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Cited by 140Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchHereditary Neurological Disorders

The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

Open access
Berger, Johannes, Wiesinger, Christoph, Eichler, Florian·2015·The Application of Clinical Genetics
DOI 10.2147/tacg.s49590PMC PMC4427263
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Abstract

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs.

AI snapshot

Written from the paper’s full text.

TL;DR

X-linked adrenoleukodystrophy (X-ALD) is caused by ABCD1 mutations and presents with heterogeneous phenotypes, chiefly adrenomyeloneuropathy (AMN) and cerebral ALD (CALD), with no generalized genotype–phenotype correlation. This review summarizes incidence estimates, ABCD1 mutation features, modifier-gene studies, and diagnostic approaches including prenatal testing and newborn screening.

Key findings

  • Average X-ALD incidence in male patients is estimated between 1:20,000 and 1:30,000; a Norwegian study found a combined male-plus-female incidence of 1:61,000, while Bezman et al reported an extrapolated combined rate of 1:16,800. Prevalence estimates are around 1:200,000 for males and 1:100,000 for females.
  • CALD lifetime risk for male X-ALD patients is estimated at at least 60%, with peak occurrence between 5 and 12 years of age; risk of developing the inflammatory form between 5 and 12 years is around 35%–40%. De novo ABCD1 mutations have been reported in 4.1% to 19% of cases.
  • The X-ALD database contains 695 non-recurrent mutations, including 343 missense mutations affecting 209 different amino acids; no generalized correlation exists between ABCD1 mutation type and AMN versus CALD phenotype.
  • Plasma VLCFA measurement detects about 85% of heterozygous female carriers, so ABCD1 mutation analysis is needed for proper identification; newborn screening using C26:0 lysophosphatidylcholine from dried blood spots has been implemented, including in New York State since 2014.

Methods

  • Narrative review comparing incidence estimates from different populations and summarizing published reports on ABCD1 mutations, modifier genes, X-inactivation, prenatal diagnosis, next-generation sequencing, and newborn screening.
  • Data sources include epidemiological studies from Europe, North and South America, Asia, and Australasia; the X-ALD mutation database; and association, segregation, and gene-expression studies of candidate modifier genes.
  • Main analysis is qualitative synthesis; no new primary data, systematic search strategy, or meta-analysis is described.

Limitations

  • The paper states that incidence/prevalence estimates are limited by clinical heterogeneity with late onset, small numbers of subjects, differences in pedigree characterization, lack of centralized recording in some countries, and underdiagnosis of mildly affected males and heterozygous females.
  • The paper states that modifier-gene studies face low subject numbers and, in some cases, problems defining non-inflammatory subjects; negative association results should not necessarily exclude a modifier gene but may indicate it is not a major determinant.
  • Evident from the text: as a narrative review, it does not report a systematic literature search or quantitative synthesis, and the molecular basis for phenotypic heterogeneity and the role of skewed X-inactivation remain unresolved.

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

Integrity signals

Registry

Crossref · 10.2147/tacg.s49590

Cites

137 of 137 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 101 cited sources checked · 11 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    The feasibility of C26:0-LPC determination has been proven by two large pilot studies based on either liquid chromatography MS/MS or flow injection analysis MS/MS.

    “The feasibility of C26:0-LPC determination has been proven by two large pilot studies based on either liquid chromatography MS/MS72 or flow injection analysis MS/MS.73”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [72] Theda C Gibbons K Defor TE Newborn screening for X-linked adrenoleukodystrophy: further evidence high throughput screening is feasible Mol Genet Metab 2014 111 1 55 57 24268529 PMC3935823 source

      Citation 73 is attached specifically to the flow-injection MS/MS pilot study. The cited paper’s Methods (§2.2) instead describe chromatography using a UPLC column before MS/MS, and its Results (§3) report analysis of 4,689 newborn samples by that LC-MS/MS method. It supports the feasibility of screening, but not the flow-injection method attributed to it. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [73] Turgeon CT Moser AB Morkrid L Streamlined determination of lysophosphatidylcholines in dried blood spots for newborn screening of X-linked adrenoleukodystrophy Mol Genet Metab 2015 114 1 46 50 25481105 source
  • Premisecitation

    Dysfunction of ABCD1 results in impaired degradation of VLCFAs in peroxisomes and consequently their accumulation in various lipid species in tissues and body fluids.

