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Cited by 2Metabolism and Genetic DisordersGenomics and Rare DiseasesGenetic and rare skin diseases.

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review

Open access
Heath, Oliver, Pandithan, Dinusha, Pitt, James, Savva, Elena, Raiti, Laura, Bracken, Jenny, Vandeleur, Moya, Delatycki, Martin B. +3 more·2023·JIMD Reports
DOI 10.1002/jmd2.12390PMC PMC10494507
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Abstract

Contiguous ABCD1/ DXS1357E deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, ABCD1 and BCAP31 (formerly known as DXS1357E). Only nine individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss‐of‐function variants in BCAP31 cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH). Isolated pathogenic intragenic variants in ABCD1 are associated with the most common peroxisomal disorder, X‐linked adrenoleukodystrophy (X‐ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood‐onset neurodegeneration and high levels of very‐long‐chain fatty acids (VLCFA). While increased VLCFA levels also feature in CADDS, the few patients described to date all presented as neonates with a severe phenotype. Here we report a tenth individual with CADDS, a male infant with dysmorphic facial features who was diagnosed through ultra‐rapid whole genome sequencing (WGS) in the setting of persistent cholestatic liver disease, sensorineural hearing loss, hypotonia and growth failure and developmental delay. Biochemical studies showed elevated VLCFA and mildly reduced plasmalogens. He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype. We also review the genetic, phenotypic, and biochemical features in previously reported individuals with CADDS.

AI snapshot

Written from the paper’s full text.

TL;DR

This case report describes a tenth individual with CADDS, a male infant diagnosed by ultra-rapid whole genome sequencing who died at 7 months after developing pancreatic exocrine insufficiency and interstitial lung disease. The authors propose these two features as possible extensions of the CADDS phenotype and review the genetic, clinical, and biochemical findings of all previously reported CADDS patients.

Key findings

  • The proband had a 67 kb de novo hemizygous Xq28 deletion involving ABCD1 and part of BCAP31 (chrX: 153714363–153781647), with elevated VLCFA (C24/C22 ratio 1.727; C26/C22 ratio 0.144) and mildly reduced plasmalogens.
  • He developed pancreatic exocrine insufficiency (faecal elastase <15 μg/g) and interstitial lung disease with diffuse interstitial opacities on chest CT, and died at 7 months of age.
  • Across the reviewed CADDS cohort, 10 individuals are now reported (9 males, 1 female); 9 died, with death from respiratory causes reported in 50% of males.
  • The authors suggest pancreatic insufficiency and interstitial lung disease may be possible extensions to the CADDS phenotype, alongside previously recognized features such as cholestasis, growth failure, hypotonia, developmental delay, and elevated VLCFA.

Methods

  • Single new case report plus literature review of previously published CADDS individuals.
  • Trio whole genome sequencing was performed with ultra-rapid 5-day turnaround, mean target coverage 30x for nuclear DNA and minimum 800x mean coverage for mitochondrial DNA; the deletion was orthogonally validated by chromosomal microarray.
  • Biochemical studies included routine blood, urine, and CSF analyses, VLCFA and plasmalogen measurement, urine metabolite testing by flow-injection tandem mass spectrometry, and FibroScan liver stiffness measurement.

Limitations

  • The paper states that FibroScan interpretation was limited by the patient’s size and the lack of well-established normal values in infants under 5 kg.
  • The paper states that the authors could not explore BAP31-related hypotheses further because the patient died before an adequate sweat test could be collected or fibroblast cultures established, and the effect of oral cholic acid could not be ascertained.
  • Evident from the text: this is a single new patient within an ultra-rare condition, and the reviewed cases have variable deletion sizes and additional genes involved, which the authors note makes comparison between CADDS patients challenging.

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

Integrity signals

Registry

Crossref · 10.1002/jmd2.12390

Cites

21 of 21 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 50 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning

    Rapid WGS has clinical utility in decreasing infant morbidity.

    “reflecting the clinical utility of rapid WGS in decreasing infant morbidity.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] Farnaes L, Hildreth A, Sweeney NM, et al. Rapid whole‐genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med. 2018; 3: 10. doi: 10.1038/s41525-018-0049-4 29644095 PMC5884823 source
    • cites [15] Sanford EF, Clark MM, Farnaes L, et al. Rapid whole genome sequencing has clinical utility in children in the PICU. Pediatr Crit Care Med. 2019; 20: 1007‐ 1020. doi: 10.1097/PCC.0000000000002056 31246743 PMC6832787 source
  • Premisecitation

    Congenital heart disease did not feature in any of the CADDS patients with PLXNB3 involvement.

