform for variant classification, and a way to shed light on functionally important segments of the protein.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Clinically, the ABCD1 Variant Database helps to address challenges posed by novel variants in the setting of newborn screening.

    “Clinically, it helps to address challenges posed by novel variants in the setting of newborn screening.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    If well-maintained, the ABCD1 Variant Database helps the ALD community at large.

    “If well-maintained, it helps the ALD community at large.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    A unique resource such as the ABCD1 Variant Database can only be maintained through open collaboration and the sharing of de-identified information.

    “A unique resource such as the ABCD1 Variant Database can only be maintained through open collaboration and the sharing of (de-identified) information.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The ABCD1 Variant Database provides a backbone for realignment of older reported variants.

    “From a scientific perspective, the database provides a backbone for realignment of older reported variants, a resource for the integration of experimental data and large datasets, a platform for variant classification, and a way to shed light on functionally important segments of the protein.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The process of prenatal genetic diagnosis and in vitro fertilization of unaffected embryos imposes significant medical, emotional, and financial distress on new families trying to have more children.

    “This process, while necessary to prevent further propagation of the disease to future generations, imposes significant medical, emotional, and financial distress on new families trying to have more children [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Eugster, 1999, Psychological aspects of in vitro fertilization: A review, Soc. Sci. Med. source

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim
43 of 43

  • The paper relies on this without support.

    Most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database since 1999.

    “Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database.”

  • The paper relies on this without support.

    Identification of index boys in new families with newborn screening has uncovered the expected maternal inheritance pattern of the pathogenic variant.

    “In terms of family planning, identification of index boys in new families with newborn screening has uncovered the expected maternal inheritance pattern of the pathogenic variant.”

  • The paper relies on this without support.

    Identification of a familial gene mutation may lead to a life-altering diagnosis of ALD in extended family members.

    “Lastly, the identification of a familial gene mutation may lead to a life-altering diagnosis of ALD in extended family members.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • ALD is the most common peroxisomal disorder and has multiple phenotypes without an established genotype-phenotype relationship.

    “ALD is the most common peroxisomal disorder and has multiple phenotypes without an established genotype–phenotype relationship [1].”

    From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [1]

    The Introduction describes ALD as having a striking clinical spectrum with no established genotype–phenotype relationship; the Abstract names adrenal insufficiency, myelopathy, and leukodystrophy. Our copy gives ALD’s estimated birth prevalence but does not establish that it is the most common peroxisomal disorder. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • ALD is caused by ABCD1 mutations.

    “ALD is caused by ABCD1 mutations [1].”

    From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [1]

  • As of 15 May 2025, the ABCD1 registry contains 172 variants annotated as likely pathogenic and 825 as pathogenic.

    “While writing this review, we updated the previous counts [100] and found a total of 172 variants annotated as “likely pathogenic” and 825 as “pathogenic” in the ABCD1 registry (https://adrenoleukodystrophy.info, accessed on 15 May 2025).”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [100]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Title gives 940 pathogenic variants, but results give 948

    Minor

    The title states 940 pathogenic variants, while the December 2021 results report 948 unique (likely) pathogenic variants.

  • Exon 6 coordinate interval is too short for its stated amino-acid range

    Minor

    The stated chromosome interval spans 36 bases, enough for at most 12 amino acids, whereas amino acids 497-545 comprise 49.

  • Exon 9 coordinate interval is too short for its stated amino-acid range

    Minor

    The stated chromosome interval spans 26 bases, enough for at most nine amino acids, whereas amino acids 623-664 comprise 42.

  • Two different former names are given for BCAP31

    Minor

    The text calls the former name DXS1375E, then uses DXS1357E for the same contiguous-deletion syndrome. The cited reference also names DXS1357E.

4 of 4

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Mallack, E. J., Gao, K., Engelen, M., & Kemp, S.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • NewYork–Presbyterian Hospital (US)
  • Emma Kinderziekenhuis (NL)
Corresponding author
Kemp, Stephan
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2022-01-14
Volume
11
Issue
2
Pages
283
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells11020283
PMC
PMC8773697
OpenAlex
W4206489241
Semantic Scholar
385a41753178105ca3e6520e135d1d4054a0b913
Cited by
60
References
64
Citations by year
2026: 11 · 2025: 13 · 2024: 13 · 2023: 11 · 2022: 12
FWCI
6.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
Funders
  • National Institute of Health (K23NS118044 to EM)
  • Netherlands Organization for Scientific Research (016.196.310 to ME)
  • Netherlands Organization for Health Research and Development (543002004 to SK)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
X-linked adrenoleukodystrophy, ABCD1 gene, pathogenic variants, variant database, very long chain fatty acids, genotype-phenotype correlation, variant clustering, newborn screening, adrenal insufficiency, leukodystrophy, myelopathy, variant pathogenicity
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Amino Acid Sequence, Humans, Infant, Newborn, Mutation, Structure-Activity Relationship, Neonatal Screening, Databases, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review