    “The dysfunction of ABCD1 results in impaired degradation of VLCFAs in peroxisomes and consequently leads to their accumulation in various lipid species in tissues and body fluids.7”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Morita M Imanaka T Peroxisomal ABC transporters: structure, function and role in disease Biochim Biophys Acta 2012 1822 9 1387 1396 22366764 source

      Section 5.1 states that ABCD1 dysfunction reduces peroxisomal VLCFA β-oxidation and increases VLCFA levels in the plasma and tissues of patients with X-ALD. The copy does not establish the further claim that VLCFAs accumulate in various lipid species in those tissues and body fluids; section 5.2 mentions VLCFA-containing complex lipids and phospholipids only in a proposed mechanism. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    ABCD1 codes for the peroxisomal transporter ABCD1, which mediates the import of very long-chain fatty acid (VLCFA) CoA esters across the peroxisomal membrane.

    “The ABCD1 gene codes for the peroxisomal transporter ATP-binding cassette subfamily D member 1 (ABCD1, formerly ALDP), which mediates the import of very long-chain fatty acid (VLCFA) CoA esters across the peroxisomal membrane.5,6”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [5] Wiesinger C Kunze M Regelsberger G Forss-Petter S Berger J Impaired very long-chain acyl-CoA beta-oxidation in human X-linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction J Biol Chem 2013 288 26 19269 19279 23671276 PMC3696697 source
    • cites [6] van Roermund CW Visser WF Ijlst L The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters FASEB J 2008 22 12 4201 4208 18757502 source
  • Interpretationreasoning

    The most plausible explanation for incorrect detection of c.1823 G>A as a non-deleterious SNP is that the same variant is present in an ABCD1 pseudogene on chromosome 2 and was mistakenly attributed to the real ABCD1 gene.

    “Therefore, the most plausible explanation for the incorrect detection of the mutation in the former study52 is that the same variant is present in an ABCD1 pseudogene located on chromosome 2 and was by mistake attributed to the real ABCD1 gene.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] Lupski JR Reid JG Gonzaga-Jauregui C Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy N Engl J Med 2010 362 13 1181 1191 20220177 PMC4036802 source

      The Results (Genome Variation; page unavailable) report an ABCD1 SNP in a patient without adrenoleukodystrophy and suggest that its classification as a disease mutation might be erroneous. The paper does not identify c.1823 G>A, an ABCD1 pseudogene on chromosome 2, or mistaken attribution to the real gene as the explanation. The citing authors present that explanation as their own inference. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    In patients with subclinical adrenal insufficiency, monitoring and early initiation of hormone replacement therapy can avoid adrenal crises and life-threatening events.

    “In addition, in patients with subclinical adrenal insufficiency, monitoring and early initiation of hormone replacement therapy can avoid adrenal crises and life-threatening events.30,67”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [30] Dubey P Raymond GV Moser AB Kharkar S Bezman L Moser HW Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening J Pediatr 2005 146 4 528 532 15812458 source
    • cites [67] Polgreen LE Chahla S Miller W Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison’s disease improves survival and neurological outcomes Eur J Pediatr 2011 170 8 1049 1054 21279382 PMC3101278 source

      The Discussion (page unavailable) mentions monitoring boys with X-linked adrenoleukodystrophy for adrenal insufficiency, while the Methods describe testing adrenal function. The paper attributes improved survival and neurological outcomes to early diagnosis of cerebral disease and hematopoietic cell transplantation. Searches for hormone or steroid replacement and adrenal crises found no passage addressing whether early replacement therapy prevents crises or life-threatening events. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisereasoning

    No curative therapy is currently available for AMN, and treatment is limited to symptomatic therapy of adrenal or gonadal insufficiency, neuropathic pain, and spasticity.

