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Cited by 156Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchAdrenal Hormones and Disorders

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index; 10 of the 57 sources its claims cite were checked for support.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy

Open access
Engelen, Marc, van Ballegoij, Wouter J.C., Mallack, Eric James, Van Haren, Keith P., Köhler, Wolfgang, Salsano, Ettore, van Trotsenburg, A.S.P., Mochel, Fanny, Sevin, Caroline, Regelmann, Molly O., Tritos, Nicholas A., Halper, Alyssa, Lachmann, Robin H., Davison, James, Raymond, Gerald V., Lund, Troy C., Orchard, Paul J., Kuehl, Joern-Sven, Lindemans, Caroline A., Caruso, Paul, Turk, Bela Rui, Moser, Ann B., Vaz, Frédéric M., Ferdinandusse, Sacha, Kemp, Stephan, Fatemi, Ali, Eichler, Florian S., Huffnagel, Irene C.·2022·Neurology
DOI 10.1212/wnl.0000000000201374PMC PMC9687408
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Abstract

gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This international modified Delphi consensus provides best-practice recommendations for diagnosis, clinical surveillance, and treatment of adrenoleukodystrophy (ALD), covering cerebral ALD, myeloneuropathy, adrenal insufficiency, and related management. It recommends regular monitoring in all male patients for adrenal failure and conversion to cerebral ALD, with hematopoietic cell transplant (HCT) as the treatment of choice for cerebral ALD.

Key findings

  • Consensus was reached on 39 discrete areas among 28 international ALD experts. Recommendations include considering cerebral ALD in boys and men with white matter abnormalities on brain MRI suggestive of ALD; ALD-related myelopathy in adult men and women with chronic myelopathy and a normal MRI; and ALD-related adrenal insufficiency in boys and men with primary adrenal insufficiency without detectable steroid-21-hydroxylase or other organ-specific antibodies.
  • Diagnostic testing: *ABCD1* genetic testing is the gold standard; plasma C26:0-lysophosphatidylcholine (C26:0-lysoPC) has superior diagnostic performance, and if unavailable, fasting plasma very-long-chain fatty acids (VLCFAs) should be obtained. In women, VLCFA sensitivity is 85%, whereas C26:0-lysoPC sensitivity is >99%.
  • Surveillance: all boys and men should be screened for cerebral ALD with baseline MRI at age 2 years, every 6 months between ages 2 and 12 years, and yearly from age 12 years; routine cerebral ALD screening is not recommended in girls and women. All boys and men should be screened for adrenal insufficiency with early morning cortisol and ACTH starting in the first 6 months of life, every 3–6 months before age 10 years, and yearly thereafter, with mineralocorticoid deficiency screening using plasma renin and serum electrolytes.
  • Treatment: allogeneic HCT is the standard treatment for cerebral ALD and can halt progression; eligibility should be determined by an ALD transplantation expert. In general, boys are considered eligible with gadolinium-enhancing demyelination, Loes score ≤9, and neurologic function score 0 or 1; adult men with enhancing lesions and no or few neurocognitive impairments. Gene therapy should be considered in boys if allogeneic donor options are poor. Myeloneuropathy treatment is supportive; adrenal insufficiency is treated with glucocorticoid replacement; data supporting Lorenzo’s oil as disease-modifying are insufficient.

Methods

  • Three ALD centers of excellence initiated the project; 30 professionals were invited, and 28 international ALD experts participated. Patient advocacy groups provided written comments, and a literature review identified 132 relevant articles, mostly small retrospective and observational studies.
  • A modified Delphi approach was used with 2 questionnaire rounds and 1 consensus meeting. Experts rated agreement on a 9-point scale; consensus was defined as >80% rating agreement between 7 and 9 or disagreement between 1 and 3. Twenty-eight experts participated in round 1, 26 in round 2, and 20 in the consensus meeting; all 28 agreed to the final recommendations.
  • The literature search covered Embase, MEDLINE, and Evidence-Based Medicine Reviews for publications from 1990 to 2019, limited to English full-text and human studies, with gray literature and snowballing; study quality was assessed with the Newcastle-Ottawa Scale.