    “congenital heart disease did not feature in any of the CADDS patients with PLXNB3 involvement.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [6] Iwasa M, Yamagata T, Mizuguchi M, et al. Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology. 2013; 33: 292‐ 298. doi: 10.1111/j.1440-1789.2012.01348.x 22994209 source
    • cites [8] van de Kamp JM, Errami A, Howidi M, et al. Genotype‐phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clin Genet. 2015; 87: 141‐ 147. doi: 10.1111/cge.12355 24597975 source
    • cites [9] Whalen S, Shaw M, Mignot C, et al. Further delineation of BCAP31‐linked intellectual disability: description of 17 new families with LoF and missense variants. Eur J Hum Genet. 2021; 29: 1405‐ 1417. doi: 10.1038/s41431-021-00821-0 33603160 PMC8440520 source

      The “Male patient with CADDS” section (page unavailable) identifies a patient whose deletion included PLXNB3, but does not state whether he had congenital heart disease. The passages on CADDS and adjacent-gene deletions (page unavailable) likewise do not address congenital heart disease; searches for heart and cardiac anomalies found no decisive passage. An omitted feature is not evidence that it was absent in every patient. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Premisecitation

    Similar features were reported in another male infant with a 60 kb deletion including BCAP31, ABCD1, and PLXNB3 who died of respiratory failure at 16 months.

    “Similar features were reported in another male infant with a 60 kb deletion including BCAP31, ABCD1, and PLXNB3 who died of respiratory failure at 16 months, 9”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Whalen S, Shaw M, Mignot C, et al. Further delineation of BCAP31‐linked intellectual disability: description of 17 new families with LoF and missense variants. Eur J Hum Genet. 2021; 29: 1405‐ 1417. doi: 10.1038/s41431-021-00821-0 33603160 PMC8440520 source
  • Findingown data

    The proband's faecal elastase was <15 μg/g at 1, 3, and 6 months.

    “faecal elastase < 15 μg/g”
    • Also stated in: § CASE REPORT · plain
      “Faecal elastase | μg/g | <15 | <15 | <15 | >200”
    Quote in the paperSubstantial claim
  • Findingown data

    The tenth individual with CADDS developed interstitial lung disease.

    “He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 46
  • May combine two claims. 24
  • The quote only partly states this claim. 1

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

    Premisecitation

    SRPK3 encodes a protein member of the serine/arginine-rich specific kinase family involved in mRNA processing, and synaptic vesicle and neurotransmitter release.

    “SRPK3 encodes a protein member of the serine/arginine‐rich specific kinase family that is known to be involved in mRNA processing, and synaptic vesicle and neurotransmitter release.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Muller JA, Betzin J, Santos‐Tejedor J, et al. A presynaptic phosphosignaling hub for lasting homeostatic plasticity. Cell Rep. 2022; 39: 110696. doi: 10.1016/j.celrep.2022.110696 35443170 source

      The sections on the SRPK2-dependent phosphoproteome and RIM1-dependent release link SRPK2 to alternative splicing and neurotransmitter release. The claim attributes those roles to SRPK3, which these passages do not establish. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    PLXNB3 encodes plexin B3, which functions as a receptor for semaphorin-5A and plays a role in axon guidance, invasive growth, and cell migration.

    “PLXNB3 encodes plexin B3 which functions as a receptor for the semaphorin‐5A molecule and plays a role in axon guidance, invasive growth, and cell migration.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Hartwig C, Veske A, Krejcova S, Rosenberger G, Finckh U. Plexin B3 promotes neurite outgrowth, interacts homophilically, and interacts with Rin. BMC Neurosci. 2005; 6: 53. doi: 10.1186/1471-2202-6-53 16122393 PMC1215486 source

      The Background (page not specified) identifies plexin B3 as interacting with semaphorin-5A and describes semaphorin-related axon repulsion, supporting the receptor and axon-guidance portions. The copy does not establish that plexin B3 plays a role in invasive growth or cell migration; the Discussion mentions migration in relation to cell-adhesion molecules more generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A zebrafish knockout study has revealed SRPK3 to be a compelling candidate gene for X-linked intellectual disability.