    “Thus, no curative therapy is currently available for AMN, and treatment is limited to symptomatic therapy of adrenal or gonadal insufficiency, neuropathic pain, and spasticity.2”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Engelen M Kemp S de Visser M X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management Orphanet J Rare Dis 2012 7 51 22889154 PMC3503704 source

      The Clinical management section (page unavailable in our copy) says there is no effective disease-modifying therapy for AMN and that follow-up mainly provides symptomatic treatment. It specifies steroid replacement for adrenal insufficiency and medication for spasticity; the Women with X-ALD subsection also recommends treating neuropathic pain as for men with AMN. The copy notes testicular insufficiency in AMN but does not describe treatment for it, so the gonadal-treatment detail is not supported. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CALD usually only affects males and presents with rapidly progressive inflammatory demyelination in the brain, leading to rapid cognitive and neurological decline.

    “In contrast, CALD usually only affects males and presents with rapidly progressive inflammatory demyelination in the brain, leading to rapid cognitive and neurological decline.3,4”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [3] Moser HW Smith KD Watkins PA Powers J Moser AB X-linked adrenoleukodystrophy Scriver R Beaudet AL Sly WS Valle D The Metabolic and Molecular Bases of Inherited Disease 8th ed New York, NY, USA McGraw-Hill Book Co 2001

      Not checked in the free run.

    • cites [4] Berger J Forss-Petter S Eichler FS Pathophysiology of X-linked adrenoleukodystrophy Biochimie 2014 98 135 142 24316281 PMC3988840 source

      The Introduction and clinical aspects section describes CALD as rapidly progressive inflammatory cerebral demyelination in male patients, accompanied by progressive neurological decline; it also says cerebral disease in females is exceedingly rare. The cited passages do not specifically report cognitive decline (searched: “cognitive”), so that part of the claim is not established by our copy. Page numbers were not available. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A high number, if not all, heterozygous females develop at least some symptoms of AMN, and the severity of symptoms increases with age.

    “During recent more detailed studies, it became apparent that a high number, if not all, of the heterozygous females develop at least some symptoms of AMN and that the severity of symptoms increases with age.12,24,89”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [12] Engelen M Barbier M Dijkstra IM X-linked adrenoleukodystrophy in women: a cross-sectional cohort study Brain 2014 137 Pt 3 693 706 24480483 source
    • cites [24] Horn MA Retterstol L Abdelnoor M Skjeldal OH Tallaksen CM Age-dependent penetrance among females with X-linked adrenoleukodystrophy Brain 2015 138 Pt 2 e325 25149409 source
    • cites [89] Habekost CT Schestatsky P Torres VF Neurological impairment among heterozygote women for X-linked adrenoleukodystrophy: a case control study on a clinical, neurophysiological and biochemical characteristics Orphanet J Rare Dis 2014 9 1 6 24410807 PMC3896743 source

  • May combine two claims.

    Premisecitation

    All cases of translation initiation mutations in ABCD1 reported to date have presented with the AMN phenotype and none with CALD.

    “Indeed, all cases of translation initiation mutations in ABCD1 reported to date have presented with the AMN phenotype and none with CALD.35,79,80”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [35] O’Neill GN Aoki M Brown RH Jr ABCD1 translation-initiator mutation demonstrates genotype-phenotype correlation for AMN Neurology 2001 57 11 1956 1962 11739809 source
    • cites [79] Engelen M van der Kooi AJ Kemp S X-linked adrenomyeloneuropathy due to a novel missense mutation in the ABCD1 start codon presenting as demyelinating neuropathy J Peripher Nerv Syst 2011 16 4 353 355 22176151 source
    • cites [80] Vachalova I Chandoga J Petrovic R Copikova-Cudrakova D Sykora M Traubner P Adrenoleukodystrophy – a new mutation identified Bratisl Lek Listy 2007 108 10–11 462 466 18306728 source

      The Discussion describes one patient with an ABCD1 initiation-codon mutation whose presentation was consistent with AMN. It does not establish that all reported initiation mutations presented as AMN or that none presented as CALD; it also notes possible early cerebral involvement in this patient. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Determination of C26:0-LPC will also identify the majority of female X-ALD carriers as well as patients affected by different peroxisomal biogenesis disorders or single enzyme deficiencies of the peroxisomal beta-oxidation pathway.