Limitations

  • Stated: the consensus approach is at risk for bias because of panelist selection and repeat review; the panel is small, clinical experience varied, and no correction was applied for differences in experience. Consensus was defined as >80% agreement, so some panelists did not agree with specific recommendations.
  • Stated: some topics did not reach consensus, including the exact timing of adrenal testing in the first year of life, invasive spasticity treatments, urinary incontinence, neuropsychological testing as a screening tool, and bone health evaluation in men. The poor ability to predict disease course informs current monitoring intervals but remains subject to change as more data emerge.
  • Evident from the text: recommendations are consensus-based because the literature was mostly small retrospective and observational studies, with a lack of prospective natural history studies and controlled clinical trials. Long-term safety data for ex vivo gene therapy are not yet available, and data on HCT effects on myeloneuropathy or adrenal insufficiency are limited.

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

Integrity signals

Registry

Crossref · 10.1212/wnl.0000000000201374

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

10 of 57 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    For biochemical testing, plasma C26:0-lysophosphatidylcholine has superior diagnostic performance.

    “For biochemical testing, plasma C26:0-lysophosphatidylcholine (C26:0-lysoPC) has superior diagnostic performance.18”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Jaspers YRJ, Ferdinandusse S, Dijkstra IME, et al. Comparison of the diagnostic performance of C26:0-lysophosphatidylcholine and very long-chain fatty acids analysis for peroxisomal disorders. Front Cell Dev Biol. 2020; 8: 690. 32903870 PMC7438929 source
  • Findingcitation

    Gadolinium enhancement just behind the leading edge of the lesion indicates active cerebral ALD disease.

    “Gadolinium enhancement just behind the leading edge of the lesion indicates active disease.25-27”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Melhem ER, Loes DJ, Georgiades CS, Raymond GV, Moser HW. X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. AJNR Am J Neuroradiol. 2000; 21(5): 839- 844. 10815658 PMC7976769
    • cites [26] Van der Knaap MSV, J. Resonance of Myelination and Myelin Disorders. In: Heilmann U, ed.: Springer; 2005: 176- 190.

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

    • cites [27] Powers JM, Liu Y, Moser AB, Moser HW. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol. 1992; 51(6): 630- 643. 1362438 source
  • Findingcitation

    Differentiating active from arrested white matter lesions can be challenging.

    “Differentiating active from arrested white matter lesions can be challenging.13,25,39,40,e1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 13,25,39,40,e1

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

  • Findingcitation

    The use of standardized clinimetric tests and electrophysiologic testing in ALD remains restricted to research settings.

    “The use of standardized clinimetric tests and electrophysiologic testing remains restricted to research settings.7,14,16,17,31,e24,e26,e27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 7,14,16,17,31,e24,e26,e27

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

  • Findingcitation

    Severe head trauma has been reported as a possible trigger for cerebral ALD.

    “Severe head trauma has been reported as possible trigger for cerebral ALD.e20-e22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites e20-e22

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

  • It may state two separate claims as one. 24
  • Probably not a substantial claim. 31

  • It may state two separate claims as one.

    Findingcitation

    The risk of developing cerebral disease is highest in childhood but remains present throughout life.

    “The risk of developing cerebral disease is highest in childhood but remains present throughout life.1,29,33-39”
    Quote in the paperSubstantial claim3 of 9 sources checked
    • cites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source
    • cites [29] Mallack EJ, Turk BR, Yan H, et al. MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. J Inherit Metab Dis. 2021; 44(3): 728- 739. 33373467 PMC8113077 source

      The Results (Surveillance guidelines; page unavailable) say the risk peaks at ages 3–12 and declines during the teenage years. The Methods exclude studies focused solely on adults, so this paper does not establish that the risk remains present throughout life. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [33] Huffnagel IC, Laheji FK, Aziz-Bose R, et al. The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration. J Clin Endocrinol Metab. 2019; 104(1): 118- 126. 30252065 source
    • cites [34] Baumann M, Korenke GC, Weddige-Diedrichs A, et al. Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy. Eur J Pediatr. 2003; 162(1): 6- 14. 12486501 source
    • cites [35] Kuhl JS, Suarez F, Gillett GT, et al. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain. 2017; 140(4): 953- 966. 28375456 source
    • cites [36] Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 2007; 6(8): 687- 692. 17618834 source
    • cites [37] Vargas CR, Coelho DD, Barschak AG, et al. X-linked adrenoleukodystrophy: clinical and laboratory findings in 15 Brazilian patients. Genet Mol Biol. 2000; 23(2): 261- 264. source