    “A zebrafish knockout study in which Srpk3 −/− fish were raised to adulthood has recently revealed SRPK3 to be a compelling candidate gene for X‐linked intellectual disability.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Kim CH, Lee YR, Thomas M, et al. Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X‐linked intellectual disability. Res Sq. 2023;rs.3.rs‐2683050. doi: 10.21203/rs.3.rs-2683050/v1 source

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

    Findingown data

    The proband's stools remained acholic amidst persistent cholestatic liver dysfunction.

    “His stools remained acholic amidst persistent cholestatic liver dysfunction (Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient appeared cachectic at 4 weeks of age.

    “At 4 weeks of age, he appeared jaundiced and cachectic, his weight was 2.65 kg (Z = − 3.88) and head circumference 34.5 cm (Z = −2.20).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Hepatic ultrasound at 1 month old showed normal echogenicity.

    “Hepatic ultrasound at 1 month old showed normal echogenicity.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had cholestasis.

    “Cholestatic treatment with ursodeoxycholic acid (10 mg/kg BD) was commenced from 4 weeks of age with limited effect.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient's weight had stagnated at 6 months (weight 3.55 kg, Z = −7.20).

    “His weight had stagnated (weight 3.55 kg, Z = −7.20)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had a triangular face with a broad forehead and a pointed chin.

    “He had triangular faces with a broad forehead and a pointed chin, and an occipital haemangioma that had remained unchanged since birth.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient's vision was intact.

    “His vision was intact and auditory brainstem response audiometry confirmed bilateral moderate SNHL.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient appeared jaundiced at 4 weeks of age.

    “At 4 weeks of age, he appeared jaundiced and cachectic, his weight was 2.65 kg (Z = − 3.88) and head circumference 34.5 cm (Z = −2.20).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Infective indices were unremarkable.

    “and unremarkable infective indices.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Brain MRI at 4 weeks showed normal myelination.

    “Brain MRI at 4 weeks showed normal myelination and no evidence of cortical dysplasia, ischemia, or haemorrhage.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had central hypotonia with prominent head lag.

    “He had central hypotonia with prominent head lag, but otherwise normal reflexes and anti‐gravity movements.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Initial investigations excluded tyrosinemia, galactosemia, Nieman Pick disease type C, and more common causes of intra- and extra-hepatic cholestasis.

    “Tyrosinemia, galactosemia and Nieman Pick disease type C, together with more common causes of intra‐and extra‐hepatic cholestasis were excluded following initial investigations.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had otherwise normal reflexes and anti-gravity movements.

    “He had central hypotonia with prominent head lag, but otherwise normal reflexes and anti‐gravity movements.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had no organomegaly.

    “There was no organomegaly.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient's weight at 4 weeks of age was 2.65 kg (Z = −3.88).

    “At 4 weeks of age, he appeared jaundiced and cachectic, his weight was 2.65 kg (Z = − 3.88) and head circumference 34.5 cm (Z = −2.20).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proband had persistent feeding difficulties with poor suck and frequent emesis.

    “Failure to thrive was compounded by persistent feeding difficulties with poor suck and frequent emesis, together with ongoing malabsorption and steatorrhea due to pancreatic insufficiency (faecal elastase < 15 μg/g; Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proband developed jaundice on day 2 with raised total bilirubin (203 μmol/L) and GGT (1287 U/L).

    “He developed jaundice on day 2 with raised total bilirubin of 203 μmol/L (reference range: 0–15 μmol/L) and GGT of 1287 U/L (RR: 0–40 U/L).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Brain MRI at 4 weeks showed no evidence of cortical dysplasia, ischemia, or haemorrhage.

    “Brain MRI at 4 weeks showed normal myelination and no evidence of cortical dysplasia, ischemia, or haemorrhage.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had stridor.

    “He had stridor”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient required continuous nasojejunal feeds because of recurrent vomiting.

    “necessitating a transition to continuous nasojejunal feeds because of recurrent vomiting.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Cholestatic treatment with ursodeoxycholic acid (10 mg/kg BD) commenced from 4 weeks of age had limited effect.

    “Cholestatic treatment with ursodeoxycholic acid (10 mg/kg BD) was commenced from 4 weeks of age with limited effect.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had an occipital haemangioma that had remained unchanged since birth.

    “He had triangular faces with a broad forehead and a pointed chin, and an occipital haemangioma that had remained unchanged since birth.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The proband was born at term, small for gestational age (birthweight 2.44 kg, Z = −2.2), to non-consanguineous Caucasian healthy parents, and was an only child.