    “In addition to the detection of male X-ALD patients, determination of C26:0-LPC will also identify the majority of female X-ALD carriers as well as patients affected by different peroxisomal biogenesis disorders or single enzyme deficiencies of the peroxisomal beta-oxidation pathway.72,74”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [72] Theda C Gibbons K Defor TE Newborn screening for X-linked adrenoleukodystrophy: further evidence high throughput screening is feasible Mol Genet Metab 2014 111 1 55 57 24268529 PMC3935823 source

      The Discussion (page unavailable) says screening may identify female heterozygotes and that positive results can reflect peroxisomal biogenesis disorders. It expects only a portion of female heterozygotes to be identified, however, not necessarily a majority. The Introduction mentions single-enzyme defects but does not establish that this test identifies patients with them. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [74] Vogel BH Bradley SE Adams DJ Newborn screening for X-linked adrenoleukodystrophy in New York State: Diagnostic protocol, surveillance protocol and treatment guidelines Mol Genet Metab 2 12 2015 Epub ahead of print 25724074 source

  • May combine two claims.

    Premisecitation

    The fatal cerebral phenotype of X-ALD is extremely rare in females and probably only occurs when both alleles are affected.

    “Indeed, the fatal cerebral phenotype of the disease is extremely rare in females and probably only occurs when both alleles are affected.4,87,88”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [4] Berger J Forss-Petter S Eichler FS Pathophysiology of X-linked adrenoleukodystrophy Biochimie 2014 98 135 142 24316281 PMC3988840 source
    • cites [87] Hershkovitz E Narkis G Shorer Z Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-Ter deletion Ann Neurol 2002 52 2 234 237 12210797 source
    • cites [88] Chen X Chen Z Huang D Liu X Gui Q Yu S Adult cerebral adrenoleukodystrophy and Addison’s disease in a female carrier Gene 2014 544 2 248 251 24768737 source

  • May combine two claims.

    Premisecitation

    Different substrate preferences were suggested for ABCD1-3: straight-chain VLCFAs for ABCD1, unsaturated VLCFAs for ABCD2, and branched-chain fatty acids, dicarboxylic acids, and bile acid precursors for ABCD3.

    “Different substrate preferences were suggested for ABCD1-3: straight-chain VLCFAs for ABCD1, unsaturated VLCFAs for ABCD2, and branched-chain fatty acids, dicarboxylic acids, and bile acid precursors for ABCD3.122–124”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [122] Genin EC Geillon F Gondcaille C Substrate specificity overlap and interaction between adrenoleukodystrophy protein (ALDP/ABCD1) and adrenoleukodystrophy-related protein (ALDRP/ABCD2) J Biol Chem 2011 286 10 8075 8084 21209459 PMC3048694 source

      The Discussion (page unavailable) describes a preference for saturated VLCFAs in ABCD1 and polyunsaturated fatty acids in ABCD2, while emphasizing that their substrate specificities overlap. The passage labeled Abstract (page unavailable) suggests that ABCD3 preferentially transports branched-chain fatty acids and bile acid precursors. Our copy does not support the additional attribution of dicarboxylic acids to ABCD3. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [123] van Roermund CW Ijlst L Wagemans T Wanders RJ Waterham HR A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids Biochim Biophys Acta 2014 1841 4 563 568 24333844 source
    • cites [124] Ferdinandusse S Jimenez-Sanchez G Koster J A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3 Hum Mol Genet 2015 24 2 361 370 25168382 source

      The supplied passages contain no match for the claim. Searches of our copy for ABCD1, ABCD2, ABCD3, dicarboxylic acids, and substrate specificity returned no passages, so I cannot verify the proposed substrate preferences from this source. (LLM, conf=0.65)

      Experimental — accuracy not yet measured

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

    Interpretationcitation

    A further explanation for the lack of compensation in vivo may be different affinities toward VLCFAs.