      The Introduction (page unavailable) says childhood X-ALD usually develops symptoms at ages four to eight, including demyelination and leukodystrophy. The Results and Discussion table (page unavailable) reports leukodystrophy in 10 of 11 childhood X-ALD patients and 2 of 4 adult-onset AMN patients. This supports cerebral involvement in childhood and adulthood, but the small case series does not establish that the risk is highest in childhood or persists throughout life. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [38] Raymond GV, Aubourg P, Paker A, et al. Survival and functional outcomes in boys with cerebral adrenoleukodystrophy with and without hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2019; 25(3): 538- 548. 30292747 source
    • cites [39] Liberato AP, Mallack EJ, Aziz-Bose R, et al. MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy. Neurology. 2019; 92(15): e1698- e708. 30902905 PMC6511088 source

  • It may state two separate claims as one.

    Premisecitation

    Women with ALD develop myeloneuropathy, whereas men can develop all three core syndromes.

    “Women develop myeloneuropathy; men can develop all 3 syndromes.7-9”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [7] Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014; 137(Pt 3): 693- 706. 24480483 source
    • cites [8] Huffnagel IC, Dijkgraaf MGW, Janssens GE, et al. Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis. 2019; 14(1): 30. 30732635 PMC6367840 source
    • cites [9] Habekost CT, Schestatsky P, Torres VF, et al. 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: 6. 24410807 PMC3896743 source

      The Background reports that some women with X-ALD develop myeloneuropathy resembling adrenomyeloneuropathy. It also names cerebral ALD and adrenomyeloneuropathy as male phenotypes, but does not identify three core syndromes or state that men can develop all three. The indexed copy provides no page numbers for these passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingcitation

    In women, the sensitivity of VLCFA analysis is 85%, whereas C26:0-lysoPC has a sensitivity of greater than 99%.

    “In women, the sensitivity of VLCFAs analysis is 85%, whereas C26:0-lysoPC has a sensitivity of >99%.18,19,22”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [18] Jaspers YRJ, Ferdinandusse S, Dijkstra IME, et al. Comparison of the diagnostic performance of C26:0-lysophosphatidylcholine and very long-chain fatty acids analysis for peroxisomal disorders. Front Cell Dev Biol. 2020; 8: 690. 32903870 PMC7438929 source

      The Discussion (page not available) reports that plasma VLCFA analysis gives false negatives in approximately 15–20% of women with ALD, consistent with roughly 80–85% sensitivity. The Results report elevated C26:0-LPC in all 19 women with ALD studied, but that small cohort does not establish a general sensitivity greater than 99% in women. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [19] Huffnagel IC, van de Beek MC, Showers AL, et al. Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy. Mol Genet Metab. 2017; 122(4): 209- 215. 29089175 source
    • cites [22] Moser AB, Kreiter N, Bezman L, et al. 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

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    ALD has a birth prevalence of 1:15,000 in male and female patients.

    “ALD has a birth prevalence of 1:15,000 (male patients and female patients).10”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Moser A, Jones RO, Hubbard WC, et al. Newborn screening for X-linked adrenoleukodystrophy. Int J Neonatal Screen. 2016; 2(4): 1- 5. PMC6715319 31467997 source

      The Introduction reports an estimated minimum birth incidence of about 1 in 17,000 for males and females combined in the United States. The Discussion reports approximately 1 in 14,700 positive newborn screens in New York, close to the claimed 1 in 15,000, but does not present that figure as the overall birth prevalence for males and females. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingcitation

    Peripheral neuropathy is a common feature of ALD but is rarely the presenting symptom.