    “He was the only child to non‐consanguineous Caucasian healthy parents and was born at term, small for gestational age (birthweight 2.44 kg, Z = −2.2) despite an otherwise uncomplicated pregnancy.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had global developmental delay.

    “He had global developmental delay”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had poor head control.

    “and poor head control”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proband was a male infant with hepatic cholestasis, hypotonia, sensorineural hearing loss, and failure to thrive, referred for metabolic assessment at 4 weeks of age.

    “The proband was a male infant with hepatic cholestasis, hypotonia, sensorineural hearing loss (SNHL), and failure to thrive referred for metabolic assessment at 4 weeks of age.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient's head circumference at 4 weeks of age was 34.5 cm (Z = −2.20).

    “At 4 weeks of age, he appeared jaundiced and cachectic, his weight was 2.65 kg (Z = − 3.88) and head circumference 34.5 cm (Z = −2.20).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Auditory brainstem response audiometry confirmed bilateral moderate sensorineural hearing loss (SNHL).

    “His vision was intact and auditory brainstem response audiometry confirmed bilateral moderate SNHL.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had profound hypotonia.

    “with profound hypotonia”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient's anterior fontanelle was not enlarged.

    “His anterior fontanelle was not enlarged.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient had increased work of breathing.

    “and increased work of breathing”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient's Fibroscan liver stiffness measurement was 12.9 kPa.

    “Liver stiffness measurement measured by Fibroscan was 12.9 kPa.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The patient died at 7 months.

    “he died at 7 months”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proband died at 7 months of age having developed pancreatic insufficiency and unexplained lung infiltrates.

    “Our patient died at 7 months of age having developed pancreatic insufficiency and unexplained lung infiltrates (Figure 1C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The proband's plasmalogens were mildly reduced and urine bile acid intermediates such as THCA remained raised in normal proportion to other markers of liver dysfunction.

    “His plasmalogens were mildly reduced and urine bile acid intermediates such as tetrahydroxycholestanoic (THCA) remained raised in normal proportion to other markers of liver dysfunction (Table 1)”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The patient had interstitial lung disease.

    “lung CT showed unexplained diffuse interstitial opacities (Figure 1C), without specific features of aspiration pneumonitis and unremarkable infective indices.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Elevated plasma VLCFA is present at birth in all individuals affected by X-ALD.

    “Elevated plasma VLCFA is present at birth in all affected individuals. 1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mosser J, Douar AM, Sarde CO, et al. Putative X‐linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993; 361: 726‐ 730. doi: 10.1038/361726a0 8441467 source

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

    Premisecitation

    BAP31 acts as a MAM tetherer and regulatory protein, supporting mitochondrial homeostasis and regulating autophagy and apoptosis.

    “It also acts as a MAM tetherer and regulatory protein, supporting mitochondrial homeostasis and regulating autophagy and apoptosis. 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Quistgaard EM. BAP31: physiological functions and roles in disease. Biochimie. 2021; 186: 105‐ 129. doi: 10.1016/j.biochi.2021.04.008 33930507 source

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

    Premisecitation

    CADDS was first described in 2002 by Corzo et al. in three male infants with large ABCD1 deletions extending into BCAP31.

    “CADDS was first described in 2002 by Corzo et al., 5 in three male infants with large ABCD1 deletions extending into BCAP31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Corzo et al., 5

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Isolated pathogenic intragenic variants in ABCD1 are associated with X-linked adrenoleukodystrophy (X-ALD).

    “Isolated pathogenic intragenic variants in ABCD1 are associated with the most common peroxisomal disorder, X‐linked adrenoleukodystrophy (X‐ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood‐onset neurodegeneration and high levels of very‐long‐chain fatty acids (VLCFA).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mosser J, Douar AM, Sarde CO, et al. Putative X‐linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993; 361: 726‐ 730. doi: 10.1038/361726a0 8441467 source

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

    Premisecitation

    X-ALD is a peroxisomal disorder and single transporter deficiency characterised by reduced beta-oxidation of VLCFA, white matter demyelination, and adrenal cortex atrophy.

    “Intragenic loss‐of‐function variants in ABCD1 are associated with X‐linked adrenoleukodystrophy (X‐ALD; MIM#300100), a peroxisomal disorder and single enzyme (transporter) deficiency characterised by reduced ß‐oxidation of VLCFA, white matter demyelination and adrenal cortex atrophy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mosser J, Douar AM, Sarde CO, et al. Putative X‐linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993; 361: 726‐ 730. doi: 10.1038/361726a0 8441467 source

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

    Premisecitation

    BAP31 functions as a protein chaperone and quality control factor involved in ER export or retention and ER-associated degradation.