    “A further explanation for the lack of compensation in vivo may be different affinities toward VLCFAs.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [122] Genin EC Geillon F Gondcaille C Substrate specificity overlap and interaction between adrenoleukodystrophy protein (ALDP/ABCD1) and adrenoleukodystrophy-related protein (ALDRP/ABCD2) J Biol Chem 2011 286 10 8075 8084 21209459 PMC3048694 source

      The Discussion (page unavailable) describes different substrate preferences for ALDP and ALDRP, which supports the possibility of a functional difference toward VLCFAs. But it says there are no clear data on differences in affinity toward C24:0 and C26:0, and it does not establish affinity differences as an explanation for the lack of compensation in vivo. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [123] van Roermund CW Ijlst L Wagemans T Wanders RJ Waterham HR A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids Biochim Biophys Acta 2014 1841 4 563 568 24333844 source
    • cites [124] Ferdinandusse S Jimenez-Sanchez G Koster J A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3 Hum Mol Genet 2015 24 2 361 370 25168382 source

      No passage from our indexed copy addresses whether different affinities for very-long-chain fatty acids could explain a lack of compensation in vivo. Searches for the claim’s wording, VLCFA, affinity, and compensation found no relevant passage. (LLM, conf=0.70)

      Experimental — accuracy not yet measured

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

    Findingown data

    The average incidence rates for X-ALD in male patients are between 1:20,000 and 1:30,000.

    “In summary, the data given in Table 1 suggest the average incidence rates for X-ALD in male patients to be between 1:20,000 and 1:30,000.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    To date, 695 non-recurrent mutations have been described in the X-ALD database, out of which 343 represent missense mutations.

    “To date, 695 non-recurrent mutations have been described in the X-ALD database, out of which 343 represent missense mutations.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD).

    “X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Horn et al. found a combined incidence rate of 1:61,000 for males plus females in the Norwegian population.

    “Further, the study of Horn et al for the first time also directly addressed the number of affected females and found a combined incidence rate of 1:61,000 for males plus females in the Norwegian population.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Horn MA Retterstol L Abdelnoor M Skjeldal OH Tallaksen CM Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance Pediatr Neurol 2013 48 3 212 219 23419472 source
    • The authors state this as an assumption: Some underestimation must be assumed in the Norwegian study of Horn et al.

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

    Premisenone given

    AMN is characterized by a slowly progressive axonopathy with first symptoms in males usually between 20 and 30 years of age and in affected females with an average onset between 40 and 50 years.

    “AMN is characterized by a slowly progressive axonopathy and first symptoms in males usually appear between 20 and 30 years of age, while affected females may develop some symptoms of AMN with an average onset between 40 and 50 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    AMN has near 100% lifetime penetrance; all male and possibly most female patients will develop at least some symptoms of AMN late in life.

    “It was recently reported that all male and possibly even most female patients will develop at least some symptoms of AMN late in life and thus AMN has a near 100% lifetime penetrance.12,14,23”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Engelen M Barbier M Dijkstra IM X-linked adrenoleukodystrophy in women: a cross-sectional cohort study Brain 2014 137 Pt 3 693 706 24480483 source
    • cites [14] Horn MA Retterstol L Abdelnoor M Skjeldal OH Tallaksen CM Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance Pediatr Neurol 2013 48 3 212 219 23419472 source
    • cites [23] Engelen M Kemp S Poll-The BT X-linked adrenoleukodystrophy: pathogenesis and treatment Curr Neurol Neurosci Rep 2014 14 10 486 25115486 source

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

    Premisenone given

    The peak occurrence of CALD is between 5 and 12 years of age.

    “While the lifetime risk for male X-ALD patients to develop CALD is estimated to be at least 60%, the peak occurrence is between 5 and 12 years of age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    X-linked adrenoleukodystrophy (X-ALD) is a monogenic disease caused by mutations in the ABCD1 gene located on Xq28.