    “Peripheral neuropathy is a common feature of ALD but is rarely the presenting symptom.7,14-16”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [7] Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014; 137(Pt 3): 693- 706. 24480483 source
    • cites [14] Horn MA, Nilsen KB, Jorum E, Mellgren SI, Tallaksen CM. Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy. Neurology. 2014; 82(19): 1678- 1683. 24719486 source
    • cites [15] Rattay TW, Just J, Roben B, et al. Nerve ultrasound characterizes AMN polyneuropathy as inhomogeneous and focal hypertrophic. Orphanet J Rare Dis. 2018; 13(1): 194. 30390710 PMC6215661 source

      The Results (page unavailable) say clinical signs of potential peripheral neuropathy were common in the studied AMN patients, supporting that part of the claim for this ALD phenotype. The Background describes AMN in adults with ALD, but neither it nor the retrieved passages say that neuropathy is rarely the presenting symptom of ALD. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [16] van Geel BM, Assies J, Haverkort EB, et al. Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with "Lorenzo's oil". J Neurol Neurosurg Psychiatry. 1999; 67(3): 290- 299. 10449548 PMC1736534 source

      The ELECTRONEUROGRAPHY section (page not specified) reports nerve-conduction abnormalities in 12 of 16 neurologically symptomatic patients, most often compatible with sensorimotor polyneuropathy. This supports peripheral neuropathy as a common feature in the studied symptomatic patients, but the paper does not establish that it is rarely the presenting symptom. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Findingnone given

    The interval between gadolinium administration and postcontrast T1-weighted image acquisition can influence study interpretation, with shorter intervals yielding a false-negative result.

    “The interval between gadolinium administration and postcontrast T1-weighted image acquisition can influence study interpretation where shorter intervals can yield a false-negative result.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Twenty-eight of the 30 invited experts participated in the first questionnaire round, 26 in the second questionnaire round, and 20 in the consensus meeting.

    “Twenty-eight of the 30 invited experts participated in the first questionnaire round, 26 in the second questionnaire round, and 20 in the consensus meeting.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingcitation

    Female patients with ALD remain asymptomatic in childhood and adolescence, while in adulthood myeloneuropathy symptoms can arise.

    “Female patients with ALD remain asymptomatic in childhood and adolescence, while in adulthood, myeloneuropathy symptoms can arise.7,14”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014; 137(Pt 3): 693- 706. 24480483 source
    • cites [14] Horn MA, Nilsen KB, Jorum E, Mellgren SI, Tallaksen CM. Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy. Neurology. 2014; 82(19): 1678- 1683. 24719486 source

  • It may state two separate claims as one.

    Findingcitation

    Cerebral ALD and primary adrenal insufficiency are extremely rare in women.

    “Cerebral ALD and primary adrenal insufficiency are extremely rare in women.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The literature review identified 132 relevant articles, mostly small retrospective and observational studies, which were insufficient for an isolated evidence-based approach.

    “First, a literature review (Figure 1) identified 132 relevant articles, which were mostly (small) retrospective and observational studies and thus insufficient for an isolated evidence-based approach.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Findingnone given

    Cerebral ALD before the age of 3 years is rare.

    “The age for the baseline MRI was set at 2 years because cerebral ALD before the age of 3 years is rare, and MRI scans obtained before the age of 2 years are difficult to interpret because of incomplete myelination.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingcitation

    Allogeneic hematopoietic cell transplantation is the standard treatment for cerebral ALD and can halt progression.

    “Allogeneic hematopoietic cell transplantation (HCT) is the standard treatment for cerebral ALD and can halt progression.34-36,38,e8-e13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 34-36,38,e8-e13

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

  • Probably not a substantial claim.

    Findingnone given

    No consensus was reached on the implementation of neuropsychological testing as a screening tool for cerebral ALD.

    “No consensus was reached on the implementation of neuropsychological testing as a screening tool for cerebral ALD.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    Virtually all men and most women with ALD eventually develop symptoms and signs of myeloneuropathy.

    “Virtually all men and most women with ALD eventually develop symptoms and signs of myeloneuropathy.8,33,e23-e25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 8,33,e23-e25

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

  • It may state two separate claims as one.