    “BAP31 functions both as a protein chaperone and quality control factor involved in ER export or retention, and ER‐associated degradation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Quistgaard EM. BAP31: physiological functions and roles in disease. Biochimie. 2021; 186: 105‐ 129. doi: 10.1016/j.biochi.2021.04.008 33930507 source

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

    Premisecitation

    Cerebral X-ALD is the most severe form of X-ALD, characterised by childhood-onset neurodegeneration from 3 years of age that, without very early bone marrow transplantation, progresses to severe disability and death.

    “Cerebral X‐ALD is the most severe form of the disorder characterised by childhood‐onset neurodegeneration from 3 years of age that, in the absence of bone marrow transplantation very early in the disease course, progresses to severe disability and death. 2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Moser HW, Smith KD, Watkins PA, Powers J, Moser AB. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. McGraw‐Hill; 2001: 3251‐ 3301.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    BCAP31 encodes BAP31, a ubiquitously expressed transmembrane protein located in the endoplasmic reticulum, including mitochondria-associated membranes.

    “BCAP31 encodes B‐cell‐receptor associated protein 31 (BAP31), a ubiquitously expressed transmembrane protein located in the endoplasmic reticulum (ER), including in mitochondria‐associated membranes (MAMs). 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Quistgaard EM. BAP31: physiological functions and roles in disease. Biochimie. 2021; 186: 105‐ 129. doi: 10.1016/j.biochi.2021.04.008 33930507 source

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

    Premisenone given

    CADDS is an ultra-rare condition with only 10 individuals reported, including this patient.

    “CADDS) is an ultra‐rare condition with only 10 individuals reported, including this patient.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Interpretation of the Fibroscan result is limited by the patient's size and the lack of well-established normal values in infants under 5 kg.

    “interpretation is limited due to the size of the patient and the lack of well‐established normal values in infants under 5 kg.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In CADDS, severe developmental delay, dystonia, deafness, and white matter abnormalities are commonly reported.

    “As in DDCH, severe developmental delay, dystonia, deafness, and white matter abnormalities are commonly reported, while the presence of raised VLCFA is like that seen in isolated ABCD1 defects.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Corzo D, Gibson W, Johnson K, et al. Contiguous deletion of the X‐linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002; 70: 1520‐ 1531. doi: 10.1086/340849 11992258 PMC419992 source
    • cites [6] Iwasa M, Yamagata T, Mizuguchi M, et al. Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology. 2013; 33: 292‐ 298. doi: 10.1111/j.1440-1789.2012.01348.x 22994209 source
    • cites [7] Calhoun AR, Raymond GV. Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature. Am J Med Genet A. 2014; 164A: 2613‐ 2617. doi: 10.1002/ajmg.a.36661 25044748 source

  • May combine two claims.

    Premisecitation

    RNA analyses and immunocytochemical studies on cultured fibroblasts from affected CADDS patients have previously confirmed the absence of BCAP31 transcripts and ALDP, respectively, in keeping with a loss-of-function effect.

    “RNA analyses and immunocytochemical studies on cultured fibroblasts from affected CADDS patients have previously confirmed the absence of BCAP31 transcripts and ALDP (the protein encoded by ABCD1), respectively, in keeping with a loss‐of‐function effect.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Corzo D, Gibson W, Johnson K, et al. Contiguous deletion of the X‐linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002; 70: 1520‐ 1531. doi: 10.1086/340849 11992258 PMC419992 source
    • cites [8] van de Kamp JM, Errami A, Howidi M, et al. Genotype‐phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clin Genet. 2015; 87: 141‐ 147. doi: 10.1111/cge.12355 24597975 source

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

    Study design and conductown data

    The effect of oral cholic acid could not be ascertained because the patient died before it could be assessed.

    “before the effect of this medication could be ascertained.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    The 12.9 kPa Fibroscan value is consistent with significant liver fibrosis.

    “This would be consistent with significant fibrosis”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The Xq28 deletions reported in CADDS vary in length between 31 and 110 kb.

    “The Xq28 deletions reported in CADDS vary in length between 31 and 110 kb (Figure 1A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Neither DDCH nor X-ALD can account for the neonatal cholestasis and early infantile death underpinning the severity in CADDS.

    “Neither DDCH nor X‐ALD, can account for the neonatal cholestasis and early infantile death underpinning the severity in CADDS.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Death from respiratory causes is reported in 50% of males with CADDS.