    “X-linked adrenoleukodystrophy (X-ALD) is a monogenic disease caused by mutations in the ABCD1 gene located on Xq28.1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Mosser J Douar AM Sarde CO Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters Nature 1993 361 6414 726 730 8441467 source

  • May combine two claims.

    Premisereasoning

    X-ALD is a monogenic, X-linked disorder, and the risk of affected parents transmitting the affected allele can be clearly predicted.

    “X-ALD is a monogenic, X-linked disorder and the risk of affected parents for transmitting the affected allele can be clearly predicted.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Bezman et al. reported a combined incidence rate of 1:16,800, an extrapolation based on male incidence rates that includes unidentified and unaffected female carriers.

    “In contrast, the combined incidence rate of 1:16,800 reported by the thorough study of Bezman et al represents an extrapolation based on male incidence rates and therefore also includes unidentified and unaffected female carriers.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Bezman L Moser AB Raymond GV Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening Ann Neurol 2001 49 4 512 517 11310629 source

  • May combine two claims.

    Premisecitation

    Measurement of total C26:0 is highly specific in male patients, but VLCFA measurement detects only about 85% of heterozygous female carriers.

    “While the measurement of total C26:0 is highly specific in male patients, measurement of VLCFAs can only detect about 85% of heterozygous female carriers.13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Moser AB Kreiter N Bezman L Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls Ann Neurol 1999 45 1 100 110 9894883 source

  • May combine two claims.

    Interpretationreasoning

    An elevated level of VLCFAs is the standard biomarker for diagnosis of X-ALD but does not predict phenotype or progression of disease.

    “Thus, an elevated level of VLCFAs represents the standard biomarker for diagnosis of X-ALD, but does not predict the phenotype or progression of disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a prospective cross-sectional cohort of 46 heterozygous X-ALD females, 18% of women under age 40 had symptoms, while 88% in the age group 60 years or older were symptomatic.

    “A recent prospective cross-sectional cohort study including 46 heterozygous X-ALD females reported that 18% of women under the age of 40 years had symptoms but in the age group 60 years or older, 88% were symptomatic.12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Engelen M Barbier M Dijkstra IM X-linked adrenoleukodystrophy in women: a cross-sectional cohort study Brain 2014 137 Pt 3 693 706 24480483 source

  • May combine two claims.

    Interpretationnone given

    The ABCD1 mutation is necessary but not sufficient for CALD; additional genetic or environmental factors are required to trigger brain inflammation.

    “The mutation in ABCD1 is necessary but not sufficient for CALD to occur, as additional genetic or environmental factors are required to trigger this devastating brain inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The majority of male X-ALD patients develops primary adrenocortical insufficiency (Addison's disease), which can be the first and often sole symptom in young male X-ALD patients.

    “The majority of male X-ALD patients develops primary adrenocortical insufficiency (Addison’s disease) which can be the first and often sole symptom in young male X-ALD patients.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Dubey P Raymond GV Moser AB Kharkar S Bezman L Moser HW Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening J Pediatr 2005 146 4 528 532 15812458 source

  • May combine two claims.

    Premisenone given

    The risk of developing the inflammatory form of X-ALD between 5 and 12 years of age is around 35%-40% and decreases during adulthood.

    “The risk of developing the inflammatory form of X-ALD between 5 and 12 years of age is around 35%–40% and decreases during adulthood.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The lifetime risk for male X-ALD patients to develop CALD is estimated to be at least 60%.

    “While the lifetime risk for male X-ALD patients to develop CALD is estimated to be at least 60%, the peak occurrence is between 5 and 12 years of age.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Prevalence rates of around 1:200,000 for males and 1:100,000 for females were estimated for the Dutch and Norwegian populations.

    “In addition to incidence rates, prevalence rates of around 1:200,000 for males and 1:100,000 for females were estimated by thorough investigations carried out for the Dutch and the Norwegian populations.14,21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Horn MA Retterstol L Abdelnoor M Skjeldal OH Tallaksen CM Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance Pediatr Neurol 2013 48 3 212 219 23419472 source
    • cites [21] van Geel BM Assies J Weverling GJ Barth PG Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in The Netherlands: a survey of 30 kindreds Neurology 1994 44 12 2343 2346 7991123 source

  • May combine two claims.