    Findingcitation

    HCT is unlikely to affect myeloneuropathy or adrenal insufficiency, but data are limited.

    “HCT is unlikely to affect myeloneuropathy or adrenal insufficiency, but data are limited.e18,e19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites e18,e19

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

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingnone given

    For the ex vivo gene-corrected autologous transplantation approach, there are no data.

    “For the very new ex vivo gene-corrected autologous transplantation approach, there are no data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The authors identified 39 discrete areas of consensus.

    “We identified 39 discrete areas of consensus.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The extent of brain involvement on MRI can be quantified with the MR severity scoring system (Loes score), ranging from 0 to 34.

    “The extent of brain involvement on MRI can be quantified with the MR severity scoring system (Loes score), ranging from 0 (no abnormalities) to 34 (severely abnormal).28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Loes DJ, Hite S, Moser H, et al. Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol. 1994; 15(9): 1761- 1766. 7847225 PMC8333737

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All 28 experts agreed to the final version of the recommendations.

    “All 28 experts agreed to the final version of the recommendations.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Cerebral ALD causes severe disability and death.

    “Cerebral ALD causes severe disability and death.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source

  • It may state two separate claims as one.

    Premisenone given

    ALD has three core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive leukodystrophy (cerebral ALD), and primary adrenal insufficiency.

    “There are 3 core clinical syndromes: a slowly progressive myeloneuropathy (adrenomyeloneuropathy), a rapidly progressive leukodystrophy (cerebral ALD), and primary adrenal insufficiency.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisenone given

    De novo pathogenic variants and variants of uncertain significance in ABCD1 are common.

    “De novo pathogenic variants and variants of uncertain significance (VUS) are common.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Two reviewers of Adelphi Values independently screened all abstracts and where applicable concomitant full text for eligibility.

    “Two reviewers of Adelphi Values (A.V.) independently screened all abstracts and where applicable concomitant full text for their eligibility.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The screening protocol for cerebral ALD and lifestyle management are topics that remain subject of discussion.

    “The screening protocol for cerebral ALD and lifestyle management are examples of topics that remain subject of discussion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No medical librarian was involved in the literature search.

    “No medical librarian was involved.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No consensus was reached on the evaluation of bone health in men.

    “No consensus was reached on the evaluation of bone health in men.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    A gray literature search of internet-based sources was conducted and the search was extended with snowballing.

    “In addition, we conducted a gray literature search of internet-based sources and extended the search with snowballing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The clinical experience of panelists varied from smaller regional to larger international cohorts with more than 100 patients.

    “We aimed to include all relevant specialists with experience in the field of ALD, but this group is small, and the clinical experience of panelists varied from smaller regional to larger international cohorts with more than 100 patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    All articles on ALD involving human participants were included, and nonhuman (animal) studies were excluded.

    “All articles on ALD involving human participants were included, and nonhuman (animal) studies were excluded.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The gray literature search included GeneReviews, UpToDate, ClinicalKey, The International Leukodystrophy Association (or Global Leukodystrophy Initiative), ALD.info, and the Society for the Study of Inborn Errors of Metabolism.

    “The gray literature search included GeneReviews, UpToDate, ClinicalKey, The International Leukodystrophy Association (or Global Leukodystrophy Initiative), ALD.info, and the Society for the Study of Inborn Errors of Metabolism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The search terms used were 'adrenoleukodystrophy' or 'x-linked adrenoleukodystrophy' or 'X-ALD.'

    “The search terms used were “adrenoleukodystrophy” or “x-linked adrenoleukodystrophy” or “X-ALD.””
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Interpretationreasoning

    This guideline addresses a need in the ALD community because of the worldwide increase in diagnoses and the number of presymptomatic individuals because of newborn screening and improved diagnostic procedures.

    “Nonetheless, this guideline addresses a need in the ALD community because of the worldwide increase in diagnoses and the number of presymptomatic individuals because of newborn screening and improved diagnostic procedures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Adrenal insufficiency is characterized by low or normal early morning cortisol levels with high levels of ACTH.