    “overall, death from respiratory causes is reported in 50% of males with CADDS. 5 , 6”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Corzo D, Gibson W, Johnson K, et al. Contiguous deletion of the X‐linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002; 70: 1520‐ 1531. doi: 10.1086/340849 11992258 PMC419992 source
    • cites [6] Iwasa M, Yamagata T, Mizuguchi M, et al. Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology. 2013; 33: 292‐ 298. doi: 10.1111/j.1440-1789.2012.01348.x 22994209 source

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

    Interpretationcitation

    BCAP31 deficiency potentially exacerbates the peroxisomal phenotype in CADDS, although the mechanisms remain unclear.

    “BCAP31 deficiency potentially exacerbates the peroxisomal phenotype in CADDS, although the mechanisms remain unclear. 6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Iwasa M, Yamagata T, Mizuguchi M, et al. Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology. 2013; 33: 292‐ 298. doi: 10.1111/j.1440-1789.2012.01348.x 22994209 source

  • May combine two claims.

    Premisecitation

    Previous studies have reported normal plasmalogen levels in blood and cultured fibroblasts, with normal peroxisomal size, number and assembly demonstrated in liver tissue by electron microscopy and immunochemistry.

    “Previous studies, have reported normal plasmalogen levels in blood and cultured fibroblasts, with normal peroxisomal size, number and assembly demonstrated in liver tissue by electron microscopy and immunochemistry. 5 , 6”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Corzo D, Gibson W, Johnson K, et al. Contiguous deletion of the X‐linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002; 70: 1520‐ 1531. doi: 10.1086/340849 11992258 PMC419992 source
    • cites [6] Iwasa M, Yamagata T, Mizuguchi M, et al. Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology. 2013; 33: 292‐ 298. doi: 10.1111/j.1440-1789.2012.01348.x 22994209 source
58 of 58

  • The paper relies on this without support.

    The pancreatic exocrine deficiency and interstitial lung disease observed in the tenth individual with CADDS are attributable to CADDS rather than to unrelated causes.

    “He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype.”

  • The paper relies on this without support.

    The literature review identified all previously reported individuals with CADDS.

    “Only nine individuals with this diagnosis have been reported in the medical literature to date.”

  • The paper relies on this without support.

    Low faecal elastase (<15 μg/g) indicates pancreatic exocrine insufficiency.

    “ongoing malabsorption and steatorrhea due to pancreatic insufficiency (faecal elastase < 15 μg/g; Table 1)”

  • The paper relies on this without support.

    The 67 kb de novo hemizygous deletion involving ABCD1 and part of BCAP31 on Xq28 is pathogenic and causative of the patient's clinical phenotype.

    “Ultra‐rapid, five‐day turnaround WGS identified a 67 kb de novo hemizygous deletion involving ABCD1 and part of BCAP31 on Xq28 (chrX: 153714363–153 781 647), that was orthogonally validated with chromosomal microarray.”
4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Moser HW, 2001, The Metabolic and Molecular Bases of Inherited Diseases, 3251

Cited by

Still being checked.

Related

Authors
Heath, O., Pandithan, D., Pitt, J., Savva, E., Raiti, L., Bracken, J., Vandeleur, M., Delatycki, M. B., Yaplito‐Lee, J., Hardikar, W., & Halligan, R.
Affiliations
  • Royal Children's Hospital (AU)
  • Victorian Clinical Genetics Services (AU)
Corresponding author
Heath, Oliver
ORCID
Venue
JIMD Reports
Publisher
Wiley
Published
2023-08-19
Volume
64
Issue
5
Pages
337-345
ISSN
  • 2192-8304 (ISSN-L)
  • 2192-8312
DOI
10.1002/jmd2.12390
PMC
PMC10494507
OpenAlex
W4385999835
Semantic Scholar
74d30529c01cda5ff97f04ef82418acb5a2060e5
Cited by
2
References
21
Citations by year
2025: 1 · 2023: 1
FWCI
0.31
Type
journal article
Language
en
Open access
Licence
Locations
  • JIMD Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
Keywords
contiguous gene syndrome, ABCD1, BCAP31, interstitial lung disease, exocrine pancreatic insufficiency, very long chain fatty acids, plasmalogens, cholestatic liver disease, sensorineural hearing loss, hypotonia, growth failure, developmental delay, phenotypic expansion, peroxisomal disorders, X-linked adrenoleukodystrophy

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.

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