    Premisereasoning

    Sons of males with X-ALD will never inherit the affected X chromosome from their father, while their daughters will automatically be carriers of the disease allele.

    “While sons of males with X-ALD will never inherit the affected X chromosome from their father, their daughters will automatically be carriers of the disease allele.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The mutation c.1823 G>A in exon 8 of ABCD1 was previously shown to cause X-ALD, as it was found in the ABCD1 coding sequence in different patients.

    “However, in a previous study, this mutation was clearly shown to cause X-ALD, as it was found in the ABCD1 coding sequence in different patients.53”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Dvorakova L Storkanova G Unterrainer G Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: the first polymorphism causing an amino acid exchange Hum Mutat 2001 18 1 52 60 11438993 source

  • May combine two claims.

    Premisecitation

    The ABCD1 pseudogenes consist of exons 7-10 of the ABCD1 gene and are derived from one ancestral duplication, probably to chromosome 2, followed by further duplications.

    “These all consist of exons 7–10 of the ABCD1 gene and are derived from one ancestral duplication, probably to chromosome 2, which was followed by further duplications in a process termed pericentromeric plasticity.47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Eichler EE Budarf ML Rocchi M Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity Hum Mol Genet 1997 6 7 991 1002 9215666 source

  • May combine two claims.

    Premisereasoning

    Contradictory results concerning skewed X-inactivation have been reported, possibly due to inadequate neurological characterization and consideration of patient age.

    “However, contradictory results concerning skewed X-inactivation have been reported, possibly due to inadequate neurological characterization and consideration of the age of the patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The majority of female carriers have elevated plasma VLCFA levels, although to a lesser extent than male patients, and the rate of beta-oxidation of VLCFAs is decreased in fibroblasts.

    “However, the majority of female carriers have elevated plasma VLCFA levels, although to a lesser extent than male patients, and the rate of beta-oxidation of VLCFAs was found to be decreased in fibroblasts.12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Engelen M Barbier M Dijkstra IM X-linked adrenoleukodystrophy in women: a cross-sectional cohort study Brain 2014 137 Pt 3 693 706 24480483 source

  • May combine two claims.

    Premisecitation

    Amino acids 694-745 are not necessary for ABCD1 function, as truncated ABCD1 1-693 restored beta-oxidation of VLCFAs in X-ALD fibroblasts.

    “This idea is further supported by the finding that amino acids 694–745 are not necessary for ABCD1 function, as truncated ABCD11–693 was also able to restore beta-oxidation of VLCFAs in X-ALD fibroblasts.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Smith KD Kemp S Braiterman LT X-linked adrenoleukodystrophy: genes, mutations, and phenotypes Neurochem Res 1999 24 4 521 535 10227685 source

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

    Premisecitation

    Since the beginning of 2014, X-ALD is included in the New York State newborn screening program.

    “Indeed, since the beginning of 2014, X-ALD is included in the New York State newborn screening program,74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Vogel BH Bradley SE Adams DJ Newborn screening for X-linked adrenoleukodystrophy in New York State: Diagnostic protocol, surveillance protocol and treatment guidelines Mol Genet Metab 2 12 2015 Epub ahead of print 25724074 source

  • May combine two claims.

    Interpretationreasoning

    No disease-causing mutations have been found after amino acid position 693, although evolutionary conservation remains high up to position 721, suggesting this region of ABCD1 is not directly involved in substrate transport.

    “Interestingly, no disease-causing mutations have been found after amino acid position 693, although evolutionary conservation remains high up to position 721, suggesting that this region of ABCD1 is not directly involved in substrate transport.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    This raises the possibility of different substrate preferences for such putative heterodimers.

    “As chimeric heterodimers of ABCD1 and ABCD2 were shown in vitro to be functional, this would raise the possibility of different substrate preferences for such putative heterodimers.126”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Independently of the genetic background, every male X-ALD patient might be at risk of developing the inflammatory form of the disease in response to environmental factors.