    “Adrenal insufficiency is characterized by low or normal early morning cortisol levels with high levels of ACTH.1,33”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source
    • cites [33] Huffnagel IC, Laheji FK, Aziz-Bose R, et al. The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration. J Clin Endocrinol Metab. 2019; 104(1): 118- 126. 30252065 source

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    The literature search was limited to full-text availability in English and a publication date between 1990 and 2019.

    “The search was limited to full-text availability in English and a publication date between 1990 to the year 2019.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationreasoning

    The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge.

    “The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The study quality was assessed using the Newcastle-Ottawa Scale for Assessing the Quality of Nonrandomized Studies in Meta-analysis.

    “The study quality was assessed using the Newcastle-Ottawa Scale for Assessing the Quality of Nonrandomized Studies in Meta-analysis, and the results are available as eTable 1 (links.lww.com/WNL/C366).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    The consensus approach is at risk for bias because of panelist selection and repeat review.

    “Furthermore, this approach is at risk for bias because of panelist selection and repeat review.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Erectile dysfunction may reflect primary gonadal insufficiency or can be caused by spinal cord disease.

    “For instance, erectile dysfunction may reflect primary gonadal insufficiency or can be caused by spinal cord disease.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    Some panelists did not agree with specific recommendations although consensus was reached.

    “Therefore, some panelists did not agree with specific recommendations although consensus was reached.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Experts were instructed to withhold from voting on recommendations outside their field of expertise.

    “Experts were instructed to withhold from voting on recommendations outside their field of expertise, but no additional correction was applied for differences in clinical experience.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    After completion, the results were reviewed and compared by a third senior reviewer to resolve discrepancies and reach consensus on inclusion in the literature review.

    “After completion, the results were reviewed and compared by a third senior reviewer (A.V.), to resolve discrepancies and reach consensus on inclusion in the literature review.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    No consensus was reached on recommendations for invasive spasticity treatments or urinary incontinence.

    “No consensus was reached on recommendations for invasive spasticity treatments (i.e., intrathecal baclofen therapy, selective dorsal rhizotomy) or urinary incontinence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    On some topics, consensus could not be reached.

    “Still, on some topics, consensus could not be reached (for instance, the exact timing of adrenal testing in the first year of life).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No additional correction was applied for differences in clinical experience.

    “Experts were instructed to withhold from voting on recommendations outside their field of expertise, but no additional correction was applied for differences in clinical experience.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductreasoning

    The authors used a consensus-based approach among ALD experts across the world to formulate recommendations despite limited scientific evidence.

    “Our consensus-based approach among ALD experts across the world allowed us to formulate recommendations despite limited scientific evidence.”
    Quote in the paperSubstantial claim
45 of 45

  • The paper relies on this without support.

    The three core ALD syndromes are not present in all individuals and are not related to genotype.

    “These syndromes are not present in all individuals and are not related to genotype.”

  • The paper relies on this without support.

    Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary.

    “Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary.”

  • The paper relies on this without support.

    Management of patients with ALD varies between centers because of a lack of prospective natural history studies and controlled clinical trials.

    “Management of patients with ALD varies between centers because of a lack of prospective natural history studies and controlled clinical trials.”

  • The paper relies on this without support.

    Clinical practice recommendations are needed to optimize outcomes in ALD.

    “Clinical practice recommendations are needed to optimize outcomes.”

  • The paper relies on this without support.

    A consensus-based modified Delphi approach among international ALD experts yields best-practice recommendations for diagnosis, clinical surveillance, and treatment.

    “We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD.”
5 of 5

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?

  • In X-ALD, the adrenal zona glomerulosa can be spared from disruption.

    “As the adrenal zona glomerulosa can be spared from disruption, plasma renin and aldosterone levels and serum electrolyte should be always checked before considering the initiation of mineralocorticoid replacement therapy (37).”

    From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [37]

    The Results sections on Adrenal Insufficiency and Treatment of Adrenal Insufficiency (page unavailable) say that only some patients develop mineralocorticoid deficiency and that plasma renin and serum electrolytes should inform replacement decisions. They do not state that the zona glomerulosa is spared or recommend checking aldosterone levels before treatment. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Lorenzo's oil fails to halt the progression of pre-existing neurological symptoms.