    “Thus, it is possible that independently of the genetic background, every male X-ALD patient might be at risk of developing the inflammatory form of the disease in response to environmental factors, but the likelihood for this to occur may depend on specific genetic modifiers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The implementation of newborn screening for X-ALD will ensure that boys affected by X-ALD will not remain undiagnosed, and thus their chance to receive HSCT at an appropriate time will increase.

    “The implementation of newborn screening for X-ALD will ensure that boys affected by X-ALD will not remain undiagnosed, and thus their chance to receive HSCT at an appropriate time will increase.”
    Quote in the paperNot a substantial claim
37 of 37

  • The authors state this as an assumption.

    Some underestimation must be assumed in the Norwegian study of Horn et al.

    “However, some underestimation must be assumed in this study.”

  • The authors state this as an assumption.

    X-ALD patients without cerebral involvement at 45 years can be considered cases of “pure AMN”.

    “As the likelihood for initiation of brain inflammation strongly diminishes with age, X-ALD patients without cerebral involvement at 45 years were considered as cases of “pure AMN””

  • The paper relies on this without support.

    The likelihood for initiation of brain inflammation strongly diminishes with age.

    “As the likelihood for initiation of brain inflammation strongly diminishes with age, X-ALD patients without cerebral involvement at 45 years were considered as cases of “pure AMN””

  • The paper relies on this without support.

    The ABCD family of transporters needs to form dimers in order to be functional.

    “Furthermore, the ABCD family of transporters needs to form dimers in order to be functional.”

  • The paper relies on this without support.

    X-ALD is a monogenic disorder.

    “Although X-ALD is a monogenic disorder, the individual genetic background, involving many different genes, may be responsible for the age of onset of AMN symptoms in male as well as in female patients.”

  • The paper relies on this without support.

    Severe head trauma can elicit rapidly progressive brain inflammation in adult X-ALD patients.

    “For example, it has been reported that severe head trauma can elicit the rapidly progressive brain inflammation in adult patients.”

  • The paper relies on this without support.

    ABCD2 and ABCD3 are located in the peroxisomal membrane.

    “In addition to ABCD1, its two closest homologs, ABCD2 (ALDRP) and ABCD3 (PMP70), are also located in the peroxisomal membrane.”
7 of 7

Claims other papers make about this one

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Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. [45]Suzuki Y Shimozawa N Yajima S Novel subtype of peroxisomal acyl-CoA oxidase deficiency and bifunctional enzyme deficiency with detectable enzyme protein: identification by means of complementation analysis Am J Hum Genet 1994 54 1 36 43 8279468 PMC1918057

Cited by

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Related

Authors
Berger, J., Wiesinger, C., & Eichler, F.
Affiliations
  • Medical University of Vienna (AT)
  • Harvard University (US)
ORCID
Venue
The Application of Clinical Genetics
Publisher
Informa UK Limited
Published
2015-05
Volume
8
Pages
109
ISSN
1178-704X (ISSN-L)
DOI
10.2147/tacg.s49590
PMC
PMC4427263
OpenAlex
W1891483234
Cited by
140
References
137
Citations by year
2026: 6 · 2025: 7 · 2024: 14 · 2023: 9 · 2022: 16 · 2021: 25 · 2020: 11 · 2019: 17 · 2018: 11 · 2017: 12 · 2016: 10 · 2015: 2
FWCI
7.65
Type
journal article
Language
en
Open access
Licence
Locations
  • The Application of Clinical Genetics (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Funders
  • Forskningsrådet i Sydöstra Sverige
  • Austrian Science Fund (P26112-B19,)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
X-linked adrenoleukodystrophy, ABCD1 gene, peroxisomal ABC transporters, heredity (biology), ABCD1 mutations, genotype-phenotype correlation, genetic modifiers, adrenomyeloneuropathy, cerebral adrenoleukodystrophy, disease incidence, prenatal diagnosis, very long chain fatty acids, lysophosphatidylcholine, newborn screening, peroxisomal disorders

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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.

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