    “However, the effectiveness of this therapeutic approach has been met with skepticism, as Lorenzo’s oil fails to halt the progression of pre-existing neurological symptoms, so that hitherto it is not routinely recommended by X-ALD guidelines (37).”

    From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [37]

    The Results > Dietary Therapy recommendation says evidence for Lorenzo’s oil as a disease-modifying treatment is insufficient and that controlled trials showing improved outcomes are lacking. This supports skepticism about its efficacy, but does not establish that it fails to halt progression of pre-existing neurological symptoms. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Lorenzo's oil is not routinely recommended by X-ALD guidelines.

    “However, the effectiveness of this therapeutic approach has been met with skepticism, as Lorenzo’s oil fails to halt the progression of pre-existing neurological symptoms, so that hitherto it is not routinely recommended by X-ALD guidelines (37).”

    From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [37]

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Agency EM. EMA's Final Opinion Confirms Restrictions on Use of Linear Gadolinium Agents in Body Scans Recommendations Conclude EMA's Scientific Review of Gadolinium Deposition in Brain and Other Tissues;2017.

Cited by

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Related

Metadata

Authors
Engelen, M., van Ballegoij, W. J. C., Mallack, E. J., Van Haren, K. P., Köhler, W., Salsano, E., van Trotsenburg, A. S. P., Mochel, F., Sevin, C., Regelmann, M. O., Tritos, N. A., Halper, A., Lachmann, R. H., Davison, J., Raymond, G. V., Lund, T. C., Orchard, P. J., Kuehl, J.-S., Lindemans, C. A., Caruso, P., Turk, B. R., Moser, A. B., Vaz, F. M., Ferdinandusse, S., Kemp, S., Fatemi, A., Eichler, F. S., & Huffnagel, I. C.
Affiliations
  • Lucile Packard Children's Hospital (US)
  • From the Department of Pediatric Neurology/Emma Children's Hospital (M.E., W.J.C.B., I.C.H.), Amsterdam UMC, Amsterdam Leukodystrophy Center, University of Amsterdam, the Netherlands; Division of Child Neurology (E.J.M.), Department of Pediatrics, Weill Cornell Medicine/NewYork-Presbyterian Hospital, NY; Department of Neurology & Pediatrics/Lucile Packard Children's Hospital (K.P.V.H.), Stanford University School of Medicine, Palo Alto, CA 4. Department of Neurology, Leukodystrophy Clinic,...
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-11-22
Volume
99
Issue
21
Pages
940-951
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000201374
PMC
PMC9687408
OpenAlex
W4297989795
Semantic Scholar
b2c10c8d07da275266244e8a4539d8dc7c600304
Cited by
156
References
40
Citations by year
2026: 34 · 2025: 62 · 2024: 41 · 2023: 17 · 2022: 2
FWCI
15.30
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • HAL (Le Centre pour la Communication Scientifique Directe) (submittedVersion, cc-by)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
Funders
  • Pfizer
  • Sanofi
  • Alexion Pharmaceuticals
  • Celgene
  • bluebird bio
  • Novo Nordisk
  • Association Européenne contre les Leucodystrophies
  • Ipsen
  • Grifols
  • MedDay Pharmaceuticals
  • National Institutes of Health
  • Sanofi Genzyme
  • National Institute of Neurological Disorders and Stroke (K23NS118044, U54 NS115052)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
adrenoleukodystrophy, cerebral adrenoleukodystrophy, Addison's disease, myeloneuropathy, clinical surveillance, hematopoietic stem cell transplantation, newborn screening, disease progression prediction, diagnostic criteria, treatment guidelines
MeSH terms
Adrenal Insufficiency, Adrenoleukodystrophy, Humans, Infant, Newborn, Male, Neonatal Screening, Hematopoietic Stem Cell Transplantation, Consensus

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.

A language model drew the claims from the paper on 2026-10-20, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-20 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (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.

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